U.S. patent application number 16/817671 was filed with the patent office on 2020-10-08 for plasma kallikrein inhibitors and uses thereof for treating hereditary angioedema attack.
This patent application is currently assigned to Dyax Corp.. The applicant listed for this patent is Dyax Corp.. Invention is credited to Joan Yesid Mendivil Medina.
Application Number | 20200317815 16/817671 |
Document ID | / |
Family ID | 1000004958144 |
Filed Date | 2020-10-08 |
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United States Patent
Application |
20200317815 |
Kind Code |
A1 |
Mendivil Medina; Joan
Yesid |
October 8, 2020 |
PLASMA KALLIKREIN INHIBITORS AND USES THEREOF FOR TREATING
HEREDITARY ANGIOEDEMA ATTACK
Abstract
Provided herein are methods of treating and preventing
hereditary angioedema attack in certain human patient
subpopulations whose disease is well controlled in a first
treatment period, which involves the use of an antibody that binds
human plasma kallikrein. Such patients can be subject to a reduced
dosage of the antibody and/or a prolonged dosing interval in a
second treatment period.
Inventors: |
Mendivil Medina; Joan Yesid;
(Cham, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dyax Corp. |
Lexington |
MA |
US |
|
|
Assignee: |
Dyax Corp.
Lexington
MA
|
Family ID: |
1000004958144 |
Appl. No.: |
16/817671 |
Filed: |
March 13, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62818189 |
Mar 14, 2019 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/40 20130101;
A61K 47/26 20130101; A61K 47/02 20130101; A61K 47/12 20130101; A61K
47/183 20130101; A61P 17/00 20180101; A61K 9/0019 20130101 |
International
Class: |
C07K 16/40 20060101
C07K016/40; A61P 17/00 20060101 A61P017/00; A61K 47/12 20060101
A61K047/12; A61K 47/26 20060101 A61K047/26; A61K 47/02 20060101
A61K047/02; A61K 47/18 20060101 A61K047/18 |
Claims
1. A method for treating hereditary angioedema (HAE) attack or
reducing the rate of HAE attack, the method comprising:
administering to a subject in need thereof an antibody that binds
human plasma kallikrein at about 300 mg every about two weeks in a
first treatment period, which is about 4-9 months; monitoring the
subject for HAE attack during the first treatment period; and
reducing the dosage of the antibody to about 300 mg every about 4
weeks in the subject, who is free of HAE attack in the first
treatment period; wherein the antibody comprises: a heavy chain
complementarity determining region (HCDR) 1 set forth as HYIMM (SEQ
ID NO: 5); a HCDR2 set forth as GIYSSGGITVYADSVKG (SEQ ID NO: 6); a
HCDR3 set forth as RRIGVPRRDEFDI (SEQ ID NO: 7); a light chain
complementarity determining region (LCDR) 1 set forth as
RASQSISSWLA (SEQ ID NO: 8); a LCDR2 set forth as KASTLES (SEQ ID
NO: 9); and a LCDR3 set forth as QQYNTYWT (SEQ ID NO: 10).
2. The method of claim 1, wherein the first treatment period is
about 6 months.
3. The method of claim 1, wherein the patient has a low body
weight.
4. The method of claim 3, wherein the patient has a body weight of
less than 35 kg.
5. The method of claim 1, wherein the patient is a pediatric
patient.
6. The method of claim 1, wherein the antibody comprises a heavy
chain immunoglobulin variable domain (V.sub.H) of SEQ ID NO: 3 and
a light chain immunoglobulin variable domain (VL) of SEQ ID NO:
4.
7. The method of claim 1, wherein the antibody is a full length
antibody or an antigen-binding fragment thereof.
8. The method of claim 1, wherein the antibody is an IgG1
molecule.
9. The method of claim 8, wherein the antibody comprises a heavy
chain of SEQ ID NO:1 and a light chain of SEQ ID NO:2.
10. The method of claim 1, wherein the antibody is formulated in a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier.
11. The method of claim 10, wherein the pharmaceutical composition
comprises sodium phosphate, citric acid, histidine, sodium
chloride, and polysorbate 80.
12. The method of claim 11, wherein the sodium phosphate is at a
concentration of about 30 mM, the citric acid is at a concentration
of about 19 mM, the histidine is at a concentration of about 50 mM,
the sodium chloride is at a concentration of about 90 mM, and the
polysorbate 80 is at about 0.01%.
13. The method of claim 1, wherein the antibody is administered
subcutaneously.
14. The method of claim 1, wherein the subject is a human patient
having, suspected of having, or at risk for HAE.
15. The method of claim 14, wherein the subject has HAE type I or
type II.
Description
RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. provisional application No. 62/818,189, filed Mar.
14, 2019, the contents of which are herein incorporated by
reference in their entirety.
BACKGROUND
[0002] Plasma kallikrein is a serine protease component of the
contact system and a potential drug target for different
inflammatory, cardiovascular, infectious (sepsis) and oncology
diseases (Sainz I. M. et al., Thromb Haemost 98, 77-83, 2007). The
contact system is activated by either factor XIIa upon exposure to
foreign or negatively charged surfaces or on endothelial cell
surfaces by prolylcarboxypeptidases (Sainz I. M. et al., Thromb
Haemost 98, 77-83, 2007). Activation of the plasma kallikrein
amplifies intrinsic coagulation via its feedback activation of
factor XII and enhances inflammation via the production of the
proinflammatory nonapeptide bradykinin. As the primary kininogenase
in the circulation, plasma kallikrein is largely responsible for
the generation of bradykinin in the vasculature. A genetic
deficiency in the C1-inhibitor protein (C1-INH), the major natural
inhibitor of plasma kallikrein, leads to hereditary angioedema
(HAE). Patients with HAE suffer from acute attacks of painful edema
often precipitated by unknown triggers (Zuraw B. L. et al., N Engl
J Med 359, 1027-1036, 2008).
SUMMARY
[0003] Provided herein are regimens for treating hereditary
angioedema (HAE) attack, reducing the rate of HAE attack, or
blocking HAE attack using antibodies capable of binding and
inhibiting human plasma kallikrein (pKal) in the active form, for
example, antibodies having the same complementarity determining
regions (CDRs) as DX-2930 (a.k.a. SHP643, lanadelumab).
[0004] In aspect, the present disclosure provides a method for
treating hereditary angioedema (HAE) attack or reducing the rate of
HAE attack, the method comprising: (i) administering (e.g.,
subcutaneously) to a subject in need thereof an antibody that binds
human plasma kallikrein at about 300 mg every about two weeks in a
first treatment period, which is about 4-9 months (e.g., 6 months);
(ii) monitoring the subject for HAE attack during the first
treatment period; and (iii) reducing the dosage of the antibody to
about 300 mg every about 4 weeks in the subject, who is free of HAE
attack in the first treatment period.
[0005] In some instances, the antibody used in the method described
herein comprises the same heavy chain complementarity-determining
regions (CDRs) and the same light chain CDRs as DX-2930. For
example, the antibody may comprise a heavy chain immunoglobulin
variable domain (V.sub.H) of SEQ ID NO: 3 and a light chain
immunoglobulin variable domain (V.sub.L) of SEQ ID NO: 4. Such an
antibody may be a full-length antibody (e.g., an IgG1 molecule).
Alternatively, the antibody may be an antigen-binding fragment
thereof. In one example, the antibody may comprise a heavy chain of
SEQ ID NO:1 and a light chain of SEQ ID NO:2.
[0006] Any of the antibodies described herein may be formulated in
a pharmaceutical composition comprising a pharmaceutically
acceptable carrier. In some embodiments, the pharmaceutical
composition may comprise sodium phosphate, citric acid, histidine,
sodium chloride, and polysorbate 80. In some examples, the
pharmaceutical composition comprises sodium phosphate at a
concentration of about 30 mM, citric acid at a concentration of
about 19 mM, histidine at a concentration of about 50 mM, sodium
chloride is at a concentration of about 90 mM, and polysorbate 80
at about 0.01%.
[0007] The subject to be treated in any of the methods described
herein may be a human patient having a low body weight, for
example, less than 35 kg. In some instances, the human patient is a
pediatric patient. The subject may be a human patient having,
suspected of having, or at risk for HAE (e.g., Type I or Type
II).
[0008] The details of one or more embodiments of the invention are
set forth in the description below. Other features or advantages of
the present invention will be apparent from the following drawing
and detailed description of several embodiments, and also from the
appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) diagram documenting the systemic
literature review used to identify studies for an indirect
treatment comparison. An asterisk (*) indicates studies describing
use of interventions that lacked real-world applicability, which
were excluded as inappropriate comparators and included attenuated
androgens (danazol, stanozolol, methyltestosterone,
fluoxymesterone, oxymetholone, and tibolone; n=17), combination
therapy of SC C1-INH/recombinant human hyaluronidase (n=1), and SC
C1-INH (n=2). A dagger (t) indicates inappropriate studies excluded
because of differences and/or lack of clarity in study design,
study population, intervention, endpoints, and/or patient
characteristics, as summarized in Table 2. A double-dagger
(.dagger-dbl.) indicates the exclusion of four unnecessary
non-randomized control trials, as one randomized control trial for
IV C1-INH (Cinryze.RTM.) was identified as appropriate for NMA. The
four nRCTs for this same intervention were excluded. C1-INH, C1
esterase inhibitor; IV, intravenous; NMA, network meta-analysis;
nRCT, non-randomized controlled trial; PRISMA, Preferred Reporting
Items for Systematic Reviews and Meta-Analyses; RCT, randomized
controlled trial; SC, subcutaneous.
[0010] FIG. 2 is a final network diagram for an indirect treatment
comparison of lanadelumab (HELP Study; Banerji et al., JAMA.
320(20):2108-21, 2018.) and IV C1-INH (CHANGE Study; Zuraw et al.,
N Engl J Med. 363(6):513-22, 2010). The CHANGE study is a crossover
study. C1-INH, C1 esterase inhibitor; IV, intravenous; q2w, every
two weeks; q4w, every four weeks; SC, subcutaneous.
[0011] FIG. 3 includes attack rate ratios (95% credible interval,
CrI) for all treatments compared to placebo. The rate ratios for
lanadelumab vs. placebo were derived from HELP study data and are
based on 26 weeks of treatment. The rate ratios for IV C1-INH vs.
placebo are derived from CHANGE study data and are based on 12
weeks of treatment. C1-INH, C1 esterase inhibitor; CrI, credible
interval; IV, intravenous; q2w, every two weeks; q4w, every four
weeks; SC, subcutaneous.
[0012] FIGS. 4A-4B include time to first attack hazard ratios (95%
credible interval, CrI) for all treatments compared to placebo
after day 0 (FIG. 4A) and after day 70 (FIG. 4B). The data for the
IV C1-INH are from the CHANGE trial. C1-INH, C1 esterase inhibitor;
CrI, credible interval; IV, intravenous; q2w, every two weeks; q4w,
every four weeks; SC, subcutaneous.
[0013] FIGS. 5A-5B include predicted survival curves for time to
first attack after day 0 (FIG. 5A) and after day 70 (FIG. 5B). The
data are labeled with predicted median (95% confidence interval)
percentage of patients who were attack-free at 60 months. The data
for the IV C1-INH are from the CHANGE trial. The data in FIG. 5A
are as follows: lanadelumab (300 SC q2w), 26.00%, lanadelumab (300
SC q4w), 13.70%, lanadelumab (150 SC q4w), 17.60%, IV C1-inhibitor,
6.50%, and placebo, 0.60%. The data in FIG. 5B are as follows:
lanadelumab (300 SC q2w), 46.20%, lanadelumab (300 SC q4w), 9.30%,
lanadelumab (150 SC q4w), 16.50%, IV C1-inhibitor, 0.90%, and
placebo, 0.00%. C1-INH, C1 esterase inhibitor; IV, intravenous;
q2w, every two weeks; q4w, every four weeks; SC, subcutaneous.
[0014] FIG. 6 is a network of evidence for the comparators in the
HELP (HELP-03) and CHANGE studies. Cinryze.RTM. is a C1-INH, C1
esterase inhibitor.
[0015] FIG. 7 is a predicted survival graph comparing time to first
attack after 0 days of treatment with placebo in the HELP (HELP-03)
and CHANGE studies.
[0016] FIG. 8 is a predicted survival graph comparing time to first
attack after 70 days of treatment with placebo in the HELP
(HELP-03) and CHANGE studies.
[0017] FIG. 9 is a predicted survival graph comparing time to first
attack after 0 days of treatment with placebo or Cinryze.RTM.
(C1-INH) in the CHANGE study.
[0018] FIG. 10 is a predicted survival graph comparing time to
first attack after 0 days of treatment with placebo, 300 mg
lanadelumab every 2 weeks (300 mg q2w), or 300 mg lanadelumab every
4 weeks (300 mg q4w) in the HELP (HELP-03) study.
[0019] FIG. 11 is a predicted survival graph comparing time to
first attack after 70 days of treatment with placebo or
Cinryze.RTM. (C1-INH) in the CHANGE study.
[0020] FIG. 12 is a predicted survival graph comparing time to
first attack after 70 days of treatment with placebo, 300 mg
lanadelumab every 2 weeks (300 mg q2w), or 300 mg lanadelumab every
4 weeks (300 mg q4w) in the HELP (HELP-03) study.
DETAILED DESCRIPTION
Definitions
[0021] For convenience, before further description of the present
invention, certain terms employed in the specification, examples
and appended claims are defined here. Other terms are defined as
they appear in the specification.
[0022] The singular forms "a", "an", and "the" include plural
references unless the context clearly dictates otherwise.
[0023] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within an
acceptable standard deviation, per the practice in the art.
Alternatively, "about" can mean a range of up to .+-.20%,
preferably up to .+-.10%, more preferably up to .+-.5%, and more
preferably still up to .+-.1% of a given value. Alternatively,
particularly with respect to biological systems or processes, the
term can mean within an order of magnitude, preferably within
2-fold, of a value. Where particular values are described in the
application and claims, unless otherwise stated, the term "about"
is implicit and in this context means within an acceptable error
range for the particular value.
[0024] The term "antibody" refers to an immunoglobulin molecule
capable of specific binding to a target, such as a carbohydrate,
polynucleotide, lipid, polypeptide, etc., through at least one
antigen recognition site located in the variable region of the
immunoglobulin molecule. An antibody may include at least one heavy
(H) chain that comprises a heavy chain immunoglobulin variable
domain (V.sub.H), at least one light chain that comprises a light
chain immunoglobulin variable domain (V.sub.L), or both. For
example, an antibody can include a heavy (H) chain variable region
(abbreviated herein as V.sub.H or HV) and a light (L) chain
variable region (abbreviated herein as V.sub.L or LV). In another
example, an antibody includes two heavy (H) chain variable regions
and two light (L) chain variable regions.
[0025] As used herein, the term "antibody" encompasses not only
intact (i.e., full-length) polyclonal or monoclonal antibodies, but
also antigen-binding fragments thereof (such as Fab, Fab',
F(ab').sub.2, Fv), single chain (scFv), domain antibody (dAb)
fragments (de Wildt et. al., Euro. J. Immunol. (1996) 26(3):
629-639), any mutants thereof, fusion proteins comprising an
antibody portion, humanized antibodies, chimeric antibodies,
diabodies, linear antibodies, single chain antibodies,
multispecific antibodies (e.g., bispecific antibodies) and any
other modified configuration of the immunoglobulin molecule that
comprises an antigen recognition site of the required specificity,
including glycosylation variants of antibodies, amino acid sequence
variants of antibodies, and covalently modified antibodies. An
antibody includes an antibody of any class, such as IgD, IgE, IgG,
IgA, or IgM (or sub-class thereof), and the antibody need not be of
any particular class. Depending on the antibody amino acid sequence
of the constant domain of its heavy chains, immunoglobulins can be
assigned to different classes. There are five major classes of
immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these
may be further divided into subclasses (isotypes), e.g., IgG1,
IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant domains
that correspond to the different classes of immunoglobulins are
called alpha, delta, epsilon, gamma, and mu, respectively. The
subunit structures and three-dimensional configurations of
different classes of immunoglobulins are well known. Antibodies may
be from any source, but primate (human and non-human primate) and
primatized are preferred.
[0026] The V.sub.H and/or V.sub.L regions may include all or part
of the amino acid sequence of a naturally-occurring variable
domain. For example, the sequence may omit one, two or more N- or
C-terminal amino acids, internal amino acids, may include one or
more insertions or additional terminal amino acids, or may include
other alterations. In one embodiment, a polypeptide that includes
immunoglobulin variable domain sequence can associate with another
immunoglobulin variable domain sequence to form an antigen binding
site, e.g., a structure that preferentially interacts with plasma
kallikrein.
[0027] The V.sub.H and V.sub.L regions can be further subdivided
into regions of hypervariability, termed "complementarity
determining regions" ("CDRs"), interspersed with regions that are
more conserved, termed "framework regions" ("FRs"). The extent of
the framework region and CDRs have been defined (see, Kabat, E. A.,
et al. (1991) Sequences of Proteins of Immunological Interest,
Fifth Edition, U.S. Department of Health and Human Services, NIH
Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol.
Biol. 196:901-917). Kabat definitions are used herein. Each VH and
VL is typically composed of three CDRs and four FRs, arranged from
amino-terminus to carboxy-terminus in the following order: FR1,
CDR1, FR2, CDR2, FR3, CDR3, FR4.
[0028] In addition to the V.sub.H or V.sub.L regions, the heavy
chain or light chain of the antibody can further include all or
part of a heavy or light chain constant region. In one embodiment,
the antibody is a tetramer of two heavy immunoglobulin chains and
two light immunoglobulin chains, wherein the heavy and light
immunoglobulin chains are inter-connected by, e.g., disulfide
bonds. In IgGs, the heavy chain constant region includes three
immunoglobulin domains, CH1, CH2 and CH3. The light chain constant
region includes a CL domain. The variable region of the heavy and
light chains contains a binding domain that interacts with an
antigen. The constant regions of the antibodies typically mediate
the binding of the antibody to host tissues or factors, including
various cells of the immune system (e.g., effector cells) and the
first component (C1q) of the classical complement system. The light
chains of the immunoglobulin may be of type kappa or lambda. In one
embodiment, the antibody is glycosylated. An antibody can be
functional for antibody-dependent cytotoxicity and/or
complement-mediated cytotoxicity.
[0029] One or more regions of an antibody can be human or
effectively human. For example, one or more of the variable regions
can be human or effectively human. For example, one or more of the
CDRs can be human, e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC
CDR2, and/or LC CDR3. Each of the light chain (LC) and/or heavy
chain (HC) CDRs can be human. HC CDR3 can be human. One or more of
the framework regions can be human, e.g., FR1, FR2, FR3, and/or FR4
of the HC and/or LC. For example, the Fc region can be human. In
one embodiment, all the framework regions are human, e.g., derived
from a human somatic cell, e.g., a hematopoietic cell that produces
immunoglobulins or a non-hematopoietic cell. In one embodiment, the
human sequences are germline sequences, e.g., encoded by a germline
nucleic acid. In one embodiment, the framework (FR) residues of a
selected Fab can be converted to the amino-acid type of the
corresponding residue in the most similar primate germline gene,
especially the human germline gene. One or more of the constant
regions can be human or effectively human. For example, at least
70, 75, 80, 85, 90, 92, 95, 98, or 100% of an immunoglobulin
variable domain, the constant region, the constant domains (CH1,
CH2, CH3, and/or CL1), or the entire antibody can be human or
effectively human.
[0030] An antibody can be encoded by an immunoglobulin gene or a
segment thereof. Exemplary human immunoglobulin genes include the
kappa, lambda, alpha (IgA1 and IgA2), gamma (IgG1, IgG2, IgG3,
IgG4), delta, epsilon and mu constant region genes, as well as the
many immunoglobulin variable region genes. Full-length
immunoglobulin "light chains" (about 25 KDa or about 214 amino
acids) are encoded by a variable region gene at the NH2-terminus
(about 110 amino acids) and a kappa or lambda constant region gene
at the COOH-terminus. Full-length immunoglobulin "heavy chains"
(about 50 KDa or about 446 amino acids), are similarly encoded by a
variable region gene (about 116 amino acids) and one of the other
aforementioned constant region genes, e.g., gamma (encoding about
330 amino acids). The length of human HC varies considerably
because HC CDR3 varies from about 3 amino-acid residues to over 35
amino-acid residues.
[0031] The term "antigen-binding fragment" of a full length
antibody refers to one or more fragments of a full-length antibody
that retain the ability to specifically bind to a target of
interest. Examples of binding fragments encompassed within the term
"antigen-binding fragment" of a full length antibody and that
retain functionality include (i) a Fab fragment, a monovalent
fragment consisting of the V.sub.L, V.sub.H, C.sub.L and CH1
domains; (ii) a F(ab').sub.2 fragment, a bivalent fragment
including two Fab fragments linked by a disulfide bridge at the
hinge region; (iii) a Fd fragment consisting of the V.sub.H and CH1
domains; (iv) a Fv fragment consisting of the V.sub.L and V.sub.H
domains of a single arm of an antibody, (v) a dAb fragment (Ward et
al., (1989) Nature 341:544-546), which consists of a V.sub.H
domain; and (vi) an isolated complementarity determining region
(CDR). Furthermore, although the two domains of the Fv fragment,
V.sub.L and V.sub.H, are coded for by separate genes, they can be
joined, using recombinant methods, by a synthetic linker that
enables them to be made as a single protein chain in which the
V.sub.L and V.sub.H regions pair to form monovalent molecules known
as single chain Fv (scFv). See e.g., U.S. Pat. Nos. 5,260,203,
4,946,778, and 4,881,175; Bird et al. (1988) Science 242:423-426;
and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883.
Antibody fragments can be obtained using any appropriate technique
including conventional techniques known to those with skill in the
art.
[0032] The term "monospecific antibody" refers to an antibody that
displays a single binding specificity and affinity for a particular
target, e.g., epitope. This term includes a "monoclonal antibody"
or "monoclonal antibody composition," which as used herein refers
to a preparation of antibodies or fragments thereof of single
molecular composition, irrespective of how the antibody was
generated. Antibodies are "germlined" by reverting one or more
non-germline amino acids in framework regions to corresponding
germline amino acids of the antibody, so long as binding properties
are substantially retained.
[0033] The inhibition constant (K.sub.i) provides a measure of
inhibitor potency; it is the concentration of inhibitor required to
reduce enzyme activity by half and is not dependent on enzyme or
substrate concentrations. The apparent K.sub.i (K.sub.i,app) is
obtained at different substrate concentrations by measuring the
inhibitory effect of different concentrations of inhibitor (e.g.,
inhibitory binding protein) on the extent of the reaction (e.g.,
enzyme activity); fitting the change in pseudo-first order rate
constant as a function of inhibitor concentration to the Morrison
equation (Equation 1) yields an estimate of the apparent K.sub.i
value. The K.sub.i is obtained from the y-intercept extracted from
a linear regression analysis of a plot of K.sub.i,app versus
substrate concentration.
v = v o - v o ( ( K i , app + I + E ) - ( K i , app + I + E ) 2 - 4
I E 2 E ) Equation 1 ##EQU00001##
[0034] Where v=measured velocity; v0=velocity in the absence of
inhibitor; K.sub.i,app=apparent inhibition constant; I=total
inhibitor concentration; and E=total enzyme concentration.
[0035] As used herein, "binding affinity" refers to the apparent
association constant or K.sub.A. The K.sub.A is the reciprocal of
the dissociation constant (K.sub.D). A binding antibody may, for
example, have a binding affinity of at least 105, 106, 107, 108,
109, 1010 and 1011 M-1 for a particular target molecule, e.g.,
plasma kallikrein. Higher affinity binding of a binding antibody to
a first target relative to a second target can be indicated by a
higher K.sub.A (or a smaller numerical value K.sub.D) for binding
the first target than the K.sub.A (or numerical value K.sub.D) for
binding the second target. In such cases, the binding antibody has
specificity for the first target (e.g., a protein in a first
conformation or mimic thereof) relative to the second target (e.g.,
the same protein in a second conformation or mimic thereof; or a
second protein). Differences in binding affinity (e.g., for
specificity or other comparisons) can be at least 1.5, 2, 3, 4, 5,
10, 15, 20, 30, 40, 50, 70, 80, 90, 100, 500, 1000, 10,000 or
10.sup.5 fold.
[0036] Binding affinity can be determined by a variety of methods
including equilibrium dialysis, equilibrium binding, gel
filtration, ELISA, surface plasmon resonance, or spectroscopy
(e.g., using a fluorescence assay). Exemplary conditions for
evaluating binding affinity are in HBS-P buffer (10 mM HEPES pH
7.4, 150 mM NaCl, 0.005% (v/v) Surfactant P20). These techniques
can be used to measure the concentration of bound and free binding
protein as a function of binding protein (or target) concentration.
The concentration of bound binding protein ([Bound]) is related to
the concentration of free binding protein ([Free]) and the
concentration of binding sites for the binding protein on the
target where (N) is the number of binding sites per target molecule
by the following equation:
[Bound]=N[Free]/((1/KA)+[Free]).
[0037] It is not always necessary to make an exact determination of
K.sub.A, though, since sometimes it is sufficient to obtain a
quantitative measurement of affinity, e.g., determined using a
method such as ELISA or FACS analysis, is proportional to K.sub.A,
and thus can be used for comparisons, such as determining whether a
higher affinity is, e.g., 2 fold higher, to obtain a qualitative
measurement of affinity, or to obtain an inference of affinity,
e.g., by activity in a functional assay, e.g., an in vitro or in
vivo assay.
[0038] The term "binding antibody" (or "binding protein" used
interchangeably herein) refers to an antibody that can interact
with a target molecule. The term "target molecule" is used
interchangeably with "ligand." A "plasma kallikrein binding
antibody" refers to an antibody that can interact with (e.g., bind)
plasma kallikrein, and includes, in particular, antibodies that
preferentially or specifically interact with and/or inhibit plasma
kallikrein. An antibody inhibits plasma kallikrein if it causes a
decrease in the activity of plasma kallikrein as compared to the
activity of plasma kallikrein in the absence of the antibody and
under the same conditions.
[0039] A "conservative amino acid substitution" is one in which the
amino acid residue is replaced with an amino acid residue having a
similar side chain. Families of amino acid residues having similar
side chains have been defined in the art. These families include
amino acids with basic side chains (e.g., lysine, arginine,
histidine), acidic side chains (e.g., aspartic acid, glutamic
acid), uncharged polar side chains (e.g., glycine, asparagine,
glutamine, serine, threonine, tyrosine, cysteine), nonpolar side
chains (e.g., alanine, valine, leucine, isoleucine, proline,
phenylalanine, methionine, tryptophan), beta-branched side chains
(e.g., threonine, valine, isoleucine) and aromatic side chains
(e.g., tyrosine, phenylalanine, tryptophan, histidine).
[0040] It is possible for one or more framework and/or CDR amino
acid residues of a binding protein to include one or more mutations
(for example, substitutions (e.g., conservative substitutions or
substitutions of non-essential amino acids), insertions, or
deletions) relative to a binding protein described herein. A plasma
kallikrein binding protein may have mutations (e.g., substitutions
(e.g., conservative substitutions or substitutions of non-essential
amino acids), insertions, or deletions) (e.g., at least one, two,
three, or four, and/or less than 15, 12, 10, 9, 8, 7, 6, 5, 4, 3,
or 2 mutations) relative to a binding protein described herein,
e.g., mutations which do not have a substantial effect on protein
function. The mutations can be present in framework regions, CDRs,
and/or constant regions. In some embodiments, the mutations are
present in a framework region. In some embodiments, the mutations
are present in a CDR. In some embodiments, the mutations are
present in a constant region. Whether or not a particular
substitution will be tolerated, i.e., will not adversely affect
biological properties, such as binding activity, can be predicted,
e.g., by evaluating whether the mutation is conservative or by the
method of Bowie, et al. (1990) Science 247:1306-1310.
[0041] An "effectively human" immunoglobulin variable region is an
immunoglobulin variable region that includes a sufficient number of
human framework amino acid positions such that the immunoglobulin
variable region does not elicit an immunogenic response in a normal
human. An "effectively human" antibody is an antibody that includes
a sufficient number of human amino acid positions such that the
antibody does not elicit an immunogenic response in a normal
human.
[0042] An "epitope" refers to the site on a target compound that is
bound by a binding protein (e.g., an antibody such as a Fab or full
length antibody). In the case where the target compound is a
protein, the site can be entirely composed of amino acid
components, entirely composed of chemical modifications of amino
acids of the protein (e.g., glycosyl moieties), or composed of
combinations thereof. Overlapping epitopes include at least one
common amino acid residue, glycosyl group, phosphate group, sulfate
group, or other molecular feature.
[0043] A "humanized" immunoglobulin variable region is an
immunoglobulin variable region that is modified to include a
sufficient number of human framework amino acid positions such that
the immunoglobulin variable region does not elicit an immunogenic
response in a normal human. Descriptions of "humanized"
immunoglobulins include, for example, U.S. Pat. Nos. 6,407,213 and
5,693,762.
[0044] An "isolated" antibody refers to an antibody that is removed
from at least 90% of at least one component of a natural sample
from which the isolated antibody can be obtained. Antibodies can be
"of at least" a certain degree of purity if the species or
population of species of interest is at least 5, 10, 25, 50, 75,
80, 90, 92, 95, 98, or 99% pure on a weight-weight basis.
[0045] The methods described herein involve administering multiple
doses of an antibody to a human subject in need thereof. The terms
"patient," "subject" or "host" may be used interchangeably. A
subject may be a subject that has undergone a prior treatment for
HAE, such as a treatment involving an antibody described herein. In
some embodiments, the subject is a pediatric subject (e.g., an
infant, child, or adolescent subject). In some embodiments, the
human subject is an adolescent less than 18 years old. In some
embodiments, the human subject is an adolescent between the ages of
12 and 18 years old. In some embodiments, the subject is between
the ages of 40 and less than 65 years old.
[0046] In some embodiments, the human subject is defined by gender.
For example, in some embodiments, the subject is female.
[0047] In some embodiments, the human subject is defined by weight.
In some embodiments, the human subject weighs less than 50 kg. In
some embodiments, the human subject weighs between 50 kg and 75 kg.
In some embodiments the human subject weighs between 75 kg and 100
kg. In some embodiments, the human subject weighs 100 kg or
more.
[0048] In some embodiments, the human subject is defined by prior
history of laryngeal attacks or absence thereof. In some
embodiments, the subject has experienced at least one (e.g., 1, 2,
3, 4, 5, or more) laryngeal attack (i.e. laryngeal HAE attack)
prior to administration of the antibodies described herein. In some
embodiments, the subject has not experienced a laryngeal attack
prior to administration of the antibodies described herein.
[0049] The terms "prekallikrein" and "preplasma kallikrein" are
used interchangeably herein and refer to the zymogen form of active
plasma kallikrein, which is also known as prekallikrein.
[0050] As used herein, the term "substantially identical" (or
"substantially homologous") is used herein to refer to a first
amino acid or nucleic acid sequence that contains a sufficient
number of identical or equivalent (e.g., with a similar side chain,
for example, conserved amino acid substitutions) amino acid
residues or nucleotides to a second amino acid or nucleic acid
sequence such that the first and second amino acid or nucleic acid
sequences have (or encode proteins having) similar activities,
e.g., a binding activity, a binding preference, or a biological
activity. In the case of antibodies, the second antibody has the
same specificity and has at least 50%, at least 25%, or at least
10% of the affinity relative to the same antigen.
[0051] Statistical significance can be determined by any art known
method. Exemplary statistical tests include: the Students T-test,
Mann Whitney U non-parametric test, and Wilcoxon non-parametric
statistical test. Some statistically significant relationships have
a P value of less than 0.05 or 0.02. Particular binding proteins
may show a difference, e.g., in specificity or binding that are
statistically significant (e.g., P value <0.05 or 0.02). The
terms "induce", "inhibit", "potentiate", "elevate", "increase",
"decrease" or the like, e.g., which denote distinguishable
qualitative or quantitative differences between two states, may
refer to a difference, e.g., a statistically significant
difference, between the two states.
[0052] A "therapeutically effective dosage" preferably modulates a
measurable parameter, e.g., plasma kallikrein activity, by a
statistically significant degree or at least about 20%, more
preferably by at least about 40%, even more preferably by at least
about 60%, and still more preferably by at least about 80% relative
to untreated subjects. The ability of a compound to modulate a
measurable parameter, e.g., a disease-associated parameter, can be
evaluated in an animal model system predictive of efficacy in human
disorders and conditions. Alternatively, this property of a
composition can be evaluated by examining the ability of the
compound to modulate a parameter in vitro.
[0053] The term "treating" as used herein refers to the application
or administration of a composition including one or more active
agents to a subject, who has HAE, a symptom of HAE, is suspected of
having HAE, or a predisposition toward or risk of having HAE, with
the purpose to cure, heal, alleviate, relieve, alter, remedy,
ameliorate, improve, or affect the disease, the symptoms of the
disease, or the predisposition toward the disease. "Prophylactic
treatment," also known as "preventive treatment," refers to a
treatment that aims at protecting a person from, or reducing the
risk for a disease to which he or she has been, or may be, exposed.
In some embodiments, the treatment methods described herein aim at
preventing occurrence and/or recurrence of HAE.
[0054] The term "preventing" a disease in a subject refers to
subjecting the subject to a pharmaceutical treatment, e.g., the
administration of a drug, such that at least one symptom of the
disease is prevented, that is, administered prior to clinical
manifestation of the unwanted condition (e.g., disease or other
unwanted state of the host animal) so that it protects the host
against developing the unwanted condition. "Preventing" a disease
may also be referred to as "prophylaxis" or "prophylactic
treatment."
[0055] A "prophylactically effective amount" refers to an amount
effective, at dosages and for periods of time necessary, to achieve
the desired prophylactic result. Typically, because a prophylactic
dose is used in subjects prior to or at an earlier stage of
disease, the prophylactically effective amount will be less than
the therapeutically effective amount.
Antibodies Binding to Plasma Kallikrein (pKal)
[0056] Plasma kallikrein binding antibodies (anti-pKal antibodies)
for use in the methods described herein can be full-length (e.g.,
an IgG (including an IgG1, IgG2, IgG3, IgG4), IgM, IgA (including,
IgA1, IgA2), IgD, and IgE) or can include only an antigen-binding
fragment (e.g., a Fab, F(ab').sub.2 or scFv fragment. The binding
antibody can include two heavy chain immunoglobulins and two light
chain immunoglobulins, or can be a single chain antibody. Plasma
kallikrein binding antibodies can be recombinant proteins such as
humanized, CDR grafted, chimeric, deimmunized, or in vitro
generated antibodies, and may optionally include constant regions
derived from human germline immunoglobulin sequences. In one
embodiment, the plasma kallikrein binding antibody is a monoclonal
antibody.
[0057] In one aspect, the disclosure features an antibody (e.g., an
isolated antibody) that binds to plasma kallikrein (e.g., human
plasma kallikrein and/or murine kallikrein) and includes at least
one immunoglobulin variable region. For example, the antibody
includes a heavy chain (HC) immunoglobulin variable domain sequence
and/or a light chain (LC) immunoglobulin variable domain sequence.
In one embodiment, the antibody binds to and inhibits plasma
kallikrein, e.g., human plasma kallikrein and/or murine
kallikrein.
[0058] In some embodiments, the antibodies described herein have
the same CDR sequences as DX-2930, e.g., heavy chain CDR sequences
set forth as SEQ ID NOs: 5-7 and light chain CDR sequences set
forth as SEQ ID NOs: 8-10. In some embodiments, the antibody
comprises the same CDR sequences as DX-2930 and a LC immunoglobulin
variable domain sequence that is at least 85, 88, 89, 90, 91, 92,
93, 94, 95, 96, 97, 98, 99, or 100% identical to a LC variable
domain described herein (e.g., overall or in framework regions). In
some embodiments, the antibody comprises the same CDR sequences as
DX-2930 and an HC immunoglobulin variable domain sequence that is
at least 85, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or
100% identical to a HC variable domain described herein (e.g.,
overall or in framework regions). In some embodiments, the antibody
comprises the same CDR sequences as DX-2930 and LC sequence that is
at least 85, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or
100% identical to a LC sequence described herein (e.g., overall or
in framework regions). In some embodiments, the antibody comprises
the same CDR sequences as DX-2930 and HC sequence that is at least
85, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%
identical to a HC sequence described herein (e.g., overall or in
framework regions).
[0059] The plasma kallikrein binding protein may be an isolated
antibody (e.g., at least 70, 80, 90, 95, or 99% free of other
proteins). In some embodiments, the plasma kallikrein binding
antibody, or composition thereof, is isolated from antibody
cleavage fragments (e.g., DX-2930) that are inactive or partially
active (e.g., bind plasma kallikrein with a K.sub.i, app of 5000 nM
or greater) compared to the plasma kallikrein binding antibody. For
example, the plasma kallikrein binding antibody is at least 70%
free of such antibody cleavage fragments; in other embodiments the
binding antibody is at least 80%, at least 90%, at least 95%, at
least 99% or even 100% free from antibody cleavage fragments that
are inactive or partially active.
[0060] The plasma kallikrein binding antibody may additionally
inhibit plasma kallikrein, e.g., human plasma kallikrein.
[0061] In some embodiments, the plasma kallikrein binding antibody
does not bind prekallikrein (e.g., human prekallikrein and/or
murine prekallikrein), but binds to the active form of plasma
kallikrein (e.g., human plasma kallikrein and/or murine
kallikrein).
[0062] In certain embodiments, the antibody binds at or near the
active site of the catalytic domain of plasma kallikrein, or a
fragment thereof, or binds an epitope that overlaps with the active
site of plasma kallikrein.
[0063] The antibody can bind to plasma kallikrein, e.g., human
plasma kallikrein, with a binding affinity of at least 10.sup.5,
10.sup.6, 10.sup.7, 10.sup.8, 10.sup.9, 10.sup.10 and 10.sup.11
M.sup.-1. In one embodiment, the antibody binds to human plasma
kallikrein with a K.sub.off slower than 1.times.10.sup.-3,
5.times.10.sup.-4 s.sup.-1, or 1.times.10.sup.-4 s.sup.-1. In one
embodiment, the antibody binds to human plasma kallikrein with a
K.sub.on faster than 1.times.10.sup.2, 1.times.10.sup.3, or
5.times.10.sup.3 M.sup.-1 s.sup.-1. In one embodiment, the antibody
binds to plasma kallikrein, but does not bind to tissue kallikrein
and/or plasma prekallikrein (e.g., the antibody binds to tissue
kallikrein and/or plasma prekallikrein less effectively (e.g., 5-,
10-, 50-, 100-, or 1000-fold less or not at all, e.g., as compared
to a negative control) than it binds to plasma kallikrein.
[0064] In one embodiment, the antibody inhibits human plasma
kallikrein activity, e.g., with a Ki of less than 10.sup.-5,
10.sup.-6, 10.sup.-7, 10.sup.-8, 10.sup.-9, and 10.sup.-10 M. The
antibody can have, for example, an IC.sub.50 of less than 100 nM,
10 nM, 1, 0.5, or 0.2 nM. For example, the antibody may modulate
plasma kallikrein activity, as well as the production of Factor
XIIa (e.g., from Factor XII) and/or bradykinin (e.g., from
high-molecular-weight kininogen (HMWK)). The antibody may inhibit
plasma kallikrein activity, and/or the production of Factor XIIa
(e.g., from Factor XII) and/or bradykinin (e.g., from
high-molecular-weight kininogen (HMWK)). The affinity of the
antibody for human plasma kallikrein can be characterized by a
K.sub.D of less than 100 nm, less than 10 nM, less than 5 nM, less
than 1 nM, less than 0.5 nM. In one embodiment, the antibody
inhibits plasma kallikrein, but does not inhibit tissue kallikrein
(e.g., the antibody inhibits tissue kallikrein less effectively
(e.g., 5-, 10-, 50-, 100-, or 1000-fold less or not at all, e.g.,
as compared to a negative control) than it inhibits plasma
kallikrein.
[0065] In some embodiments, the antibody has an apparent inhibition
constant (K.sub.i,app) of less than 1000, 500, 100, 5, 1, 0.5 or
0.2 nM.
[0066] Plasma kallikrein binding antibodies may have their HC and
LC variable domain sequences included in a single polypeptide
(e.g., scFv), or on different polypeptides (e.g., IgG or Fab).
[0067] In one embodiment, the HC and LC variable domain sequences
are components of the same polypeptide chain. In another, the HC
and LC variable domain sequences are components of different
polypeptide chains. For example, the antibody is an IgG, e.g.,
IgG1, IgG2, IgG3, or IgG4. The antibody can be a soluble Fab. In
other implementations the antibody includes a Fab2', scFv,
minibody, scFv::Fc fusion, Fab::HSA fusion, HSA::Fab fusion,
Fab::HSA::Fab fusion, or other molecule that comprises the antigen
combining site of one of the binding proteins herein. The VH and VL
regions of these Fabs can be provided as IgG, Fab, Fab2, Fab2',
scFv, PEGylated Fab, PEGylated scFv, PEGylated Fab2,
VH::CH1::HSA+LC, HSA::VH::CH1+LC, LC::HSA+VH::CH1, HSA::LC+VH::CH1,
or other appropriate construction.
[0068] In one embodiment, the antibody is a human or humanized
antibody or is non-immunogenic in a human. For example, the
antibody includes one or more human antibody framework regions,
e.g., all human framework regions, or framework regions at least
85, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% identical to
human framework regions. In one embodiment, the antibody includes a
human Fc domain, or an Fc domain that is at least 95, 96, 97, 98,
or 99% identical to a human Fc domain.
[0069] In one embodiment, the antibody is a primate or primatized
antibody or is non-immunogenic in a human. For example, the
antibody includes one or more primate antibody framework regions,
e.g., all primate framework regions, or framework regions at least
85, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% identical to
primate framework regions. In one embodiment, the antibody includes
a primate Fc domain, or an Fc domain that is at least 95, 96, 97,
98, or 99% identical to a primate Fc domain. "Primate" includes
humans (Homo sapiens), chimpanzees (Pan troglodytes and Pan
paniscus (bonobos)), gorillas (Gorilla gorilla), gibons, monkeys,
lemurs, aye-ayes (Daubentonia madagascariensis), and tarsiers. In
some embodiments, the affinity of the primate antibody for human
plasma kallikrein is characterized by a K.sub.D of less than 1000,
500, 100, 10, 5, 1, 0.5 nM, e.g., less than 10 nM, less than 1 nM,
or less than 0.5 nM.
[0070] In certain embodiments, the antibody includes no sequences
from mice or rabbits (e.g., is not a murine or rabbit
antibody).
[0071] In some embodiments, the antibody used in the methods
described herein may be DX-2930 as described herein or a functional
variant thereof.
[0072] In one example, a functional variant of DX-2930 comprises
the same complementary determining regions (CDRs) as DX-2930. In
another example, the functional variants of DX-2930 may contain one
or more mutations (e.g., conservative substitutions) in the FRs of
either the V.sub.H or the V.sub.L as compared to those in the
V.sub.H and V.sub.L of DX-2930. Preferably, such mutations do not
occur at residues which are predicted to interact with one or more
of the CDRs, which can be determined by routine technology. In
other embodiments, the functional variants described herein contain
one or more mutations (e.g., 1, 2, or 3) within one or more of the
CDR regions of DX-2930. Preferably, such functional variants retain
the same regions/residues responsible for antigen-binding as the
parent. In yet other embodiments, a functional variant of DX-2930
may comprise a V.sub.H chain that comprises an amino acid sequence
at least 85% (e.g., 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99%)
identical to that of the V.sub.H of DX-2930 and/or a V.sub.L chain
that has an amino acid sequence at least 85% (e.g., 90%, 92%, 94%,
95%, 96%, 97%, 98%, or 99%) identical to that of the V.sub.L of
DX-2930. These variants are capable of binding to the active form
of plasma kallikrein and preferably do not bind to
prekallikrein.
[0073] The "percent identity" of two amino acid sequences is
determined using the algorithm of Karlin and Altschul Proc. Natl.
Acad. Sci. USA 87:2264-68, 1990, modified as in Karlin and Altschul
Proc. Natl. Acad. Sci. USA 90:5873-77, 1993. Such an algorithm is
incorporated into the NBLAST and XBLAST programs (version 2.0) of
Altschul, et al. J. Mol. Biol. 215:403-10, 1990. BLAST protein
searches can be performed with the XBLAST program, score=50,
wordlength=3 to obtain amino acid sequences homologous to the
protein molecules of interest. Where gaps exist between two
sequences, Gapped BLAST can be utilized as described in Altschul et
al., Nucleic Acids Res. 25(17):3389-3402, 1997. When utilizing
BLAST and Gapped BLAST programs, the default parameters of the
respective programs (e.g., XBLAST and NBLAST) can be used.
[0074] In some embodiments, the antibody used in the methods and
compositions described herein may be the DX-2930 antibody. The
heavy and light chain full and variable sequences for DX-2930 are
provided below, with signal sequences in italics. The CDRs are
boldfaced and underlined.
TABLE-US-00001 DX-2930 Heavy Chain Amino Acid Sequence (451 amino
acids, 49439.02 Da) (SEQ ID NO: 1)
MGWSCILFLVATATGAHSEVQLLESGGGLVQPGGSLRLSCAASGFTFSHY
IMMWVRQAPGKGLEWVSGIYSSGGITVYADSVKGRFTISRDNSKNTLYLQ
MNSLRAEDTAVYYCAYRRIGVPRRDEFDIWGQGTMVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP
PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW
YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI
AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV
MHEALHNHYTQKSLSLSPG DX-2930 Light Chain Amino Acid Sequence (213
amino acids, 23419.08 Da) (SEQ ID NO: 2)
MGWSCILFLVATATGAHSDIQMTQSPSTLSASVGDRVTITCRASQSISSW
LAWYQQKPGKAPKLLIYKASTLESGVPSRFSGSGSGTEFTLTISSLQPDD
FATYYCQQYNTYWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV
CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK
ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC DX-2930 Heavy Chain Variable Domain
Amino Acid Sequence (SEQ ID NO: 3)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYIMMWVRQAPGKGLEWVSG
IYSSGGITVYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAYRR
IGVPRRDEFDIWGQGTMVTVSS DX-2930 Light Chain Variable Domain Amino
Acid Sequence (SEQ ID NO: 4)
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYK
ASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNTYWTFGQG TKVEIK
TABLE-US-00002 TABLE 1A CDRs for DX-2930. CDR Amino acid sequence
Heavy chain CDR1 HYIMM (SEQ ID NO: 5) Heavy chain CDR2
GIYSSGGITVYADSVKG (SEQ ID NO: 6) Heavy chain CDR3 RRIGVPRRDEFDI
(SEQ ID NO: 7) Light chain CDR1 RASQSISSWLA (SEQ ID NO: 8) Light
chain CDR2 KASTLES (SEQ ID NO: 9) Light chain CDR3 QQYNTYWT (SEQ ID
NO: 10)
Antibody Preparation
[0075] An antibody as described herein (e.g., DX-2930) can be made
by any method known in the art. See, for example, Harlow and Lane,
(1988) Antibodies: A Laboratory Manual, Cold Spring Harbor
Laboratory, New York and Greenfield, (2013) Antibodies: A
Laboratory Manual, Second edition, Cold Spring Harbor Laboratory
Press.
[0076] The sequence encoding the antibody of interest, e.g.,
DX-2930, may be maintained in vector in a host cell and the host
cell can then be expanded and frozen for future use. In an
alternative, the polynucleotide sequence may be used for genetic
manipulation to "humanize" the antibody or to improve the affinity
(affinity maturation), or other characteristics of the antibody.
For example, the constant region may be engineered to more resemble
human constant regions to avoid immune response if the antibody is
used in clinical trials and treatments in humans. It may be
desirable to genetically manipulate the antibody sequence to obtain
greater affinity to the target antigen and greater efficacy in
inhibiting the activity of PKal. It will be apparent to one of
skill in the art that one or more polynucleotide changes can be
made to the antibody and still maintain its binding specificity to
the target antigen.
[0077] Some antibodies, e.g., Fabs, can be produced in bacterial
cells, e.g., E. coli cells (see e.g., Nadkarni, A. et al., 2007
Protein Expr Purif 52(1):219-29). For example, if the Fab is
encoded by sequences in a phage display vector that includes a
suppressible stop codon between the display entity and a
bacteriophage protein (or fragment thereof), the vector nucleic
acid can be transferred into a bacterial cell that cannot suppress
a stop codon. In this case, the Fab is not fused to the gene III
protein and is secreted into the periplasm and/or media.
[0078] Antibodies can also be produced in eukaryotic cells. In one
embodiment, the antibodies (e.g., scFv's) are expressed in a yeast
cell such as Pichia (see, e.g., Powers et al., 2001, J. Immunol.
Methods. 251:123-35; Schoonooghe S. et al., 2009 BMC Biotechnol.
9:70; Abdel-Salam, H A. et al., 2001 Appl Microbiol Biotechnol
56(1-2):157-64; Takahashi K. et al., 2000 Biosci Biotechnol Biochem
64(10):2138-44; Edqvist, J. et al., 1991 J Biotechnol
20(3):291-300), Hanseula, or Saccharomyces. One of skill in the art
can optimize antibody production in yeast by optimizing, for
example, oxygen conditions (see e.g., Baumann K., et al. 2010 BMC
Syst. Biol. 4:141), osmolarity (see e.g., Dragosits, M. et al.,
2010 BMC Genomics 11:207), temperature (see e.g., Dragosits, M. et
al., 2009 J Proteome Res. 8(3):1380-92), fermentation conditions
(see e.g., Ning, D. et al. 2005 J. Biochem. and Mol. Biol. 38(3):
294-299), strain of yeast (see e.g., Kozyr, A V et al. 2004 Mol
Biol (Mosk) 38(6):1067-75; Horwitz, A H. et al., 1988 Proc Natl
Acad Sci USA 85(22):8678-82; Bowdish, K. et al. 1991 J Biol Chem
266(18):11901-8), overexpression of proteins to enhance antibody
production (see e.g., Gasser, B. et al., 2006 Biotechol. Bioeng.
94(2):353-61), level of acidity of the culture (see e.g., Kobayashi
H., et al., 1997 FEMS Microbiol Lett 152(2):235-42), concentrations
of substrates and/or ions (see e.g., Ko J H. et al., 2996 Appl
Biochem Biotechnol 60(1):41-8). In addition, yeast systems can be
used to produce antibodies with an extended half-life (see e.g.,
Smith, B J. et al. 2001 Bioconjug Chem 12(5):750-756).
[0079] In one preferred embodiment, antibodies are produced in
mammalian cells. Preferred mammalian host cells for expressing the
clone antibodies or antigen-binding fragments thereof include
Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells,
described in Urlaub and Chasin, 1980, Proc. Natl. Acad. Sci. USA
77:4216-4220, used with a DHFR selectable marker, e.g., as
described in Kaufman and Sharp, 1982, Mol. Biol. 159:601 621),
lymphocytic cell lines, e.g., NSO myeloma cells and SP2 cells, COS
cells, HEK293T cells (J. Immunol. Methods (2004) 289(1-2):65-80),
and a cell from a transgenic animal, e.g., a transgenic mammal. For
example, the cell is a mammary epithelial cell.
[0080] In some embodiments, plasma kallikrein binding antibodies
are produced in a plant or cell-free based system (see e.g.,
Galeffi, P., et al., 2006 J Transl Med 4:39).
[0081] In addition to the nucleic acid sequence encoding the
diversified immunoglobulin domain, the recombinant expression
vectors may carry additional sequences, such as sequences that
regulate replication of the vector in host cells (e.g., origins of
replication) and selectable marker genes. The selectable marker
gene facilitates selection of host cells into which the vector has
been introduced (see e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and
5,179,017). For example, typically the selectable marker gene
confers resistance to drugs, such as G418, hygromycin or
methotrexate, on a host cell into which the vector has been
introduced. Preferred selectable marker genes include the
dihydrofolate reductase (DHFR) gene (for use in dhfr.sup.- host
cells with methotrexate selection/amplification) and the neo gene
(for G418 selection).
[0082] In an exemplary system for recombinant expression of an
antibody, or antigen-binding portion thereof, a recombinant
expression vector encoding both the antibody heavy chain and the
antibody light chain is introduced into dhfr.sup.- CHO cells by
calcium phosphate-mediated transfection. Within the recombinant
expression vector, the antibody heavy and light chain genes are
each operatively linked to enhancer/promoter regulatory elements
(e.g., derived from SV40, CMV, adenovirus and the like, such as a
CMV enhancer/AdMLP promoter regulatory element or an SV40
enhancer/AdMLP promoter regulatory element) to drive high levels of
transcription of the genes. The recombinant expression vector also
carries a DHFR gene, which allows for selection of CHO cells that
have been transfected with the vector using methotrexate
selection/amplification. The selected transformant host cells are
cultured to allow for expression of the antibody heavy and light
chains and intact antibody is recovered from the culture medium.
Standard molecular biology techniques are used to prepare the
recombinant expression vector, transfect the host cells, select for
transformants, culture the host cells and recover the antibody from
the culture medium. For example, some antibodies can be isolated by
affinity chromatography with a Protein A or Protein G coupled
matrix.
[0083] For antibodies that include an Fc domain, the antibody
production system may produce antibodies in which the Fc region is
glycosylated. For example, the Fc domain of IgG molecules is
glycosylated at asparagine 297 in the CH2 domain. This asparagine
is the site for modification with biantennary-type
oligosaccharides. It has been demonstrated that this glycosylation
is required for effector functions mediated by Fcg receptors and
complement C1q (Burton and Woof, 1992, Adv. Immunol. 51:1-84;
Jefferis et al., 1998, Immunol. Rev. 163:59-76). In one embodiment,
the Fc domain is produced in a mammalian expression system that
appropriately glycosylates the residue corresponding to asparagine
297. The Fc domain can also include other eukaryotic
post-translational modifications.
[0084] Antibodies can also be produced by a transgenic animal. For
example, U.S. Pat. No. 5,849,992 describes a method of expressing
an antibody in the mammary gland of a transgenic mammal. A
transgene is constructed that includes a milk-specific promoter and
nucleic acids encoding the antibody of interest and a signal
sequence for secretion. The milk produced by females of such
transgenic mammals includes, secreted-therein, the antibody of
interest. The antibody can be purified from the milk, or for some
applications, used directly.
Pharmaceutical Compositions
[0085] An antibody as described herein (e.g., DX-2930) can be
present in a composition, e.g., a pharmaceutically acceptable
composition or pharmaceutical composition. The antibody as
described herein (e.g., DX-2930) can be formulated together with a
pharmaceutically acceptable carrier. In some embodiments, 150 mg or
300 mg of DX-2930 antibody are present in a composition optionally
with a pharmaceutically acceptable carrier, e.g., a
pharmaceutically acceptable composition or pharmaceutical
composition.
[0086] A pharmaceutically acceptable carrier includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents, and the like that
are physiologically compatible. Preferably, the carrier is suitable
for subcutaneous, intravenous, intramuscular, parenteral, spinal,
or epidermal administration (e.g., by injection or infusion),
although carriers suitable for inhalation and intranasal
administration are also contemplated.
[0087] The pharmaceutically acceptable carrier in the
pharmaceutical composition described herein may include one or more
of a buffering agent, an amino acid, and a tonicity modifier. Any
suitable buffering agent or combination of buffering agents may be
used in the pharmaceutical composition described herein to maintain
or aid in maintaining an appropriate pH of the composition.
Non-limiting examples of buffering agents include sodium phosphate,
potassium phosphate, citric acid, sodium succinate, histidine,
Tris, and sodium acetate. In some embodiments, the buffering agents
may be at a concentration of about 5-100 mM, 5-50 mM, 10-50 mM,
15-50 mM, or about 15-40 mM. For example, the one or more buffering
agents may be at a concentration of about 15 mM, 16 mM, 17 mM, 18
mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM,
28 mM, 29 mM, 30 mM, 31 mM, 32 mM, 33 mM, 35 mM, 36 mM, 37 mM, 38
mM, 39 mM, or about 40 mM. In some examples, the pharmaceutically
acceptable carrier comprises sodium phosphate and citric acid,
which may be at a concentration of about 30 mM and about 19 mM,
respectively.
[0088] In some embodiments, the pharmaceutically acceptable carrier
includes one or more amino acids, which may decrease aggregation of
the antibody and/or increase stability of the antibody during
storage prior to administration. Exemplary amino acids for use in
making the pharmaceutical compositions described herein include,
but are not limited to, alanine, arginine, asparagine, aspartic
acid, glycine, histidine, lysine, proline, or serine. In some
examples, the concentration of the amino acid in the pharmaceutical
composition may be about 5-100 mM, 10-90 mM, 20-80 mM, 30-70 mM,
40-60 mM, or about 45-55 mM. In some examples, the concentration of
the amino acid (e.g., histidine) may be about 40 mM, 41 mM, 42 mM,
43 mM, 44 mM, 45 mM, 46 mM, 47 mM, 48 mM, 49 mM, 50 mM, 51 mM, 52
mM, 53 mM, 54 mM, 55 mM, 56 mM, 57 mM, 58 mM, 59 mM, or about 60
mM. In one example, the pharmaceutical composition contains
histidine at a concentration of about 50 mM.
[0089] Any suitable tonicity modifier may be used for preparing the
pharmaceutical compositions described herein. In some embodiments,
the tonicity modifier is a salt or an amino acid. Examples of
suitable salts include, without limitation, sodium chloride, sodium
succinate, sodium sulfate, potassium chloride, magnesium chloride,
magnesium sulfate, and calcium chloride. In some embodiments, the
tonicity modifier in the pharmaceutical composition may be at a
concentration of about 10-150 mM, 50-150 mM, 50-100 mM, 75-100 mM,
or about 85-95 mM. In some embodiments, the tonicity modifier may
be at a concentration of about 80 mM, 81 mM, 82 mM, 83 mM, 84 mM,
85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94
mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, or about 100 mM. In one
example, the tonicity modifier may be sodium chloride, which may be
at a concentration of about 90 mM.
[0090] The pharmaceutically acceptable carrier in the
pharmaceutical compositions described herein may further comprise
one or more pharmaceutically acceptable excipients. In general,
pharmaceutically acceptable excipients are pharmacologically
inactive substances. Non-limiting examples of excipients include
lactose, glycerol, xylitol, sorbitol, mannitol, maltose, inositol,
trehalose, glucose, bovine serum albumin (BSA), dextran, polyvinyl
acetate (PVA), hydroxypropyl methylcellulose (HPMC),
polyethyleneimine (PEI), gelatin, polyvinylpyrrolidone (PVP),
hydroxyethylcellulose (HEC), polyethylene glycol (PEG), ethylene
glycol, glycerol, dimethysulfoxide (DMSO), dimethylformamide (DMF),
polyoxyethylene sorbitan monolaurate (Tween-20), polyoxyethylene
sorbitan monooleate (Tween-80), sodium dodecyl sulphate (SDS),
polysorbate, polyoxyethylene copolymer, potassium phosphate, sodium
acetate, ammonium sulfate, magnesium sulfate, sodium sulfate,
trimethylamine N-oxide, betaine, zinc ions, copper ions, calcium
ions, manganese ions, magnesium ions, CHAPS, sucrose monolaurate
and 2-O-beta-mannoglycerate. In some embodiments, the
pharmaceutically acceptable carrier comprises an excipient between
about 0.001%-0.1%, 0.001%-0.05%, 0.005-0.1%, 0.005%-0.05%,
0.008%-0.05%, 0.008%-0.03% or about 0.009%-0.02%. In some
embodiments, the excipient is at about 0.005%, 0.006%, 0.007%,
0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%,
0.08%, 0.09%, or about 0.1%. In some embodiments, the excipient is
polyoxyethylene sorbitan monooleate (Tween-80). In one example, the
pharmaceutically acceptable carrier contains 0.01% Tween-80.
[0091] In some examples, the pharmaceutical composition described
herein comprises the anti-pKal antibody as also described herein
(e.g., DX-2930), and one or more of sodium phosphate (e.g., sodium
phosphate dibasic dihydrate), citric acid (e.g., citric acid
monohydrate), histidine (e.g., L-histidine), sodium chloride, and
Polysorbate 80. For example, the pharmaceutical composition may
comprise the antibody, sodium phosphate, citric acid, histidine,
sodium chloride, and Polysorbate 80. In some examples, the antibody
is formulated in about 30 mM sodium phosphate, about 19 mM citric
acid, about 50 mM histidine, about 90 mM sodium chloride, and about
0.01% Polysorbate 80. The concentration of the antibody (e.g.,
DX-2930) in the composition can be about 150 mg/mL or 300 mg/mL. In
one example, the composition comprises or consists of about 150 mg
DX-2930 per 1 mL solution, about 30 mM sodium phosphate dibasic
dihydrate, about 19 mM (e.g., 19.6 mM) citric acid monohydrate,
about 50 mM L-histidine, about 90 mM sodium chloride, and about
0.01% Polysorbate 80. In another example, the composition comprises
or consists of about 300 mg DX-2930 per 1 mL solution, about 30 mM
sodium phosphate dibasic dihydrate, about 19 mM (e.g., 19.6 mM)
citric acid monohydrate, about 50 mM L-histidine, about 90 mM
sodium chloride, and about 0.01% Polysorbate 80.
[0092] A pharmaceutically acceptable salt is a salt that retains
the desired biological activity of the compound and does not impart
any undesired toxicological effects (see, e.g., Berge, S. M., et
al., 1977, J. Pharm. Sci. 66:1-19). Examples of such salts include
acid addition salts and base addition salts. Acid addition salts
include those derived from nontoxic inorganic acids, such as
hydrochloric, nitric, phosphoric, sulfuric, hydrobromic,
hydroiodic, phosphorous, and the like, as well as from nontoxic
organic acids such as aliphatic mono- and dicarboxylic acids,
phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic
acids, aliphatic and aromatic sulfonic acids, and the like. Base
addition salts include those derived from alkaline earth metals,
such as sodium, potassium, magnesium, calcium, and the like, as
well as from nontoxic organic amines, such as
N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, procaine, and the
like.
[0093] The compositions may be in a variety of forms. These
include, for example, liquid, semi-solid and solid dosage forms,
such as liquid solutions (e.g., injectable and infusible
solutions), dispersions or suspensions, tablets, pills, powders,
liposomes and suppositories. The form can depend on the intended
mode of administration and therapeutic application. Many
compositions are in the form of injectable or infusible solutions,
such as compositions similar to those used for administration of
humans with antibodies. An exemplary mode of administration is
parenteral (e.g., intravenous, subcutaneous, intraperitoneal,
intramuscular). In one embodiment, the plasma kallikrein binding
protein is administered by intravenous infusion or injection. In
another embodiment, the plasma kallikrein binding protein is
administered by intramuscular injection. In another embodiment, the
plasma kallikrein binding protein is administered by subcutaneous
injection. In another preferred embodiment, the plasma kallikrein
binding protein is administered by intraperitoneal injection.
[0094] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal, epidural and intrasternal injection and
infusion. In some embodiments, the antibody is administered
subcutaneously.
[0095] The composition can be formulated as a solution,
microemulsion, dispersion, liposome, or other ordered structure
suitable to high drug concentration. Sterile injectable solutions
can be prepared by incorporating the binding protein in the
required amount in an appropriate solvent with one or a combination
of ingredients enumerated above, as required, followed by filtered
sterilization. Generally, dispersions are prepared by incorporating
the active compound into a sterile vehicle that contains a basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum drying and freeze-drying that yields a
powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered solution thereof. The
proper fluidity of a solution can be maintained, for example, by
the use of a coating such as lecithin, by the maintenance of the
required particle size in the case of dispersion and by the use of
surfactants. Prolonged absorption of injectable compositions can be
brought about by including in the composition an agent that delays
absorption, for example, monostearate salts and gelatin.
[0096] An antibody as described herein (e.g., DX-2930) can be
administered by a variety of methods, including intravenous
injection, subcutaneous injection, or infusion. For example, for
some therapeutic applications, the antibody can be administered by
intravenous infusion at a rate of less than 30, 20, 10, 5, or 1
mg/min to reach a dose of about 1 to 100 mg/m.sup.2 or 7 to 25
mg/m.sup.2. The route and/or mode of administration will vary
depending upon the desired results. In certain embodiments, the
active compound may be prepared with a carrier that will protect
the compound against rapid release, such as a controlled release
formulation, including implants, and microencapsulated delivery
systems. Biodegradable, biocompatible polymers can be used, such as
ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
collagen, polyorthoesters, and polylactic acid. Many methods for
the preparation of such formulations are available. See, e.g.,
Sustained and Controlled Release Drug Delivery Systems, J. R.
Robinson, ed., 1978, Marcel Dekker, Inc., New York.
[0097] Pharmaceutical compositions can be administered with medical
devices. For example, in one embodiment, a pharmaceutical
composition disclosed herein can be administered with a device,
e.g., a needleless hypodermic injection device, a pump, or
implant.
[0098] In certain embodiments, an antibody as described herein
(e.g., DX-2930) can be formulated to ensure proper distribution in
vivo. For example, the blood-brain barrier (BBB) excludes many
highly hydrophilic compounds. To ensure that the therapeutic
compounds disclosed herein cross the BBB (if desired), they can be
formulated, for example, in liposomes. For methods of manufacturing
liposomes, see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548; and
5,399,331. The liposomes may comprise one or more moieties that are
selectively transported into specific cells or organs, thus enhance
targeted drug delivery (see, e.g., V. V. Ranade, 1989, J. Clin.
Pharmacol. 29:685).
[0099] Dosage regimens are adjusted to provide the optimum desired
response (e.g., a therapeutic response). For example, a single
bolus may be administered, several divided doses may be
administered over time or the dose may be proportionally reduced or
increased as indicated by the exigencies of the therapeutic
situation. It is especially advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the
subjects to be treated; each unit contains a predetermined quantity
of active compound calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier. The
specification for the dosage unit forms can be dictated by and
directly dependent on (a) the unique characteristics of the active
compound and the particular therapeutic effect to be achieved, and
(b) the limitations inherent in the art of compounding such an
active compound for the treatment of sensitivity in
individuals.
[0100] An exemplary, non-limiting range for a therapeutically or
prophylactically effective amount of an antibody as described
herein (e.g., DX-2930) is about 150 mg or 300 mg. As will be
understood by one of ordinary skill in the art, a therapeutically
or prophylactically effective amount of an antibody may be lower
for a pediatric subject than for an adult subject. In some
embodiments, the effective amount that is administered to a
pediatric subject is a fixed dose or a weight based dose. In some
embodiments, effective amount that is less than about 150 mg or 300
mg is administered to a pediatric subject. In some embodiments, a
therapeutically or prophylactically effective amount of an antibody
is administered every two weeks or every four weeks for a first
treatment period. In some embodiments, the antibody may be
administered to the subject for a second treatment period. In some
embodiments, the therapeutically or prophylactically effective
amount of the antibody in the first treatment period is different
than the therapeutically or prophylactically effective amount of
the antibody in the second treatment period. In some embodiments,
the therapeutically or prophylactically effective amount of the
antibody in the first treatment period is 150 mg and the
therapeutically or prophylactically effective amount of the
antibody in the second treatment period is 300 mg. In some
embodiments, the therapeutically or prophylactically effective
amount of the antibody in the first treatment period is the same as
the therapeutically or prophylactically effective amount of the
antibody in the second treatment period. In one example,
therapeutically or prophylactically effective amount of the
antibody in the first treatment period and the second treatment
period is 300 mg.
[0101] In some embodiments, an exemplary, non-limiting range for a
therapeutically or prophylactically effective amount of an antibody
as described herein (e.g., DX-2930) is about 300 mg. In some
embodiments, a therapeutically or prophylactically effective amount
of an antibody is administered in a single dose. If the subject
experiences a HAE attack, the antibody may be further administered
to the subject in multiple doses, such in doses of about 300 mg
administered every two weeks.
Kits
[0102] An antibody as described herein (e.g., DX-2930) can be
provided in a kit, e.g., as a component of a kit. For example, the
kit includes (a) a DX-2930 antibody, e.g., a composition (e.g., a
pharmaceutical composition) that includes the antibody, and,
optionally (b) informational material. The informational material
can be descriptive, instructional, marketing or other material that
relates to a method described herein and/or the use of an antibody
as described herein (e.g., DX-2930), e.g., for a method described
herein. In some embodiments, the kit comprises one or more doses of
DX-2930. In some embodiments, the one or more doses are 150 mg or
300 mg.
[0103] The informational material of the kit is not limited in its
form. In one embodiment, the informational material can include
information about production of the compound, molecular weight of
the compound, concentration, date of expiration, batch or
production site information, and so forth. In one embodiment, the
informational material relates to using the antibody to treat,
prevent, or diagnosis of disorders and conditions, e.g., a plasma
kallikrein associated disease or condition.
[0104] In one embodiment, the informational material can include
instructions to administer an antibody as described herein (e.g.,
DX-2930) in a suitable manner to perform the methods described
herein, e.g., in a suitable dose, dosage form, mode of
administration or dosing schedule (e.g., a dose, dosage form,
dosing schedule or mode of administration described herein). In
another embodiment, the informational material can include
instructions to administer an antibody as described herein (e.g.,
DX-2930) to a suitable subject, e.g., a human, e.g., a human
having, or at risk for, a plasma kallikrein associated disease or
condition. For example, the material can include instructions to
administer an antibody as described herein (e.g., DX-2930) to a
patient with a disorder or condition described herein, e.g., a
plasma kallikrein associated disease, e.g., according to a dosing
schedule described herein. The informational material of the kits
is not limited in its form. In many cases, the informational
material, e.g., instructions, is provided in print but may also be
in other formats, such as computer readable material.
[0105] An antibody as described herein (e.g., DX-2930) can be
provided in any form, e.g., liquid, dried or lyophilized form. It
is preferred that an antibody be substantially pure and/or sterile.
When an antibody is provided in a liquid solution, the liquid
solution preferably is an aqueous solution, with a sterile aqueous
solution being preferred. When an antibody is provided as a dried
form, reconstitution generally is by the addition of a suitable
solvent. The solvent, e.g., sterile water or buffer, can optionally
be provided in the kit.
[0106] The kit can include one or more containers for the
composition containing an antibody as described herein (e.g.,
DX-2930). In some embodiments, the kit contains separate
containers, dividers or compartments for the composition and
informational material. For example, the composition can be
contained in a bottle, vial, or syringe, and the informational
material can be contained in association with the container. In
other embodiments, the separate elements of the kit are contained
within a single, undivided container. For example, the composition
is contained in a bottle, vial or syringe that has attached thereto
the informational material in the form of a label. In some
embodiments, the kit includes a plurality (e.g., a pack) of
individual containers, each containing one or more unit dosage
forms (e.g., a dosage form described herein) of an antibody as
described herein (e.g., DX-2930). For example, the kit includes a
plurality of syringes, ampules, foil packets, or blister packs,
each containing a single unit dose of an antibody as described
herein (e.g., DX-2930). The containers of the kits can be air
tight, waterproof (e.g., impermeable to changes in moisture or
evaporation), and/or light-tight.
[0107] The kit optionally includes a device suitable for
administration of the composition, e.g., a syringe, or any such
delivery device. In one embodiment, the device is an implantable
device that dispenses metered doses of the antibody. The disclosure
also features a method of providing a kit, e.g., by combining
components described herein.
Treatment
[0108] In some aspects, the disclosure provides the use of an
antibody as described herein (e.g., DX-2930) in treating HAE. In
particular, the present disclosure provides a treatment regimen
that allows for reducing the dosage of DX-2930 and/or extending the
dosing schedule (e.g., from once every two weeks to once every four
weeks) for patients whose disease is well controlled (e.g., free of
attack in a period of time such as 4-9 months) and/or for patients
with low body weight (e.g., pediatric patients).
[0109] (i) Hereditary Angioedema
[0110] Hereditary angioedema (HAE) is also known as "Quincke
edema," C1 esterase inhibitor deficiency, C1 inhibitor deficiency,
and hereditary angioneurotic edema (HANE). HAE is characterized by
unpredictable, recurrent attacks of severe subcutaneous or
submucosal swelling (angioedema), which can affect, e.g., the
limbs, face, genitals, gastrointestinal tract, and airway (Zuraw,
2008). Symptoms of HAE include, e.g., swelling in the arms, legs,
lips, eyes, tongue, and/or throat; airway blockage that can involve
throat (larynx) swelling, sudden hoarseness and/or cause death from
asphyxiation (Bork et al., 2012; Bork et al., 2000). Approximately
50% of all HAE patients will experience a laryngeal attack in their
lifetime, and there is no way to predict which patients are at risk
of a laryngeal attack (Bork et al., 2003; Bork et al., 2006). HAE
symptoms also include repeat episodes of abdominal cramping without
obvious cause; and/or swelling of the intestines, which can be
severe and can lead to abdominal cramping, vomiting, dehydration,
diarrhea, pain, shock, and/or intestinal symptoms resembling
abdominal emergencies, which may lead to unnecessary surgery
(Zuraw, 2008). Swelling may last up to five or more days. About
one-third of individuals with this HAE develop a non-itchy rash
called erythema marginatum during an attack. Most patients suffer
multiple attacks per year.
[0111] HAE is an orphan disorder, the exact prevalence of which is
unknown, but current estimates range from 1 per 10,000 to 1 per
150,000 persons, with many authors agreeing that 1 per 50,000 is
likely the closest estimate (Bygum, 2009; Goring et al., 1998; Lei
et al., 2011; Nordenfelt et al., 2014; Roche et al., 2005).
[0112] Plasma kallikrein plays a critical role in the pathogenesis
of HAE attacks (Davis, 2006; Kaplan and Joseph, 2010). In normal
physiology, C1-INH regulates the activity of plasma kallikrein as
well as a variety of other proteases, such as C1r, C1 s, factor
XIa, and factor XIIa. Plasma kallikrein regulates the release of
bradykinin from high molecular weight kininogen (HMWK). Due to a
deficiency of C1-INH in HAE, uncontrolled plasma kallikrein
activity occurs and leads to the excessive generation of
bradykinin. Bradykinin is a vasodilator which is thought to be
responsible for the characteristic HAE symptoms of localized
swelling, inflammation, and pain (Craig et al., 2012; Zuraw et al.,
2013).
[0113] Swelling of the airway can be life threatening and causes
death in some patients. Mortality rates are estimated at 15-33%.
HAE leads to about 15,000-30,000 emergency department visits per
year.
[0114] Trauma or stress, e.g., dental procedures, sickness (e.g.,
viral illnesses such as colds and the flu), menstruation, and
surgery can trigger an attack of angioedema. To prevent acute
attacks of HAE, patients can attempt to avoid specific stimuli that
have previously caused attacks. However, in many cases, an attack
occurs without a known trigger. Typically, HAE symptoms first
appear in childhood and worsen during puberty. On average,
untreated individuals have an attack every 1 to 2 weeks, and most
episodes last for about 3 to 4 days
(ghr.nlm.nih.gov/condition/hereditary-angioedema). The frequency
and duration of attacks vary greatly among people with hereditary
angioedema, even among people in the same family.
[0115] There are three types of HAE, known as types I, II, and III,
all of which can be treated by the methods described herein. It is
estimated that HAE affects 1 in 50,000 people, that type I accounts
for about 85 percent of cases, type II accounts for about 15
percent of cases, and type III is very rare. Type III is the most
newly described form and was originally thought to occur only in
women, but families with affected males have been identified.
[0116] HAE is inherited in an autosomal dominant pattern, such that
an affected person can inherit the mutation from one affected
parent. New mutations in the gene can also occur, and thus HAE can
also occur in people with no history of the disorder in their
family. It is estimated that 20-25% of cases result from a new
spontaneous mutation.
[0117] Mutations in the SERPING1 gene cause hereditary angioedema
type I and type II. The SERPING1 gene provides instructions for
making the C1 inhibitor protein, which is important for controlling
inflammation. C1 inhibitor blocks the activity of certain proteins
that promote inflammation. Mutations that cause hereditary
angioedema type I lead to reduced levels of C1 inhibitor in the
blood. In contrast, mutations that cause type II result in the
production of a C1 inhibitor that functions abnormally.
Approximately 85% of patients have Type I HAE, characterized by
very low production of functionally normal C1-INH protein, while
the remaining approximately 15% of patients have Type II HAE and
produce normal or elevated levels of a functionally impaired C1-INH
(Zuraw, 2008). Without the proper levels of functional C1
inhibitor, excessive amounts of bradykinin are generated from high
molecular weight kininogen (HMWK), and there is increased vascular
leakage mediated by bradykinin binding to the B2 receptor (B2-R) on
the surface of endothelial cells (Zuraw, 2008). Bradykinin promotes
inflammation by increasing the leakage of fluid through the walls
of blood vessels into body tissues. Excessive accumulation of
fluids in body tissues causes the episodes of swelling seen in
individuals with hereditary angioedema type I and type II.
[0118] Mutations in the F12 gene are associated with some cases of
hereditary angioedema type III. The F12 gene provides instructions
for making coagulation factor XII. In addition to playing a
critical role in blood clotting (coagulation), factor XII is also
an important stimulator of inflammation and is involved in the
production of bradykinin. Certain mutations in the F12 gene result
in the production of factor XII with increased activity. As a
result, more bradykinin is generated and blood vessel walls become
more leaky, which leads to episodes of swelling. The cause of other
cases of hereditary angioedema type III remains unknown. Mutations
in one or more as-yet unidentified genes may be responsible for the
disorder in these cases.
[0119] HAE can present similarly to other forms of angioedema
resulting from allergies or other medical conditions, but it
differs significantly in cause and treatment. When hereditary
angioedema is misdiagnosed as an allergy, it is most commonly
treated with antihistamines, steroids, and/or epinephrine, which
are typically ineffective in HAE, although epinephrine can be used
for life-threatening reactions. Misdiagnoses have also resulted in
unnecessary exploratory surgery for patients with abdominal
swelling, and in some HAE patients abdominal pain has been
incorrectly diagnosed as psychosomatic.
[0120] Like adults, children with HAE can suffer from recurrent and
debilitating attacks. Symptoms may present very early in childhood,
and upper airway angioedema has been reported in HAE patients as
young as the age of 3 (Bork et al., 2003). In one case study of 49
pediatric HAE patients, 23 had suffered at least one episode of
airway angioedema by the age of 18 (Farkas, 2010). An important
unmet medical need exists among children with HAE, especially
adolescents, since the disease commonly worsens after puberty
(Bennett and Craig, 2015; Zuraw, 2008).
[0121] C1 inhibitor therapies, as well as other therapies for HAE,
are described in Kaplan, A. P., J Allergy Clin Immunol, 2010,
126(5):918-925.
[0122] Acute treatment of HAE attacks is provided to halt
progression of the edema as quickly as possible. C1 inhibitor
concentrate from donor blood, which is administered intravenously,
is one acute treatment; however, this treatment is not available in
many countries. In emergency situations where C1 inhibitor
concentrate is not available, fresh frozen plasma (FFP) can be used
as an alternative, as it also contains C1 inhibitor.
[0123] Purified C1 inhibitor, derived from human blood, has been
used in Europe since 1979. Several C1 inhibitor treatments are now
available in the U.S. and two C1 inhibitor products are now
available in Canada. Berinert P (CSL Behring), which is
pasteurized, was approved by the F.D.A. in 2009 for acute attacks.
Cinryze (ViroPharma), which is nanofiltered, was approved by the
F.D.A. in 2008 for prophylaxis. Rhucin (Pharming) is a recombinant
C1 inhibitor under development that does not carry the risk of
infectious disease transmission due to human blood-borne
pathogens.
[0124] Treatment of an acute HAE attack also can include
medications for pain relief and/or IV fluids.
[0125] Other treatment modalities can stimulate the synthesis of C1
inhibitor, or reduce C1 inhibitor consumption. Androgen
medications, such as danazol, can reduce the frequency and severity
of attacks by stimulating production of C1 inhibitor.
[0126] Helicobacter pylori can trigger abdominal attacks.
Antibiotics to treat H. pylori will decrease abdominal attacks.
[0127] Newer treatments attack the contact cascade. Ecallantide
(KALBITOR.RTM., DX-88, Dyax) inhibits plasma kallikrein and has
been approved in the U.S. Icatibant (FIRAZYR.RTM., Shire) inhibits
the bradykinin B2 receptor, and has been approved in Europe and the
U.S.
[0128] Diagnosis of HAE can rely on, e.g., family history and/or
blood tests. Laboratory findings associated with HAE types I, II,
and III are described, e.g., in Kaplan, A. P., J Allergy Clin
Immunol, 2010, 126(5):918-925. In type I HAE, the level of C1
inhibitor is decreased, as is the level of C4, whereas C1q level is
normal. In type II HAE, the level of C1 inhibitor is normal or
increased; however, C1 inhibitor function is abnormal. C4 level is
decreased and C1q level is normal. In type III, the levels of C1
inhibitor, C4, and C1q can all be normal.
[0129] Symptoms of HAE can be assessed, for example, using
questionnaires, e.g., questionnaires that are completed by
patients, clinicians, or family members. Such questionnaires are
known in the art and include, for example, visual analog scales.
See, e.g., McMillan, C. V. et al. Patient. 2012; 5(2):113-26. In
some embodiments, the subject has HAE type I or HAE type II. HAE
type I or HAE type II may be diagnosed using any method known in
the art, such as by clinical history consistent with HAE (e.g.,
subcutaneous or mucosal, nonpruritic swelling episodes) or
diagnostic testing (e.g., C1-INH functional testing and C4 level
assessment).
[0130] (ii) Reducing Dosage of DX-2930 in HAE Treatment
[0131] The disclosure provides methods of treating (e.g.,
ameliorating, stabilizing, or eliminating one or more symptoms) of
hereditary angioedema (HAE) by administering to an HAE patient with
an anti-pKal antibody such as DX-2930 at a first dosing schedule,
for example 300 mg every two weeks, for a first treatment period
(e.g., 4-9 weeks). Occurrence of HAE attack is monitored in the
patient subject to the first period of treatment following standard
medical practice. When the patient is free of HAE attack in the
first treatment period, dosage of the antibody can be reduced
and/or dosing interval of the antibody can be prolonged, for
example, reduced to 300 mg every four weeks or 300 mg every six
weeks.
[0132] In some embodiments, the human patient may have a low body
weight. As used herein, a low body weight, when applied to an
adult, refers to the body weight of the adult that is significantly
lower than the average body weight of adults with matched physical
features, such as height, age, gender, etc. For example, an adult
patient having a low body weight may have a body weight that is at
least 20% (e.g., 30%, 40%, 50%, or above) lower than the average of
body weight of adults with matched physical features as noted
above. In some instances, the human patient is an adult HAE patient
having a body weight lower than 40 kg (e.g., lower than 35 kg,
lower than 30 kg, lower than 25 kg, etc.). In other instances, the
human patient having a low body weight may be a pediatric patient
(e.g., younger than 15 yrs). Such a pediatric patient may have a
body weight less than 30 kg (e.g., lower than 25 kg, lower than 20
kg, lower than 15 kg, or lower than 10 kg, etc.).
[0133] In some embodiments, the subject may be defined by gender.
For example, in some embodiments, the subject is female. In other
embodiments, the subject is male.
[0134] In some embodiments, the human subject is defined by prior
history of laryngeal attacks or absence thereof. In some
embodiments, the subject has experienced at least one (e.g., 1, 2,
3, 4, 5, or more) laryngeal attack (i.e. laryngeal HAE attack)
prior to administration of the antibodies described herein. In some
embodiments, the subject has not experienced a laryngeal attack
prior to administration of the antibodies described herein.
[0135] Treating includes administering an amount effective to
alleviate, relieve, alter, remedy, ameliorate, improve or affect
the disorder, the symptoms of the disorder or the predisposition
toward the disorder. The treatment may also delay onset, e.g.,
prevent onset, or prevent deterioration of a disease or
condition.
[0136] Methods of administering DX-2930 antibodies are also
described in "Pharmaceutical Compositions." Suitable dosages of the
antibody used can depend on the age and weight of the subject and
the particular drug used. The antibody can be used as competitive
agents to inhibit, reduce an undesirable interaction, e.g., between
plasma kallikrein and its substrate (e.g., Factor XII or HMWK). The
dose of the antibody can be the amount sufficient to block 90%,
91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, or 99.9% of the
activity of plasma kallikrein in the patient, especially at the
site of disease. In some embodiments, 150 mg or 300 mg of the
antibody is administered every two weeks or every four weeks. In
some embodiments, the antibody is administered to the subject in a
first treatment period comprising administration of 150 mg or 300
mg of the antibody every two weeks or every four weeks. In some
embodiments, the antibody is administered to the subject in a
second treatment period following the first treatment period. In
some embodiments, 300 mg of the antibody is administered in a
single dose. If the subject experiences an HAE attack after the
single dose, the antibody may be administered at 300 mg every two
weeks in the first treatment period.
[0137] In one embodiment, the antibodies are used to inhibit an
activity (e.g., inhibit at least one activity of plasma kallikrein,
e.g., reduce Factor XIIa and/or bradykinin production) of plasma
kallikrein, e.g., in vivo. The binding proteins can be used by
themselves or conjugated to an agent, e.g., a cytotoxic drug,
cytotoxin enzyme, or radioisotope.
[0138] The antibodies can be used directly in vivo to eliminate
antigen-expressing cells via natural complement-dependent
cytotoxicity (CDC) or antibody dependent cellular cytotoxicity
(ADCC). The antibodies described herein can include complement
binding effector domain, such as the Fc portions from IgG1, -2, or
-3 or corresponding portions of IgM which bind complement. In one
embodiment, a population of target cells is ex vivo treated with an
antibody described herein and appropriate effector cells. The
treatment can be supplemented by the addition of complement or
serum containing complement. Further, phagocytosis of target cells
coated with an antibody described herein can be improved by binding
of complement proteins. In another embodiment target, cells coated
with the antibody which includes a complement binding effector
domain are lysed by complement.
[0139] Methods of administering DX-2930 antibodies are described in
"Pharmaceutical Compositions." Suitable dosages of the molecules
used will depend on the age and weight of the subject and the
particular drug used. The antibodies can be used as competitive
agents to inhibit or reduce an undesirable interaction, e.g.,
between a natural or pathological agent and the plasma
kallikrein.
[0140] A therapeutically effective amount of an antibody as
described herein, can be administered to a subject having,
suspected of having, or at risk for HAE, thereby treating (e.g.,
ameliorating or improving a symptom or feature of a disorder,
slowing, stabilizing and/or halting disease progression) the
disorder.
[0141] The antibody described herein can be administered in a
therapeutically effective amount. A therapeutically effective
amount of an antibody is the amount which is effective, upon single
or multiple dose administration to a subject, in treating a
subject, e.g., curing, alleviating, relieving or improving at least
one symptom of a disorder in a subject to a degree beyond that
expected in the absence of such treatment.
[0142] Dosage regimens can be adjusted to provide the optimum
desired response (e.g., a therapeutic response). For example, a
single bolus may be administered, several divided doses may be
administered over time or the dose may be proportionally reduced or
increased as indicated by the exigencies of the therapeutic
situation. In other examples, a bolus may be administered followed
by several doses over time or the dose may be proportionally
reduced or increased as indicated by the exigencies of the
therapeutic situation. In other examples, a dose may be divided
into several doses and be administered over time. It is especially
advantageous to formulate parenteral compositions in dosage unit
form for ease of administration and uniformity of dosage. Dosage
unit form as used herein refers to physically discrete units suited
as unitary dosages for the subjects to be treated; each unit
contains a predetermined quantity of active compound calculated to
produce the desired therapeutic effect in association with the
required pharmaceutical carrier.
[0143] Any of the subjects described herein may have undergone
prior treatment of HAE, such as a prophylactic or therapeutic
treatment of HAE. Aspects of the present disclosure also provide
methods of administering an antibody as described herein (e.g.,
DX-2930) to a subject that has received one or more prior treatment
for HAE. In some embodiments, the prior treatment of HAE is a
treatment that involves an antibody described herein (e.g.,
DX-2930). In some embodiments, the subject was previously
administered multiple doses of DX-2930 every two weeks or every
four weeks. In some embodiments, the subject was previously
administered DX-2930 at 150 mg every two weeks. In some
embodiments, the subject was previously administered DX-2930 at 300
mg every two weeks. In some embodiments, the subject was previously
administered DX-2930 at 300 mg every four weeks. In some
embodiments, the multiple doses of the antibody of the prior
treatment are administered at least two times, at least three
times, at least four times, at least five times, at least six
times, at least seven times, at least eight times, at least nine
times, at least ten times, at least eleven times, at least twelve
time, at least thirteen times.
[0144] In some embodiments, the subject has received one or more
prior treatment for HAE, which may involve any of the therapeutic
agent for HAE known in the art. Exemplary anti-HAE agents include,
but are not limited to, C1-inhibitors (e.g., Cinryze.RTM.,
Berinert.RTM., or Ruconest.RTM.), plasma kallikrein inhibitors
(e.g., Kalbitor.RTM.), bradykinin receptor inhibitors (e.g.,
Firazyr.RTM.), annenuated androgens (e.g., danazol), and
anti-fibrinolytics (e.g., traexamic acid). In some examples, a
subject may undergo a tapering period before receiving the
anti-pKal antibody treatment as described herein. A tapering period
refers to a period, prior to the anti-pKal antibody treatment,
during which a subject who is on an anti-HAE treatment (e.g.,
C1-INH, oral androgen, and/or oral anti-fibrinolytics) gradually
reduces the dosage, frequency, or both of the anti-HAE agent such
that the subject can gradually transit from the prior HAE treatment
to the anti-pKal antibody treatment as described herein. In some
embodiments, the tapering involving a gradual or step-wise method
of reducing the dosage of the prior treatment and/or the frequency
with which the prior treatment is administered. The tapering period
may last 2-4 weeks and can vary based on factors of an individual
patent. In some examples, the prior treatment terminates before the
anti-pKal antibody treatment starts. In other examples, the prior
treatment may terminate within a suitable timeframe (e.g., 2 weeks,
3 weeks, or 4 weeks) after the subject is given his or her first
dose of the anti-pKal antibody.
[0145] Alternatively, a subject who is on a prior HAE treatment may
be transitioned to the anti-pKal antibody treatment as described
herein directly without the tapering period.
[0146] In other embodiments, the subject is free of any prior
treatment of HAE before the first treatment, first treatment
period, and/or the follow-on single and multiple dose treatments as
described herein (the second treatment period). In some
embodiments, the subject is free of any treatment other than with
the antibodies described herein during the first treatment period
and/or during the second treatment period. In some embodiments, the
subject is free of any prior treatment of HAE for at least two
weeks (e.g., at least two, three, four, five weeks or more) before
the first treatment or first treatment period, during the first
treatment or first treatment period, and/or during the second
treatment period. In some embodiments, the subject is free of
long-term prophylaxis for HAE (e.g., C1 inhibitor, attenuated
androgens, anti-fibrinolytics) for at least the two weeks prior to
the first treatment or first treatment period, during the first
treatment period, and/or during the second treatment period. In
some embodiments, the subject is free of an HAE treatment involving
an angiotensin-converting enzyme (ACE) inhibitor for at least the
four weeks prior to the first treatment or first treatment period,
during the first treatment period, and/or during the second
treatment period. In some embodiments, the subject is free of an
estrogen-containing medication for at least the four weeks prior to
the first treatment or first treatment period, during the first
treatment period, and/or during the second treatment period. In
some embodiments, the subject is free of androgens (e.g.
stanozolol, danazol, oxandrolone, methyltestosterone, testosterone)
for at least the two weeks prior to the first treatment or first
treatment period, during the first treatment period and/or during
the second treatment period.
[0147] Any of the methods described herein may further comprise
monitoring the patient for side effects (e.g., elevation of
creatine phosphatase levels) and/or inhibition levels of pKal by
the antibody (e.g., serum or plasma concentration of the antibody
or the pKal activity level) before and after the treatment or
during the course of treatment. If one or more adverse effect is
observed, the dose of the antibody might be reduced or the
treatment might be terminated. If the inhibition level is below a
minimum therapeutic level, further doses of the antibody might be
administered to the patient. Patients may also be evaluated for the
generation of antibody against the administered antibody; activity
of C1-inhibitor, C4, and/or C1q; quality of life; incidence of any
HAE attacks, health-related quality of life, anxiety and/or
depression (e.g., Hospital Anxiety and Depression Scale (HADS)),
work productivity (e.g., Work Productivity and Activity Impairment
Questionnaire (WPAI)), preference of the subcutaneous
administration of the antibody (e.g., D-2930) relative to other
injectibles, quality of life (e.g, angioedema-quality of life
(AE-QOL), EuroQoL Group 5-dimension report).
[0148] In some embodiments, the plasma or serum concentration of
the antibody (e.g., DX-2930) may be measured during the course of
the treatment (e.g., after the initial dosage) for assessing the
efficacy of the treatment. If the plasma or serum concentration of
the antibody is lower than about 80 nM, a follow-up dosage may be
needed, which may be the same or higher than the initial dosage.
The plasma or serum concentration of the antibody may be measured
by determining the protein level of the antibody in a plasma or
serum sample obtained from the subject, e.g., by an immune assay or
MS assay. The plasma or serum concentration of the antibody may
also be measured by determining the inhibitory level of pKal in a
plasma or serum sample obtained from a subject treated with the
antibody. Such assays may include the synthetic substrate assay or
the Western blot assay for measuring cleaved kininogen as described
herein.
[0149] Alternatively or in addition, the plasma or serum level of
creatine kinase and/or one or more coagulation parameters (e.g.,
activated partial thromboplastin time (aPTT), prothrombin time
(PT), bleeding events) can be monitored during the course of the
treatment. If the plasma or serum level of creatine kinase is found
to elevate during the treatment, the dosage of the antibody may be
reduced or the treatment may be terminated. Similarly, if one or
more coagulation parameters are found to be significantly affected
during the treatment, the dosage of the antibody may be modified or
the treatment may be terminated.
[0150] In some embodiments, an optimal dosage (e.g., optimal
prophylactic dosage or optimal therapeutic dosage) of the antibody
(e.g., DX-2930) may be determined as follows. The antibody is given
to a subject in need of the treatment at an initial dose. The
plasma concentration of the antibody in the subject is measured. If
the plasma concentration is lower than 80 nM, the dose of the
antibody is increased in a subsequent administration. A dosage of
the antibody that maintains the antibody plasma concentration above
about 80 nM can be chosen as the optimal dosage for the subject.
The creatine phosphokinase level of the subject can be monitored
during the course of treatment and the optimal dosage for that
subject can be further adjusted based on the creatine phosphokinase
level, e.g., the dosage of the antibody might be reduced is
elevation of creatine phosphokinase is observed during
treatment.
[0151] (iii) Combination Therapies
[0152] An antibody as described herein (e.g., DX-2930) can be
administered in combination with one or more of the other therapies
for treating a disease or condition associated with plasma
kallikrein activity, e.g., a disease or condition described herein.
For example, an antibody as described herein (e.g., DX-2930) can be
used therapeutically or prophylactically (e.g., before, during, or
after the course of treatment) with another anti-plasma kallikrein
Fab or IgG (e.g., another Fab or IgG described herein), another
plasma kallikrein inhibitor, a peptide inhibitor, small molecule
inhibitor, or surgery. Examples of plasma kallikrein inhibitors
that can be used in combination therapy with a plasma kallikrein
binding antibodies described herein include plasma kallikrein
inhibitors described in, e.g., WO 95/21601 or WO 2003/103475.
[0153] One or more plasma kallikrein inhibitors can be used in
combination with an antibody as described herein (e.g., DX-2930).
For example, the combination can result in a lower dose of the
inhibitor being needed, such that side effects are reduced.
[0154] An antibody as described herein (e.g., DX-2930) can be
administered in combination with one or more current therapies for
treating HAE. For example, DX-2930 antibody can be co-used with a
second anti-HAE therapeutic agent such as ecallantide, a C1
esterase inhibitor (e.g., CINRYZE.TM.), aprotinin (TRASYLOL.RTM.),
and/or a bradykinin B2 receptor inhibitor (e.g., icatibant
(FIRAZYR.RTM.)).
[0155] The term "combination" refers to the use of the two or more
agents or therapies to treat the same patient, wherein the use or
action of the agents or therapies overlaps in time. The agents or
therapies can be administered at the same time (e.g., as a single
formulation that is administered to a patient or as two separate
formulations administered concurrently) or sequentially in any
order. Sequential administrations are administrations that are
given at different times. The time between administration of the
one agent and another agent can be minutes, hours, days, or weeks.
The use of a plasma kallikrein binding antibody described herein
can also be used to reduce the dosage of another therapy, e.g., to
reduce the side effects associated with another agent that is being
administered. Accordingly, a combination can include administering
a second agent at a dosage at least 10, 20, 30, or 50% lower than
would be used in the absence of the plasma kallikrein binding
antibody. In some embodiments, a subject can be given a
C1-inhibitor as a loading IV dose or SC dose simultaneously with
the first dose of an anti-pKal antibody (e.g., DX-2930) as
described herein. The subject can then continue with the anti-pKal
antibody treatment (without further doses of the C1-inhibitor).
[0156] A combination therapy can include administering an agent
that reduces the side effects of other therapies. The agent can be
an agent that reduces the side effects of a plasma kallikrein
associated disease treatment.
[0157] (iv) Assays for Assessing a Treatment Regimen
[0158] Also within the scope of the present disclosure are assay
methods for assessing efficacy of any of the treatment methods
described herein. In some embodiments, the plasma or serum
concentration of one or more biomarkers (e.g., 2-chain HMWK)
associated with HAE may be may be measured prior to and/or during
the course of the treatment (e.g., after the initial dosage) for
assessing the efficacy of the treatment. In some embodiments, the
plasma or serum concentration (level) of one or more biomarkers
associated with HAE obtained at a time point after administration
of a dosage is compared to the concentration of the biomarker in a
sample obtained at an earlier time point after administration of a
dosage or prior to administration of the initial dosage. In some
embodiments, the biomarker is 2-HMWK.
[0159] The level of the biomarker may be measured by detecting the
biomarker in a plasma or serum sample obtained from the subject,
e.g., by an immunoassay, such as Western blot assay or ELISA, using
an antibody that specifically detects the biomarker. In some
embodiments, the level of 2-HWMK in a plasma or serum sample
obtained from the subject is assessed by an immunoassay. Antibodies
for use in immunoassays for the detection of 2-HWMK are known in
the art and selection of such an antibody for use in the methods
described herein will be evident to one of ordinary skill in the
art.
[0160] Without further elaboration, it is believed that one skilled
in the art can, based on the above description, utilize the present
invention to its fullest extent. The following specific embodiments
are, therefore, to be construed as merely illustrative, and not
limitative of the remainder of the disclosure in any way
whatsoever. All publications cited herein are incorporated by
reference for the purposes or subject matter referenced herein.
EXAMPLES
Example 1: Indirect Treatment Comparison of DX-2930 and Intravenous
C1 Esterase Inhibitor Treatments for Long-Term Prophylaxis of
Hereditary Angioedema Attacks
Study Overview
[0161] A systematic literature review was undertaken to identify
and summarize the existing evidence for efficacy and safety of
long-term prophylactic treatment of patients with type I and type
II hereditary angioedema (HAE) for an indirect treatment comparison
(ITC). Additionally, data from the HELP study (Banerji et al., JAMA
320(20):2108-21, 2018) were analyzed to establish the optimal
parametric survival models for use in an ITC with the evidence
identified by the systematic literature review. All analyses were
conducted using R (R Core Team, 2018, www.R-project.org).
[0162] The HELP study assessed the efficacy and safety of
subcutaneous lanadelumab (DX-2930) in preventing acute angioedema
attacks in patients with type I and type II HAE in which three
lanadelumab dosing regimens (300 mg every two weeks [q2w], 300 mg
every four weeks [q4w], and 150 mg q4w) were investigated and
compared with placebo (Banerji et al., JAMA 320(20):2108-21,
2018).
Materials and Methods
[0163] A systematic literature search through June 2017 was
conducted using MEDLINE, Embase, MEDLINE In-Process, and the
Cochrane Library database. A search of conference proceedings was
conducted for the years 2016 and 2017 and included EAACI; American
College of Allergy, Asthma and Immunology; World Allergy Congress;
and European Society for Immunodeficiency. An additional search of
key health technology assessment agencies included the National
Institute for Health and Care Excellence (NICE), Canadian Agency
for Drugs and Technologies in Health Common Drug Review, Scottish
Medicines Consortium, and All Wales Medicines Strategy Group. The
search focused on studies for long-term prophylaxis of angioedema
attacks in patients with type I or type II HAE who were .gtoreq.12
years of age based on the criteria described in Table 1B.
TABLE-US-00003 TABLE 1B Key Inclusion and Exclusion Criteria for
Literature Search Category Inclusion Criteria Exclusion Criteria
Population Patient with type I and type II HAE Healthy volunteers
Any race Pediatric population (age <12 years) Age .gtoreq.12
years Type III HAE Disease other than HAE Interventions
Prophylactic treatments (short- or Nonpharmacologic treatments
long-term; mono- and/or combination Fresh frozen plasma, solvent
therapy): detergent plasma, antifibrinolytic Berinert .RTM. agents
Cinryze .RTM. (formerly Cetor) Acute treatments Lanadelumab
(DX-2930) Icatibant (Firazyr .RTM.), ecallantide Danazol (Kalbitor
.RTM.), recombinant C1 Stanozolol esterase inhibitor (Ruconest
.RTM.) Oxandrolone Surgery Methyl testosterone Studies assessing
interventions not in Testosterone the list Comparators No
restrictions Outcomes No restrictions Study design RCTs
irrespective of blinding status Case reports, case series Non-RCTs
Pharmacokinetic and economic Observational studies studies
Single-arm studies Preclinical studies Cohort studies (prospective
and Reviews, letters, and comment retrospective) articles Long-term
follow-up studies Systematic reviews and meta- analyses of
RCTs/non-RCTs.sup.a Language No restrictions.sup.b HAE, hereditary
angioedema; RCT, randomized controlled trial. .sup.aSystematic
reviews and meta-analyses of RCTs and non-RCTs were included and
flagged for bibliography screening to determine if literature
searches missed any potentially relevant studies. .sup.bNon-English
language publications were included and explored if no sufficient
evidence was identified from publications written in English.
[0164] The development and reporting of this analysis followed
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines (Moher et al., PLoS Med. 6(7):e1000097, 2009).
Randomized controlled trials were considered the highest standard
of evidence for ITC, and data from nonrandomized studies were also
considered if no randomized controlled trial data were
available.
[0165] Abstracts and full-text articles were evaluated for
inclusion by two independent reviewers, and data extraction from
the selected literature was performed by one reviewer and
independently validated by a second reviewer; any uncertainties
were resolved by a third reviewer. A descriptive assessment of the
included randomized controlled trials was performed by two
independent reviewers using comprehensive assessment criteria based
on the recommendations in the NICE manufacturer's submission
template (Single technology appraisal (STA): user guide for company
evidence submission template. UK: National Institute for Health and
Care Excellence;
www.nice.org.uk/process/pmg24/chapter/instructions-for-companies#quality--
assessment-of-the-relevant-randomised-controlled-trials, 2015).
Parametric Survival Models
[0166] Kaplan-Meier curves were derived for the time to first HAE
attack (defined as all investigator-confirmed attacks) after day 0
and day 70 for each lanadelumab dosing regimen and placebo using
patient-level data from the HELP study (Banerji et al., JAMA
320(20):2108-21, 2018). A univariate Cox proportional hazards model
with treatment as the only covariate was fit to estimate the
relative treatment effect (i.e., HR) for each lanadelumab dose
compared with placebo.
[0167] To extrapolate long-term survival curves to be used in the
NMA, standard parametric survival models (Exponential, Weibull,
log-normal, log-logistic, Gompertz, and generalized gamma survival
models) (Latimer, Decision Support Unit, National Institute for
Health and Clinical Excellence;
nicedsu.org.uk/wp-content/uploads/2016/03/NICE-DSU-TSD-Survival-analysis.-
updated-March-2013.v2.pdf, 2011) were fit to the Kaplan-Meier data.
If the standard models did not fit to the observed data, a more
flexible proportional hazards spline model was considered, which is
an extension of the standard Weibull model that models the log
cumulative hazard as a natural cubic spline function of log time
(Royston et al., Stat Med. 21(15):2175-97, 2002). Methods employed
to assess the fit of the model were clinical plausibility of
extrapolations, goodness-of-fit measures, and visual inspection by
overlaying fitted survival curves with observed survival data.
Attack Rate and Time to First HAE Attack
[0168] Outcomes of interest for this ITC were event (HAE attack)
rate and time to event (first HAE attack). Attack rate was defined
as the number of attacks experienced in a 28-day cycle, with
relative treatment effects estimated as rate ratios (RRs). Time to
first attack was defined as the time a patient with HAE had their
first attack after day 0 (date of first administered dose of
prophylactic therapy) or day 70 (approximate day at which steady
state plasma lanadelumab concentration is reached). For time to
first attack, relative treatment effects were estimated as hazard
ratios (HRs).
[0169] A Bayesian NMA, relying on Markov chain Monte Carlo methods,
was developed to evaluate the outcomes of attack rate and time to
first attack. Relative efficacy was estimated using a treatment
effect model to allow synthesis of direct and indirect evidence in
one analysis while accounting for correlation arising from
multi-arm trials (Dias et al., Decision Support Unit, National
Institute for Health and Clinical Excellence;
nicedsu.org.uk/wp-content/uploads/2017/05/TSD2-General-meta-analysis-corr-
ected-2Sep2016v2.pdf, 2011). Some studies in the evidence network
did not report time to first attack. However, because the
proportion of patients who had not experienced an HAE attack was
reported for every study, an extension of the NMA method was used
to synthesize the count data and time-to-event data in the same
analysis (Woods et al., BMC Med Res Methodol. 10:54, 2010).
Treatment effects were compared using credible intervals (CrIs);
for cases in which the CrI for treatment versus placebo did not
include the value 1, the results were considered statistically
significant. Both HELP and CHANGE were randomized, double-blind
trials in patients with confirmed HAE (Banerji et al., JAMA.
320(20):2108-21, 2018; Zuraw et al., N Engl J Med. 363(6):513-22,
2010). Fixed- and random-effects models were considered for the
NMA, and the choice of model was based on an assessment of study
design, inclusion criteria, and patient characteristics.
Predicted Survival Curves
[0170] Predicted survival curves were derived for each treatment
arm separately for time to first attack after day 0 and day 70 by
combining the HRs from the ITC and the spline survival curve fitted
to the placebo data from the HELP study. These curves were used to
estimate the proportion of attack-free patients and 95% confidence
intervals (CIs) at 60 months after the start of prophylactic
treatment (day 0 or day 70) for each comparator in the ITC.
Results
Systematic Literature Review
[0171] A systematic literature review was undertaken. A summary of
the records identified is presented in FIG. 1. The search
identified 1299 records, of which 52 (22 records from seven
randomized controlled trials [RCTs] and 30 records from 23
nonrandomized controlled trials [nRCTs]) met the eligibility
criteria and were selected for detailed feasibility assessment for
possible inclusion in the ITC with lanadelumab results from the
HELP study. Twenty-two records were excluded because they were
secondary publications for which a primary publication had already
been identified among the 52 records that met the eligibility
criteria. Of the remaining records in the feasibility assessment,
20 lacked real-world applicability and were therefore excluded as
inappropriate comparators. Included in these were two RCTs (Gelfand
et al., N Engl J Med. 295(26):1444-8, 1976; Sheffer et al., Ann Int
Med. 86(3):306-8, 1977) and 15 nRCTs (Fust et al., Eur J Clin
Invest. 41(3):256-62, 2011; Agostoni et al., Medicine (Baltimore).
71(4):206-15, 1992; Bork et al., Ann Allergy Asthma Immunol.
100(2):153-61, 2008; Caminoa et al., Allergy. 68(suppl 97):61,
2013; Cicardi et al., J Allergy Clin Immunol. 99(2):194-6, 1997;
Davis et al., Johns Hopkins Med J. 135(6):391-8, 1974; Farkas et
al., J Oral Maxillofac Surg. 57(4):404-8, 1999; Kreuz et al.,
Transfusion. 49(9):1987-95, 2009; Obtulowicz et al., Int Rev
Allergol Clin Immunol. 3(3):163-6, 1997; Ott et al., Clin
Endocrinol (Oxf). 66(2):180-4, 2007; Psarros et al., Int Arch
Allergy Immunol. 164(4):326-32, 2014; Rosen et al., Birth Defects:
Orig Artic Ser. 16(1):499-507; 1980; Steiner et al., Orphanet J
Rare Dis. 11:43; 2016; Winnewisser et al., J Int Med. 241(1):39-46,
1997; Zotter et al., Orphanet J Rare Dis. 9:205, 2014) describing
the use of attenuated androgens and one RCT (Riedl et al., Allergy
Asthma Proc. 37(6):489-500, 2016) describing the use of a
combination therapy of SC C1-INH/recombinant human hyaluronidase in
patients with HAE, since these interventions are not recommended by
the WAO/EAACI guidelines for HAE management as long-term
prophylaxis (Maurer et al., Allergy. 73(8):1575-96, 2018); two RCTs
(Longhurst et al., N Engl J Med. 376(12):1131-40, 2017; Zuraw et
al., Allergy. 70(10):1319-28, 2015) describing the use of SC C1-INH
were excluded because this product is not commercially available
outside the United States and Canada (CSL Behring. Global product
list; www.cslbehring.com/products/global-products-list; retrieved
2019 Feb. 20), limiting the real-world applicability of any
comparison.
[0172] One record reported results from a phase 3 study of an IV
C1-INH (Zuraw et al., N Engl J Med. 363(6):513-22, 2010) and was
deemed appropriate for ITC with lanadelumab results from the HELP
study. Because this RCT was appropriate for ITC, and because nRCTs
were only considered if no RCTs for a given intervention could be
identified, the four nRCTs for this intervention (Bernstein et al.,
J Allergy Clin Immunol Pract. 2(1):77-84 2014; Aygoren-Pursun et
al., J Allergy Clin Immunol. 137(2):AB251, 2016; Rasmussen et al.,
Ann Allergy Asthma Immunol. 116(5):476-7, 2016; Zuraw et al., Am J
Med. 125(9):938.e1-.e7, 2012) were subsequently excluded. The
remaining five studies (Banerji et al., N Engl J Med.
376(8):717-28, 2017; Bork et al., Oral Surg Oral Med Oral Pathol
Oral Radiol Endod. 112(1):58-64, 2011; Bouillet et al., Allergy.
72(Suppl 103):593, 2017; Farkas et al., Allergy. 67(12):1586-93,
2012; Levi et al., J Allergy Clin Immunol. 117(4):904-8, 2006) were
excluded because of differences and/or lack of clarity in study
design, study population, intervention, endpoints, and/or patient
characteristics (Table 2). The network diagram for the two studies
included in the ITC is shown in FIG. 2. The design for each study
is summarized in Table 3, and baseline demographic characteristics
and results for primary outcomes for both studies are presented in
Table 4.
TABLE-US-00004 TABLE 2 Summary of Feasibility Assessment of Select
Records Identified by Systematic Literature Review for Potential
Inclusion in the Indirect Treatment Comparison.sup.a Key Criteria
for Patients, Treatment, Dose, Inclusion/Exclusion From Study Study
Design n Regimen Indirect Treatment Comparison Banerji 2017 [64]
Randomized, 11 Lanadelumab 400 mg Excluded based on study design
double-blind, q2w SC and endpoints: placebo- 5 Lanadelumab 300 mg
Phase 2 dose-escalation study controlled q2w SC Outcomes focused on
PK/PD clinical trial 4 Lanadelumab 100 mg Attack rate measured as
adverse q2w SC event up to 120 days after final 4 Lanadelumab 30 mg
dose q2w SC 13 Placebo Levi 2006 [68] Nonrandomized 43 IV C1-INH
(Cetor .RTM. Excluded based on intervention and clinical trial 1000
units every 5-7 lack of endpoint data: days) Attack rate is
reported only graphically, no values are available Bork 2011 [65]
Retrospective, 33 IV C1-INH (Berinert .RTM. Excluded based on study
observational 500 U; single dose) population: study 18 IV C1-INH
(Berinert .RTM. Investigated as short-term 1000 U; single dose)
prophylaxis for prevention of an attack following a surgical
procedure Bouillet 2017 Retrospective, 132 IV C1-INH Excluded based
on study [66] observational (Berinert .RTM.).sup.b population:
study Used only as an acute treatment after an attack Farkas 2012
[67] Retrospective, 87 IV C1-INH (Berinert .RTM. Excluded based on
study observational 500 U; single dose) population: study 38
Danazol (oral; 2.5-10 Investigated as short-term mg/kg per day for
5 prophylaxis for prevention of an days) attack following a dental,
9 Tranexamic acid (oral; diagnostic, or surgical procedure 20-40
mg/kg per day for 5 days) C1-INH, C1 esterase inhibitor; IV,
intravenous; PD, pharmacodynamics; PK, pharmacokinetics; q2w, every
2 weeks; SC, subcutaneous. .sup.aDoes not include assessment of the
feasibility of records that were included in the ITC (n = 1) or
excluded as secondary publications (n = 22), inappropriate
comparators (n = 20), or unnecessary nRCTs (n = 4). .sup.bDetailed
dosing information was not reported.
TABLE-US-00005 TABLE 3 Trial Design of the HELP and CHANGE Studies
Used for Indirect Treatment Comparison Characteristic HELP
Study.sup.b CHANGE Study.sup.a Study design Double-blind,
placebo-controlled Double-blind, placebo-controlled Trial type
Parallel Crossover.sup.a Disease state Confirmed HAE diagnosis
Confirmed HAE diagnosis inclusion criteria C1-INH functional level
<40% or Low antigenic or functional C1-INH 40%-50% if C4 level
below normal level or known HAE-causing mutation range in C1-INH
gene .gtoreq.1 of the following: Low C4 level Age .ltoreq.30 years
at reported onset of Normal C1q level first angioedema symptoms
.gtoreq.2 attacks per month (for prophylaxis Family history
consistent with study) HAE types I or II C1q level within normal
range Experience baseline rate of .gtoreq.1 investigator-confirmed
HAE attack per four weeks during run-in period Primary endpoint
Number of investigator-confirmed attacks Number of attacks during
each treatment (day 0-182) period (normalized to number of days
participated) Administration Subcutaneous Intravenous Washout
period .gtoreq.2 weeks None Treatment period 26 weeks 12
weeks.sup.a C1-INH, C1 esterase inhibitor; HAE, hereditary
angioedema. .sup.aThe CHANGE study included two parts: part A,
which evaluated IV C1-INH use in acute attacks, and part B, which
evaluated its use in prophylaxis. Only part B is summarized here
and was a crossover study that consisted of two 12-week treatment
periods in which patients were randomly assigned to receive either
IV C1-INH or placebo during the first treatment period and then
crossed over, in a second treatment period, to the treatment that
was not received during the first treatment period (Zuraw et al., N
Engl J Med. 363(6): 513-22, 2010). .sup.bBanerji et al., JAMA
320(20): 2108-21, 2018
TABLE-US-00006 TABLE 4 Demographic Characteristics and Primary
Outcomes From the HELP and CHANGE Studies Used for Indirect
Treatment Comparison HELP Study.sup.b Lanadelumab Lanadelumab
Lanadelumab 300 mg q2w 300 mg q4w 150 mg q4w Placebo Characteristic
(n = 27) (n = 29) (n = 28) (n = 41) Mean (SD) age, y 40.3 (13.3)
39.5 (12.8) 43.4 (14.9) 40.1 (16.8) Female patients, n (%) 15
(55.6) 19 (65.5) 20 (71.4) 34 (82.9) Type II HAE, n (%) 4 (14.8) 2
(6.9) 3 (10.7) 3 (7.3) Patients with .gtoreq.2 attacks/month 20
(74.1) 20 (69.0) 18 (64.3) 29 (70.7) prior to study entry, n (%)
Primary endpoint Rate of investigator- 0.26 (0.15, 0.46) 0.53
(0.36, 0.77) 0.48 (0.31, 0.74) 1.97 (1.64, 2.36) confirmed HAE
attacks per 4 wk (day 0-182), LS mean (95% CI) Change vs placebo, %
-86.9 (-92.8, -76.2)* -73.3 (-82.4, -59.5)* -75.6 (-84.7, -61.2)*
NA (95% CI) Rate of investigator- 0.16 (0.07, 0.35) 0.37 (0.22,
0.60) 0.42 (0.26, 0.68) 1.88 (1.54, 2.30) confirmed HAE attacks per
4 wk (day 70-182), LS mean (95% CI) Change vs placebo, % -91.5
(-96.1, -81.1)* -80.6 (-88.5, -67.3)* -77.6 (-86.7, -62.3)* NA (95%
CI) HAE attack rate per 12 wk, NA NA NA NA mean.sup.a Change vs
placebo, mean NA NA NA NA (95% CI) CHANGE Study.sup.a IV C1-INH
Placebo Characteristic (n = 11) (n = 11) Mean (SD) age, y 41.7
(19.3) 34.5 (14.8) Female patients, n (%) 9 (81.8) 11 (100) Type II
HAE, n (%) 2 (18.2) 2 (18.2) Patients with .gtoreq.2 attacks/month
11 (100) 11 (100) prior to study entry, n (%) Primary endpoint Rate
of investigator- NA NA confirmed HAE attacks per 4 wk (day 0-182),
LS mean (95% CI) Change vs placebo, % NA NA (95% CI) Rate of
investigator- NA NA confirmed HAE attacks per 4 wk (day 70-182), LS
mean (95% CI) Change vs placebo, % NA NA (95% CI) HAE attack rate
per 12 wk, 6.26 12.73 mean.sup.a Change vs placebo, mean -6.47
(-4.21,-8.73)* NA (95% CI) C1-INH, C1 esterase inhibitor; CI,
confidence interval; HAE, hereditary angioedema; IV, intravenous;
LS, least squares; NA, not applicable; q2w, every two weeks; q4w,
every four weeks; SD, standard deviation. .sup.aAn attack was
defined as a discrete episode during which the subject progressed
from no angioedema to symptoms of angioedema; attacks that
progressed from one site to another, or that began to regress and
then became worse before complete resolution, were considered to be
a single attack (Zuraw et al., N Engl J Med. 363(6): 513-22, 2010).
.sup.bBanerji et al., JAMA 320(20): 2108-21, 2018 *P < 0.001 vs
placebo.
Time to First Attack (HELP Study)
[0173] As demonstrated in the HELP study, time to first HAE attack
was increased relative to placebo after each time point for all
three lanadelumab dosing regimens, corresponding to reduced risks
of experiencing a first attack after day 0 and day 70 from the
start of treatment. After day 0, the median number of days to first
attack was 59 (95% CI: 28--not estimable [NE]) for patients
receiving lanadelumab 300 mg q2w; 28 (95% CI: 10-101) for
lanadelumab 300 mg q4w; and 26 (95% CI: 11-NE) for lanadelumab 150
mg q4w, compared with 8 (95% CI: 6-18) for patients receiving
placebo. After day 70, more than 50% of patients receiving
lanadelumab 300 mg q2w and 150 mg q4w had no attacks through the
end of the 6-month treatment period; thus, the median number of
days to first attack was NE. The median time to first attack after
day 70 in patients receiving lanadelumab 300 mg q4w was 61 days
(95% CI: 25-NE) compared with 12 days (95% CI: 6-16) for patients
receiving placebo.
[0174] As observed in the HELP study, 2.4% of patients receiving
placebo were attack-free from day 0 to the end of the treatment
period compared with 44%, 31%, and 39% of patients receiving
lanadelumab 300 mg q2w, 300 mg q4w, and lanadelumab 150 mg q4w,
respectively (Table 5). Similar or greater percentages of
attack-free patients were observed with lanadelumab treatment from
day 70 to the end of the treatment period. Proportions of
attack-free lanadelumab-treated patients were also derived from the
Kaplan-Meier estimates of time to first attack after treatment to
confirm the validity of the Kaplan-Meier survival analysis. These
estimated percentages of attack-free patients were generally
consistent with the observed results from each day 0 and day 70 to
the end of the 6-month treatment period (Table 5).
TABLE-US-00007 TABLE 5 Observed and Estimated Percentages of
Attack-Free Patients in the HELP Study After Day 0 and Day 70 to
End of Treatment Lanadelumab Lanadelumab Lanadelumab Attack-free
300 mg q2w 300 mg q4w 150 mg q4w Placebo patients, n (%) (n = 27)
(n = 29) (n = 28) (n = 41) After Day 0 to End of Treatment
Observed, n (%) 12 (44.4) 9 (31.0) 11 (39.3) 1 (2.4) Estimated, n
(% [95% CI]).sup.a 27 (44.4 [29.2, 29 (31.0 [18.0, 28 (39.3 [24.8,
41 (2.4 [0.4, 67.8]) 53.4]) 62.3]) 16.9]) After Day 70 to End of
Treatment Observed, n (%).sup.b 20 (76.9) 13 (44.8) 15 (53.6) 1
(2.7) Estimated, n (% [95% CI]).sup.a,b 26 (76.9 [62.3, 29 (43.0
[28.0, 28 (53.6 [37.9, 37 (2.7 [0.4, 94.9]) 65.8]) 75.6]) 18.7])
CI, confidence interval; q2w, every two weeks; q4w, every four
weeks. .sup.aKaplan-Meier estimates of time to first attack after
treatment were used to derive the proportions of patients who
remained attack-free. .sup.bDoes not include patients who
discontinued prior to day 70: lanadelumab 300 mg q2w, n = 26;
lanadelumab 300 mg q4w, n = 29; lanadelumab 150 mg q4w, n = 28;
placebo, n = 37.
Model Selection for Time to First Attack Endpoints
[0175] Various parametric survival models were applied to data for
time to first attack after days 0 and 70. Of the six standard
parametric models, the Akaike information criterion (AIC) values
indicated that the Gompertz model fit the Kaplan-Meier data best
for the duration of the study (i.e., after day 0 and day 70). The
Gompertz model predicted that patients who were attack-free from
day 0 through the end of the study would remain attack-free
indefinitely after the study ended. Conservatively based on the
possibility of pharmacological drug tolerance and loss of response
in which treatment effectiveness may lessen with prolonged exposure
(Roda et al., Clin Transl Gastroenterol. 7:e135, 2016; Salva
Lacombe et al., Drugs. 51(4):552-70, 1996), however, the Gompertz
model was considered clinically implausible.
[0176] Thus, because none of the standard distributions for
parametric survival analysis fit the observed data well, the more
flexible parametric model of a proportional hazards spline was fit
to the data. A spline model with one internal knot (k=1) was found
to fit the data best, and this was confirmed based on visual
comparison with the Kaplan-Meier data and clinical plausibility of
a reduction over time in the relative effect of each lanadelumab
dose versus placebo. The addition of further internal knots (k=2-5)
to the spline model did not lead to corresponding improvement in
model fit.
Indirect Treatment Comparison Via Network Meta-Analysis
[0177] A fixed-effects model was chosen for the NMA because no
systematic differences were identified between the patient
populations in the HELP study and CHANGE trial; both patient
populations were similar in age, sex, and percentage of patients
with type I or type II HAE (Tables 3 and 4, above). It was
therefore assumed that each trial was estimating the same treatment
effect and any variation between studies was due only to sampling
variation.
[0178] Attack Rate
[0179] RRs showed a significant reduction in attack rate for
patients who received lanadelumab (all dosing regimens) or IV
C1-INH compared with placebo (FIG. 3). Reductions in attack rate
(per 4-week cycle) were 87%, 73%, and 76% for the lanadelumab 300
mg q2w, 300 mg q4w, and 150 mg q4w treatment arms, respectively
(corresponding to respective median RRs [95% CrI] of 0.13
[0.07-0.24], 0.27 [0.18-0.40], and 0.24 [0.15-0.39]) and 51% for IV
C1-INH (corresponding to median RR [95% CrI] of 0.49 [0.40-0.60])
compared with placebo.
[0180] Time to First Attack
[0181] When comparing treatments with placebo, a significantly
lower risk of first attack after day 0 was observed for all
lanadelumab dosing regimens (median HR [95% CrI]: 300 mg q2w, 0.27
[0.13-0.55]; 300 mg q4w, 0.39 [0.21-0.74]; 150 mg q4w, 0.34
[0.17-0.66]), corresponding to a 61%-73% reduction in risk of first
attacks after day 0 (FIG. 4A). Results were similar for risk of
first attacks after day 70 (median HR [95% CrI]: 300 mg q2w, 0.09
[0.04-0.22]; 300 mg q4w, 0.27 [0.14-0.53]; 150 mg q4w, 0.20
[0.10-0.41]), with corresponding reductions of 73%-91% (FIG. 4B).
In contrast, although a reduction in the risk of first attack was
observed with IV C1-INH treatment compared with placebo, these
reductions were not statistically significant (median HR [95% CrI]:
day 0, 0.54 [0.23-1.19]; day 70, 0.53 [0.23-1.19]).
[0182] Predicted Survival Curves for 60-Month Duration
[0183] Predicted survival curves for 60-month duration based on
time to first attack were derived for each treatment after day 0
and day 70 (FIGS. 5A-5B) by combining the HRs from the ITC and the
spline survival curve fit to the HELP study placebo data. The
highest predicted proportions of attack-free patients were observed
with lanadelumab 300 mg q2w over both time points. When data for
time to first attack after day 0 were extrapolated out to 60
months, the predicted percentages of attack-free patients were 26%,
6.5%, and 0.6% for treatment with lanadelumab 300 mg q2w, IV
C1-INH, and placebo, respectively. When time to first attack data
were extrapolated out to 60 months, the predicted percentages of
attack-free patients were 46%, 0.9%, and 0% after day 70 for
lanadelumab 300 mg q2w, IV C1-INH, and placebo, respectively.
[0184] A proportional hazards spline model with one internal knot
(k=1) was found to best fit observed time to first attack data from
the HELP study. These data demonstrated that a key benefit for
receiving lanadelumab compared with placebo for prophylaxis of HAE
attacks was the increase in duration of attack-free period. The
highest predicted proportions of attack-free patients were observed
with lanadelumab 300 mg q2w over all time points, whereas the
lowest predicted proportions of patients who were attack-free were
observed with IV C1-INH and placebo. Based on the approximately
14-day half-life of lanadelumab (range, 13.8-15.0 days), time to
steady-state concentrations of lanadelumab has been estimated to be
approximately 70 days. Thus, after day 70, when lanadelumab had
reached steady-state concentration, more than 50% of patients in
the lanadelumab 300-mg q2w treatment arm did not have an attack
during the rest of the 6-month study period, and the median number
of days to first attack after day 70 in the 300-mg q4w arm was 61
compared with 12 in the placebo arm. Based on the predicted
survival curves, the proportion of attack-free patients after the
first six months of treatment with lanadelumab 300 mg q2w (45% and
72%) increased as time to first attack was assessed later (after
day 0 and day 70, respectively); a similar pattern was observed
with the lanadelumab 300 mg q4w (31% and 37%, respectively) and 150
mg q4w (36% and 47%, respectively) treatment arms, but patients
receiving C1-INH showed an opposite pattern of decreases (20% and
13%, respectively) with subsequent assessment. These findings
remained generally consistent upon extrapolation of these data out
to 60 months.
[0185] Accordingly, HAE patients on lanadelumab treatment for a
period (e.g., 6 months) and showed free of HAE attach may receive a
reduced dosage of lanadelumab, for example, from 300 mg/2 weeks to
300 mg/4 weeks.
Example 2: Indirect Treatment Comparison of DX-2930 and Intravenous
C1 Esterase Inhibitor Treatments Using Individual Patient Data from
the HELP-03 and CHANGE Studies
Objectives
[0186] The objective was to perform an indirect treatment
comparison (ITC) of lanadelumab (300 mg subcutaneous every 2 weeks
(300 mg SC q2w), 300 mg subcutaneous every four weeks (300 mg SC q
2w)) and Cinryze.RTM. (C1-INH) 1000 units intravenous (1000 U IV)
using individual patient data (IPD) from the HELP-03 (HELP) and
CHANGE studies. Using IPD in lieu of aggregated data is
advantageous for several reasons. First, IPD provides more
information, which reduces heterogeneity across networks and
resolves potential issues of inconsistency. Further, IPD
facilitates estimation of subgroup effects, aids convergence, and
overall, yields more precise estimates. Additionally, IPD allows
within-study associations to be distinguished from across-study
associations. Utilizing IPD, even only from a few studies, can also
reduce ecological bias, which is often problematic when the
evidence is sparse and the sample sizes are small.
Outcomes of Interest
[0187] Both the HELP and CHANGE studies cited the number of HAE
attacks per 28 days. A prior study by BresMed reported the time to
first HAE attack following treatment at day 0 and 70 in the HELP
study. This outcome measure was estimated using IPD reported in the
CHANGE study. Only the HELP study disclosed the proportion of
patients who experience .gtoreq.50% reduction in the number of
attacks. While the CHANGE study did not report this outcome
measure, it was not considered relevant for the ITC.
Conclusion
[0188] Overall, the similarity assumption was not deemed to hold
between the HELP and CHANGE studies with respect to the baseline
HAE attack rate per 28 days. This was confirmed by expert clinician
opinion. Other covariates of interest (e.g., age, gender, and
weight) also differed between the studies, but these were
considered to have a lesser impact on the results. Therefore, it
was determined that the base case analysis would account for HAE
attack rate per 28 days at baseline, while regression models in
sensitivity analyses would include other key covariates which might
potentially modify treatment effects. Any differences between the
base case and sensitivity analysis findings might indicate that the
results of the base case were not robust and may possibly be driven
by the study differences. In this case, a second sensitivity
analysis is planned to evaluate whether an assessment of attacks
per patient or investigators influences the results of the attack
rates per 28 days. To account for this, the analysis will include
only patient-reported HAE attacks in both studies.
Common Comparator
[0189] As shown in the network of evidence in FIG. 6, the common
comparator for Cinryze.RTM. (C1-INH) and lanadelumab in the HELP
and CHANGE studies was placebo. The HELP study compared three
different lanadelumab dose regimens to placebo, whereas the CHANGE
study was a cross-over study comparing Cinryze.RTM. to placebo.
Excluding the lanadelumab 150 mg dose (not approved for this
indication) reduced the number of comparisons and circumvented the
issue of multiplicity (e.g., multiple hypothesis testing). If
multiple hypotheses are tested simultaneously, the alpha error
increases, and therefore the significance level requires adjustment
(e.g., Bonferroni). Identifying statistically significant
differences at the significance level <5% may be difficult.
Therefore, it is advised that multiple hypothesis testing be
avoided.
Methods
[0190] Statistical approaches to evidence synthesis can be
characterized primarily as frequentist or Bayesian methods.
Frequentist methods, such as adjusted indirect comparisons (e.g.,
Bucher method, matched-adjusted indirect comparison [MAIC], and
simulated treatment comparison [STC]), allow the indirect
comparison of two interventions in a single step. The term network
meta-analysis (NMA) refers to the simultaneous comparison of a
larger network of interventions. In a Bayesian method, minimally
informative priors are usually assigned treatment effects.
[0191] For the purposes of this ITC, a frequentist approach was
preferred over a Bayesian approach due to the limited evidence base
(N=2 studies). Currently, various frequentist approaches for
including IPD in statistical models for evidence synthesis exist.
These methods differ mainly on the basis of inclusion or exclusion
of a common comparator arm ("anchor").
[0192] As a second step, the Bucher method is often used to combine
the relative treatment effects in anchored comparisons for
obtaining the final ITC results. Only two interventions may be
compared at once. If multiple comparisons are of interest, multiple
analyses must be conducted. The corresponding point estimates are
expected to be very similar to those obtained through a Bayesian
analysis. However, the 95% confidence intervals are usually not as
wide as the credible intervals of a Bayesian analysis.
[0193] Following an extensive feasibility assessment, the present
ITC was performed using a frequentist-based anchored approach.
Importantly, this approach preserved randomization. In the base
case analysis, regression models included the HAE attack rate per
28 days at baseline. Other covariates of interest (e.g., age,
gender, and weight) were added in sensitivity analyses to
investigate the overall impact of these variables on the results. A
second sensitivity analysis evaluated the impact of
patient-reported HAE attacks not confirmed by investigators on the
base case results.
Poisson Regression--HAE Attack Rate Per 28 Days
[0194] Poisson regression analyses were performed to estimate rate
ratios (RRs) for the HAE attack rates per 28 days. Poisson
regression requires that the following assumptions are met: (1)
observations are independent, (2) the counts follow a Poisson
distribution, and (3) the conditional mean and variance of the
model are identical.
[0195] Given that the outcome of interest (HAE attack rate per 28
days) is expressed as count data, Poisson regression was deemed
appropriate, and the number of attacks per treatment period was
considered in the models. Following Banjeri et al., the models
included an offset variable in order to adjust for differences in
follow-up time. The offset was defined as the logarithm of the
number of days a patient was observed during the treatment
period.
[0196] Measures of treatment effects (model inputs) were expressed
as the estimated RR of attacks per 28 days. For the lanadelumab
regimens (300 mg q2w and 300 mg q4w), this measure was represented
as the ratio of the rate of attacks per 28 days during the
respective treatment relative to that with placebo. For
Cinryze.RTM. (C1-INH), the RR indicated the ratio of the rate of
attacks per 28 days during treatment with Cinryze.RTM. relative to
that with placebo. The estimated RRs generated by the Poisson
models were then input into the ITC.
Non-Parametric Estimation and Cox Regression
[0197] For the outcome "time to first attack" a Cox regression
analysis was conducted to estimate the hazard ratio (HR) of first
attack with each of the lanadelumab regimens (300 mg q2w and 300 mg
q4w) relative to placebo, and the HR of a first attack with
Cinryze.RTM. relative to placebo. As described, the estimated HRs
were then input into the ITC (via the Bucher method) comparing the
lanadelumab dose regimens and Cinryze.RTM.. While Cox regression is
semi-parametric and therefore, does not specify requirements
regarding the form of the baseline hazard, the following
assumptions must be met: (1) the proportional hazard, (2) linear
relationship between covariates, and (3) independent
observations.
[0198] Kaplan-Meier curves were derived via non-parametric
estimation to model the outcome "time to first attack after 0 and
70 days". Patients were censored at the date of their last data
capture. The graphs showed that the hazard functions were
proportional over time and therefore, statistical measures to
account for non-proportional hazards were not required.
[0199] In the base case, the model was adjusted for the number of
HAE attacks per 28 days at baseline. For the sensitivity analyses,
the model also included relevant covariates (age, gender, and
weight). Due to the small sample size in the CHANGE study, no
formal variable selection was conducted. Estimates obtained from
these adjusted models were compared to unadjusted estimates from a
model excluding the covariates.
[0200] Since the CHANGE study was a cross-over study, individuals
who were observed twice (under placebo and Cinryze.RTM. treatment)
were not independent. As described, mixed models, including fixed
factors for treatment, period, and sequence, and a random effect
for study subjects, were employed to account for repeated
measurements in the study.
Results
1. HAE Attack Rate Per 28 Days
[0201] Table 6 shows that the respective baseline attack rates for
placebo and Cinryze.RTM. treatment were identical. The CHANGE
cross-over study did not include a run-in period. The attack rate
per 28 days was higher with placebo during the treatment period
compared to the baseline attack rate with Cinryze.RTM. treatment.
The mean number of attacks per treatment period was considerably
lower for Cinryze.RTM. than for placebo. Treatment duration was
comparable between the two interventions. The time to first attack
after 0 and 70 days of treatment was considerably shorter with
placebo than with Cinryze.RTM. treatment.
TABLE-US-00008 TABLE 6 Descriptive Statistics on HAE Attacks in the
CHANGE Study. Num- Standard Mini- Maxi- Variable ber (N) Mean
Deviation mum mum Placebo Treatment Baseline rate 22 3.80 1.95 1.84
8.00 Rate per 28 days during 22 4.24 1.55 1.98 6.83 treatment
period Number of attacks per 22 12.73 4.80 6.00 22.00 treatment
period Duration of treatment 22 84.05 5.96 67.00 96.00 period
(days) Time to first attack after 22 4.77 7.85 0.00 32.00 0 days of
treatment Time to first attack after 21 3.48 3.41 0.00 14.00 70
days of treatment Cinryze .RTM. Treatment Baseline rate 22 3.80
1.95 1.84 8.00 Rate per 28 days during 22 2.09 1.85 0.00 5.88
treatment period Number of attacks per 22 6.14 5.43 0.00 17.00
treatment period Duration of treatment 22 80.05 10.42 34.00 86.00
period (days) Time to first attack after 22 20.68 28.16 0.00 82.00
0 days of treatment Time to first attack after 21 7.10 4.30 0.00
14.00 70 days of treatment
TABLE-US-00009 TABLE 7 Descriptive Statistics on HAE Attacks in the
HELP Study. Num- Standard Mini- Maxi- Variable ber (N) Mean
Deviation mum mum Placebo Treatment Baseline rate 41 4.02 3.26 0.97
14.67 Rate per 28 days during 41 2.45 2.08 0.00 8.31 treatment
period Number of attacks per 41 13.95 12.01 0.00 54.00 treatment
period Duration of treatment 41 168.39 45.37 13.00 197.00 period
(days) Time to first attack after 41 21.41 34.45 2.00 183.00 0 days
of treatment Time to first attack after 37 21.43 28.68 1.00 113.00
70 days of treatment Lanadelumab 300 mg q4w Baseline rate 29 3.71
2.51 0.97 10.50 Rate per 28 days during 29 0.60 0.80 0.00 2.91
treatment period Number of attacks per 29 3.62 4.80 0.00 19.00
treatment period Duration of treatment 29 178.17 21.68 73.00 188.00
period (days) Time to first attack after 29 74.90 77.96 1.00 185.00
0 days of treatment Time to first attack after 29 62.62 46.18 2.00
115.00 70 days of treatment Lanadelumab 300 mg q2w Baseline rate 27
3.52 2.33 0.97 9.00 Rate per 28 days during 27 0.31 0.50 0.00 1.85
treatment period Number of attacks per 27 1.70 2.83 0.00 12.00
treatment period Duration of treatment 27 177.74 28.56 35.00 186.00
period (days) Time to first attack after 27 97.04 80.53 1.00 186.00
0 days of treatment Time to first attack after 26 92.42 40.04 6.00
116.00 70 days of treatment
[0202] As shown in Table 7, both lanadelumab 300 mg q2w and 300 mg
q4w reduced the mean number of attacks per treatment period
compared to placebo. The mean baseline attack rates were comparable
across the three study arms. Treatment duration was shortest in the
placebo arm, while the time to first attack was longer with
lanadelumab treatment (300 mg q2w and 300 mg q4w) compared to
placebo.
HAE Attack Rate Per 28 Days--Poisson Regression
[0203] Further, the estimated mean HAE attack rate per 28 days was
1.99 (95% CI: 1.56; 2.52) with Cinryze.RTM. treatment and 4.03 (95%
CI: 3.31; 4.91) with placebo. The corresponding RR (0.49) indicated
that patients treated with Cinryze.RTM. had 0.49 times the rate of
HAE attacks compared to those treated with placebo. This difference
was statistically significant (since the corresponding 95% CI does
not include 1). The resulting percent change for the mean attack
rate was -51% for patients treated with Cinryze.RTM. relative to
placebo.
TABLE-US-00010 TABLE 8 Base Case Results in the CHANGE Study. 95%
CI Treatment Estimate Lower Upper Model-based treatment C1-INH 1.99
1.56 2.52 period HAE attack rate Placebo 4.03 3.31 4.91 (attacks/28
days) Rate ratio 0.4926 0.3950 0.6142 % change in mean attack -51%
-60% -39% rate
[0204] As shown in Table 9, the estimated mean HAE attack rate per
28 days was 0.26 (95% CI: 0.15; 0.45) with lanadelumab 300 mg q2w,
0.54 (95% CI: 0.37, 0.77) with lanadelumab q2w, and 2.0 (95% CI:
1.69; 2.38) with placebo treatment. The corresponding RRs indicated
that patients treated with lanadelumab 300 mg q2w and lanadelumab
q4w had 0.13 and 0.27 times the rate of HAE attacks, respectively,
compared to patients treated with placebo. These estimates were
statistically significant as evidenced by exclusion of the value
"1" in the corresponding 95% CIs. The resulting percent change in
mean attack rate was -87% for patients treated with lanadelumab 300
mg q2w and -73% for those treated with lanadelumab 300 mg q2w
relative to placebo.
TABLE-US-00011 TABLE 9 Base Case Results in the HELP Study. 95% CI
Treatment Estimate Lower Upper Model-based treatment Lanadelumab
0.26 0.15 0.45 period HAE attack rate 300 mg q2w (attacks/28 days)
Lanadelumab 0.54 0.37 0.77 300 mg q4w Placebo 2.00 1.69 2.38 Rate
ratio Lanadelumab 0.1309 0.0742 0.2309 300 mg q2w vs. placebo
Lanadelumab 0.2674 0.1803 0.3965 300 mg q4w vs. placebo % change in
mean attack Lanadelumab -87% -93% -77% rate 300 mg q2w vs. placebo
Lanadelumab -73% -82% -60% 300 mg q4w vs. placebo
[0205] Indirect comparison using the Bucher method (Table 10)
showed that patients treated with lanadelumab 300 mg q2w and
lanadelumab 300 mg q4w had 0.27 times and 0.54 times the rate of
HAE attacks, respectively, compared to those treated with
Cinryze.RTM.. These results were statistically significant as
evidenced by exclusion of the value "1" in the corresponding 95%
CIs. The resulting percent changes in the mean attack rate relative
to Cinryze.RTM. were -73% and -46% for patients treated with
lanadelumab 300 mg q2w and lanadelumab 300 mg q4w, respectively.
The point estimates and credible/confidence intervals generated in
this ITC of IPD appeared consistent with the findings in Bayesian
NMA.
TABLE-US-00012 TABLE 10 Indirect Comparison of Lanadelumab and
Cinryze .RTM. using the Bucher Method (Base Case). ITC Bayesian 95%
CI 95% CI NMA Treatment 1 Treatment 2 RR Lower Upper RR Lanadelumab
Cinryze .RTM. 0.2657 0.1451 0.4864 0.27 (0.14; 300 mg q2w 0.51) %
change in mean attack rate -73% (CI; -85%; -51%) Lanadelumab
Cinryze .RTM. 0.5429 0.3478 0.8473 0.54 (0.34; 300 mg q4w 0.86) %
change in mean attack rate -46% (CI: -65%, -15%)
Sensitivity Analysis Accounting for Patient-Reported HAE Attacks in
the HELP Study
[0206] As shown in Table 11, the estimated mean HAE attack rate per
28 days was 0.27 (CI: 0.16; 0.46) with lanadelumab 300 mg q2w, 0.55
(CI: 0.38; 0.78) with lanadelumab 300 mg q4w, and 2.02 (95% CI:
1.71; 2.39) with placebo. The corresponding RRs indicated that
patients treated with lanadelumab 300 mg q2w and those treated with
lanadelumab 300 mg q4w had 0.13 and 0.27 times the rate of HAE
attacks, respectively, compared to those treated with placebo.
These estimates were statistically significant since the
corresponding 95% CI does not include 1. The percent changes in
mean attack rate relative to placebo were -87% and -73% for
patients treated with lanadelumab 300 mg q2w and for those treated
with lanadelumab 300 mg q4w, respectively.
TABLE-US-00013 TABLE 11 Results for Patient-reported HAE attacks
(HELP study). 95% CI Treatment RR Lower Upper Model-based treatment
Lanadelumab 0.27 0.16 0.46 period HAE attack rate 300 mg q2w
(attacks/28 days) Lanadelumab 0.55 0.38 0.78 300 mg q4w Placebo
2.02 1.71 2.39 Rate ratio Lanadelumab 0.1327 0.0758 0.2324 300 mg
q2w vs. placebo Lanadelumab 0.2704 0.1832 0.3992 300 mg q4w vs.
placebo % change in mean attack Lanadelumab -87% -92% -77% rate 300
mg q2w vs. placebo Lanadelumab -73% -82% -60% 300 mg q4w vs.
placebo
[0207] In the base case, indirect comparison via the Bucher method
showed that patients treated with lanadelumab 300 mg q2w had 0.27
times the rate of HAE attacks compared to those treated with
Cinryze.RTM. (Table 12), while those treated with lanadelumab 300
mg q4w experienced 0.55 times the rate of HAE attacks compared to
those treated with Cinryze.RTM.. These estimates were statistically
significant since the corresponding 95% CI does not include 1. The
percent changes in the mean attack rate relative to Cinryze.RTM.
were -73% and -45% for treatment with lanadelumab 300 mg q2w and
lanadelumab 300 mg q4w, respectively. A comparable sensitivity
analysis was not conducted in the Bayesian NMA.
TABLE-US-00014 TABLE 12 Indirect Comparison Using the Bucher method
(Patient- reported HAE Attacks from HELP Study). ITC 95% CI 95% CI
Bayesian Treatment 1 Treatment 2 RR Lower Upper NMA Lanadelumab
Cinryze .RTM. 0.2694 0.1482 0.4896 N/A 300 mg q2w % change in mean
attack rate -73% (95% CI: -85%; -51%) Lanadelumab Cinryze .RTM.
0.5490 0.3532 0.8535 NA 300 mg q4w % change in mean attack rate
-45% (95% CI -65%; -15%)
Sensitivity Analysis Accounting for all Covariates (Normalized
Baseline Attack Rate, Age, Gender, Weight)
[0208] As shown in Table 13, the estimated mean HAE attack rate per
28 days was 2.21 (95% CI: 1.43; 3.41) with Cinryze.RTM. and 4.37
(95% CI: 2.89; 6.60) with placebo. The corresponding RR of 0.51
indicated that patients treated with Cinryze.RTM. had 0.51 times
the mean rate of HAE attacks compared to those treated with
placebo. This result was statistically significant since the
corresponding 95% CI does not include 1. The resulting percent
change in the mean attack rate with Cinryze.RTM. treatment relative
to placebo was -49%.
TABLE-US-00015 TABLE 13 Results for HAE Attacks Accounting for All
Covariates of Interest (CHANGE Study). 95% CI Treatment Estimate
Lower Upper Model-based Cinryze .RTM. 2.21 1.43 3.41 treatment
period Placebo 4.37 2.89 6.60 HAE attack rate (attacks per 28 days)
Rate ratio 0.5053 0.4032 0.6332 % change in mean -49% -60% -37%
attack rate
[0209] As shown in Table 14, the estimated mean HAE attack rate per
28 days was 0.27 (95% CI; 0.16; 0.46) for lanadelumab 300 mg q2w,
0.54 (95% CI; 0.37; 0.78) for lanadelumab 300 mg q4w, and 2.00 (95%
CI; 1.63; 2.45) for placebo. The corresponding RRs showed that
patients treated with lanadelumab 300 mg q2w and those treated with
lanadelumab 300 mg q4w had 0.14 and 0.27 times the rate of HAE
attacks, respectively, compared to patients who received placebo.
These results were statistically significant since the
corresponding 95% CI does not include 1. The resulting percent
changes in the mean attack rate relative to placebo were -86% and
-73% for lanadelumab 300 mg q2w and lanadelumab 300 mg q4w,
respectively.
TABLE-US-00016 TABLE 14 Results for HAE Attacks Accounting for All
Covariates of Interest (HELP study). 95% CI Treatment Estimate
Lower Upper Model-based treatment Lanadelumab 0.27 0.16 0.48 period
HAE attack rate 300 mg q2w (attacks/28 days) Lanadelumab 0.54 0.37
0.78 300 mg q4w Placebo 2.00 1.63 2.45 Rate ratio Lanadelumab
0.1371 0.0763 0.2465 300 mg q2w vs. placebo Lanadelumab 0.2693
0.1808 0.4011 300 mg q4w vs. placebo % change in mean attack
Lanadelumab -86% -92% -75% rate 300 mg q2w vs. placebo Lanadelumab
-73% -82% -60% 300 mg q4w vs. placebo
[0210] For the base case, indirect comparison via the Bucher method
showed that patients treated with lanadelumab 300 mg q2w and
lanadelumab 300 mg q4w experienced 0.27 times and 0.53 times the
rate of HAE attacks, respectively, compared to those treated with
Cinryze.RTM. (Table 15). These results were statistically
significant as evidenced by exclusion of the value "1" in the
corresponding 95% CIs. The resulting percentage change in mean
attack rate relative to Cinryze.RTM. was -73% and -47% for patients
treated with lanadelumab 300 mg q2w and lanadelumab 300 mg q4w,
respectively. No Bayesian NMA results were available for this
sensitivity analysis.
TABLE-US-00017 TABLE 15 Indirect Comparison of Lanadelumab in
Different Dosing Regimens and Cinryze .RTM. Using the Bucher Method
(All Covariates of Interest). ITC 95% CI 95% CI Bayesian Treatment
1 Treatment 2 RR Lower Upper NMA Lanadelumab Cinryze .RTM. 0.2714
0.1456 0.5061 N/A 300 mg q2w % change in mean attack rate -73% (95%
CI: -85%; -49%) Lanadelumab Cinryze .RTM. 0.5329 0.3396 0.8634 NA
300 mg q4w % change in mean attack rate -47% (95% CI -66%;
-15%)
[0211] This section summarizes the results of the ITC of
lanadelumab (300 mg q2w and 300 mg q4w) and Cinryze.RTM.. The base
case and two sensitivity analyses demonstrated statistically
significant differences in the HAE attack rates per 28 days between
lanadelumab (300 mg q2w and 300 mg q4w) and Cinryze.RTM..
[0212] Two independent Poisson regression models generated RR
estimates identifying the relative treatment effects of lanadelumab
(300 mg q2w and 300 mg q4w) vs. placebo and Cinryze.RTM. vs.
placebo. The base case accounted for the normalized HAE attack rate
per 28 days at baseline, while a mixed model was used to account
for the cross-over design of the CHANGE study. Using the Bucher
method, the corresponding results were applied as inputs into the
ITC.
[0213] The first sensitivity analysis included all HAE attacks
reported in the HELP study, regardless of whether or not the
attacks had been confirmed by an investigator. Regression models
for a second sensitivity analysis initially included age, gender,
and weight. The two sensitivity analyses yielded results consistent
with the base case and did not change the conclusions. These
findings were also confirmed by the lack of statistically
significant effects for the covariates (apart from normalized
baseline attack rate) on the results.
2. Comparability of Placebo Effects in CHANGE and HELP Studies
[0214] The output of the non-parametric estimation showed that the
mean time (days) to the first attack after 0 days of placebo was
considerably shorter in the CHANGE study than in the HELP study
(4.773 days [SE 1.673] vs. 19.634 days [SE 4.212]). In FIG. 7, the
probability of "no first attack" after 0 days of treatment is
plotted on the y-axis while the observation time horizon is plotted
on the x-axis. Placebo treatment in the CHANGE and HELP studies was
not equally effective; patients in the CHANGE study experienced
first attacks considerably earlier than those in the HELP study,
and the corresponding observation time horizon was much
shorter.
[0215] The output of the non-parametric estimation showed that the
mean time (days) to the first attack after 70 days of placebo was
considerably shorter in the CHANGE study than in the HELP study
(3.143 days [SE 0.563] vs. 21.378 days [SE 4.687]). In FIG. 8, the
probability of "no first attack" after 70 days of treatment is
plotted on the y-axis, while the observation time horizon is
plotted on the x-axis. Placebo treatment in the CHANGE and HELP
studies was not equally effective; patients in the CHANGE study
experienced first attacks considerably earlier than those in the
HELP study, and the corresponding observation time horizon was much
shorter.
[0216] This section summarizes the findings of the analysis
comparing the placebo effects between the CHANGE and HELP studies.
Placebo effects with respect to the time to first attack after 0
days of treatment and time to first attack after 70 days of
treatment were not comparable between the two studies. This was
assessed via the Kaplan-Meier graphs, various statistical tests
(log-rank, Wilcoxon, likelihood ratio tests), and Cox regression
models, which included the normalized attack at baseline, age,
gender, and weight as covariates and accounted for differences in
study design. There was no placebo effect in the CHANGE study,
where individuals experienced fewer attacks at baseline then during
placebo treatment. A placebo effect was observed in the HELP
study.
[0217] In a randomized controlled trial, patients are randomly
assigned to treatment arms to ensure comparability of relevant
covariates between the groups. An ITC is conducted in the event
that head-to-head treatment comparisons are lacking. The similarity
assumption between studies must hold to ensure that results of the
ITC are valid. Therefore, covariates of interest must be comparable
between the corresponding study arms. This is usually ascertained
during the process of feasibility assessment.
[0218] Placebo effects are often not comparable between the studies
included in an ITC. However, evaluating the implications of these
differences is not straightforward. With respect to the present
ITC, differences between placebo effects might have favored either
Cinryze.RTM. or lanadelumab. The absence of a placebo effect in the
CHANGE study implied that patients during C1-INH treatment may have
only benefited from the effect of the active treatment without
additional placebo effects. This would be expected to occur even if
Cinryze.RTM. were not efficacious. In contrast, a placebo effect
was observed in the HELP study. Therefore, patients treated with
lanadelumab may have benefited from the efficacy of active
treatment as well as the additional placebo effect. This difference
may have favored lanadelumab over Cinryze.RTM. in the present
analysis.
[0219] In a linear regression on the change from baseline for the
HAE attack rate per 28 days, the outcome measure of interest is the
rate difference. The rate difference in change from baseline in
comparison to placebo was higher in the CHANGE study than in the
HELP study since no placebo effect was observed in the former,
leading to ITC results favoring Cinryze.RTM..
[0220] In Poisson regression, however, the relative treatment
effect is defined as the RR at follow-up, and the baseline attack
rate is included as a covariate. Compared to linear regression, the
analysis uses a different measure of outcome. As a result, the
differences regarding the placebo effect between the two studies
had little impact on the analysis, and demonstrating a
statistically significant difference favoring lanadelumab over
Cinryze.RTM. was feasible.
[0221] As for time to first attack after 0 and 70 days of
treatment, attacks occurred more frequently and considerably
earlier during placebo treatment in the CHANGE study than in the
HELP study. As discussed, assessing the implications of these
findings is not straightforward.
3. Time to First Attack--Non-Parametric Estimation and Cox
Regression
[0222] In the non-parametric estimation, the mean time to first
attack (in days) after 0 days of placebo treatment was considerably
shorter in the CHANGE study than in the HELP study (4.773 days [SE
1.673] vs. 19.634 days [SE 4.212]).
[0223] As shown in FIG. 9, the probability of "no first attack"
after 0 days of treatment is plotted on the y-axis, while the
observation time horizon is plotted on the x-axis. Placebo was less
effective than Cinryze.RTM. treatment in the CHANGE study. Patients
who received placebo experienced their first attacks considerably
earlier than during Cinryze.RTM. treatment. Given that the two
curves do not intersect, the proportional hazards assumptions may
be deemed to hold. That confirms that Cox regression is a valid
method for estimating hazard ratios (HRs) for the ITC.
[0224] As shown in FIG. 10, the probability of "no first attack"
after 0 days of treatment is plotted on the y-axis, while the
observation time horizon is plotted on the x-axis. In the HELP
study, placebo was less effective than the two lanadelumab dose
regimens. Patients receiving placebo experienced first attacks
considerably earlier than those during lanadelumab treatment. Given
that none of the curves intersect, the proportional hazards
assumption may be deemed to hold. This confirms that Cox regression
is a valid method for estimating HRs for the ITC.
[0225] The different analytical methods used may contribute to
discrepant findings. The present ITC employed a frequentist Cox
regression model, which accounted for repeated measurements
(including fixed effects for treatment period and sequence and
random effects for study subjects), and the baselined HAE attack
rate was normalized. In the prior NMA, which employed a Bayesian
approach, these measures were not taken and only the results of
random effects models used for comparisons were reported.
[0226] In comparing lanadelumab 300 mg q2w and lanadelumab 300 mg
q4w to placebo, the Cox regression generated HRs of 0.27 (95% CI:
0.15; 0.50) and 0.38 (95% CI: 0.22; 0.67), respectively (Table 16).
The Bayesian NMA produced comparable HRs of 0.27 with corresponding
95% credible interval (CrI) of (0.13; 0.55) and 0.39 with 95% CrI
of (0.21; 0.74), respectively.
TABLE-US-00018 TABLE 16 Base Case Results from HELP Study. Bayesian
NMA (FE):HR and 95% Standard Confidence credible Contrast HR Error
Limits interval (Crl) Lanadelumab 0.2689 0.0843 0.1454 0.4972 0.27
(0.13; 300 mg q2w 0.55) vs placebo Lanadelumab 0.3837 0.1079 0.2211
0.6657 0.39 (0.21; 300 mg q4w 0.74) vs placebo
TABLE-US-00019 TABLE 17 Base Case Results from CHANGE Study.
Bayesian NMA:HR Standard (RE, FE not Contrast HR Error Confidence
Limits reported) Cinryze .RTM. vs. 0.3669 0.1287 0.1845 0.7298
0.7298 placebo
[0227] Indirect comparison via the Bucher method showed that
individuals treated with lanadelumab 300 mg q2w had 0.73 times the
hazard of a first HAE attack after 0 days of treatment compared to
individuals treated with Cinryze.RTM. (Table 18). Treatment with
lanadelumab 300 mg q4w increased the hazard of an attack by 1.05
times compared to Cinryze.RTM.. This finding was not statistically
significant as evidenced by inclusion of the value "1" in the
corresponding 95% CIs. The point estimates generated in the ITC
using IPD differed from the results of the Bayesian NMA, primarily
due to the different methodologies applied (as previously
described). As the interval bounds appeared similar, the
conclusions did not change.
TABLE-US-00020 TABLE 18 Indirect Comparison of Lanadelumab (300 mg
q2w and 300 mg q4w) and Cinryze .RTM. using the Bucher Method (Base
Case). Bayesian ITC NMA 95% CI 95% CI HR Treatment 1 Treatment 2 HR
Lower Upper (95% Crl) Lanadelumab Cinryze .RTM. 0.7327 0.2913
1.8429 0.51 (0.22; 300 mg q2w 1.3) Lanadelumab Cinryze .RTM. 1.0456
0.4332 2.5239 0.73 (0.26; 300 mg q4w 2.09)
[0228] In comparing Cinryze.RTM. and placebo, the Cox regression
generated a HR of 0.37 (95% CI; 0.18; 0.76) (Table 19). These
results were consistent with the base case.
TABLE-US-00021 TABLE 19 Base results in the CHANGE Study. Contrast
HR SE 95% CI Lower 95% CI Upper Cinryze .RTM. vs. 0.3738 0.1349
0.1843 0.7582 placebo
[0229] In comparing lanadelumab 300 mg q2w and lanadelumab 300 mg
q4w to placebo, the Cox regression generated HRs of 0.27 (95% CI:
0.14; 0.51) and 0.37 (95% CI: 0.21; 0.66), respectively (Table 20).
These estimates are consistent with previous findings. Including
additional covariates did not affect the primary findings.
TABLE-US-00022 TABLE 20 Base Case Results in the HELP Study.
Contrast HR SE 95% CI Lower 95% CI Upper Lanadelumab 300 0.2675
0.0890 0.1394 0.5133 mg q2w vs. placebo Lanadelumab 300 0.3733
0.1071 0.2127 0.6552 mg q4w vs. placebo
[0230] Indirect comparison via the Bucher method estimated that
patients treated with lanadelumab 300 mg q2w had 0.72 times the
hazard of a first HAE attack after 0 days of treatment compared to
those treated with Cinryze.RTM. treatment (Table 21). Lanadelumab
300 mg q4w treatment resulted with nearly the same hazard of HAE
attacks when compared to Cinryze.RTM.. This finding was not
statistically significant as evidence by inclusion of the value "1"
in the corresponding 95% CIs. The results were consistent with the
base case.
TABLE-US-00023 TABLE 21 Indirect Comparison of Lanadelumab and
Cinryze .RTM. Using the Bucher Method (Base Case). ITC Treatment 1
Treatment 2 HR 95% CI Lower 95% CI Upper Lanadelumab Cinryze .RTM.
0.7157 0.2735 1.8727 300 mg q2w Lanadelumab Cinryze .RTM. 0.9988
0.4045 2.4659 300 mg q4w
[0231] In the non-parametric estimation, the mean time to first
attack (in days) after 70 days of placebo treatment was
considerably shorter in the CHANGE study than in the HELP study
(3.1429 days [SE 0.5625] vs. 21.378 days [SE 4.687]).
[0232] The probability of "no first attack" after 70 days of
treatment is plotted on the y-axis of the graph in FIG. 11, while
the observation time horizon is plotted on the x-axis. In the
CHANGE study, placebo was less effective than Cinryze.RTM.
treatment. Patients treated with placebo experienced their first
attack considerably earlier than during treatment with
Cinryze.RTM.. Given that the two curves do not intersect, it can
concluded that the Cox regression is a valid method for estimating
HRs for the ITC.
[0233] As shown in FIG. 12, the probably of "no first attack" after
70 days of treatment is plotted on the y-axis of and the
observation time horizon is plotted on the x-axis. Placebo
treatment was less effective than lanadelumab treatment (300 mg q2w
and 300 mg q4w) in the HELP study. Patients treated with placebo
experienced first attacks considerably earlier than those treated
with lanadelumab. Given that none of the curves intersect, it can
be concluded that the Cox is a valid method for estimating HRs for
the ITC.
[0234] In comparing Cinryze.RTM. and placebo, the Cox regression
generated a HR of 0.34 (95% CI: 0.16; 0.72). In the Bayesian NMA,
the corresponding HR was 0.53 (0.00; 318.88) (Table 22).
TABLE-US-00024 TABLE 22 Base Case Results in the CHANGE Study.
Bayesian NMA (FE):HR and Standard Confidence 95% credible Contrast
HR Error Limits interval (Crl) Cinryze .RTM. vs. 0.3421 0.1287
0.1636 0.7153 0.53 (0.00; placebo 318.88)
[0235] In comparing lanadelumab 300 mg q2w and lanadelumab 300 mg
q4w to placebo, the Cox regression yielded HRs of 0.07 (95% CI;
0.03; 0.16) and 0.21 (95% CI; 0.11; 0.40), respectively (Table 23).
In the Bayesian NMA, the corresponding HRs were 0.09 (95% CI; 0.04;
0.22) and 0.27 (95% CI; 0.14; 0.53), respectively.
TABLE-US-00025 TABLE 23 Base Case Results in the HELP Study.
Bayesian 95% CI 95% CI NMA Contrast HR SE Lower Upper (FE):HR
Lanadelumab 0.0651 0.0306 0.0259 0.1638 0.09 (0.04; 300 mg q2w
0.22) vs. placebo Lanadelumab 0.2116 0.0686 0.1121 0.3996 0.27
(0.14; 300 mg q4w 0.53) vs. placebo
[0236] Indirect comparison via the Bucher method showed that
patients treated with lanadelumab 300 mg q2w had 0.19 times the
hazard of a first HAE attack after 70 days of treatment compared to
those treated with Cinryze.RTM. (Table 24). These results were
statistically significant as evidenced by exclusion of the value
"1" in the corresponding 95% CIs (95% CI: 0.0584; 0.6200). The
hazard of HAE attacks during treatment with lanadelumab 300 mg q4w
was 0.62 times the hazard of attacks during Cinryze.RTM. treatment.
These results comparing treatment with lanadelumab 300 mg q4w to
treatment with Cinryze.RTM. were not statistically significant, as
evidenced by the inclusion of "1" in the corresponding 95% CIs (95%
CI: 0.2336, 1.6381). The point estimates generated in the ITC using
IPD differed from the results of the Bayesian NMA. As the interval
bounds appeared similar, the conclusions did not change.
TABLE-US-00026 TABLE 24 Indirect Comparison of Lanadelumab and
Cinryze .RTM. via the Bucher Method (Base Case). ITC 95% CI 95% CI
Bayesian Treatment 1 Treatment 2 HR Lower Upper NMA:HR Lanadelumab
Cinryze .RTM. 0.1903 0.0584 0.6200 0.17 (0.05; 300 mg q2w 0.57)
Lanadelumab Cinryze .RTM. 0.6186 0.2336 1.6381 0.51 (0.18; 300 mg
q4w 1.49)
[0237] In comparing lanadelumab 300 mg q2w and lanadelumab 300 mg
q4w to placebo, the Cox regression yielded HRs of 0.05 (95% CI;
0.02; 0.14) and 0.19 (95% CI; 0.10; 0.38), respectively (Table 25).
The addition of the covariate inclusion did not have an impact.
TABLE-US-00027 TABLE 25 Base Case Results in the HELP Study.
Comparison HR SE 95% CI Lower 95% CI Upper Lanadelumab 300 0.0516
0.0266 0.0188 0.1417 mg q2w vs. placebo Lanadelumab 300 0.1930
0.0658 0.0990 0.3764 mg q4w vs. placebo
[0238] In comparing Cinryze.RTM. and placebo, the Cox regression
generated a HR of 0.32 (95% CI: 0.14; 0.71) (Table 26). These
results were consistent with the base case findings.
TABLE-US-00028 TABLE 26 Base Case Results in the CHANGE Study.
Contrast HR SE 95% CI Lower 95% Upper HR Cinryze .RTM. vs. 0.3193
0.1295 0.1441 0.7072 placebo
[0239] Indirect comparison via the Bucher method showed that
patients treated with lanadelumab 300 mg q2w had 0.15 times the
hazard of a first HAE attack after 70 days of treatment compared to
those treated with Cinryze.RTM. (Table 27). These results were
statistically significant as evidenced by exclusion of the value
"1" in the corresponding 95% CIs (95% CI: 0.0431; 0.5286).
Treatment with lanadelumab 300 mg q4w resulted in 0.56 times the
hazard of HAE attacks when compared with Cinryze.RTM.. These
results comparing treatment with lanadelumab 300 mg q4w to
treatment with Cinryze.RTM. were not statistically significant, as
evidenced by the inclusion of "1" in the corresponding 95% CIs (95%
CI: 0.2086, 1.5262).
TABLE-US-00029 TABLE 27 Indirect Comparison of Lanadelumab and
Cinryze .RTM. via the Bucher Method (Base Case). ITC Treatment 1
Treatment 2 HR 95% CI Lower 95% CI Upper Lanadelumab Cinryze .RTM.
0.1508 0.0431 0.5286 300 mg q2w Lanadelumab Cinryze .RTM. 0.5643
0.2086 1.5262 300 mg q4w
Conclusion
[0240] Consistent with the results of the Bayesian NMA using
aggregate data, the present regression-based frequentist ITC
demonstrated that lanadelumab 300 mg q2w and lanadelumab 300 mg q4w
were statistically more effective than Cinryze.RTM. at reducing the
rate of HAE attacks per 28 days (RR 0.27, 95% CI [0.15; 0.49] and
RR 0.54, 95% CI [0.35; 0.85], respectively). A sensitivity
analysis, which included patient-reported HAE attacks in the HELP
study, confirmed these findings and yielded RR point estimates and
95% Cis in line with the primary results. A second sensitivity
analysis including the covariates age, gender, and weight produced
similar findings and further supported the outcomes of the base
case analysis.
[0241] With respect to the time to first attack after 0 days of
treatment and the time to first attack after 70 days of treatment,
the present ITC drew conclusions similar to those noted in the
Bayesian NMA. Lanadelumab 300 mg q2w and lanadelumab 300 mg q4w
were not statistically more effective compared to Cinryze.RTM. in
prolonging the time to a first attack after 0 days of treatment (HR
0.73, 95% CI [0.29; 1.84] and HR 1.05, 95% CI [0.43, 2.52],
respectively). Lanadelumab 300 mg q2w and lanadelumab 300 mg q4w,
however, appeared to exhibit greater efficacy in increasing the
time to a first attack after 70 days of treatment compared to
Cinryze.RTM. (HR 0.19, 95% CI [0.06; 0.62] and HR 0.62, 95% CI
[0.23; 1.64], respectively). Only the difference between
lanadelumab 300 mg q2w and Cinryze.RTM. was statistically
significant. In the sensitivity analyses for the time to first
attack after 0 and 70 days of treatment, models including age,
gender, and weight yielded lower HR point estimates; however, the
findings did not change any of the base case conclusions.
[0242] Although the conclusions of the present ITC were consistent
with those of the Bayesian NMA, the corresponding point estimates
and uncertainty intervals differed. This was presumably due to the
lack of accounting for repeated measurements in the Bayesian NMA
(with respect to the CHANGE cross-over study), as well as
differences in data input types.
Other Embodiments
[0243] All of the features disclosed in this specification may be
combined in any combination. Each feature disclosed in this
specification may be replaced by an alternative feature serving the
same, equivalent, or similar purpose. Thus, unless expressly stated
otherwise, each feature disclosed is only an example of a generic
series of equivalent or similar features.
[0244] From the above description, one skilled in the art can
easily ascertain the essential characteristics of the present
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions. Thus, other embodiments
are also within the claims.
EQUIVALENTS
[0245] While several inventive embodiments have been described and
illustrated herein, those of ordinary skill in the art will readily
envision a variety of other means and/or structures for performing
the function and/or obtaining the results and/or one or more of the
advantages described herein, and each of such variations and/or
modifications is deemed to be within the scope of the inventive
embodiments described herein. More generally, those skilled in the
art will readily appreciate that all parameters, dimensions,
materials, and configurations described herein are meant to be
exemplary and that the actual parameters, dimensions, materials,
and/or configurations will depend upon the specific application or
applications for which the inventive teachings is/are used. Those
skilled in the art will recognize, or be able to ascertain using no
more than routine experimentation, many equivalents to the specific
inventive embodiments described herein. It is, therefore, to be
understood that the foregoing embodiments are presented by way of
examples only and that, within the scope of the appended claims and
equivalents thereto, inventive embodiments may be practiced
otherwise than as specifically described and claimed. Inventive
embodiments of the present disclosure are directed to each
individual feature, system, article, material, kit, and/or method
described herein. In addition, any combination of two or more such
features, systems, articles, materials, kits, and/or methods, if
such features, systems, articles, materials, kits, and/or methods
are not mutually inconsistent, is included within the inventive
scope of the present disclosure.
[0246] All definitions, as defined and used herein, should be
understood to control over dictionary definitions, definitions in
documents incorporated by reference, and/or ordinary meanings of
the defined terms.
[0247] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one."
[0248] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0249] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e. "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of." "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0250] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0251] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0252] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
Sequence CWU 1
1
101469PRTArtificial SequenceSynthetic Polypeptide 1Met Gly Trp Ser
Cys Ile Leu Phe Leu Val Ala Thr Ala Thr Gly Ala1 5 10 15His Ser Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 20 25 30Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 35 40 45His
Tyr Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 50 55
60Trp Val Ser Gly Ile Tyr Ser Ser Gly Gly Ile Thr Val Tyr Ala Asp65
70 75 80Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
Thr 85 90 95Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val Tyr 100 105 110Tyr Cys Ala Tyr Arg Arg Ile Gly Val Pro Arg Arg
Asp Glu Phe Asp 115 120 125Ile Trp Gly Gln Gly Thr Met Val Thr Val
Ser Ser Ala Ser Thr Lys 130 135 140Gly Pro Ser Val Phe Pro Leu Ala
Pro Ser Ser Lys Ser Thr Ser Gly145 150 155 160Gly Thr Ala Ala Leu
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175Val Thr Val
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190Phe
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200
205Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
Glu Pro225 230 235 240Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
Cys Pro Ala Pro Glu 245 250 255Leu Leu Gly Gly Pro Ser Val Phe Leu
Phe Pro Pro Lys Pro Lys Asp 260 265 270Thr Leu Met Ile Ser Arg Thr
Pro Glu Val Thr Cys Val Val Val Asp 275 280 285Val Ser His Glu Asp
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300Val Glu Val
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn305 310 315
320Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
Leu Pro 340 345 350Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
Gln Pro Arg Glu 355 360 365Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
Glu Glu Met Thr Lys Asn 370 375 380Gln Val Ser Leu Thr Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile385 390 395 400Ala Val Glu Trp Glu
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415Thr Pro Pro
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430Leu
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440
445Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460Ser Leu Ser Pro Gly4652231PRTArtificial
SequenceSynthetic Polypeptide 2Met Gly Trp Ser Cys Ile Leu Phe Leu
Val Ala Thr Ala Thr Gly Ala1 5 10 15His Ser Asp Ile Gln Met Thr Gln
Ser Pro Ser Thr Leu Ser Ala Ser 20 25 30Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser 35 40 45Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 50 55 60Leu Ile Tyr Lys Ala
Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe65 70 75 80Ser Gly Ser
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu 85 90 95Gln Pro
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Thr Tyr 100 105
110Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
115 120 125Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
Lys Ser 130 135 140Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
Tyr Pro Arg Glu145 150 155 160Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu Gln Ser Gly Asn Ser 165 170 175Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp Ser Thr Tyr Ser Leu 180 185 190Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 195 200 205Tyr Ala Cys
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 210 215 220Ser
Phe Asn Arg Gly Glu Cys225 2303122PRTArtificial SequenceSynthetic
Polypeptide 3Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
Phe Ser His Tyr 20 25 30Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys
Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Tyr Ser Ser Gly Gly Ile Thr
Val Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Tyr Arg Arg Ile Gly
Val Pro Arg Arg Asp Glu Phe Asp Ile Trp 100 105 110Gly Gln Gly Thr
Met Val Thr Val Ser Ser 115 1204106PRTArtificial SequenceSynthetic
Polypeptide 4Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala
Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
Ile Ser Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
Pro Lys Leu Leu Ile 35 40 45Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Tyr Asn Thr Tyr Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys 100 10555PRTArtificial SequenceSynthetic
Polypeptide 5His Tyr Ile Met Met1 5617PRTArtificial
SequenceSynthetic Polypeptide 6Gly Ile Tyr Ser Ser Gly Gly Ile Thr
Val Tyr Ala Asp Ser Val Lys1 5 10 15Gly713PRTArtificial
SequenceSynthetic Polypeptide 7Arg Arg Ile Gly Val Pro Arg Arg Asp
Glu Phe Asp Ile1 5 10811PRTArtificial SequenceSynthetic Polypeptide
8Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala1 5 1097PRTArtificial
SequenceSynthetic Polypeptide 9Lys Ala Ser Thr Leu Glu Ser1
5108PRTArtificial SequenceSynthetic Polypeptide 10Gln Gln Tyr Asn
Thr Tyr Trp Thr1 5
* * * * *
References