U.S. patent application number 16/711089 was filed with the patent office on 2020-04-16 for methods for treating idiopathic pulmonary fibrosis.
This patent application is currently assigned to FibroGen, Inc.. The applicant listed for this patent is FibroGen, Inc.. Invention is credited to Seth PORTER, John L. Stauffer.
Application Number | 20200113533 16/711089 |
Document ID | / |
Family ID | 49514725 |
Filed Date | 2020-04-16 |
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United States Patent
Application |
20200113533 |
Kind Code |
A1 |
PORTER; Seth ; et
al. |
April 16, 2020 |
METHODS FOR TREATING IDIOPATHIC PULMONARY FIBROSIS
Abstract
The present invention relates to methods and medicaments useful
for treating idiopathic pulmonary fibrosis (IPF) by administering
anti-CTGF antibodies. Methods for prognosing individuals with IPF
are also provided.
Inventors: |
PORTER; Seth; (San Carlos,
CA) ; Stauffer; John L.; (Cupertino, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FibroGen, Inc. |
San Francisco |
CA |
US |
|
|
Assignee: |
FibroGen, Inc.
San Francisco
CA
|
Family ID: |
49514725 |
Appl. No.: |
16/711089 |
Filed: |
December 11, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16028235 |
Jul 5, 2018 |
10555713 |
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16711089 |
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15263767 |
Sep 13, 2016 |
10039515 |
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16028235 |
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14398380 |
Oct 31, 2014 |
9480449 |
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PCT/US2013/031599 |
Mar 14, 2013 |
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15263767 |
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61642366 |
May 3, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2039/505 20130101;
A61K 39/3955 20130101; A61B 6/5217 20130101; C07K 16/22 20130101;
A61B 6/032 20130101; A61B 6/50 20130101; A61K 49/0004 20130101 |
International
Class: |
A61B 6/00 20060101
A61B006/00; A61K 49/00 20060101 A61K049/00; A61B 6/03 20060101
A61B006/03; C07K 16/22 20060101 C07K016/22 |
Claims
1-24. (canceled)
25. A method for increasing forced vital capacity (FVC) in a
subject with idiopathic pulmonary fibrosis (IPF), the method
comprising administering at least 30 mg/kg of an anti-connective
tissue growth factor (CTGF) antibody that has the same amino acid
sequence as the antibody produced by the cell line identified by
ATCC Accession No. PTA-6006, thereby increasing the subject's
FVC.
26. The method of claim 25, further comprising the administration
of an additional therapeutic agent selected from the group
consisting of pirfenidone, nintedanib, corticosteroids,
antibiotics, immunosuppressivw drugs and supplemental oxygen.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. Provisional Application 61/642366 filed May 3, 2012
and is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to methods and medicaments
useful for treating idiopathic pulmonary fibrosis. Methods for
prognosing individuals with IPF are also provided.
BACKGROUND OF THE INVENTION
[0003] IPF is a chronic and progressive lung disease that results
in respiratory failure and death. Median survival is about 2 to 4
years from diagnosis. The etiology of IPF remains unknown, but the
disease is characterized by fibrotic interstitial infiltrates that
are consistent with the histopathologic pattern of usual
interstitial pneumonia. (Gross T J et al. N Engl J Med (2001);
345:(7):517-525.) As interstitial fibrosis advances with
accompanying distortion of lung architecture, the lung becomes less
compliant, increasing the effort associated with breathing, leading
to dyspnea. Typically, lung function declines slowly over time, but
some patients experience rapid declines that can lead to
hospitalization or death, particularly in later stages of the
disease. (Martinez F J et al. Ann Intern Med (2005)
142:963-967.)
[0004] In the United States, as many as 89,000 people are afflicted
with IPF, with about 34,000 newly diagnosed annually. (Raghu G et
al., Am J Respir Crit Care Med (2006) 174: (7):810-816.) Prevalence
of IPF ranges from 14.0 to 42.7 cases per 100,000 persons and the
annual incidence ranges from 6.8 to 16.3 cases per 100,000 persons,
depending on the strictness of the diagnostic criteria employed.
(Raghu G et al., supra.) The prevalence of IPF increases with age,
with most IPF patients 60 years of age or older at the time of
diagnosis. The disease is more common in men than in women
(Fernandez Perez E R et al. Chest (2010) 137:(1):129-137.) with
most patients current or former smokers. A familial form of IPF may
account for as many as 20% of IPF cases. (Loyd J E, Eur Respir Rev
(2008) 17:(109):163-167.)
[0005] While the pathogenesis of IPF is not clearly defined, the
disease is believed to be caused by repetitive epithelial injury.
(Selman Met al. Ann Intern Med (2001) 134:136-151; Selman M. Proc
Am Thorac Soc (2006) (4):364-372.) According to this hypothesis,
alveolar cell injury and activation initiate a dysregulated,
exaggerated fibrotic healing process characterized by myofibroblast
proliferation and progressive deposition of extracellular matrix
(ECM) in genetically susceptible individuals. (Selman M et al.
(2001) supra; Selman M. (2006) supra.)
[0006] There are currently no FDA-approved drugs for the treatment
of IPF. Recently conducted phase 3 clinical trials of pirfenidone,
sildenafil, bosentan, etanercept, and interferon gamma-1b have
failed to demonstrate efficacy in their primary endpoints. N-acetyl
cysteine (NAC), corticosteroids, and the immunosuppressive drugs
cyclophosphamide and azathioprine are commonly prescribed, but
there is little evidence that use of these drugs improves patient
outcome or alters the natural course of the disease. (Collard H R
et al. Chest (2004) 125: (6):2169-2174, Walter N et al, Proc Am
Thorac Soc (2006) 3: (4):377-381.) In fact, the combination of
prednisone, azathioprine, and NAC produced a worse outcome than NAC
or placebo in a recent IPF study. (NIH News, Oct. 24, 2011.) Lung
transplantation is the only treatment that improves survival
(Walter, supra.), but most IPF patients are not eligible for
transplantation because of their age or comorbid conditions. IPF
patients usually are managed with supportive measures such as
symptomatic treatment of cough and dyspnea, supplemental oxygen for
hypoxemia, smoking cessation, pulmonary rehabilitation, and
prophylaxis and control of respiratory tract infections.
[0007] The progressive and fatal course of IPF coupled with the
absence of approved drugs underscore the need for new methods and
agents to treat this devastating disease. The present invention
meets this unmet medical need by providing novel methods and agents
for use in treating IPF. In particular, the present invention
provides agents and methods for reducing, stabilizing or reversing
the progression and severity of IPF and for preventing or treating
one or more symptoms of IPF by inhibiting connective tissue growth
factor (CTGF) activity.
SUMMARY OF THE INVENTION
[0008] In one aspect of the invention, a method is provided for
treating IPF in a subject in need thereof, wherein the method
comprises administering to the subject an effective amount of an
anti-CTGF antibody, thereby treating IPF. In some embodiments, the
method for treating IPF with an anti-CTGF antibody reducing the
pathologic rate of decline of a pulmonary function parameter by at
least 5%. In further embodiments, the pulmonary function parameter
is selected from the group consisting of vital capacity (VC),
residual volume (RV), forced expiratory volume (FEV), forced vital
capacity (FVC), forced vital capacity percent (FVC %) predicted,
forced expiratory flow (FEF), peak expiratory flow rate (PEFR),
inspiratory reserve volume (IRV), functional residual capacity
(FRC), inspiratory capacity (IC), total lung capacity (TLC),
expiratory reserve volume (ERV), tidal volume (TV), and maximum
voluntary ventilation (MVV).
[0009] The additional embodiments, the method for treating IPF with
an anti-CTGF antibody comprises increasing the subject's FVC by at
least 0.05 liters compared to a baseline FVC measurement. In
further embodiments, the method for treating IPF comprises
increasing the subject's FVC % predicted by at least 0.5% compared
to a baseline FVC % predicted measurement.
[0010] In other embodiments, the method for treating IPF with an
anti-CTGF antibody comprises producing at least a 5% increase,
compared to a baseline measurement, in diffusing capacity of the
lung for carbon monoxide (DLCO) corrected for hemoglobin, DLCO
percent (DLCO %) predicted, or arterial oxyhaemoglobin saturation
(SaO.sub.2). In further embodiments, the method for treating IPF
produces a decrease of at least 5% in alveolar-arterial oxygen
tension gradient (A-a) PO.sub.2.
[0011] In additional embodiments, the method for treating IPF with
an anti-CTGF antibody comprises at least a 5% reduction, compared
to a baseline measurement, in the extent of pulmonary infiltration
of fibroblasts or myofibroblasts, at least a 5% reduction in the
rate of collagen deposition, at least a 5% reduction in the degree
type II pneumocyte hyperplasia, at least a 5% reduction in the
degree of smooth muscle hyperplasia or at least a 5% reduction in
the formation of fibroblastic foci.
[0012] In other embodiments, the method for treating IPF comprises
stabilizing or producing at least a 2% reduction, compared to a
baseline measurement, in one or more pulmonary radiographic
parameters selected from the group consisting of ground glass
opacities, fibrosis, and honeycomb formation.
[0013] In further embodiments, the method for treating IPF
comprises extending the subject's progression-free survival or
overall survival of at least 1 month compared to historic controls.
In other embodiments, the treatment method comprises decreasing the
subject's risk of death at 1 year post-diagnosis by at least 10%
compared to historical controls.
[0014] In still other embodiments, the method for treating IPF
comprises preventing a worsening of dyspnea or the development of
new dyspnea, reducing the frequency or intensity of coughing,
preventing a worsening of hypoxemia; reducing the number or
severity of acute exacerbations of IPF, reducing the number of
IPF-related hospital admissions, reducing the need for supplemental
oxygen, or improving the assessment of health-related quality of
life.
[0015] In some embodiments, the method for treating IPF comprises
the use of an anti-CTGF antibody that has the same amino acid
sequence as the antibody produced by the cell line identified by
ATCC Accession No. PTA-6006. In other embodiments, the anti-CTGF
antibody used in the treatment method binds to CTGF competitively
with an antibody produced by the cell line identified by ATCC
Accession No. PTA-6006.
[0016] In further embodiments, the method for treating IPF
comprises administering at least 15 mg/kg of an anti-CTGF antibody.
In other embodiments, at least 1.00 g of an anti-CTGF antibody is
administered. In additional embodiments, the treatment method is
associated with a C.sub.min of at least 10.0 .mu.g/ml for the
anti-CTGF antibody when measured at 21 days post-administration. In
other embodiments, the treatment method produces an area under the
curve for the anti-CTGF antibody for the period of 0-21 days
post-administration of at least 1,000 .mu.g*h/ml.
[0017] In some embodiments, the method for treating IPF further
comprises administering an additional therapeutic agent selected
from the group consisting of corticosteroids, antibiotics,
immunosuppressive drugs, supplemental oxygen, and mechanical
ventilation.
[0018] In some embodiments, the subject to be treated with the
treatment method has a forced vital capacity percent (FVC %)
predicted of greater than about 55%, less than 50% parenchymal
fibrosis, less than 25% honeycombing within the whole lung or has
been diagnosed with IPF for less than 5 years.
[0019] In one aspect, the invention provides a pharmaceutical
composition comprising an anti-CTGF antibody for treating IPF.
[0020] These and other embodiments of the present invention will
readily occur to those of skill in the art in light of the
disclosure herein, and all such embodiments are specifically
contemplated.
[0021] Each of the limitations of the invention can encompass
various embodiments of the invention. It is, therefore, anticipated
that each of the limitations of the invention involving any one
element or combinations of elements can be included in each aspect
of the invention. This invention is not limited in its application
to the details of construction and the arrangement of components
set forth in the following description or illustrated in the
drawings. The invention is capable of other embodiments and of
being practiced or of being carried out in various ways. Also, the
phraseology and terminology used herein is for the purpose of
description and should not be regarded as limiting. The use of
"including," "comprising," or "having," "containing," "involving,"
and variations thereof herein, is meant to encompass the items
listed thereafter and equivalents thereof as well as additional
items.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 illustrates the change from baseline in forced vital
capacity (FVC) in liters at Weeks 24 and 36 following initiation of
anti-CTGF antibody treatment versus the baseline FVC percent (FVC
%) predicted of subjects with moderate to severe IPF. The change in
FVC over time correlates with baseline FVC % predicted values.
Subjects above about a baseline FVC % predicted of 55% demonstrate,
in general, stable or improved (positive change) FVC, while
subjects below about a baseline FVC % predicted of 55% demonstrate,
in general, a decline in FVC. Baseline FVC % predicted was
calculated from the mean of a subject's FVC % predicted values from
screening 1 visit and treatment Day 1. The median baseline FVC %
predicted was 63.2%.
[0023] FIG. 2 illustrates the change in FVC (liters) from baseline
over time in subjects treated with an anti-CTGF antibody that had a
baseline FVC % predicted of at least 55% (>BL 55%). For
comparison, the normal decline in FVC seen in a similarly matched
normal population (Normal) is shown along with the pathologic
decline in FVC of IPF patients in the composite placebo arm (IPF
Placebo) derived from recent clinical trials, n=1,122. The
anti-CTGF antibody treated subjects experienced a decline in FVC at
Week 24 post-initiation of therapy that approached the decline seen
in the IPF patients in the placebo arm. By Week 36 post-initiation
of therapy, however, the anti-CTGF antibody treated subjects
experienced an increase in FVC so that the overall decline for the
anti-CTGF antibody treated subjects approximated that seen in the
normal reference population. IPF patients in the placebo arm were
calculated at Week 36 to have a -0.12 liter change from baseline
and at Week 48 a -0.17 liter change from baseline.
[0024] FIG. 3 illustrates the change in FVC (liters) from baseline
over time in subjects that responded (Responders) to treatment with
an anti-CTGF antibody. For comparison, the normal decline (Normal)
seen in a similarly matched normal population is shown along with
the pathologic decline in FVC of IPF patients in the composite
placebo arm (IPF Placebo) derived from recent clinical trials,
n=1,122. Responders demonstrated a gain in FVC across all time
points for a net gain from baseline of about 0.04 liters at Week
36. IPF patients in the placebo arm were calculated at Week 36 to
have a -0.12 liter change from baseline and at Week 48 a -0.17
liter change from baseline.
[0025] FIG. 4 illustrates the percent change in the extent of
pulmonary fibrosis from baseline in the most severe lung lobe at
Week 24 of subjects with IPF that were treated with an anti-CTGF
antibody, n=12. HRCT scans were examined using a computer-aided
detection (CAD) analysis system that measured three pulmonary
radiographic parameters: ground glass opacities (GG), fibrosis (F)
and honeycomb formation (HC). Subjects are ordered from left to
right along the x-axis according to the extent of change in the
mean CAD analysis fibrotic (F) score with subjects demonstrating
the greatest reductions in fibrosis arranged on the left hand side.
Also included is the measurement of total lung disease termed
quantitative interstitial lung disease (QILD) that is the summation
of a subject's GG, F and HC values. Half of the subjects
demonstrated measurable improvement (reversal, <-2% change) in
these pulmonary radiographic parameters while a quarter of the
subjects demonstrated stable disease (.+-.2% change in pulmonary
radiographic parameters). Most subjects showed a reversal in the
extent of ground glass opacities.
[0026] FIG. 5 illustrates the percent change in the extent of
pulmonary fibrosis from baseline in whole lung at Week 24 of
subjects with IPF that were treated with an anti-CTGF antibody,
n=12. HRCT scans were examined using a CAD analysis system that
measured three pulmonary radiographic parameters: GG, F and HC.
Subjects retained the ordering from FIG. 4. Additionally, QILD
values are shown. Half of the subjects demonstrated measurable
improvement (reversal, <-2% change) in these pulmonary
radiographic parameters, while a quarter of the subjects
demonstrated stable disease (+2% pulmonary radiographic
parameters). Most subjects showed a reversal in the extent of
ground glass opacities.
[0027] FIG. 6 illustrates the association between improvement in
lung structure and improvement in lung function in subjects treated
with an anti-CTGF antibody. The improvement in lung structure is
shown by the reduction (reversal) of pulmonary radiographic
parameters ground glass opacities and fibrosis, i.e., the negative
values. The improvement in lung function is shown by the increase
in FVC % predicted values (positive change). Generally, subjects
with a higher baseline FVC % predicted value, in general, responded
better to anti-CTGF antibody therapy.
[0028] FIG. 7 illustrates that subjects treated with an anti-CTGF
antibody (CLN1, ALL) experienced a reduction of the pathologic rate
of decline of pulmonary function at all time points, as measured by
the change in FVC % predicted from baseline, compared to a
composite placebo arm derived from recent IPF clinical trials,
n=1,019 The graph further illustrates that subjects with a FVC %
predicted baseline value greater than 55% (BL>55%) experienced
an even greater reduction in the pathologic rate of decline of
pulmonary function compared to all the subjects treated with the
anti-CTGF antibody or historical controls.
[0029] FIG. 8 illustrates, at Week 24, the change from baseline in
the pulmonary radiographic parameter fibrosis (F) for whole lung
for the completed study using a CAD analysis system, n=46 (includes
2 subjects that withdrew early). The pulmonary radiographic
parameter fibrosis decreased (<-2% change) or was stable (.+-.2%
change) in 58.7% of the subjects (n=27). An increase (>+2%
change) in the pulmonary radiographic parameter fibrosis was seen
in 41.3% of the subjects (n=19). The dashed horizontal lines
indicate the range of measurement error .+-.2%.
[0030] FIG. 9 illustrates, at Week 24, the change from baseline in
QILD for whole lung for the completed study using a CAD analysis
system, n=46 (includes 2 subjects that withdrew early). Decreased
(<-2% change) or stable QILD (.+-.2% change) was noted in 60% of
the subjects (n=28). Increased (>+2% change) QILD was seen in
40% of the subjects (n=18). The dashed horizontal lines indicate
the range of measurement error +2%.
[0031] FIG. 10 illustrates, at Week 48, the change from baseline in
the pulmonary radiographic parameter fibrosis (F) for whole lung
for the completed study using a CAD analysis system, n=38. The
pulmonary radiographic parameter fibrosis decreased (<-2%
change) or was stable (.+-.2% change) in 52.6% of the subjects
(n=20). An increase (>+2% change) in the pulmonary radiographic
parameter fibrosis was seen in 47.4% of the subjects (n=18). The
dashed horizontal lines indicate the range of measurement error
.+-.2%.
[0032] FIG. 11 illustrates, at Week 48, the change from baseline in
QILD for whole lung for the completed study using a CAD analysis
system, n=38. Decreased (<-2% change) or stable QILD (.+-.2%
change) was noted in 52.6% of the subjects (n=20). Increased
(>+2% change) QILD was seen in 47.4% of the subjects (n=18). The
dashed horizontal lines indicate the range of measurement error
.+-.2%.
[0033] FIG. 12 compares the change from baseline in QILD at Weeks
24 and 48 for individual subjects using a CAD analysis system,
n=38. The degree of change in QILD values for individual subjects
are fairly consistent for the two time points. Subjects that showed
a decrease (<-2%) in QILD at Week 24 usually continued to show a
decrease in QILD at Week 48. Subjects that had stable QILD at Week
24 (.+-.2% change) usually continued to show stable QILD at Week
48. Similarly, subjects that showed an increase (>+2%) in QILD
at Week 24 usually continued to show an increase in QILD at Week
48.
[0034] FIG. 13 illustrates the correlation between QILD results at
Week 24 for whole lung and the change in FVC % predicted from
baseline over the course of the study. Subjects that had an
increase (>+2%) in QILD from baseline at Week 24 (Increased
QILD) had a pathologic rate of decline in FVC % predicted from
baseline that was similar to the pathologic rate of decline in FVC
% predicted from baseline seen in historical placebos from recent
IPF clinical trials , n=1,019. Subjects that had a decrease
(<-2%) in QILD from baseline at Week 24 (Decreased QILD) or
stable (.+-.2%) QILD from baseline at Week 24 (Stable QILD) showed
similar rates of decline in FVC % predicted from baseline. The
difference in the rate of decline in FVC % predicted from baseline
between subjects that had increased QILD from baseline at Week 24
and the combined subjects that had stable QILD or decreased QILD
from baseline at Week 24, was statistically significant at Week 24
(p<0.004) and Week 48 (p<0.05).
[0035] FIG. 14 illustrates that the change in FVC % predicted from
baseline is associated with the change from baseline in the
pulmonary radiographic parameter fibrosis, as determined using a
CAD analysis system.
[0036] FIG. 15 illustrates that the change in FVC % predicted from
baseline is associated with the change from baseline in QILD, as
determined using a CAD analysis system.
[0037] FIG. 16 illustrates the rate of decline in FVC % predicted
values from baseline over time for subjects above and below a
threshold -3% change in FVC % predicted at Week 48. Subjects above
the threshold value (>-3%) at Week 48 (40% of total subjects)
had at Week 12, a slight increase in pulmonary function that was
maintained for at least 48 weeks. In contrast, subjects below the
threshold value (<-3%) at Week 48 (60% of total subjects) showed
a continual decline in pulmonary function that was similar to the
results seen in historical placebos from recent IPF clinical
trials, n=1019.
[0038] FIG. 17 illustrates the positive change (reversal) in FVC %
predicted from baseline at Week 12 for the first 14 subjects
enrolled in Cohort 2, compared to the results of Cohort 1 and
historical controls. Subjects in Cohort 2 received 30 mg/kg of an
anti-CTGF antibody. The initial measurement shows that the change
in FVC % predicted from baseline for the 30 mg/kg group is higher
than that seen in the subjects that received 15 mg/kg, including
those subjects in Cohort 1 that had a baseline FVC % predicted of
greater than 55%.
DESCRIPTION OF THE INVENTION
[0039] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods, devices, and materials are now
described. All publications cited herein are incorporated herein by
reference in their entirety for the purpose of describing and
disclosing the methodologies, reagents, and tools reported in the
publications that might be used in connection with the present
invention. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such disclosure
by virtue of prior invention.
[0040] The practice of the present invention will employ, unless
otherwise indicated, conventional methods of chemistry,
biochemistry, molecular biology, cell biology, genetics, immunology
and pharmacology, within the skill of the art. Such techniques are
explained fully in the literature. See, e.g., Gennaro, A. R., ed.
(1990) Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing Co.; Colowick, S. et al., eds., Methods In Enzymology,
Academic Press, Inc.; Handbook of Experimental Immunology, Vols.
I-IV (D. M. Weir and C. C. Blackwell, eds., 1986, Blackwell
Scientific Publications); Maniatis, T. et al., eds. (1989)
Molecular Cloning: A Laboratory Manual, 2nd edition, Vols. I-III,
Cold Spring Harbor Laboratory Press; Ausubel, F. M. et al., eds.
(1999) Short Protocols in Molecular Biology, 4th edition, John
Wiley & Sons; Ream et al., eds. (1998) Molecular Biology
Techniques: An Intensive Laboratory Course, Academic Press); PCR
(Introduction to Biotechniques Series), 2nd ed. (Newton &
Graham eds., 1997, Springer Verlag).
Definitions
[0041] As used herein, the term "about" refers to .+-.10% of the
numerical value of the number with which it is being used.
Therefore, about 50% means in the range of 45%-55%.
[0042] As used herein and in the appended claims, the singular form
"a," "an," and "the" include plural references unless the context
clearly dictates otherwise. For example, a reference to "an
anti-CTGF agent" includes a plurality of such agents; a reference
to an "antibody" is a reference to one or more antibodies and to
equivalents thereof known to those skilled in the art; and so
forth.
[0043] As used herein, the term "subject," "host," "individual,"
and "patient" are used interchangeably to refer to a mammal. In a
preferred embodiment, the mammal is a primate, and more preferably
a human being.
[0044] As used herein, the term "blood" encompasses whole blood,
serum or plasma. When a specific antibody concentration in plasma,
e.g., a target antibody plasma level, is discussed, it is to be
understood to include the antibody concentration in whole blood,
serum or plasma.
[0045] The terms "idiopathic pulmonary fibrosis" and "IPF" describe
a chronic, progressive fibrosing interstitial pneumonia of unknown
cause, limited to the lungs and associated with the radiologic
and/or histopathologic pattern of usual interstitial pneumonia
(UIP).
[0046] Subjects with IPF have a UIP pattern on high resolution
computerized tomography (HRCT) scan with the following three
features: (1) subpleural, basal predominance of fibrosis; (2)
reticular abnormality; and (3) presence of honeycombing with or
without traction bronchiectasis. Additionally, IPF subjects do not
have any of the following features inconsistent with an UIP
pattern: (i) upper or mid-lung predominance of fibrosis; (ii)
peribronchovascular predominance fibrosis; (iii) extensive ground
glass abnormality (extent>reticular abnormality); (iv) profuse
micronodules (bilateral, predominately upper lobes); (v) discrete
cysts (multiple, bilateral away from areas of honeycombing); (vi)
diffuse mosaic attenuation/air trapping (bilateral, in three or
more lobes); and (vii) consolidation in bronchopulmonary segment(s)
and/or lobe(s). These criteria represent the official statement of
the American Thoracic Society (ATS), The European Respiratory
Society (ERS), The Japanese Respiratory Society (JRS), And The
Latin American Thoracic Association (ALAT). (See Raghu G, et al. Am
J Respir Crit Care Med. (2011) 183: (6):788-824.)
[0047] Subjects with IPF can also have a possible UIP pattern on
HRCT scan with histopathological confirmation of UIP. The subjects
have the following two features present on their HRCT scan: (1)
subpleural, basal predominance of fibrosis; and (2) reticular
abnormality. Additionally, the following features that are
inconsistent with a UIP pattern are absent: (i) upper or mid-lung
predominance of fibrosis; (ii) peribronchovascular predominance of
fibrosis; (iii) extensive ground glass abnormality
(extent>reticular abnormality); (iv) profuse micronodules
(bilateral, predominately upper lobes); (v) discrete cysts
(multiple, bilateral away from areas of honeycombing); (vi) diffuse
mosaic attenuation/air trapping (bilateral, in three or more
lobes); and (vii) consolidation in bronchopulmonary segment(s)
and/or lobe(s). (See Raghu G, et al. supra)
[0048] For histopathological confirmation of UIP pattern, the
following four criteria are met: (1) evidence of marked
fibrosis/architectural distortion, .+-.honeycombing in a
predominantly subpleural/paraseptal distribution; (2) presence of
patchy involvement of lung parenchyma by fibrosis; (3) presence of
fibroblast foci; and (4) absence of features against a diagnosis of
UIP suggesting an alternate diagnosis, e.g., hyaline membranes,
organizing pneumonia, granulomas, marked interstitial inflammatory
cell infiltrate away from honeycombing, predominant airway centered
changes, etc. (See Raghu, supra)
[0049] As used herein, the terms "treating", "treatment," and
"therapy," in the context of the invention, mean the administration
of an anti-CTGF antibody to subjects with IPF or at risk for
developing IPF. In some embodiments, the subjects with IPF are
"unresponsive to conventional treatment," i.e., unresponsive to
conventional prior art treatments of IPF including corticosteroids,
cyclophosphamide, and azathioprine. In further embodiments, the IPF
subjects treated with anti-CTGF antibodies have responded to
conventional treatment and the anti-CTGF antibodies are being
administered after the cessation of conventional treatments or in
addition to conventional treatments. In other embodiments, the IPF
subjects treated with anti-CTGF antibody are those subjects that
are treatment naive and include newly diagnosed IPF subjects.
[0050] As used herein, the terms "effective amount" or
"therapeutically effective amount" in the context of administering
an anti-CTGF antibody to a subject, refer to the amount of an
anti-CTGF antibody that is sufficient to produce a beneficial or
therapeutic effect including a partial or complete cure of IPF, or
the alleviation, amelioration, stabilization, improvement, or
reversal of the disease or any associated symptoms of the disease.
In some embodiments, an associated symptom of IPF is the pathologic
rate of decline in one or more pulmonary function parameters,
discussed below. In specific embodiments, an "effective amount" of
an anti-CTGF antibody refers to an amount of an anti-CTGF antibody
that is sufficient to produce at least one or more of the following
effects compared to baseline, i.e., pretreatment: (i) a reduction
in a pathologic rate of decline for one or more pulmonary function
parameters; (ii) a stabilization (arrest or stasis) in the
pathologic rate of decline in one or more pulmonary function
parameters; or (iii) a reversal in pathologic rate of decline in
one or more pulmonary function parameters, including the
normalization of one or more pulmonary function parameters.
[0051] Lung capacity and associated pulmonary function parameters
naturally decline due to aging. Numerous normal populations have
been studied and the rate of decline of lung capacity and various
pulmonary function parameters have been calculated and are readily
available in the art. (Crapo et al. (1981) Am. Rev. Respir. Dis.
123:659-664.) For example, a 65 year-old Caucasian male who is 183
cm (6'0'') tall has a predicted FVC of 4.95 liters. At age 66 this
same male has a predicted FVC of 4.92 liters. This difference of
0.03 liters represents the expected decline due to aging by 1 year.
Similarly, a 62 year-old Caucasian woman who is 167 cm (about
5'6'') has a predicted FVC of 2.67 liters. At age 63, this same
female has a predicted FVC of 2.64 liters. This difference of 0.03
liters represents the expected decline due to aging by 1 year.
[0052] In contrast to the natural decline due to aging, subjects
with IPF have an abnormally steep rate of decline in lung capacity
or in one or more pulmonary function parameters, i.e., a
"pathologic rate of decline." As used herein, a "pathologic rate of
decline" is a rate of decline in lung capacity or in one or more
pulmonary function parameters that is at least 5% greater than the
decline due to normal aging. In some embodiments, a pathologic rate
of decline is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 100%, 125%, 150%, 200%, 300%, 400%, 500%, 600%,
700%, 800% or 1000% greater than the predicted rate of decline for
a normal person of similarly matched race or ethnicity, gender,
age, height, and weight. Rates of decline can be expressed as the
change from baseline per 1 week, 2 weeks, 4 weeks, 8 weeks, 12
weeks, 24 weeks, 36 weeks, 48 weeks, or 12 months. In particular
embodiments, the pathologic rate of decline in lung capacity is the
change in forced vital capacity (FVC) from baseline of at least
about -0.05 liters, -0.10 liters, -0.15 liters, -0.20 liters or
-0.25 liters per 12 months. In other embodiments, the pathological
rate of decline is the change from baseline forced vital capacity
percent (FVC %) predicted of at least about -2%, -3%, -4%, -5%,
-6%, -7%, -8% or -10% per 12 months.
[0053] In some embodiments, a method is provided for increasing FVC
% predicted in a subject with IPF by administering an effective
amount of an anti-CTGF antibody. In further embodiments, treatment
with an effective amount of an anti-CTGF antibody increases FVC %
predicted by at least 0.5%, 1%, 1.5%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%,
6.0%, 7.0%, 8.0%, 9.0%, 10%, 15%, 20%, 30%, 40% or 50% compared to
baseline FVC % predicted. In further embodiments, treatment with
the anti-CTGF antibody is for at least 3 weeks, 6 weeks, 9 weeks,
12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30
weeks, 33 weeks, 36 weeks or 48 weeks. In other embodiments,
treatment is for 3 weeks or less, 6 weeks or less, 9 weeks or less,
12 weeks or less, 18 weeks or less, 24 weeks or less, 36 weeks or
less, 48 weeks or less, 12 months or less, 16 months or less, 20
months or less, or 24 months or less from starting treatment with
an anti-CTGF antibody. For example, if a subject with IPF has a
baseline FVC % predicted of 65%, treatment with an anti-CTGF
antibody raises the subject's FVC % predicted to 66.5% at week 36
post-initiation of therapy.
[0054] Numerous pulmonary function parameters known in the art can
be used to determine an effective amount of an anti-CTGF antibody,
i.e., an amount to reduce, stabilize or reverse a pathologic rate
of decline in one or more pulmonary function parameters; or to
monitor patient response to anti-CTGF antibody therapy. These
pulmonary function parameters include the following:
[0055] Vital capacity (VC) is the total volume of air that can be
moved in and out of the lungs. VC is equal to the combined
inspiratory reserve volume, tidal volume, and expiratory reserve
volume.
[0056] Forced vital capacity (FVC) is the vital capacity from a
maximally forced expiratory effort.
[0057] FVC % predicted is a subject's measured FVC expressed as the
percentage of the predicted FVC for the subject. As used herein,
all FVC % predicted values are absolute values and not relative
values.
[0058] Residual volume (RV) is the volume of air remaining in the
lungs after a maximal exhalation.
[0059] Forced expiratory volume (FEV) is the expiratory volume of
air from a maximally forced expiratory effort, usually measured
over a set period of time, e.g., 1 second, FEV1; 6 seconds, FEV6;
etc.
[0060] Forced inspiratory flow (FIF) is the inspiratory volume of
air from a maximally forced inspiratory effort, usually measured
over a set period of time, e.g., 1 second, FIF1; 6 seconds, FIFE;
etc.
[0061] Peak expiratory flow rate (PEFR) is the highest forced
expiratory flow rate.
[0062] Inspiratory reserve volume (IRV) is the maximal volume that
can be inhaled after a normal inspiration, measured from the
end-inspiratory level.
[0063] Tidal volume (TV) is the volume of air inhaled or exhaled
during one respiratory cycle, typically measured at rest.
[0064] Inspiratory capacity (IC) is the sum of the inspiratory
reserve volume and the tidal volume.
[0065] Functional residual capacity (FRC) is the sum of the
expiratory reserve volume and the residual volume. Typically, FRC
represents the volume of air in the lungs at the end of a normal
expiration.
[0066] Total lung capacity (TLC) is the sum of the vital capacity
and residual volume that represents the total volume of air that
can be contained in the lung.
[0067] Expiratory reserve volume (ERV) is the maximal volume of air
that can be exhaled after a normal expiration, measured from the
end-expiratory position.
[0068] Maximum voluntary ventilation (MVV) is the volume of air
expired in a specified time period during repetitive maximal
effort.
[0069] FEV1/FVC ratio means the ratio between forced expiratory
volume in one second and forced vital capacity.
[0070] Many of these pulmonary function parameters are readily
obtainable through the use of a spirometer as is well-known in the
art. Residual volume can be obtained through indirect methods such
as radiographic planimetry, body plethysmography, closed circuit
dilution (including the helium dilution technique), and nitrogen
washout.
[0071] In some embodiments, a method is provided for reducing,
stabilizing, or reversing a pathologic rate of decline in one or
more pulmonary function parameters, comprising the administration
of an effective amount of an anti-CTGF antibody. In further
embodiments, treatment with an effective amount of an anti-CTGF
antibody reduces the pathologic rate of decline of one or more
pulmonary function parameters by at least 5%, 10%, 15%, 20%, 30%,
40%, 50%, 60%, 80%, or 100%. In particular embodiments, the
pulmonary function parameter is FVC % predicted. In further
embodiments, the reduction, stabilization or reversal in the
pathologic rate of decline is achieved in 3 weeks or less, 6 weeks
or less, 9 weeks or less, 12 weeks or less, 18 weeks or less, 24
weeks or less, 36 weeks or less, 48 weeks or less, 12 months or
less, 16 months or less, 20 months or less, or 24 months or less
from starting treatment with an anti-CTGF antibody.
[0072] In some embodiments, a method is provided for increasing FVC
of a subject with IPF by administering an effective amount of an
anti-CTGF antibody. In further embodiments, treatment with an
effective amount of an anti-CTGF antibody increases FVC by at least
0.05 liters, 0.1 liters, 0.15 liters, 0.20 liters, 0.25 liters or
0.3 liters compared to baseline FVC. In further embodiments,
treatment with the anti-CTGF antibody is for at least 3 weeks, 6
weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks,
27 weeks, 30 weeks, 33 weeks, 36 weeks or 48 weeks. In other
embodiments, treatment is for 3 weeks or less, 6 weeks or less, 9
weeks or less, 12 weeks or less, 18 weeks or less, 24 weeks or
less, 36 weeks or less, 48 weeks or less, 12 months or less, 16
months or less, 20 months or less, or 24 months or less from
starting treatment with an anti-CTGF antibody. For example, if a
subject with IPF has a baseline FVC 2.61 liters, treatment with an
anti-CTGF antibody raises the subject's FVC to 2.66 liters at week
48 post-initiation of therapy
[0073] Additionally, an effective amount of an anti-CTGF antibody
also refers to an amount of an anti-CTGF antibody that is
sufficient to produce: (i) an increase in diffusing capacity of the
lung for carbon monoxide (DLCO) corrected for hemoglobin compared
to baseline, i.e., pretreatment: (ii) an increase in the DLCO
percent (DLCO %) predicted compared to baseline; (iii) an increase
in arterial oxyhaemoglobin saturation (SaO.sub.2) compared to
baseline; or (iv) a decrease in alveolar-arterial oxygen tension
gradient (A-a) PO.sub.2 compared to baseline. In some embodiments,
the increase in DLCO, DLCO % predicted, or SaO.sub.2 is at least
5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, or 90% above the baseline value. In other
embodiments, the decrease in (A-a)PO.sub.2 is at least 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, or 90% below the baseline value. DLCO, DLCO % predicted,
SaO.sub.2, or (A-a) PO.sub.2 can be measured at rest or after
exercise, e.g., the standardized 6-minute walk test.
[0074] In further embodiments, an effective amount of an anti-CTGF
antibody can induce a desired change in DLCO, DLCO % predicted,
SaO.sub.2, or (A-a) PO.sub.2 value in 3 weeks or less, 6 weeks or
less, 9 weeks or less, 12 weeks or less, 18 weeks or less, 24 weeks
or less, 36 weeks or less, 48 weeks or less, 12 months or less, 16
months or less, 20 months or less, or 24 months or less from
starting treatment with an anti-CTGF antibody.
[0075] Further, an effective amount of an anti-CTGF antibody
additionally refers to the amount of an anti-CTGF antibody that is
sufficient to produce a reduction, stabilization, or reversal of at
least one or more of the following histopathologic features
compared to baseline: (i) degree of pulmonary infiltration of
fibroblasts and/or myofibroblasts; (ii) rate of collagen
deposition; (iii) degree of type II pneumocyte hyperplasia; (iv)
degree of smooth muscle hyperplasia, or (v) formation of
fibroblastic foci (buds of young proliferating fibroblasts adjacent
to alveoli). Typically, these histopathological features are more
commonly seen in subpleural regions of the lower lung zones. In
some embodiments, an effective amount of an anti-CTGF antibody is
sufficient to produce a reduction of at least 1%, 2%, 3%, 4%, 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, or 95% in at least one or more histopathologic
feature compared to baseline. In further embodiments, the reduction
in one or more histopathological feature is achieved in 3 weeks or
less, 6 weeks or less, 9 weeks or less, 12 weeks or less, 18 weeks
or less, 24 weeks or less, 36 weeks or less, 48 weeks or less, 12
months or less, 16 months or less, 20 months or less, or 24 months
or less from starting treatment with an anti-CTGF antibody.
[0076] Additionally, an effective amount of an anti-CTGF antibody
additionally refers to the amount of an anti-CTGF antibody that is
sufficient to produce a reduction, stabilization, or reversal of at
least one or more of the following pulmonary radiographic
parameters compared to baseline: (i) degree of ground glass
opacities; (ii) degree of fibrosis; and (iii) degree of honeycomb
appearance of pulmonary architecture. Typically, these pulmonary
radiographic parameters are evaluated by HRCT scans. For example,
see Kim et al. Clin Exp Rheumatol. (2010) 28(5 Suppl 62):S26-S35;
Kim et al. Eur Radiol (2011) 21: 2455-2465. As used herein,
"stabilization" means the pulmonary radiographic parameter is
substantially unchanged from baseline, i.e., within the error of
measurement for the particular technique. As used herein, a
"reduction" in a pulmonary radiographic parameter means a lessening
of the severity of the parameter. Reductions of <-2% in a
pulmonary radiographic parameter compared to baseline for whole
lung, are categorized as "reversals." For example, if CAD analysis
of a HRCT scan from Week 24 shows that the pulmonary radiographic
parameter fibrosis is -5% compared to the baseline value, then the
response is categorized as a reversal of the extent of lung
fibrosis. Reductions in pulmonary radiographic parameters can also
be measured serially, e.g., a comparison of HRCT scans at Weeks 24
and 48 compared to baseline may show an initial stabilization at
Week 24 that continues to a reversal of the pulmonary radiographic
parameter at Week 48.
[0077] In some embodiments, an effective amount of an anti-CTGF
antibody is sufficient to produce a reduction, stabilization, or
reversal in at least one or more pulmonary radiographic parameters
compared to baseline. In other embodiments, an effective amount of
an anti-CTGF antibody is sufficient to reduce at least one
pulmonary radiographic parameter compared to baseline by at least
1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45% or 50%. For example, treatment with an effective amount of
an anti-CTGF antibody reduces the pulmonary radiographic parameter
ground glass opacities, fibrosis or honey comb appearance or QILD
by at least 2% for whole lung compared to a baseline measurement
resulting in a reversal of the pulmonary radiographic parameter. In
further embodiments, the reduction, stabilization, or reversal in
one or more pulmonary radiographic parameters is achieved in 3
weeks or less, 6 weeks or less, 9 weeks or less, 12 weeks or less,
18 weeks or less, 24 weeks or less, 36 weeks or less, 48 weeks or
less, 12 months or less, 16 months or less, 20 months or less, or
24 months or less from starting treatment with an anti-CTGF
antibody.
[0078] An effective amount of an anti-CTGF antibody also refers to
the amount of an anti-CTGF antibody that is sufficient to produce
an extension in the median progression-free survival or median
overall survival of IPF subjects treated with an anti-CTGF antibody
over the survival seen in IPF subjects that are not treated with an
anti-CTGF antibody. In some embodiments, the extension in median
progression-free survival or median overall survival is produced
with the administration of only an anti-CTGF antibody, while in
other embodiments, the extension in either type of survival is
produced through the combined treatment with an anti-CTGF antibody
and one or more conventional treatments. In some embodiments, the
extension in median progression-free survival or median overall
survival is at least two weeks, 1 month, 2 months, 3 months, 4
months, 5 months, 6 months, 7 months, 8 months, 10 months, 12
months, 14 months, 16 months, 18 months, 20 months, 24 months, 28
months, 32 months, 36 months, 40 months, or 48 months beyond the
median progression-free survival or median overall survival of
conventionally treated IPF patients, i.e., treated with
corticosteroids and/or immunosuppressive drugs or historic
controls, e.g., placebo treated. In particular embodiments, an
effective amount of an anti-CTGF antibody produces a 5-year
survival rate of at least 30%, 35%, 40%, 45% or 50%.
[0079] Further, an effective amount of an anti-CTGF antibody also
refers to the amount of an anti-CTGF antibody that is sufficient to
decrease the risk of death due to IPF. In some embodiments,
treatment with an effective amount of an anti-CTGF antibody reduces
the 1-year risk, 2-year risk, 3-year risk, 4-year risk, 5-year
risk, or 10-year risk of death by at least 5%, 10%, 15% , 20%, 25%,
30%, 35%, 40%, 50%, 60%, 70%, 80%, or 90% compared to
conventionally treated subjects or historic controls, i.e., placebo
treated.
[0080] An effective amount of an anti-CTGF antibody additionally
refers to the amount of an anti-CTGF antibody that is sufficient to
produce one or more of the following: (i) the prevention of a
worsening of dyspnea; (ii) the prevention of the development of new
dyspnea; (iii) the reduction in the frequency or intensity of
coughing; (iv) the prevention of a worsening of hypoxemia; (v) the
reduction in the number or severity of acute exacerbations of IPF;
(vi) the reduction in the number of respiratory-related hospital
admissions; (vii) the reduction in the need for supplemental
oxygen; (viii) the reduction in days of disability; or (ix) the
improvement in the assessment of health-related quality of life
(QoL). In particular embodiments, an effective amount on an
anti-CTGF antibody reduces the frequency or intensity of coughing,
reduces the number or severity of acute exacerbations of IPF,
reduces the number of respiratory-related hospital admissions,
reduces the need for supplemental oxygen and/or reduces the number
of days of disability by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%
compared to conventionally treated subjects or historic controls,
i.e., placebo treated.
[0081] A "prophylactically effective amount" is the amount of an
anti-CTGF antibody that can prevent the onset of one or more
symptoms or functional impairments associated with IPF. In some
embodiments, a prophylactically effective amount of an anti-CTGF
antibody is the amount that is effective in preventing a
pathological rate of decline in one or more pulmonary function
parameters. In other embodiments, a prophylactically effective
amount of an anti-CTGF antibody is the amount that is effective in
preventing the appearance of one or more pulmonary radiographic
parameters.
[0082] Prophylactic administration is warranted in subjects that
are at risk for developing IPF including former and current smokers
and subjects that are genetically predisposed to the development of
IPF, including those subjects that have a family history of IPF. A
prophylactically effective amount of an anti-CTGF antibody used to
prevent the onset of one or more symptoms of IPF can be the same
amount or a different amount from a therapeutically effective
amount of an anti-CTGF antibody. In some embodiments, the
prophylactically effective amount of an anti-CTGF antibody is less
than the therapeutically effective amount.
[0083] In some embodiments, the combination therapy of an anti-CTGF
antibody with one or more other agents provides a synergistic
improvement in therapeutic efficacy relative to the individual
therapeutic agents when administered alone. The term "synergy" is
used to describe a combined effect of two or more active agents
that is greater than the sum of the individual effects of each
respective active agent. Thus, where the combined effect of two or
more agents results in "synergistic inhibition" of an activity or
process, it is intended that the inhibition of the activity or
process is greater than the sum of the inhibitory effects of each
respective active agent. The term "synergistic therapeutic effect"
refers to a therapeutic effect observed with a combination of two
or more therapies wherein the therapeutic effect (as measured by
any of a number of parameters) is greater than the sum of the
individual therapeutic effects observed with the respective
individual therapies.
[0084] By using the term "isolated" to describe an isolated
antibody, antibody fragment, or antibody mimetic, it is intended
that the molecule is not in its natural milieu. No particular level
of purification is required. Recombinantly produced molecules are
considered isolated for purposes of the invention, as are native
molecules, e.g., polyclonal antibodies, that have been separated,
fractionated, or partially or substantially purified by any
suitable technique.
[0085] As used herein, "connective tissue growth factor" and "CTGF"
refer to a matricellular protein belonging to a family of proteins
identified as CCN proteins (Cysteine-rich 61 (Cyr61), Connective
tissue growth factor (CTGF), Nephroblastoma overexpressed (Nov)).
This family contains six distinct members (CYR61 (CCN1), CTGF
(CCN2), NOV (CCN3), WISP-1(wnt-1 inducible secreted protein-1,
CCN4), WISP-2 (CCN5), and WISP-3 (CCN6)) that share a high degree
of amino acid sequence homology. (See, e.g., O'Brian et al. (1990)
Mol Cell Biol 10:3569-3577; Joliot et al. (1992) Mol Cell Biol
12:10-21; Ryseck et al. (1991) Cell Growth and Diff 2:225-233;
Simmons et al. (1989) Proc Natl Acad Sci USA 86:1178-1182; Pennica
et al. (1998) Proc Natl Acad Sci USA, 95:14717-14722; and Zhang et
al. (1998) Mol Cell Biol 18:6131-6141.)
[0086] CTGF may also be referred to within the art as "hypertrophic
chondrocyte-specific protein 24," "insulin-like growth
factor-binding protein," and "CCN2." "CTGF" further refers to a
substantially purified CTGF derived from any species, particularly
a mammalian species, including rat, rabbit, bovine, ovine, porcine,
murine, equine, and hominid, preferably the human species, and from
any source, whether natural, synthetic, semi-synthetic, or
recombinant.
[0087] Although the present invention demonstrates that agents that
inhibit CTGF activity are beneficial in treating IPF and/or
ameliorating one or more symptoms of IPF, the invention
specifically contemplates the inhibition of the activity of other
CCN family members, particularly Cyr61. In some embodiments, an
antibody against Cyr61 is administered to an IPF patient for the
purpose of curing or ameliorating one or more symptoms of IPF.
Antibodies
[0088] The term "antibody" is used in the broadest sense and
specifically covers monoclonal antibodies (including full length
monoclonal antibodies), polyclonal antibodies, multispecific
antibodies (e.g., bispecific antibodies), and antibody fragments,
so long as they exhibit the desired biological activity, and
antibody mimetics.
[0089] The term "monoclonal antibody" as used herein refers to an
antibody obtained from a population of substantially homogeneous
antibodies, i.e., the individual antibodies comprising the
population are identical except for possible mutations, e.g.,
naturally occurring mutations, that may be present in minor
amounts. Thus, the modifier "monoclonal" indicates the character of
the antibody as not being a mixture of discrete antibodies. In
certain embodiments, such a monoclonal antibody typically includes
an antibody comprising a polypeptide sequence that binds a target,
wherein the target-binding polypeptide sequence was obtained by a
process that includes the selection of a single target binding
polypeptide sequence from a plurality of polypeptide sequences. For
example, the selection process can be the selection of a unique
clone from a plurality of clones, such as a pool of hybridoma
clones, phage clones, or recombinant DNA clones. It should be
understood that a selected target binding sequence can be further
altered, for example, to improve affinity for the target, to
humanize the target binding sequence, to improve its production in
cell culture, to reduce its immunogenicity in vivo, to create a
multispecific antibody, etc., and that an antibody comprising the
altered target binding sequence is also a monoclonal antibody of
this invention. In contrast to polyclonal antibody preparations,
which typically include different antibodies directed against
different determinants (epitopes), each monoclonal antibody of a
monoclonal antibody preparation is directed against a single
determinant on an antigen.
[0090] The modifier "monoclonal" indicates the character of the
antibody as being obtained from a substantially homogeneous
population of antibodies, and is not to be construed as requiring
production of the antibody by any particular method. For example,
the monoclonal antibodies to be used in accordance with the present
invention may be made by a variety of techniques, including, for
example, the hybridoma method (e.g., Kohler and Milstein, Nature,
256:495-97 (1975); Harlow et al., Antibodies: A Laboratory Manual
(Cold Spring Harbor Laboratory Press, 2nd ed. 1988); recombinant
DNA methods (see, e.g., U.S. Pat. No. 4,816,567); phage-display
technologies (see, e.g., Clackson et al., Nature, 352: 624-628
(1991); Marks et al., J Mol Biol 222: 581-597 (1992); and Lee et
al., J Immunol Methods 284(1-2): 119-132(2004)), and technologies
for producing human or human-like antibodies in animals that have
parts or all of the human immunoglobulin loci or genes encoding
human immunoglobulin sequences (see, e.g., WO 1998/24893; WO
1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et al., Proc
Natl Acad Sci USA 90: 2551 (1993); U.S. Pat. Nos. 5,545,807;
5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016).
[0091] Monoclonal antibodies specifically include "chimeric"
antibodies in which a portion of the heavy and/or light chain is
identical with or homologous to corresponding sequences in
antibodies derived from a particular species or belonging to a
particular antibody class or subclass, while the remainder of the
chain(s) is identical with or homologous to corresponding sequences
in antibodies derived from another species or belonging to another
antibody class or subclass (see, e.g., U.S. Pat. No. 4,816,567; and
Morrison et al., Proc Natl Acad Sci USA 81:6851-6855 (1984)).
[0092] "Humanized" forms of non-human (e.g., murine) antibodies are
chimeric antibodies that contain minimal sequence derived from
non-human immunoglobulin. In some embodiments, a humanized antibody
is a human immunoglobulin (recipient antibody) in which residues
from a one or more hypervariable regions (HVRs) of the recipient
are replaced by residues from one or more HVRs of a non-human
species (donor antibody) such as mouse, rat, rabbit, or nonhuman
primate having the desired specificity, affinity, and/or capacity.
For further details, see, e.g., Jones et al., Nature 321:522-525
(1986); Riechmann et al., Nature 332:323-329 (1988); and U.S. Pat.
Nos. 6,982,321 and 7,087,409.
[0093] A "human antibody" is one which possesses an amino acid
sequence which corresponds to that of an antibody produced by a
human and/or has been made using any of the techniques for making
human antibodies (see e.g., Hoogenboom and Winter, J. Mol. Biol.,
227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991);
Boerner et al., J. Immunol., 147(1):86-95 (1991); Li et al., Proc.
Natl. Acad. Sci. USA, 103:3557-3562 (2006) and U.S. Pat. Nos.
6,075,181 and 6,150,584).
[0094] A "naked antibody" for the purposes herein is an antibody
that is not conjugated to a cytotoxic moiety or radiolabel. In some
embodiments, the anti-CTGF antibody is a naked antibody.
[0095] The anti-CTGF antibodies of the invention may be specific
for CTGF endogenous to the species of the subject to be treated or
may be cross-reactive with CTGF from one or more other species. In
some embodiments, the antibody for use in the present methods is
obtained from the same species as the subject in need. In other
embodiments, the antibody is a chimeric antibody wherein the
constant domains are obtained from the same species as the subject
in need and the variable domains are obtained from another species.
For example, in treating a human subject the antibody for use in
the present methods may be a chimeric antibody having constant
domains that are human in origin and variable domains that are
mouse in origin. In preferred embodiments, the antibody for use in
the present methods binds specifically to the CTGF endogenous to
the species of the subject in need. Thus, in certain embodiments,
the antibody is a human or humanized antibody, particularly a
monoclonal antibody, that specifically binds human CTGF (GenBank
Accession No. NP_001892).
[0096] Exemplary antibodies for use in the IPF treatment methods of
the present invention are described, e.g., in U.S. Pat. No.
5,408,040; PCT/US1998/016423; PCT/US1999/029652 and International
Publication No. WO 99/33878. Preferably, the anti-CTGF antibody for
use in the IPF treatment method is a monoclonal antibody.
Preferably the antibody is a neutralizing antibody. In particular
embodiments, the antibody is the antibody described and claimed in
U.S. Pat. Nos. 7,405,274 and 7,871,617. In some embodiments, the
antibody for treatment of IPF has the amino acid sequence of the
antibody produced by the cell line identified by ATCC Accession No.
PTA-6006. In other embodiments, the antibody binds to CTGF
competitively with an antibody produced by ATCC Accession No.
PTA-6006. In further embodiments, the antibody binds to the same
epitope as the antibody produced by ATCC Accession No. PTA-6006. A
particular antibody for use in the IPF treatment methods is CLN1 or
mAb1 as described in U.S. Pat. No. 7,405,274, or an antibody
substantially equivalent thereto or derived therefrom. In some
embodiments, the anti-CTGF antibody is CLN1, an antibody identical
to the antibody produced by the cell line identified by ATCC
Accession No. PTA-6006 that is encompassed by the claims of U.S.
Pat. Nos. 7,405,274 and 7,871,617.
[0097] As referred to herein, the phrase "an antibody that
specifically binds to CTGF" includes any antibody that binds to
CTGF with high affinity. Affinity can be calculated from the
following equation:
Affinity = K a = [ Ab Ag ] [ Ab ] [ Ag ] = 1 K d ##EQU00001##
where [Ab] is the concentration of the free antigen binding site on
the antibody, [Ag] is the concentration of the free antigen, [AbAg]
is the concentration of occupied antigen binding sites, K.sub.a is
the association constant of the complex of antigen with antigen
binding site, and Ka is the dissociation constant of the complex. A
high-affinity antibody typically has an affinity at least on the
order of 10.sup.8 M.sup.-1, 10.sup.9 M.sup.-1 or 10.sup.10
M.sup.-1. In particular embodiments, an antibody for use in the
present methods will have a binding affinity for CTGF between of
10.sup.8 M.sup.-1 and 10.sup.10 M.sup.-1, between 10.sup.8 M.sup.-1
and 10.sup.9 M.sup.-1 or between 10.sup.9M.sup.-1 and 10.sup.10
M.sup.-1. In some embodiments the high-affinity antibody has an
affinity of about 10.sup.8 M.sup.-1, 10.sup.9 M.sup.-1 or 10.sup.10
M.sup.-1.
[0098] "Antibody fragments" comprise a functional fragment or
portion of an intact antibody, preferably comprising an antigen
binding region thereof A functional fragment of an antibody will be
a fragment with similar (not necessarily identical) specificity and
affinity to the antibody which it is derived. Non-limiting examples
of antibody fragments include Fab, F(ab').sub.2, and Fv fragments
that can be produced through enzymatic digestion of whole
antibodies, e.g., digestion with papain, to produce Fab fragments.
Other non-limiting examples include engineered antibody fragments
such as diabodies (Holliger P et al. Proc Natl Acad Sci USA. 1993,
90: 6444-6448); linear antibodies (Zapata et al. 1995 Protein Eng,
8(10):1057-1062); single-chain antibody molecules (Bird K D et al.
Science, 1988, 242: 423-426); single domain antibodies, also known
as nanobodies (Ghahoudi M A et al. FEBS Lett. 1997, 414: 521-526);
domain antibodies (Ward E S et al. Nature. 1989, 341: 544-546); and
multispecific antibodies formed from antibody fragments.
Antibody Mimetics
[0099] Antibody mimetics are proteins, typically in the range of
3-25 kD, that are designed to bind an antigen with high specificity
and affinity like an antibody, but are structurally unrelated to
antibodies. Frequently, antibody mimetics are based on a structural
motif or scaffold that can be found as a single or repeated domain
from a larger biomolecule. Examples of domain-derived antibody
mimetics include AdNectins that utilize the 10th fibronectin III
domain (Lipov k D. Protein Eng Des Sel, 2010, 24:3-9); Affibodies
that utilize the Z domain of staphylococcal protein A (Nord K et
al. Nat Biotechnol. 1997, 15: 772-777), and DARPins that utilize
the consensus ankyrin repeat domain (Amstutz P. Protein Eng Des
Sel. 2006, 19:219-229). Alternatively, antibody mimetics can also
be based on the entire structure of a smaller biomolecule, such as
Anticalins that utilize the lipocalin structure (Beste G et al.
Proc Natl Acad Sci USA. 1999, 5:1898-1903). In some embodiments,
the anti-CTGF antibody is an antibody mimetic.
Pharmaceutical Compositions
[0100] The anti-CTGF antibodies, including antibody fragments and
antibody mimetics, used in the methods of the present invention can
be delivered directly or in pharmaceutical compositions containing
carriers and/or excipients, as is well known in the art. The
anti-CTGF antibodies may be administered intravenously as a bolus
or by continuous infusion over a period of time. Alternately, the
anti-CTGF antibodies may be administered by intramuscular,
subcutaneous, intradermal, subdermal or intraperitoneal injection,
topical administration, oral administration or by inhalation. The
route of administration may influence the type and composition of
the formulation used in the anti-CTGF antibody preparation.
Pharmaceutical compositions of particular interest include
compositions suitable for injectable use and compositions suitable
for nebulization or aerosolization.
[0101] The composition can be a liquid solution, suspension,
emulsion, tablet, pill, capsule, sustained release formulation,
powder, or lyophilized cake. Injectable forms include sterile
aqueous solutions, dispersions and sterile powders for the
extemporaneous preparation of sterile injectable solutions or
dispersions.
[0102] Anti-CTGF antibody formulations for use in accordance with
the present invention may be prepared by mixing an anti-CTGF
antibody with pharmaceutically acceptable carriers, excipients or
stabilizers that are nontoxic to subjects at the dosages and
concentrations employed. Anti-CTGF antibody formulations may
include buffers such as phosphate, citrate, and other organic
acids; antioxidants including ascorbic acid and methionine;
preservatives such as octadecyldimethylbenzyl ammonium chloride,
hexamethonium chloride, benzalkonium chloride, benzethonium
chloride, phenol, or benzyl alcohol; alkyl parabens including
methyl or propyl paraben, catechol, resorcinol, cyclohexanol,
3-pentanol, and m-cresol; carriers; hydrophilic polymers such as
polyvinylpyrrolidone; monosaccharides, disaccharides, and other
carbohydrates including glucose, mannose, or dextrins; chelating
agents such as EDTA; sugars such as sucrose, mannitol, trehalose or
sorbitol; salt-forming counter-ions such as sodium; metal
complexes; and/or non-ionic surfactants or polyethylene glycol.
[0103] In particular, anti-CTGF antibody formulations may further
comprise low molecular weight polypeptides; carriers such as serum
albumin, gelatin, or immunoglobulins; and amino acids such as
glycine, glutamine, asparagine, histidine, arginine, or lysine. The
anti-CTGF antibody formulations can be lyophilized as described in
PCT/US1996/012251. Additionally, sustained-release preparations may
also be prepared. Frequently, polymers such as poly(lactic acid),
poly(glycolic acid), or copolymers thereof serve as
controlled/sustained release matrices, in addition to others well
known in the art.
[0104] Numerous other pharmaceutically acceptable carriers,
excipients, and stabilizers are available in the art, some of which
are listed in various pharmacopoeias, e.g., US Pharmacopeia,
Japanese Pharmacopeia, European Pharmacopeia, and British
Pharmacopeia. Other sources include Gennaro, ed. (2000) Remington's
Pharmaceutical Sciences, supra; and Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 10.sup.th Ed. (2001),
Hardman, Limbird, and Gilman, eds. MacGraw Hill Intl.; the Inactive
Ingredient Search database maintained by the FDA and the Handbook
of Pharmaceutical Additives, ed. Ash, Synapse Information
Resources, Inc., 3rd Ed. 2007.
[0105] Compositions formulated for parenteral administration by
injection are usually sterile and can be presented in unit dosage
forms, e.g., in ampoules, syringes, injection pens, or in
multi-dose containers, the latter usually containing a
preservative. In certain instances, such as with a lyophilized
product or a concentrate, the parenteral formulation would be
reconstituted or diluted prior to administration.
[0106] The anti-CTGF antibodies can be supplied or administered at
any desired concentration. In some embodiments, the anti-CTGF
antibody concentration is at least 1 mg/ml, 5 mg/ml, 10 mg/ml, 20
mg/ml, 25 mg/ml, 50 mg/ml, 75 mg/ml, 100 mg/ml, 125 mg/ml, 150
mg/ml, or 200 mg/ml. In other embodiments, the anti-CTGF antibody
concentration is no more than about 5 mg/ml, 10 mg/ml, 20 mg/ml, 25
mg/ml, 50 mg/ml, 75 mg/ml, 100 mg/ml, 125 mg/ml, 150 mg/ml, 200
mg/ml, 250 mg/ml, or 300 mg/ml. In further embodiments, the
anti-CTGF antibody concentration is between 5 mg/ml to 20 mg/ml, 20
mg/ml to 50 mg/ml, 50 mg/ml to 100 mg/ml, 100 mg/ml to 200 mg/ml,
or 200 mg/ml to 300 mg/ml.
Dosage
[0107] A therapeutically effective amount of an anti-CTGF antibody
can be administered in one or more administrations, applications or
dosages. The skilled artisan will appreciate that certain factors
may influence the dosage and timing required to effectively treat a
subject, including but not limited to the severity or extent of the
disease, the administration route, previous treatments, concurrent
medications, performance status, weight, gender, race or ethnicity,
and/or age of the subject.
[0108] In some embodiments, the method for treating IPF in a
subject in need thereof comprises administering at least 0.5 g, at
least 1.0 g, at least 1.5 g, at least 2.0 g, at least 2.5 g, or at
least 3.0 g of an anti-CTGF antibody per a one, two, or three week
period. In specific embodiments, the anti-CTGF antibody is
administered at a dose of about 1.05 g or about 2.1 g every three
weeks, based on a 70 kg standard man.
[0109] In a further embodiment, the method for treating IPF in a
subject in need thereof comprises administering at least 10 mg/kg,
15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or 60
mg/kg of an anti-CTGF antibody per a per a one, two, or three week
period. In particular embodiments, the anti-CTGF antibody is
administered at a dose of about 15 mg/kg or about 30 mg/kg every
three weeks.
[0110] In some embodiments, a method for treating IPF presented
herein involves the administration to a subject in need thereof of
an anti-CTGF antibody at a dose that achieves a target plasma
concentration of the anti-CTGF antibody in the subject. In some
embodiments, the target plasma concentration of an anti-CTGF
antibody is a maximum antibody concentration (C.sub.max) in the
plasma, typically seen immediately after i.v. administration to the
subject. In particular embodiments, the method for treating IPF
achieves a C.sub.max of at least 10 .mu.g/ml, 50 .mu.g/ml, 100
.mu.g/mL, 200 .mu.g/mL, 300 .mu.g/mL, or 400 .mu.g/mL.
[0111] In other embodiments, the target plasma concentration is a
minimum antibody concentration (C.) in the plasma, also known as a
trough antibody concentration, that is typically measured
immediately before a subsequent antibody administration to the
subject. In some embodiments, the C.sub.min plasma concentration of
the anti-CTGF antibody is at least 0.1 .mu.g/ml, 1.0 .mu.g/ml, 5
.mu.g/ml, 10 .mu.g/mL, 20 .mu.g/ml, 30 .mu.g/ml, 40 .mu.g/ml, 50
.mu.g/ml, 60 .mu.g/ml, 70 .mu.g/ml, 80 .mu.g/ml, 90 .mu.g/ml, 100
.mu.g/ml, 125 .mu.g/ml, 150 .mu.g/ml, 200 .mu.g/ml, 300 .mu.g/ml,
or 400 .mu.g/ml. In further embodiments, C.sub.min is measured for
a treatment cycle of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 28 days. In a
particular embodiment, the C.sub.min is at least 10.0 .mu.g/mL when
measured at about 21 days after administration of an anti-CTGF
antibody dose.
[0112] In further embodiments, a method for treating IPF in a
subject in need thereof comprises the administration of an
anti-CTGF antibody at a dose that achieves a target antibody
exposure (area under the curve, AUC) over a specific time period.
Typically, AUC is expressed as .mu.g*h/ml. In some embodiments, a
method for treating IPF in a subject in need thereof comprises the
administration to a subject an anti-CTGF antibody at a dose that
achieves an AUC in plasma of at least 1,000 .mu.g*h/ml, 10,000
.mu.g*h/ml, 25,000 .mu.g*h/ml, 50,000 .mu.g*h/ml, 60,000
.mu.g*h/ml, 80,000 .mu.g*h/ml, 100,000 .mu.g*h/ml, 120,000
.mu.g*h/ml, or 140,000 .mu.g*h/ml. In some embodiments, the AUC is
calculated from about 0-4 days, 0-5 days, 0-6 days, 0-7 days, 0-8
days, 0-9 days, 0-10 days, 0-11 days, 0-12 days, 0-13 days, 0-14
days, 0-16 days, 0-18 days 0-21 days, or 0-28 days. In a particular
embodiment, the AUC is at least 1,000 .mu.g*h/ml when measured from
0-21 days post-administration (AUC.sub.0-21).
[0113] To achieve or exceed a desired plasma anti-CTGF antibody
concentration, i.e., C.sub.max, C.sub.min, or AUC, an anti-CTGF
antibody or a pharmaceutical composition thereof may be
administered at a dose from 0.5 mg/kg to 60 mg/kg, i.e., 0.5 mg of
an anti-CTGF antibody/kg patient body weight to 60 mg of an
anti-CTGF antibody/kg patient body weight, depending upon the route
of administration. In particular embodiments, a desired plasma
anti-CTGF antibody concentration can be achieved or exceeded with
an i.v. administration of a dose of at least 5 mg/kg, 10 mg/kg 15
mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg,
50 mg/kg, or 60 mg/kg. In specific embodiments, a desired plasma
anti-CTGF antibody concentration can be achieved or exceeded with
an administration of an anti-CTGF antibody at a dose of about 15
mg/kg or 30 mg/kg.
[0114] In some embodiments, the patient is treated for a minimum of
2 weeks, 3 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 15weeks, 18
weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 36 weeks, 40 weeks,
48 weeks, 1 year, or 2 years. In other embodiments, the patient is
treated every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks,
8 weeks, 10 weeks, or 12 weeks as indicated by the patient's
healthcare practitioner. In additional embodiments, the patient is
treated for a maximum of 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18
weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 36 weeks, 40 weeks,
48 weeks, 1 year, 2 years, 3 years, 4 years, or 5 years. In further
embodiments, the treatment duration is between 1 week to 24 weeks,
24 weeks to 48 weeks, 48 weeks to 2 years, 3 weeks to 2 years or 3
weeks to 3 years.
[0115] In some embodiments, the subject's anti-CTGF antibody plasma
concentration is titrated, i.e., the anti-CTGF antibody dose may be
adjusted so to achieve or exceed a target plasma concentration that
is associated with a desired therapeutic response. In some
embodiments, a method is provided for treating IPF in a subject in
need thereof comprising: a) administering a first dose of an
anti-CTGF antibody; b) measuring a first anti-CTGF antibody plasma
concentration in the patient; c) comparing the first anti-CTGF
antibody plasma concentration to a first target anti-CTGF antibody
plasma concentration; and d) administering a second dose of the
anti-CTGF antibody calculated to achieve or exceed the first target
anti-CTGF antibody plasma concentration when a second measurement
of anti-CTGF antibody plasma concentration is performed at
substantially the same time interval post-administration as the
measurement of the first antibody plasma concentration. In
particular embodiments, the first target anti-CTGF antibody plasma
concentration is 0.1 .mu.g/ml, 1.0 .mu.g/ml, 5 .mu.g/ml, 10
.mu.g/mL, 20 .mu.g/mL, or 40 .mu.g/mL when measured 21 days
post-administration.
[0116] In some embodiments, the anti-CTGF antibody is administered
at least two times with the first dose being a loading dose and the
second and subsequent doses being maintenance doses. The term
"loading dose" as used herein refers to an initial antibody dose
administered within a set time period to rapidly achieve a desired
therapeutic antibody concentration or associated therapeutic
effect.
[0117] In some embodiments, the loading dose is at least 1 mg/kg, 5
mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 20 mg/kg, 22.5 mg/kg, 25
mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg,
75 mg/kg, or 100 mg/kg. In other embodiments, the loading dose is
the antibody dose that is sufficient to achieve an antibody
concentration in plasma of at least 0.1 .mu.g/ml, 1.0 .mu.g/ml, 5
.mu.g/ml, 10 .mu.g/ml, 20 .mu.g/ml, 25 .mu.g/ml, 30 .mu.g/ml, 40
.mu.g/ml, 50 .mu.g/ml, 60 .mu.g/ml, 75 .mu.g/ml, 75 .mu.g/ml, 100
.mu.g/ml, 125 .mu.g/ml, 150 .mu.g/m, or 200 .mu.g/ml when measured
about 21 days post-administration (C.sub.min).
[0118] The term "maintenance dose" as used herein refers to an
antibody dose sufficient to maintain a desired therapeutic antibody
concentration or associated therapeutic effect that was achieved
with the loading dose. For example, a maintenance dose may maintain
a reduction, stabilization or reversal in the pathologic rate of
decline in FVC that was achieved with a loading dose. Typically,
the maintenance dose is lower than the loading dose.
[0119] In some embodiments, the maintenance dose is administered at
least about 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 20, or 24 weeks
post-administration of the loading dose. In other embodiments, the
maintenance dose is administered no more than about 1, 2, 3, 4, 5,
6, 7, 8, 10, 12, 16, 20, or 24 weeks post-administration of the
loading dose. In further embodiments, the maintenance dose is
administered within about 1 to 2 weeks, 1 to 3 weeks, 1 to 4 weeks,
1 to 6 weeks, 1 to 8 weeks, 2 to 10 weeks, 6 to 12 weeks, 10 to 20
weeks, or 12 to 25 weeks post-administration of the loading
dose.
[0120] In some embodiments, the anti-CTGF antibody or a
pharmaceutical composition comprising the antibody is administered
through a bolus injection intravenously. In other embodiments, the
anti-CTGF antibody is administered as an infusion that can be for a
duration of not less than 10 minutes, 20 minutes, 30 minutes, 1
hour, 2 hours, 4 hours, or 8 hours. In further embodiments, the
anti-CTGF antibody is administered subcutaneously in a concentrated
form. In other embodiments, the anti-CTGF antibody is administered
as an aerosolized powder or a nebulized solution for
inhalation.
[0121] In specific embodiments, a method for treating IPF presented
herein involves the administration to a subject in need thereof of
an anti-CTGF antibody or a pharmaceutical composition thereof at a
dosage and/or a frequency of administration that produces a
functional outcome, e.g,. reversal of decline in FVC. In other
embodiments, a method for treating IPF presented herein involves
the administration to a subject in need thereof of an anti-CTGF
antibody or a pharmaceutical composition thereof at a dosage and/or
a frequency of administration that produces an outcome that can be
imaged such as a reduction or reversal in a pulmonary radiographic
parameter or inflammation, as assessed by HRCT scan, chest x-ray,
histopathologically, or another modality.
Subjects Suitable for Treatment
[0122] The methods of the invention are appropriate for the
treatment of subjects diagnosed with IPF or UIP using any method
recognized in the art including HRCT, chest x-rays, transbronchial
biopsy and/or surgical lung biopsy. The methods of the invention
are also appropriate for the treatment of subjects suspected of
having IPF based on the presence of one or more characteristics
known in the art to be indicative of the presence of IPF. These
characteristics include progressive dyspnea and cough, bibasilar
inspiratory crackles, digital clubbing, and non-specific bilateral,
reticular infiltrates in the periphery of the lower lung zones
visible on a chest radiograph. Further characteristics indicative
of IPF include reduced lung volumes, a proportionate reduction in
the pulmonary diffusing capacity or a normal to increased FEV1/FVC
ratio demonstrated in pulmonary function tests. Other
characteristics indicative of IPF include resting arterial blood
hypoxemia, oxyhaemoglobin desaturation, or an increased
alveolar-arterial oxygen pressure difference, any of which may
worsen with exercise. Additional abnormalities during exercise that
may indicate the presence of IPF include reduced peak oxygen
consumption, diminished ventilatory reserve, high-frequency/low
tidal volume breathing pattern, and high submaximal ventilation
related in part to elevated physiologic dead space and arterial
desaturation. A further characteristic indicative for IPF is the
presence of pulmonary hypertension.
[0123] In some embodiments, one or more of the following pulmonary
function parameters are used to select subjects for therapy with an
anti-CTGF antibody or to monitor response to anti-CTGF antibody
therapy: VC, FVC, FVC % predicted, RV, FEV, PEFR, IRV, FIF, FRC,
IC, TLC, ERV, TV, or MVV. In particular embodiments, the pulmonary
function parameters TLC, FVC, and FVC % predicted are used to
select and/or monitor subjects.
[0124] Subjects that are particularly suited for treatment with the
method of the invention are those that have a FVC % predicted value
of at least 35%, 40%, 45%, 50%, 55%, 60%, 63%, 65%, 70%, 75%, 80%,
85%, 90%, or 95% of a normal person of similarly matched race or
ethnicity, gender, age, height and weight. In other embodiments,
subjects suitable for treatment with the method of the invention
are those that have a FVC % predicted value of not more than 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. In
further embodiments, subjects suitable for treatment have a FVC %
predicted value of between 40% to 95%, 50% to 90%, 55% to 85%, 60%
to 80%, 55% to 80%, 60% to 70%, 70% to 90%, 60% to 90%, or 70% to
95%. In particular embodiments, the subjects have a FVC % predicted
value of about 55%-85%.
[0125] Additional subjects that are particularly suited to
treatment with the method of the invention are those that have at
least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%
of the predicted TLC of a normal person of similarly matched race
or ethnicity, gender, age, height and weight. In other embodiments,
subjects suitable for treatment with the method of the invention
are those that have a not more than 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, or 95% of the predicted TLC. In further
embodiments, subjects suitable for treatment have between 40% to
95%, 45% to 90%, 50% to 85%, 55% to 85%, 50% to 70%, 60% to 80%, or
70% to 95% of the predicted TLC.
[0126] Further subjects that are particularly suited to treatment
with the method of the invention are those that have at least 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the
predicted FEV1 of a normal person of similarly matched race or
ethnicity, gender, age, height and weight. In other embodiments,
subjects suitable for treatment with the method of the invention
are those that have a not more than 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, or 95% of the predicted FEV1. In further
embodiments, subjects suitable for treatment have between 40% to
95%, 45% to 90%, 50% to 85%, 55% to 85%, 50% to 70%, 60% to 80%, or
70% to 95% of the predicted FEV1.
[0127] In further embodiments, the subjects suitable for treatment
with an anti-CTGF antibody have a pathologic rate of decline in one
or more pulmonary function parameters of at least 5%, 10%, 15%,
20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 200%,
300%, 400%, 500%, 600%, 700%, 800% or 1,000% over the expected rate
of decline for a normal person of similarly matched race or
ethnicity, gender, age, height and weight.
[0128] Subjects that are particularly suited for treatment with the
method of the invention further include those that have a DLCO %
predicted value corrected for blood hemoglobin of at least 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or
95%. In other embodiments, subjects suitable for treatment with the
method of the invention are those that have a DLCO % predicted
value corrected for blood hemoglobin of at least 25%, but not more
than 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.
In further embodiments, subjects suitable for treatment have a DLCO
% predicted value corrected for blood hemoglobin between 30% to
95%, 40% to 90%, 45% to 85%, 50% to 90% or 60% to 80%.
[0129] Additional subjects that are particularly suited for
treatment with the method of the invention are those that have a
SaO.sub.2 of at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%,
95%, 96%, 97%, 98%, or 99%. In other embodiments, subjects suitable
for treatment with the method of the invention are those that have
a SaO.sub.2 of at least 70%, but not more than 80%, 85%, 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In further embodiments,
subjects suitable for treatment have a SaO.sub.2 of between 70% to
95%, 70% to 99%, or 80% to 99%.
[0130] Other subjects that are particularly suited for treatment
with the method of the invention are those that have a [A-a]
PO.sub.2 of at least 10 mmHg, 20 mmHg, 30 mmHg, 40 mmHg, 50 mmHg,
75 mmHg, 100 mmHg, 125 mmHg, 150 mmHg, 175 mmHg, 200 mmHg, or 250
mmHg. In other embodiments, subjects suitable for treatment have a
[A-a] PO.sub.2 between 10 mmHg to 50 mmHg, 10 mmHg to 100 mmHg, 10
mmHg to 200 mmHg, 20 mmHg to 250 mmHg, 50 mmHg to 250 mmHg, or 100
mmHg to 250 mmHg.
[0131] Further subjects that are particularly suited to treatment
with the method of the invention are those subjects that are not
more than 20 years old, 25 years old, 30 years old, 35 years old,
40 years old, 45 years old, 50 years old, 55 years old, 60 years
old, 65 years old, 70 years old, 75 years old, 80 years old, 85
years old, or 90 years old. In other embodiments, subjects that are
particularly suited to treatment with the method of the invention
are those subjects that are not less than 20 years old, 25 years
old, 30 years old, 35 years old, 40 years old, 45 years old, 50
years old, 55 years old, 60 years old, 65 years old, 70 years old,
75 years old, 80 years old, 85 years old, or 90 years old. In
further embodiments, subjects that are particularly suited to
treatment with the method of the invention are those subjects that
are between 30 years old to 80 years old, 40 years old to 90 years
old, 50 years old to 100 years old or 55 years old to 95 years
old.
[0132] The methods are also suitable for the treatment of subjects
with IPF who were previously treated with conventional therapies,
including corticosteroids and/or immunosuppressive drugs, and
failed to respond.
[0133] The methods of the invention are additionally suitable for
subjects who are at risk of developing IPF. Those at risk include
former and current smokers; those of the male gender; those with an
age of 60 years or more; those with gastroesophageal reflux disease
or those with a genetic predisposition for developing IPF.
Combination Therapy
[0134] In some embodiments, the methods for treating IPF provided
herein involve administration of an anti-CTGF antibody in
combination with one or more additional therapies. As used herein,
the term "in combination" refers to the administration of the
anti-CTGF antibody prior to, concurrent with, or subsequent to the
administration of one or more additional therapies for use in
treating IPF. The use of the term "in combination" does not
restrict the order in which the anti-CTGF antibody and the one or
more additional therapies are administered to a subject. The
additional therapies may be administered by the same route or a
different route of administration than used for the anti-CTGF
antibody.
[0135] Current drug therapies for IPF include the administration of
anti-inflammatories and immunosuppressives. Anti-inflammatory drugs
include corticosteroids such as beclomethasone, betamethasone,
budesonide, clobetasol, flunisolide, fluocinolone, fluocinonide,
fluticasone, halobetasol, hydrocortisone, methylprednisolone,
mometasone, prednisolone, prednisone, and triamcinolone. In some
embodiments, the corticosteroid is administered as an aerosol,
while, in other embodiments, the corticosteroid is administered
orally. In particular embodiments, an anti-CTGF antibody is
administered in combination with prednisone.
[0136] Anti-inflammatory drugs further include non-steroidal
anti-inflammatories (NSAIDs) such as non-selective COX inhibitors
and selective COX-2 inhibitors. Non-selective COX inhibitors
include but are not limited to salicylic acid derivatives (e.g.,
aspirin, sodium salicylates, choline magnesium trisalicylate,
salsalate, diflunisal, sulfasalazine, mesalamine and olsalazine),
para-aminophenol derivatives (e.g., acetaminophen), indole and
indene acetic acids (e.g., tolmetin, diclofenac, and ketorolac),
heteroaryl acetic acids (e.g., abuprofen, flurbiprofen, ketoprofen,
fenprofen, ibuprofen, naproxen, and oxaprozin), anthranilic acids
or fenamates (e.g., mefenamic acid and meclofenamic acid), enolic
acids (e.g., oxicams such as piroxicam and meloxicam), and
alkanones (e.g., nabumetone). Selective COX-2 inhibitors include,
but are not limited to, diaryl-substituted furanones (e.g.,
rofecoxib), diaryl-substituted pyrazoles (e.g., celecoxib), indole
acetic acids (e.g., etodolac), and sulfonanilides (e.g.,
nimesulide).
[0137] In further embodiments, the methods of the invention include
the administration of an anti-CTGF antibody in combination of with
one or more TNF inhibitors that include, but are not limited to,
etanercept (Enbrel.RTM.), adalimumab (HUMIRA.RTM.), or infliximab
(Remicade.RTM.).
[0138] Examples of immunosuppressive drugs that can be administered
in combination with anti-CTGF antibodies include, but are not
limited to, methotrexate, cyclophosphamide, mizoribine,
chlorambucil, cyclosporine, tacrolimus (FK506; ProGraf.TM.),
mycophenolate mofetil (CellCept.RTM.), azathioprine
(6-mercaptopurine), sirolimus (rapamycin), deoxyspergualin,
leflunomide, and its malononitriloamide analogs. In some
embodiments, the anti-CTGF antibody is administered in combination
with azathioprine. In other embodiments, one or more
immunosuppressive drugs are administered as an aerosol. (See U.S.
Pat. No. 8,158,110.)
[0139] In some embodiments, the anti-CTGF antibodies may be
administered in combination with one or more antioxidants.
Antioxidant agents include, but are not limited to, glutathione,
taurine, niacin, and N-acetylcysteine (NAC). In particular
embodiments, the anti-CTGF antibody is administered in combination
with NAC. In further embodiments, the anti-CTGF antibodies may be
administered in combination with one or more anti-fibrotic agents,
including, but not limited to, colchicine, relaxin, halfuginone,
suramin, prostaglandin E2, or d-penicillamine.
[0140] In further embodiments, an anti-CTGF antibody is
administered in combination with at least one additional
therapeutic agent selected from the group consisting of:
pirfenidone (Esbriet.RTM.); intedanib (Vargatef.RTM.); an
anti-(human monocyte chemoattractant protein-1) antibody, e.g.,
Carlumab; an anti-IL13 antibody, e.g., QAX-576, thalidomide; a
c-Jun N-terminal kinase (JNK) inhibitor, e.g., CC-930; an anti-CD
20 antibody, e.g., Rituximab.RTM., interferon-gamma 1b
(Actimmune.RTM.); imatinib mesylate (Gleevac.RTM.); inhaled carbon
monoxide; azathioprine; an anti-TGF-.beta. antibody, e.g., GC1008;
recombinant human serum amyloid P/pentraxin 2 (PRM-151); placental
mesenchymal stem cells; minocycline; an anti-lysyl oxidase-like 2
(LOXL20) antibody, e.g., GS 6624; a 5-lipoxygenase inhibitor, e.g.,
Zileuton.RTM.; octreotide (Sandostatin.RTM.); a copper chelating
agent (tetrathiomolybdate); an endothelin receptor antagonist,
e.g., bosentan; a lysophosphatidic acid 1 (LPA1) receptor
antagonist, e.g., AM152; and an angiotensin II receptor
antagnonist, e.g., Losartan.RTM.. Combination treatment further
includes the aerosolized administration of an additional agent,
such as interferon-y (U.S. patent application Ser. No.
12/319851).
[0141] In specific embodiments, the interval of time between the
administration of an anti-CTGF antibody and the administration of
one or more additional therapies may be about 0 to 15 minutes, 0 to
30 minutes, 30 minutes to 60 minutes, 1 to 2 hours, 2 to 6 hours, 2
to 12 hours, 12 to 24 hours, 1 to 2 days, 2 to 4 days, 4 to 7 days,
1 to 2 weeks, 2 to 4 weeks, 4 to 12 weeks, 12 to 24 weeks, or 24 to
52 weeks. In certain embodiments, an anti-CTGF antibody and one or
more additional therapies are administered less than 1 day, 1 week,
2 weeks, 3 weeks, 4 weeks, one month, 2 months, 3 months, 6 months,
or 1 year apart.
[0142] In certain embodiments, the anti-CTGF antibody is
administered in combination with a medication for controlling or
relieving symptoms associated with IPF. In some embodiments, the
symptom associated with IPF is coughing, gastroesophageal reflux
disease (GERD), weight loss, fatigue, or malaise. In further
embodiments, the anti-CTGF antibody is administered in combination
with pulmonary rehabilitation that may include exercise,
nutritional counseling, smoking cessation counseling, psychological
counseling, group counseling, breathing techniques, or techniques
for conserving energy. In other embodiments, the anti-CTGF antibody
is administered in combination with oxygen therapy or supplemental
oxygen. In further embodiments, the anti-CTGF antibody is
administered in combination with immunization to prevent influenza
or pneumnococcal infection.
[0143] In some embodiments, the interval of time between the
administration of an anti-CTGF antibody and the administration of
one or more supportive or symptomatic therapies may be about 0 to
15 minutes, 0 to 30 minutes, 30 minutes to 60 minutes, 1 to 2
hours, 2 to 6 hours, 2 to 12 hours, 12 to 24 hours, 1 to 2 days, 2
to 4 days, 4 to 7 days, 1 to 2 weeks, 2 to 4 weeks, 4 to 12 weeks,
12 to 24 weeks, or 24 to 52 weeks. In certain embodiments, an
anti-CTGF antibody and one or more support or symptomatic therapies
for IPF symptoms are administered less than 1 day, 1 week, 2 weeks,
3 weeks, 4 weeks, one month, 2 months, 3 months, 6 months, or 1
year apart.
[0144] In some embodiments, the administration of an anti-CTGF
antibody and one or more additional therapies have an additive
effect, while in other embodiments the combination of therapies
have a synergistic effect. In specific embodiments, a synergistic
effect of a combination therapy permits the use of lower dosages
(e.g., sub-optimal conventional doses) of the additional therapy,
e.g., prednisone. In other embodiments, the synergistic effect of a
combination therapy allows for a less frequent administration of
the additional therapy to a subject. In certain embodiments, the
ability to utilize lower dosages of an additional therapy and/or to
administer the additional therapy less frequently reduces the
toxicity associated with the administration of the additional
therapy, without reducing the efficacy of the additional therapy.
In some embodiments, a synergistic effect results in improved
efficacy of an anti-CTGF antibody and/or the additional therapies
in treating IPF. In some embodiments, the treatment method reduces,
stabilizes or reverses pulmonary fibrosis in a subject with IPF
without producing the number or severity of adverse events that are
associated with the use of corticosteroids or immunosuppressive
agents.
[0145] The combination of an anti-CTGF antibody and one or more
additional therapies can be administered to a subject in the same
pharmaceutical composition. Alternatively, an anti-CTGF antibody
and one or more additional therapies can be administered
concurrently to a subject in separate pharmaceutical compositions.
An anti-CTGF antibody and one or more additional therapies may also
be administered to a subject by the same or different routes of
administration.
Articles of Manufacture
[0146] The present compositions may, if desired, be presented in a
pack or dispenser device containing one or more unit dosage forms
containing the anti-CTGF antibody. Such a pack or device may, for
example, comprise metal or plastic foil, glass and rubber stoppers,
such as in vials, or syringes. The container holds or contains an
anti-CTGF antibody composition that is effective for treating IPF
and may have a sterile access port (for example the container may
be an intravenous solution bag or a vial having a stopper
pierceable by a hypodermic injection needle). The container holding
the anti-CTGF antibody compositions may further be labeled for the
treatment of IPF. The pack or dispenser device may be accompanied
by instructions for administration including specific guidance
regarding dosing amounts for the anti-CTGF antibody.
[0147] The article of manufacture may further comprise an
additional container comprising a pharmaceutically acceptable
diluent buffer, such as bacteriostatic water for injection (BWFI),
phosphate-buffered saline, Ringer's solution, and/or dextrose
solution. The article of manufacture may further include other
materials desirable from a commercial and user standpoint,
including other buffers, diluents, filters, needles, and
syringes.
[0148] These and other embodiments of the present invention will
readily occur to those of ordinary skill in the art in view of the
disclosure herein.
EXAMPLES
[0149] The invention will be further understood by reference to the
following examples, which are intended to be purely exemplary of
the invention. The present invention is not limited in scope by the
exemplified embodiments, which are intended as illustrations of
single aspects of the invention only. Any methods that are
functionally equivalent are within the scope of the invention.
Various modifications of the invention in addition to those
described herein will become apparent to those skilled in the art
from the foregoing description and accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
Example 1: A Phase I Study of Anti-CTGF Monoclonal Antibody CLN1 in
Idiopathic Pulmonary Fibrosis
[0150] A Phase I, open-label, single-dose, sequential-group,
dose-escalation study of CLN1 was performed in 21 subjects with
well-defined IPF. The subjects were Caucasians with a mean.+-.SD
age of 63.+-.9 years (range, 42-79 years); and 76% were males. The
mean duration of IPF at study entry was 571.+-.608 days (range,
64-2893 days).
[0151] A human anti-CTGF antibody, CLN1, was infused intravenously
over 2 hours at a dose of 1 mg/kg (n=6), 3 mg/kg (n=9), and 10
mg/kg (n=6). All doses of CLN1 were well tolerated with no
infusion-related or dose-limiting toxicity observed. The subjects
were monitored for safety for up to 1 year following administration
where all doses of CLN1 demonstrated acceptable safety
profiles.
[0152] Baseline pulmonary function parameter testing (TLC, RV, FVC,
FEV1) and blood gas measurements (DLCO, [A-a] PO.sub.2, and
SaO.sub.2) were performed days -15 to -4 pretreatment. (Table 1)
Subjects demonstrated significantly compromised pulmonary function
parameters with a pattern of restrictive ventilatory dysfunction
with reduced gas transfer.
[0153] Following treatment with the anti-CTGF antibody, subjects
were retested for pulmonary function parameters and blood gas
measurements 28 days, 6 months and 1 year after treatment. No
significant mean changes from baseline pulmonary function
parameters were seen in any dose group 28 days post-treatment
(Table 1). Further, 5 (23.8%) subjects had clinically significant
negative changes in FVC values, defined as a decrease of >10%
from baseline; and 3 (14.3%) had a >10% decrease in total lung
capacity (TLC) values. No subjects had an increase in FVC or TLC
values >10% within 28 days post-treatment. Additionally, no
significant mean changes in blood gas measurements were seen in any
dose group 28 days post-treatment (Table 1). In two (9.5%)
subjects, DLCO decreased >10% from baseline. In three (14.3%)
subjects, (A-a) PO.sub.2 increased 12-16 mmHg from baseline to Day
28.
TABLE-US-00001 TABLE 1 Pulmonary function test results at baseline
and Day 28 CLN1 Dose Group (mg/kg) Time of 1 3 10 Parameter
Assessment (n = 6) (n = 9) (n = 6) TLC (l) Baseline 4.23 (0.76)
4.27 (1.29) 4.30 (1.25) Day 28 4.14 (0.89) 4.30 (1.25) 4.14 (1.27)
TLC % of predicted value (%) Baseline 63.8 (13.7) 67.4 (13.7) 63.8
(14.6) FVC (l) Baseline 2.58 (0.54) 2.87 (1.05) 2.76 (0.79) Day 28
2.45 (0.58) 2.72 (1.03) 2.81 (0.78) FVC % of predicted value, %
Baseline 61.7 (16.3) 69.2 (16.0) 60.5 (13.0) FEV.sub.1 (l) Baseline
2.09 (0.41) 2.30 (0.72) 2.15 (0.62) Day 28 2.01 (0.53) 2.26 (0.78)
2.12 (0.67) FEV.sub.1/FVC % Baseline 81.0 (8.3) 81.8 (6.5) 78.2
(8.7) DLCO (mL/mmHg/min) Baseline 10.9 (2.0) 11.4 (4.5) 13.1 (3.1)
(corrected for Hgb) Day 28 10.6 (1.8) 11.2 (5.0) 15.8 (4.8) DLCO %
of predicted value (%) Baseline 36.3 (9.2) 38.1 (10.3) 42.0 (14.1)
SaO2 (%) Baseline 92.3 (5.5) 93.4 (2.5) 96.0 (1.3) Day 28 92.5
(5.9) 92.8 (4.1) 96.3 (2.0) (A-a) PO.sub.2 (mmHg) Baseline 24.0
(8.8) 25.6 (18.6) 48.8 (28.1) Day 28 20.8 (9.2) 27.9 (16.1) 38.3
(23.3)
[0154] Data are presented as mean (standard deviation). TLC: total
lung capacity; FVC: forced vital capacity; FEV.sub.1: forced
expiratory volume in 1 second; Hgb: haemoglobin; DLCO: diffusing
capacity of the lung for carbon monoxide; SaO.sub.2: arterial
oxyhaemoglobin saturation; (A-a) PO.sub.2: alveolar-arterial oxygen
tension gradient.
[0155] At the end of the 12-month follow-up period, 15 of the 21
(71.4%) subjects had completed the final 12-month
protocol-specified assessments. Of the remaining six (28.6%)
subjects, three had died from progressive disease, two had
withdrawn consent, and one was withdrawn by the investigator
because of worsening IPF, requiring bilateral lung transplant.
Throughout the 6- and 12-month follow-up periods, the majority of
subjects continued to display signs of disease progression
including increased respiratory abnormalities and clinically
significant changes in pulmonary function parameters and blood gas
measurements.
Example 2: A Phase 2a, Open-Label, Single-Arm Study to Evaluate the
Safety, Tolerability, and Efficacy of CLN1 in Subjects with
Idiopathic Pulmonary Fibrosis
Study Design
[0156] The study is a Phase 2a, open-label, single-arm multicenter
trial in subjects with moderate to severe IPF. The safety,
tolerability, and efficacy of an anti-CTGF antibody (CLN1) at a
dose of 15 mg/kg every 3 weeks were studied in 46 subjects that
completed 12 weeks of treatment, 32 subjects that completed 24
weeks of treatment, and 15 subjects that completed 36 weeks of
treatment.
[0157] The planned initial duration of a subject's participation is
60 weeks, including a screening period of up to 6 weeks, a 45-week
treatment period, and a 9-week follow-up period. As the preliminary
results demonstrated disease stabilization or reversal in a
sub-population of subjects, the study was expanded to provide these
responding subjects with the option to continue treatment for an
additional year.
[0158] Eligible subjects, 35 to 80 years of age, required a
clinical diagnosis of IPF as defined by the American Thoracic
Society and European Respiratory Society international consensus
statement (Am J Respir Crit Care Med (2000) 161: (2 Pt 1):646-664),
along with one of the following: an HRCT scan obtained during
screening that showed definite IPF, or an HRCT scan obtained during
screening that was consistent with IPF plus a surgical lung biopsy
within 36 months prior to enrollment that showed definite usual
interstitial pneumonia (UIP). The diagnosis of IPF needed to be
.ltoreq.5 years' duration, and subjects needed to have evidence of
progression of IPF within the 3 to 12 months preceding enrollment
expressed as a worsening of disease based on HRCT scans, a decline
in FVC % predicted by at least 10%, or other objective evidence of
disease progression. Inclusion criteria further included the
requirement of 10%-50% parenchymal fibrosis by HRCT; less than 25%
honeycombing within the whole lung; a FVC % predicted of between
45%-85%; and a DLCO % predicted of greater than 30%.
[0159] Eligible subjects underwent an initial screening evaluation
that included a review of each individual's medical history and
available chest imaging studies. The screening evaluation further
included a complete physical examination and baseline clinical
laboratory measurements. Eligible subjects returned for a chest
HRCT scan to determine if radiographic criteria for the extent of
lung fibrosis were met. Subjects that remained eligible were
enrolled into the study and began treatment. Subjects are monitored
for safety after each infusion. Enrollment closed after 54 subjects
were entered.
[0160] The initial anti-CTGF antibody dose (CLN1) was based on the
Day 1 weight for the first 12 weeks. Subsequent doses of the
anti-CTGF antibody were based on the first weight at the beginning
of each subsequent 12-week period. The first administration of
anti-CTGF antibody was given in no less than 2 hours. If the first
administration was well tolerated and no drug-related adverse
events (AEs) were observed during the infusion or subsequent 1-hour
observation period, the second administration of the anti-CTGF
antibody was given in no less than 1 hour. If the second
administration was well tolerated and without drug-related AEs, all
subsequent infusion periods were shortened to no less than half an
hour.
[0161] Clinical laboratory tests to assess safety were performed at
the first screening visit, at every visit for the first three
infusions and then continued at 6-week intervals. Clinical
laboratory tests are performed through Week 48. Efficacy parameters
(pulmonary function parameters, blood gas measurements and patient
reported outcomes (dyspnea and QoL)) are assessed at Weeks 12, 24,
36 and 48. Chest HRCT are obtained at Week 24 and Week 48.
[0162] Pulmonary function parameters were analyzed for change from
baseline (determination of the rate of decline) in FVC, FVC %
predicted, TLC, and FRC. DLCO was analyzed for change from baseline
(determination of the rate of decline) in DLCO % or DLCO %
predicted, adjusted for hemoglobin.
[0163] Follow-up HRCT scans at Week 24 were compared with the
baseline HRCT scan by visual scoring ("better," "no change,"
"worse") in a blinded manner. The follow-up HRCT scans were also
compared with the baseline HRCT scan through a CAD analysis scoring
system (MedQIA, Los Angeles, Calif.) that is similar to that
disclosed by Kim et al. (Kim et al. Clin Exp Rheumatol. (2010) 28(5
Suppl 62):S26-S35; Kim et al. Eur Radiol (2011) 21: 2455-2465). The
percent change in three pulmonary radiographic parameters were
measured: ground glass opacities, fibrosis and honeycomb formation
by lung zone or lobe and also for the whole lung. Additionally,
QILD was also calculated for each subject.
Data
[0164] A preliminary analysis of data is presented below. The data
includes pulmonary function parameter data from 46 subjects who
completed 12 weeks of treatment, 32 subjects who completed 24 weeks
of treatment, and 15 subjects who completed 36 weeks of treatment.
In addition, the data included baseline and 24-week HRCT scans from
12 subjects.
[0165] Disease severity at baseline, measured as FVC % predicted,
ranged from 42.5 to 86.0%, with a median of 63.2%, n=47. Mean FVC
was 2.61 L.
[0166] Subjects treated with an anti-CTGF antibody (CLN1) at 15
mg/kg every 3 weeks experienced a change in FVC from baseline at
Week 12 post-initiation of therapy of -0.04 liters (n=46), the same
as the change seen in IPF subjects from a composite placebo arm
derived from recent IPF clinical trials, -0.04 liters. (Table 2.)
At Week 24 post-initiation of therapy, the change in FVC from
baseline was -0.09 liters (n=32) that again approximates the change
seen in IPF subjects from the composite placebo arm derived from
recent IPF clinical trials. At Week 36, the anti-CTGF antibody
treated subjects demonstrated stabilization in the rate of the
pathologic decline in FVC from baseline with a net change of -0.08
liters (n=15) from baseline compared with the extrapolated change
of -0.12 liters seen in IPF subjects from the composite placebo arm
derived from recent clinical trials.
TABLE-US-00002 TABLE 2 Change in FVC from baseline FVC Change from
Baseline (liters) Baseline FVC Interval All Subjects % predicted
>55% Responders Week 12 -0.04 0.00 +0.05 CLN1 N = 46 N = 34 N =
14 Week 12 -0.04 (historical placebos)* Week 24 -0.09 -0.07 +0.06
CLN1 N = 32 N = 26 N = 14 Week 24 -0.08 (historical placebos)* Week
36 -0.08 -0.02 +0.04 CLN1 N = 15 N = 12 N = 9 Week 36 -0.12
(historical placebos)* *IPF subjects in composite placebo arm
derived from recent clinical trials, n = 1,122. Mean =
approximately -0.16 liters at Week 48. (Richeldi L et al., N Engl J
Med 2011; 365: 1079-1087; Noble PW et al., Lancet May 14, 2011 DOI:
10.1016/S0140-6736(11)60405-4; Azuma A et al. Am J Respir Crit Care
Med. 2005 May 1; 171(9): 1040-47; Taniguchi H. et al. Eur Respir J
2010; 35: 821-829; Demedts M et al. N Engl J Med 2005; 353:
2229-2242; Raghu G et al. N Engl J Med 2004; 350: 125-133; King TE
Jr et al, Am J Respir Crit Care Med. 2011 Jul 1; 184(1): 92-99;
Daniels CE et al, Am J Respir Crit Care Med. 2010 Mar 15; 181(6):
604-10; Raghu G et al, Am J Respir Crit Care Med. 2008 Nov 1;
178(9): 948-55; Noth I et al. Am J Respir Crit Care Med 2012; 186:
88-95; Raghu G et al. N Engl J Med 2012; 366: 1968-1977)
1977)
[0167] An examination of the change in FVC (liters) from baseline
at Week 24 and Week 36 post-initiation of therapy based on the
subjects' baseline FVC % predicted value showed that overall,
subjects with a higher baseline FVC % predicted value responded
better to treatment. FIG. 1 The regression lines for changes in FVC
vs. baseline FVC % predicted showed that subjects with a baseline
FVC % predicted value of at least the median baseline value of 63%
experienced a stabilization of disease or increase in FVC (reversal
of the pathologic decline) at Week 24 and Week 36.
[0168] An analysis of the change in FVC (in liters) from baseline
of subjects treated with an anti-CTGF antibody that had a baseline
FVC % predicted of at least 55% demonstrated that after approaching
the change in FVC seen in IPF subjects at Week 24, there was an
improvement in FVC at Week 36, a reversal in the pathologic rate of
decline. FIG. 2 and Table 2
[0169] An examination of the change in FVC (in liters) from
baseline in subjects that demonstrated an improvement (reversal in
the pathologic decline) in FVC at Week 12 post-initiation of
treatment with an anti-CTGF antibody revealed that the improvement
in FVC persisted through Week 36 with a net gain in FVC of about
0.04 liters. FIG. 3 and Table 2 In contrast, the change in FVC for
IPF subjects in the composite placebo arm derived from recent
clinical trials was about -0.12 liters from baseline at Week
36.
[0170] Examination of another pulmonary function parameter, FVC %
predicted, revealed that subjects treated with the anti-CTGF
antibody (CLN1) at 15 mg/kg every 3 weeks experienced a change in
FVC % predicted from baseline at Week 12 post-initiation of therapy
of -0.80% (reduction in the pathologic rate of decline) compared to
a change of -1.36% seen in subjects from the composite placebo arm
derived from recent IPF clinical trials. Table 3 At Week 24
post-initiation of therapy, the change in FVC % predicted for
subjects treated with an anti-CTGF antibody was -1.93% compared to
a change of -2.73% for the subjects in the composite placebo arm
derived from recent IPF clinical trials. At Week 36, the anti-CTGF
antibody treated subjects had a change from baseline of -1.11% that
demonstrates a reversal in the pathologic rate of decline in FVC %
predicted compared to Week 24. In contrast, at Week 36 IPF subjects
from the composite placebo arm had a change from baseline in FVC %
predicted of -4.09%.
[0171] Inspection of results revealed that subjects treated with an
anti-CTGF antibody that had a baseline FVC % predicted of at least
55% showed no appreciable change from baseline FVC % predicted at
Week 12. Table 3 At Week 24, the change in FVC % predicted from
baseline was -1.24%, later rebounding to +0.09% above baseline at
Week 36, demonstrating a reversal in pathologic rate of decline of
the FVC % predicted values for these subjects.
[0172] Surprisingly, at Week 12 about 30% of the subjects
demonstrated a positive change in FVC % predicted from baseline.
Table 3 These subjects with a mean +1.27% change in FVC % predicted
were termed "responders" and demonstrate that treatment with an
anti-CTGF antibody can reverse the pathological rate of decline in
pulmonary function. The positive response was durable, lasting
until at least Week 36.
TABLE-US-00003 TABLE 3 Change in FVC % predicted from baseline. FVC
% Predicted Change from Baseline Baseline FVC Interval All Subjects
% predicted >55% Responders Week 12 -0.80% +0.02% +1.27% CLN1 N
= 46 N = 34 N = 14 Week 12 -1.36% (historical placebos)* Week 24
-1.93% -1.24% +1.71% CLN1 N = 32 N = 26 N = 14 Week 24 -2.73%
(historical placebos)* Week 36 -1.59% +0.09% +1.43% CLN1 N = 15 N =
12 N = 9 Week 36 -4.09% (historical placebos)* *IPF subjects in
composite placebo arm derived from recent clinical trials, n =
1,019. Mean FVC % predicted change from baseline = -5.46% at Week
48. (Richeldi L et al., N Engl J Med 2011; 365: 1079-1087; Noble PW
et al., Lancet May 14, 2011 DOI: 10.1016/S0140-6736(11)60405-4;
Demedts M et al. N Engl J Med 2005; King TE Jr et al, Lancet 2009;
374: 222-2228; 353: 2229-2242; Raghu G et al. N Engl J Med 2004;
350: 125-133; Zisman DA et al. N Engl J Med 2010; 363: 620-628;
Noth I et al. Am J Respir Crit Care Med 2012; 186: 88-95)
[0173] HRCT scans from 12 subjects at Week 24 were compared to
their respective baseline HRCT scan to assess changes in pulmonary
fibrosis of individual lung lobes or the whole lung using CAD
analysis. Three pulmonary radiographic parameters were examined:
ground glass opacities, fibrosis and honeycomb formation.
Additionally, QILD was also determined. About half of the subjects
demonstrated a reversal in the extent of two or more pulmonary
radiographic parameters in both the most severe lung lobe (FIG. 4)
and whole lung (FIG. 5). About a quarter of the subjects appeared
to have stable disease based on both the most severe lung lobe and
whole lung CAD analysis. The direction and extent of change in the
pulmonary radiographic parameters between the most severe lung lobe
and the whole lung were similar for individual subjects. These data
represent the first demonstration of a reversal in the extent of
pulmonary fibrosis in IPF subjects.
[0174] An examination of the CAD analysis results and Week 24 FVC %
predicted values compared to baseline FVC % predicted values
demonstrated that the reversals in pulmonary radiographic
parameters and the increases in FVC % predicted values were
correlated. (FIG. 6) Further, subjects with higher baseline FVC %
predicted values, in general, responded better to anti-CTGF
antibody therapy. More specifically, a threshold baseline FVC %
predicted value, >63%, was found, wherein, subjects who entered
the trial with a baseline FVC % predicted >63%, generally showed
an improvement in lung fibrosis following treatment with an
anti-CTGF antibody, as evidenced by a decrease in the extent of
pulmonary radiographic parameters.
Ongoing Data Collection and Analysis
[0175] At appropriate time points maximum plasma concentration
(Cmax) and trough level (Cmin) of the anti-CTGF antibody (CLN1) are
determined. The area under the curve (AUC) for antibody exposure is
calculated for subjects using either linear or log-linear
extrapolation.
[0176] Pulmonary function and DLCO testing is continued through
Week 48 and the changes in FVC, FVC % predicted, TLC, FRC, DLCO and
DLCO % predicted are analyzed for clinically meaningful responses,
such as .gtoreq.10% and .gtoreq.5% improvements in baseline
measurements.
[0177] Follow-up HRCT scans at Week 48 are obtained and compared
with the baseline HRCT and Week 24 scans by visual scoring and CAD
analysis as detailed above for the 24 Week HRCT scans. The
proportion of responders and its 95% confidence interval are
calculated.
[0178] The median progression-free survival is estimated using the
Kaplan-Meier method from the analysis of the proportion of subjects
who meet the disease progression criteria during the study.
Clinical Trial Update
[0179] A total of 54 subjects were enrolled in the study, now
termed "Cohort 1," of which 53 subjects were treated. Forty four
subjects were seen at Week 24 with 39 subjects completing treatment
and follow up. Fifteen subjects withdrew with 5 of the withdrawals
voluntary, 3 because of lung transplantation and 6 related to
adverse events that were not associated with the anti-CTGF antibody
treatment.
[0180] Patient demographics of the enrolled subjects include a mean
age of 67.3. Eighty three percent of the subjects were male.
Disease severity at baseline, measured as FVC % predicted ranged
from 42.5% to 86% with a median of FVC % predicted of 63.2% and a
mean FVC % predicted of 62.5%. The median DLCO % predicted was
47.0% and the mean DLCO % predicted was 49.5%.
[0181] Analysis of plasma samples from subjects for anti-CTGF
antibody concentration following the first infusion demonstrated a
mean Day 1 Cmax of 336 .mu.g/ml, SD.+-.86 .mu.g/ml, n=35 and a Week
3 mean Cmin of 23 .mu.g/ml, SD.+-.10 .mu.g/ml, n=34. The Week 24
(8.sup.th infusion) mean Cmax was 341 .mu.g/ml, SD.+-.115, n=33,
similar to the Cmax from the first infusion. The Week 27 Cmin of 42
.mu.g/ml, SD+25 .mu.g/ml, n=30 was higher than the Week 3 Cmin
value. The Week 45 mean Cmax was 225 .mu.g/ml, SD=84 .mu.g/ml,
n=19. Week 48 mean Cmin was 47 .mu.g/ml, SD=22 .mu.g/ml, n=18.
[0182] Testing of pulmonary function parameters demonstrated that
the slowing of the pathologic rate of decline in pulmonary function
seen with the initial subjects continued. FIG. 7 The rate of
decline in FVC % predicted from baseline for all treated subjects
was reduced compared to placebo treated historical controls.
Additionally, it was noted that subjects enrolled with a baseline
FVC % predicted greater than 55% experienced an even greater
reduction in the rate of decline of this pulmonary function
parameter compared to all subjects treated with an anti-CTGF
antibody or historical controls.
[0183] The surprising decrease and stabilizations in radiographic
pulmonary parameters seen with the initial 12 subjects at Week 24
continued when the HRCT scans of whole lungs from 46 subjects were
examined by CAD analysis and compared to their respective baseline
HRCT scan. FIGS. 8 and 9. Approximately 59% of the subjects had a
decrease (reversal) or stabilization of the radiographic pulmonary
parameter, fibrosis. FIG. 8. Similarly, 60% of the subjects had a
decrease (reversal) or stabilization of QILD. FIG. 9. CAD analysis
of the most severe lung lobe demonstrated similar response rates to
whole lung. Additionally, all three radiographic pulmonary
parameters proved to be mutable with anti-CTGF antibody therapy.
Further, a decrease in QILD was usually associated by a decrease in
at least two radiographic pulmonary parameters. Similarly, an
increase in QILD was usually associated by an increase in at least
two radiographic pulmonary parameters.
[0184] The decrease (reversal) and stabilization of radiographic
pulmonary parameters seen at Week 24 endured to at least Week 48,
with slight reductions in the total percentage of subjects within
these groups. FIGS. 10 and 11. The response of individual subjects
to the anti-CTGF antibody therapy generally persisted over the
treatment period. FIG. 12. Subjects that showed a decrease
(reversal) in QILD at Week 24 usually continued to show a decrease
(reversal) in QILD at Week 48. Subjects that had stable QILD at
Week 24 usually continued to show stable QILD at Week 48.
Similarly, subjects that showed an increase in QILD at Week 24
usually continued to show an increase in QILD at Week 48. The
results demonstrate that CAD analysis of HRCT scans can be used to
prognosis subjects with IPF that are treated with an anti-CTGF
antibody. In particular, the extent of QILD at Week 24 can be used
to select subjects for further treatment with an anti-CTGF
antibody. For example, subjects that demonstrate a decrease or
stabilization of QILD at Week 24 can be selected to continue
treatment with an anti-CTGF antibody, while subjects that
demonstrate an increase in QILD can be switched to a different
treatment protocol.
[0185] To further explore the relationship between changes in
radiographic pulmonary parameters and pulmonary functional
parameters, subjects were segregated based on QILD results at Week
24 and their change in FVC % predicted from baseline FVC %
predicted compared over time. FIG. 13 Subjects at Week 24 with an
increase in QILD compared to baseline QILD continued to lose
pulmonary function at a rate similar to historical placebos. In
contrast, subjects at Week 24 with a decrease in QILD or stable
QILD compared to their baseline QILD had a similar slowing in the
pathologic rate of decline of this pulmonary function parameter.
The difference in the rate of loss of pulmonary function between
those subjects that showed an increase in QILD from baseline at 24
weeks and the subjects from the combined group of subjects that at
24 weeks had a decrease in QILD or stable QILD compared to baseline
was statistically significant (p<0.004). The difference in
pulmonary function between these groups continued through at least
Week 48 (p<0.05). These results demonstrate correlation between
stabilization or improvement in lung morphology via HRCT and
improvement in pulmonary function. These results further confirm
that changes in lung morphology determined by serial radiographic
measurements can be used to prognosis subjects that receive
anti-CTGF antibody therapy for IPF. In particular, these results
demonstrate that changes in the extent of QILD at Week 24 can be
used to prognosis subjects. Subjects with stable or decreased QILD
at Week 24 compared to baseline generally have a marked reduction
in the pathologic rate of decline of FVC % predicted. This
reduction in the rate of decline is maintained at least through
Week 48 with continued treatment with an anti-CTGF antibody. On the
other hand, subjects that have increased QILD at Week 24 compared
to baseline generally continue to show a rate of decline in FVC %
predicted that is similar to historical controls. Subjects at Week
24 that have increased QILD compared to their QILD at baseline can
be switched to a different treatment protocol that may include a
higher anti-CTGF antibody dose.
[0186] The relationship between the improvements in radiographic
pulmonary parameters and improvements in pulmonary function
parameters for subjects treated with an anti-CTGF antibody were
further examined by correlation analyses. FIGS. 14 and 15 and Table
6 The analyses show that the reduction in pulmonary fibrosis from
baseline, as measured radiographically, correlates with the
improvement in pulmonary function, as measured by the change in FVC
% predicted from baseline, in subjects that received anti-CTGF
antibody therapy.
TABLE-US-00004 TABLE 6 Pearson Correlation Analysis .DELTA. FVC %
Predicted vs .DELTA. FVC % Predicted .DELTA. Fibrosis vs .DELTA.
QILD (Shown in FIG. 14) (Shown in FIG. 15) Week 24 Week 48 Week 24
Week 48 N 44 38 44 38 r.sub.s -0.6004 -0.5575 -0.4934 -0.3514 p
value 0.000016 0.000277 0.000667 0.030502
[0187] The change in FVC % predicted outcomes at Week 48 was
examined for subjects that experienced less than a -3% change from
baseline and subjects that experienced greater than a -3% change
from baseline at Week 48. FIG. 16 The results show that at Week 48,
subjects that experienced a change in FVC % predicted above -3%
compared to baseline (40% of total subjects) initial gained a
slight increase in pulmonary function at Week 12 that was
maintained to at least Week 48. In contrast, at Week 48 subjects
that experienced change in FVC % predicted below -3% compared to
baseline (60% of total subjects) showed a continual decline in
pulmonary function that was similar to the results seen in
historical placebo controls. The results demonstrate that in
general, subjects that experience at most a modest decline (<-3%
change) in FVC % predicted gained pulmonary function following
treatment with an anti-CTGF antibody.
[0188] Subjects that experienced less than a -3% change in FVC %
predicted from baseline at Week 48 were allowed to continue
treatment for a second year (15 mg/kg IV Q 3 weeks for a total of
45 weeks) to test the hypothesis that longer treatment with an
anti-CTGF antibody would maintain or even improve pulmonary
function parameters. Nineteen subjects elected to continue
treatment and will be monitored as before with testing of pulmonary
function parameters every 12 weeks and HRCT scans at Weeks 24 and
48 of this second treatment course.
[0189] In summary, the clinical data from Cohort ldemonstrate that
treatment with an anti-CTGF antibody can slow the pathologic rate
of decline in pulmonary function in subjects with IPF. Further, in
some subjects, treatment with an anti-CTGF antibody can improve
pulmonary function or stop the decline (stabilize) in pulmonary
function. Additionally, treatment with an anti-CTGF antibody can
reverse pulmonary fibrosis or prevent the progression (stabilize)
of pulmonary fibrosis as evidenced by changes in radiographic
images over time. Notably, the improvements seen in pulmonary
function are associated with the improvements in pulmonary
structure, i.e., reversal or stabilization of radiographic
pulmonary parameters. The results support the continued treatment
of subjects with the anti-CTGF antibody CLN1 at 15 mg/kg and the
initiation of a second therapy arm to study the therapeutic
response to a higher antibody dose.
Cohort 2
[0190] Based on the surprising results achieved with the
administration of 15 mg/kg of an anti-CTGF antibody, coupled with
knowledge that the use of the anti-CTGF antibody, CLN1, in other
indications at a dose of up to 45 mg/kg IV Q 2 weeks has not
identified any significant safety concerns, a second cohort for
treatment of IPF was initiated. Subjects are being treated with 30
mg/kg IV Q 3 weeks. The entry criteria for Cohort 2 is the same as
Cohort 1 with the exception that eligible subjects require a FVC %
predicted .gtoreq.55%. To date, 32 subjects are enrolled.
[0191] Initial pulmonary function study results at Week 12 for 14
subjects suggest that a higher antibody dose can further improve
pulmonary function parameters. FIG. 17 Subjects experienced a
reversal in the expected rate of decline from baseline of FVC %
predicted values, i.e., the change in their FVC % predicted values
rose was positive demonstrating an improvement in pulmonary
function compared to baseline.
Safety Profile
[0192] Treatment with the anti-CTGF antibody, CLN1, is well
tolerated. The pattern of adverse events was consistent with the
demographics and underlying disease in the population being
studied. At Week 36, no serious adverse events were assessed as
related to treatment with CLN1 and there were 3 deaths, all related
to progression of IPF, and one acute exacerbation of IPF to date in
enrolled subjects.
[0193] Through the completion of Cohort 1, no significant safety
concerns related to the administration of CLN1 were identified.
Additionally, there were no further deaths or acute exacerbations
of IPF.
* * * * *