U.S. patent application number 17/202582 was filed with the patent office on 2021-08-26 for capsid assembly modulator dosing regimen.
The applicant listed for this patent is Janssen Sciences Ireland Unlimited Company. Invention is credited to Claire Elisabeth BALMAIN, Maria JANSENS, Oliver LENZ, Jan SNOEYS, Frederic VAN DYCKE, Joris Jozef VANDENBOSSCHE, Koen VANDYCK, Dominique Josiane W. VERSTRAETE, Jeysen Zivan YOGARATNAM.
Application Number | 20210260025 17/202582 |
Document ID | / |
Family ID | 1000005568462 |
Filed Date | 2021-08-26 |
United States Patent
Application |
20210260025 |
Kind Code |
A1 |
VANDYCK; Koen ; et
al. |
August 26, 2021 |
CAPSID ASSEMBLY MODULATOR DOSING REGIMEN
Abstract
The present disclosure is directed to methods of using a capsid
assembly inhibitor for the treatment of hepatitis B virus
infection.
Inventors: |
VANDYCK; Koen;
(Paal-Beringen, BE) ; LENZ; Oliver;
(Sint-Katelijne Waver, BE) ; BALMAIN; Claire
Elisabeth; (Antwerp, BE) ; SNOEYS; Jan;
(Westmalle, BE) ; VANDENBOSSCHE; Joris Jozef;
(Tervuren, BE) ; VERSTRAETE; Dominique Josiane W.;
(Lokeren, BE) ; YOGARATNAM; Jeysen Zivan;
(Danville, CA) ; JANSENS; Maria; (Turnhout,
BE) ; VAN DYCKE; Frederic; (Nijlen, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Sciences Ireland Unlimited Company |
Co Cork |
|
IE |
|
|
Family ID: |
1000005568462 |
Appl. No.: |
17/202582 |
Filed: |
March 16, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16352754 |
Mar 13, 2019 |
10973801 |
|
|
17202582 |
|
|
|
|
62642997 |
Mar 14, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/522 20130101;
A61P 31/20 20180101; A61K 31/4439 20130101; A61K 31/40 20130101;
A61K 47/38 20130101; A61K 31/675 20130101; A61K 31/454 20130101;
A61K 38/21 20130101 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 47/38 20060101 A61K047/38; A61K 31/4439 20060101
A61K031/4439; A61K 38/21 20060101 A61K038/21; A61K 31/675 20060101
A61K031/675; A61K 31/522 20060101 A61K031/522; A61P 31/20 20060101
A61P031/20; A61K 31/454 20060101 A61K031/454 |
Claims
1-30. (canceled)
31. A method of treating a hepatitis B virus (HBV) infection or a
HBV-induced disease in a subject, comprising administering a
pharmaceutical composition comprising (a) Compound A: ##STR00010##
or a pharmaceutically acceptable salt thereof, and (b) a
stabilizer; wherein the amount of the compound (A) is 50-500 mg,
and compound (A) is in the form of a spray dried powder.
32. The method of claim 31, wherein the stabilizer is selected from
at least one polymer chosen from the group consisting of HPMC,
HPMC-AS, and HPMC E5.
33. The method of claim 32, wherein said at least one polymer is in
an amount of 50-1500 mg.
34. The method of claim 31, wherein the composition comprises the
compound (A) and stabilizer at a ratio in a range of 1:1 to 1:3 by
weight.
35. The method of claim 31, wherein the composition comprises 250
mg of Compound (A).
36. The method of claim 31, wherein the composition comprises 50 mg
of Compound (A).
37. The method of claim 31, wherein the composition comprises 100
mg of Compound (A).
38. The method of claim 31, wherein the composition further
comprises microcrystalline cellulose and silicified
microcrystalline cellulose.
39. The method of claim 31, further comprising administering a
transcription inhibitor.
40. The method of claim 39, wherein the transcription inhibitor is
a nucleoside analog.
41. The method of claim 40, wherein the nucleoside analog is
tenofovir disoproxil fumarate, tenofovir alafenamide, or entecavir
monohydrate.
42. The method of claim 40, wherein the nucleoside analog is
tenofovir, or a pharmaceutically acceptable salt, or prodrug
thereof.
43. The method of claim 42, wherein the tenofovir is administered
in an amount of 60-600 mg.
44. The method of claim 40, wherein the nucleoside analog is
entecavir, or a pharmaceutically acceptable salt thereof.
45. The method of claim 44, wherein the entecavir is administered
in an amount of 0.1-1 mg.
46. The method of claim 1, further comprising administering an
immune modulator, or at least one siRNA or antisense
oligonucleotide, or at least one Nucleic Acid Polymer, more
particularly at least one immune modulator.
47. The method of claim 46, the immune modulator is interferon.
48. The method of claim 31, wherein the subject is HBV-treatment
naive.
49. The method of claim 31, wherein the HBV-induced disease is
cirrhosis, liver failure or hepatocellular carcinoma.
50. A pharmaceutical composition comprising (a) Compound A:
##STR00011## or a pharmaceutically acceptable salt thereof, and (b)
a stabilizer; wherein the amount of the compound (A) is 50-500 mg,
and compound (A) is in the form of a spray dried powder.
51. The pharmaceutical composition of claim 50, wherein the
stabilizer is selected from at least one polymer chosen from among
HPMC and HPMC-AS.
52. The pharmaceutical composition of claim 51, wherein said at
least one polymer is in an amount of 50-1500 mg.
53. The pharmaceutical composition of claim 51, wherein the
composition comprises the compound (A) and stabilizer at a ratio of
1:3 by weight.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a Divisional of U.S. patent application
Ser. No. 16/352,754, filed on Mar. 13, 2019, which application
claims priority to U.S. Provisional Application No. 62/642,997
filed on Mar. 14, 2018, which is incorporated herein in its
entirety.
BACKGROUND
[0002] Chronic hepatitis B virus (HBV) infection is a persistent,
potentially progressive necroinflammatory liver disease associated
with chronic HBV infection. Worldwide about 240-400 million persons
are chronically infected with HBV, and chronic HBV infection is a
major global cause of severe liver morbidity and liver-related
mortality (Hepatitis B Factsheet, World Health Organization, 2013;
Hoofnagle J H, et al., Management of Hepatitis B: Summary of a
Clinical Research Workshop, Hepatology, 2007, 45(4):1056-1075; EASL
Clinical Practice Guidelines: Management of chronic hepatitis B
virus infection, J. Hepatology, 2012, 57:167-185 (EASL 2012);
Lesmana L A, et al. Hepatitis B: overview of the burden of disease
in the Asia-Pacific region, Liver International, 2006, 26:3-10; Lok
A S F and McMahon B J, Chronic Hepatitis B: Update 2009,
Hepatology, September 2009:1-36 (Lok 2009)).
[0003] With the continued worldwide prevalence of HBV-associated
mortality and severe morbidity, there remains a need for improved
HBV antiviral therapies that can achieve sustained viral response
during and after treatment.
SUMMARY
[0004] The present disclosure is directed to methods of using a
capsid assembly inhibitor for the treatment of hepatitis B virus
infection. In an aspect, provided herein is a method of preventing
or treating HBV infection in a subject, said method comprising
administering to said subject a Compound of Formula 1:
##STR00001##
[0005] or a pharmaceutically acceptable salt thereof,
[0006] wherein:
[0007] A is N or CH;
[0008] R.sup.1 is, independently at each occurrence, selected from
halo, CF.sub.3, and CN;
[0009] R.sup.2 is C.sub.1-C.sub.3 alkyl;
[0010] R.sup.3 is, independently at each occurrence, selected from
C.sub.1-C.sub.3 alkyl and halo;
[0011] R.sup.4 is C.sub.1-C.sub.4 alkyl, which is independently
substituted 1 or 2 times with halo or CF.sub.3;
[0012] n is 0, 1, 2, or 3; and
[0013] m is 0, 1, or 2;
[0014] at a daily dose of 50-500 mg wherein a Compound of Formula 1
is administered in at least one dosage form having a formulation
comprising a stabilizer.
[0015] In some embodiments, the Compound of Formula I is Compound
A:
##STR00002##
[0016] or a pharmaceutically acceptable salt thereof.
[0017] In other embodiments, the Compound of Formula I is Compound
B:
##STR00003##
[0018] or a pharmaceutically acceptable salt thereof.
[0019] In an embodiment of the method, the daily dose is 75-250
mg.
[0020] In another embodiment of the method, the daily dose is 250
mg.
[0021] In still another embodiment of the method, the stabilizer is
at least one of Hypromellose (HPMC) and Hypromellose acetate
succinate (HPMC-AS). Hypromellose (HPMC) may e.g., be HPMC E5
(i.e., HPMC with a viscosity of 5 mPa.$).
[0022] In an embodiment of the method, the amount of a Compound of
Formula 1 and the amount of stabilizer are present in the dosage
form at a ratio of 1:1 by weight. In another embodiment of the
method, the amount of a Compound of Formula 1 and the amount of
stabilizer are present in the dosage form at a ratio of 1:2 by
weight. In another embodiment of the method, the amount of a
Compound of Formula 1 and the amount of stabilizer are present in
the dosage form at a ratio of 1:3 by weight. In another embodiment
of the method, the amount of a Compound of Formula 1 and the amount
of stabilizer are present in the dosage form at a ratio of 1:4 by
weight. In yet another embodiment of the method, the amount of a
Compound of Formula 1 and the amount of stabilizer are present in
the dosage form at a ratio of 1:5 by weight.
[0023] In an embodiment of the method, a Compound of Formula 1 is
administered in a single dosage form.
[0024] In an embodiment of the method, a Compound of Formula 1 is
administered to prevent HBV infection in the subject.
[0025] In an embodiment of the method, the method further comprises
administering a transcription inhibitor to the subject. In an
embodiment of the method, transcription inhibitor is a nucleoside
analog. In an embodiment of the method, the nucleoside analog is
tenofovir, or a pharmaceutically acceptable salt or prodrug
thereof, tenofovir alafenamide, or a pharmaceutically acceptable
salt or prodrug thereof, or entecavir, or a pharmaceutically
acceptable salt thereof. In an embodiment of the method, the
nucleoside analog is tenofovir disoproxil fumarate or entecavir
monohydrate. In an embodiment of the method, the nucleoside analog
is tenofovir disoproxil fumarate. In an embodiment of the method,
the nucleoside analog is entecavir monohydrate.
[0026] In an embodiment of the method, the tenofovir disoproxil
fumarate is administered in an amount of 60-600 mg. In another
embodiment of the method, the tenofovir disoproxil fumarate is
administered in an amount of 300 mg. In yet another embodiment of
the method, the entecavir monohydrate is administered in an amount
of 0.1-1 mg. In still another embodiment of the method, the
entecavir monohydrate is administered in an amount of 0.5 mg.
[0027] In an embodiment of the method, the method further comprises
administering an immune modulator. In an embodiment of the method,
the immune modulator is interferon, for example interferon alpha or
pegylated interferon alpha. In an embodiment of the method, the
subject is treatment naive.
[0028] In some embodiments, the method further comprises
administering at least one Nucleic Acid Polymer (NAP), more
particularly at least one NAP which inhibits the release of
subviral particles from hepatocytes.
[0029] In some embodiments, the method further comprises
administering at least one short interfering RNA (siRNA) or
antisense oligonucleotide (ASO), more particularly at least one
siRNA or ASO selected from the group of siRNAs and ASOs which
inhibit the expression of one or more genes that are necessary for
replication or pathogenesis of HBV.
[0030] In another aspect, provided herein is a pharmaceutical
composition comprising a Compound of Formula 1 in an amount of
50-500 mg. In an embodiment of the pharmaceutical composition, the
composition further comprises 50-1500 mg stabilizer. In an
embodiment of the pharmaceutical composition, the amount of a
Compound of Formula 1 is 75-250 mg. In an embodiment of the
pharmaceutical composition, the amount of a Compound of Formula 1
is 250 mg.
[0031] The pharmaceutical composition can comprise at least one
polymer chosen from among HPMC-AS and HPMC E5, and wherein said at
least one polymer is in an amount of 50-1500 mg. In an embodiment,
at least one dosage form of the pharmaceutical composition
comprises at least one polymer chosen from among HPMC (for example
HPMC E5) and HPMC AS.
[0032] In another aspect, provided herein is a method of decreasing
formation of HBV cccDNA in a subject infected with HBV or at risk
of being infected with HBV, said method comprising administering to
said subject a Compound of Formula 1 at a daily dose of 50-500 mg
wherein a Compound of Formula 1 is administered in at least one
dosage form having a formulation comprising a stabilizer.
[0033] In another aspect, provided herein is a method of decreasing
HBsAg in a subject infected with HBV or at risk of being infected
with HBV, said method comprising administering to said subject a
Compound of Formula 1 at a daily dose of 50-500 mg wherein a
Compound of Formula 1 is administered in at least one dosage form
having a formulation comprising a stabilizer.
[0034] In yet another aspect, provided herein is a method of
preventing HBV infection in a subject at risk of being infected
with HBV by decreasing formation of HBV cccDNA, said method
comprising administering to said subject a Compound of Formula 1 at
a daily dose of 50-500 mg wherein a Compound of Formula 1 is
administered in at least one dosage form having a formulation
comprising a stabilizer.
[0035] In various embodiments of the methods provided herein, the
method further comprises administering a nucleos(t)ide
analogue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 depicts the study design for the First-In-Human study
of Compound A in healthy patients and patients with chronic
HBV.
[0037] FIG. 2 depicts the plasma concentration of Compound A in
human subjects following 28 day treatment.
[0038] FIG. 3 depicts the effect of Compound A on HBV DNA. * and
*** refer respectively to one and three patients with HBV DNA less
than the lower limit of quantitation in the HBV DNA assay. Placebo
data is pooled from both sessions. Values are mean.+-.SD
[0039] FIG. 4 depicts the study design for testing the safety and
tolerability of Compound A in healthy human subjects.
[0040] FIG. 5 depicts the pharmacokinetics of Compound A in healthy
human subjects.
DETAILED DESCRIPTION
[0041] The present disclosure is directed to methods of using a
capsid assembly inhibitor for the treatment of hepatitis B virus
infection. It has now been found that administration of capsid
assembly modulators (CAMs) can interfere with HBV capsid assembly,
which is a key step in virus production, and are therefore an
attractive new area of development. Unexpectedly, it has been found
that administration of a Compound of Formula 1 to a patient with
chronic HBV infection may result in reduction of HBsAg, HBeAg or
induce seroconversion in that patient. More particularly, such
results can be achieved through administration to the patient of a
safe and therapeutically effective dose of a Compound of Formula 1
such as a daily dose of 50-500 mg of a Compound of Formula 1.
Definitions
[0042] As used in the specification and in the claims, the term
"comprising" can include the embodiments "consisting of" and
"consisting essentially of." The terms "comprise(s)," "include(s),"
"having," "has," "can," "contain(s)," and variants thereof, as used
herein, are intended to be open-ended transitional phrases, terms,
or words that require the presence of the named ingredients/steps
and permit the presence of other ingredients/steps. However, such
description should be construed as also describing compositions or
processes as "consisting of" and "consisting essentially of" the
enumerated compounds, which allows the presence of only the named
compounds, along with any pharmaceutically acceptable carriers, and
excludes other compounds.
[0043] All ranges disclosed herein are inclusive of the recited
endpoint and independently combinable (for example, the range of
"from 50 mg to 500 mg" is inclusive of the endpoints, 50 mg and 500
mg, and all the intermediate values). The endpoints of the ranges
and any values disclosed herein are not limited to the precise
range or value; they are sufficiently imprecise to include values
approximating these ranges and/or values.
[0044] As used herein, approximating language can be applied to
modify any quantitative representation that can vary without
resulting in a change in the basic function to which it is related.
Accordingly, a value modified by a term or terms, such as "about"
and "substantially," cannot be limited to the precise value
specified, in some cases. In at least some instances, the
approximating language can correspond to the precision of an
instrument for measuring the value. The modifier "about" should
also be considered as disclosing the range defined by the absolute
values of the two endpoints. For example, the expression "from
about 50 to about 500" also discloses the range "from 50 to 500."
The term "about" can refer to plus or minus 10% of the indicated
number. For example, "about 10%" can indicate a range of 9% to 11%,
and "about 1" can mean from 0.9 to 1.1. Other meanings of "about"
can be apparent from the context, such as rounding off, so, for
example "about 1" can also mean from 0.5 to 1.4.
[0045] As used herein, the term "treatment" or "treating," is
defined as the application or administration of a therapeutic
agent, i.e., a compound of the invention (alone or in combination
with another pharmaceutical agent), to a patient, or application or
administration of a therapeutic agent to an isolated tissue or cell
line from a patient (e.g., for diagnosis or ex vivo applications),
who has HBV infection, chronic HBV infection, a symptom of HBV
infection or the potential to develop HBV infection, with the
purpose to cure, heal, alleviate, relieve, alter, remedy,
ameliorate, improve or affect HBV infection, the symptoms of HBV
infection or the potential to develop HBV infection. Such
treatments can be specifically tailored or modified, based on
knowledge obtained from the field of pharmacogenomics.
[0046] The term "prevent," "preventing," or "prevention" as used
herein comprises the prevention of at least one symptom associated
with or caused by the state, disease or disorder being
prevented.
[0047] As used herein, the term "patient," "individual" or
"subject" refers to a human or a non-human mammal. Non-human
mammals include, for example, livestock and pets, such as ovine,
bovine, porcine, canine, feline and murine mammals. Preferably, the
patient, subject or individual is human.
[0048] As used herein, the term "pharmaceutically acceptable"
refers to a material, such as a carrier or diluent, which does not
abrogate the biological activity or properties of the compound, and
is relatively non-toxic, i.e., the material can be administered to
an individual without causing undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained.
[0049] As used herein, the term "pharmaceutically acceptable salt"
refers to derivatives of the disclosed compounds wherein the parent
compound is modified by converting an existing acid or base moiety
to its salt form. Examples of pharmaceutically acceptable salts
include, but are not limited to, mineral or organic acid salts of
basic residues such as amines; alkali or organic salts of acidic
residues such as carboxylic acids; and the like. The
pharmaceutically acceptable salts of the present invention include
the conventional non-toxic salts of the parent compound formed, for
example, from non-toxic inorganic or organic acids. The
pharmaceutically acceptable salts of the present invention can be
synthesized from the parent compound which contains a basic or
acidic moiety by conventional chemical methods. Generally, such
salts can be prepared by reacting the free acid or base forms of
these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two; generally, nonaqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and
Journal of Pharmaceutical Science, 66, 2 (1977), each of which is
incorporated herein by reference in its entirety.
[0050] As used herein, the term "composition" or "pharmaceutical
composition" refers to a mixture of at least one compound useful
within the invention with a pharmaceutically acceptable carrier.
The pharmaceutical composition facilitates administration of the
compound to a patient or subject. Multiple techniques of
administering a compound exist in the art including, but not
limited to, intravenous, oral, aerosol, parenteral, ophthalmic,
pulmonary and topical administration.
[0051] As used herein, the term "pharmaceutically acceptable
carrier" means a pharmaceutically acceptable material, composition
or carrier, such as a liquid or solid filler, stabilizer,
dispersing agent, suspending agent, diluent, excipient, thickening
agent, solvent or encapsulating material, involved in carrying or
transporting a compound useful within the invention within or to
the patient such that it can perform its intended function.
Typically, such constructs are carried or transported from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation, including
the compound useful within the invention, and not injurious to the
patient. Some examples of materials that can serve as
pharmaceutically acceptable carriers include: sugars, such as
lactose, glucose and sucrose; starches, such as corn starch and
potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter and suppository waxes; oils, such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol; polyols, such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and aluminum hydroxide; surface active agents; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol; phosphate buffer solutions; and other non-toxic compatible
substances employed in pharmaceutical formulations. As used herein,
"pharmaceutically acceptable carrier" also includes any and all
coatings, antibacterial and antifungal agents, and absorption
delaying agents, and the like that are compatible with the activity
of the compound useful within the invention and are physiologically
acceptable to the patient. Supplementary active compounds can also
be incorporated into the compositions. The "pharmaceutically
acceptable carrier" can further include a pharmaceutically
acceptable salt of the compound useful within the invention. Other
additional ingredients that can be included in the pharmaceutical
compositions used in the practice of the invention are known in the
art and described, for example in Remington's Pharmaceutical
Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.),
which is incorporated herein by reference.
[0052] The term "stabilizer," as used herein, refers to polymers
capable of chemically inhibiting or preventing degradation of a
Compound of Formula 1. Stabilizers are added to formulations of
compounds to improve chemical and physical stability of the
compound.
[0053] The term "combination," "therapeutic combination,"
"pharmaceutical combination," or "combination product" as used
herein refer to a non-fixed combination or a kit of parts for the
combined administration where two or more therapeutic agents can be
administered independently, at the same time or separately within
time intervals, especially where these time intervals allow that
the combination partners show a cooperative, e.g., synergistic,
effect.
[0054] As used herein, "treatment naive" refers to a patient not
having previously received treatment with a drug, investigational
or approved, for HBV infection, in particular a nucleos(t)ide drug.
"Treatment naive" also refers to a patient not having been on
treatment with HBV antiviral medicines within six months of
entering a clinical study.
[0055] Alternatively, patients treated according to the methods of
the disclosure can be "treatment experienced." As used herein,
"treatment experienced" refers to a patient who has had at least
one previous course of an HBV antiviral therapy, in particular a
nucleos(t)ide drug. In some embodiments, the last dose in this
previous course occurred at least three months prior to
implementing a method according to the present disclosure.
[0056] HBV infections that may be treated according to the
disclosed methods include HBV genotype A, B, C, and/or D
infections. However, in an embodiment, the methods disclosed may
treat any HBV genotype ("pan-genotypic treatment"). HBV genotyping
may be performed using methods known in the art, for example,
INNO-LIPA.RTM. HBV Genotyping, Innogenetics N.V., Ghent,
Belgium).
[0057] The term "synergistic effect" refers to the action of two
agents, such as, for example, a capsid assembly modulator and a
nucleos(t)ide analogue, producing an effect, for example, slowing
the symptomatic progression of HBV-infection or symptoms thereof,
which is greater than the simple addition of the effects of each
drug administered alone. A synergistic effect can be calculated,
for example, using suitable methods such as the Sigmoid-Emax
equation (Holford, N. H. G. and Scheiner, L. B., Clin.
Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity
(Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:
313-326 (1926)) and the median-effect equation (Chou, T. C. and
Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984) and Chou,
Pharmacol. Rev. 58: 621-681 (2006). Each equation referred to above
can be applied to experimental data to generate a corresponding
graph to aid in assessing the effects of the drug combination. The
corresponding graphs associated with the equations referred to
above are the concentration-effect curve, isobologram curve and
combination index curve, respectively. In some embodiments, the
combination of compounds exhibits a synergistic effect (i.e.,
greater than additive effect) in the treatment of HBV
infection.
[0058] Synergy volumes of <-100,-100 to-50,-50 to-25,-25 to 25,
25 to 50, 50 to 100, and >100 indicate strong antagonism,
moderate antagonism, slight antagonism, insignificant
synergism/antagonism (additivity), slight synergism, moderate
synergism, and strong synergism respectively.
[0059] Synergy can be defined as an improvement in any beneficial
effect of each of a Compound of Formula 1 or a nucleos(t)ide
analogue, alone or in combination. The improvement may exceed an
additive effect of the combination or may only occur as a result of
the combination. For example, in an embodiment, the effect is
complete or sustained reduction of viral load, HBsAg and/or
anti-HBsAb during and/or after treatment. For example, in an
embodiment, the effect is sustained virological response (SVR)
and/or sustained viral clearance.
Dosing/Administration
[0060] In one aspect, the present disclosure is directed to methods
of treating HBV infection in a patient in need thereof, comprising
administering to the patient a Compound of the Formula 1:
##STR00004##
[0061] or a pharmaceutically acceptable salt thereof,
[0062] wherein:
[0063] A is N or CH;
[0064] R.sup.1 is, independently at each occurrence, selected from
halo, CF.sub.3, and CN;
[0065] R.sup.2 is C.sub.1-C.sub.3 alkyl;
[0066] R.sup.3 is, independently at each occurrence, selected from
C.sub.1-C.sub.3 alkyl and halo;
[0067] R.sup.4 is C.sub.1-C.sub.4 alkyl, which is independently
substituted 1 or 2 times with halo or CF.sub.3;
[0068] n is 0, 1, 2, or 3; and
[0069] m is 0, 1, or 2.
[0070] In some embodiments, the amount of a Compound of Formula 1
is from about 50 mg per day to about 500 mg per day (e.g. 50, 75,
100, 150, 200, 250, 300, 350, 400, 450, 500 mg). In some
embodiments, the amount of a Compound of Formula 1 is from 75 mg
per day to 250 mg per day. In some embodiments, the amount of a
Compound of Formula 1 is 75 mg per day. In some embodiments, the
amount of a Compound of Formula 1 is 150 mg per day. In some
embodiments, the amount of a Compound of Formula 1 is 250 mg per
day.
[0071] In some embodiments, the dose or daily dose of the Compound
of Formula 1, more particularly of compound (A) or (B), is 5-300
mg, more particularly 25-300 mg, more particularly 50-300 mg, more
particularly 75-300 mg, more particularly 80-300 mg, more
particularly 100-300 mg, more particularly 100-250 mg.
[0072] In some embodiments, the dose or daily dose of the Compound
of Formula 1, more particularly of compound (A) or (B), is 5-250
mg, more particularly 25-250 mg, more particularly 50-250 mg, more
particularly 75-250 mg, more particularly 80-250 mg, more
particularly 100-250 mg.
[0073] In some embodiments, the dose or daily dose of the Compound
of Formula 1, more particularly of compound (A) or (B), is 50-300
mg, more particularly 75-250 mg, more particularly 100-250 mg.
[0074] In an embodiment of the methods of treating HBV infection in
a patient in need thereof provided herein, the Compound of Formula
1 is the following compound:
##STR00005##
or a pharmaceutically acceptable salt thereof (hereinafter
"Compound A"), in an amount from about 50 mg per day to about 500
mg per day (e.g. 50, 75, 100, 150, 200, 250, 300, 350, 400, 450,
500 mg). In some embodiments, the amount of Compound A is from 75
mg per day to 250 mg per day. In some embodiments, the amount of
Compound A is 75 mg per day. In some embodiments, the amount of
Compound A is 150 mg per day. In some embodiments, the amount of
Compound A is 250 mg per day.
[0075] Compound A, including the synthesis thereof, is disclosed in
PCT Publication No. WO/2014/184350 (or the US counterparts
thereof), which is hereby incorporated by reference in its
entirety.
[0076] In another embodiment of the methods of treating HBV
infection in a patient in need thereof provided herein, the
Compound of Formula 1 is the following compound:
##STR00006##
or a pharmaceutically acceptable salt thereof (hereinafter
"Compound B"), in an amount from about 50 mg per day to about 500
mg per day (e.g. 50, 75, 100, 150, 200, 250, 300, 350, 400, 450,
500 mg). In some embodiments, the amount of Compound B is from 75
mg per day to 250 mg per day. In some embodiments, the amount of
Compound B is 75 mg per day. In some embodiments, the amount of
Compound B is 150 mg per day. In some embodiments, the amount of
Compound B is 250 mg per day.
[0077] Compound B, including the synthesis thereof, is disclosed in
PCT Publication No. WO/2015/118057 (or the US counterparts
thereof), which is hereby incorporated by reference in its
entirety.
[0078] The method of the present disclosure aims at reducing serum
HBV DNA, serum HBV RNA, and quantitative serum HBsAg and HBeAg in
patients. The methods of treating HBV infection provided herein, in
particular, treat HBV infection by reducing serum HBV DNA in a
patient, by reducing serum HBV RNA in a patient and/or by reducing
serum HBsAg and HBeAg in a patient and/or by inducing
seroconversion (against sAg and/or eAg) in a patient.
[0079] In certain embodiments of the methods of treating HBV
infection provided herein, the treatment is curative and the
patient does not have to continue treatment after the specified
treatment time. In a particular embodiment of the method of
treating HBV provided herein, the treatment is finite.
[0080] The present disclosure provides methods of treating HBV
infection in a patient in need thereof, comprising administering to
the patient a Compound of Formula 1, or a pharmaceutically
acceptable salt thereof, in an amount from 50 mg per day to 500 mg
per day, wherein a Compound of Formula 1 is administered once per
day. In embodiments, the patient is administered a Compound of
Formula 1 for a duration of 28 days. In some embodiments, the
amount of a Compound of Formula 1 administered to the patient is
from 75 mg per day to 250 mg per day. In some embodiments, the
amount of a Compound of Formula 1 administered to the patient is 75
mg per day. In some embodiments, the amount of a Compound of
Formula 1, or a pharmaceutically acceptable salt thereof, is 150 mg
per day. In a particular embodiment, the amount of a Compound of
Formula 1 administered to the patient is 250 mg per day.
[0081] In an alternative embodiment, the present disclosure
provides methods of preventing HBV infection in a patient at risk
of being infected with HBV, comprising administering to the patient
a Compound of Formula 1, or a pharmaceutically acceptable salt
thereof, in an amount from 50 mg per day to 500 mg per day, wherein
a Compound of Formula 1 is administered once per day. Thus, in a
particular embodiment, the present disclosure provides methods of
preventing HBV infection in a patient at risk of being infected
with HBV, comprising administering to the patient a Compound of
Formula 1, or a pharmaceutically acceptable salt thereof, in an
amount of 250 mg per day.
[0082] In some embodiments, the methods further comprise
administering an immune modulator, such as interferon. In some
embodiments, the subject is treatment naive.
[0083] In some embodiments, the methods further comprise
administering at least one Nucleic Acid Polymer (NAP), more
particularly at least one NAP which inhibits the release of
subviral particles from hepatocytes.
[0084] In some embodiments, the method further comprises
administering at least one short interfering RNA (siRNA) or
antisense oligonucleotide (ASO), more particularly at least one
siRNA or ASO selected from the group of siRNAs and ASOs which
inhibit the expression of one or more genes that are necessary for
replication or pathogenesis of HBV.
[0085] In some embodiments of the methods, a Compound of Formula 1
is co-administered with a transcription inhibitor. In some
embodiments, the transcription inhibitor is a nucleos(t)ide
analogue. In some embodiments, the nucleos(t)ide inhibitor is
tenofovir or a pharmaceutically acceptable salt thereof or a
prodrug thereof (such as tenofovir disoproxil fumarate (TDF),
tenofovir alafenamide (TAF), or a pharmaceutically acceptable salt
thereof), or entecavir or a pharmaceutically acceptable salt
thereof. In some embodiments, a Compound of Formula 1 is
co-administered with tenofovir disoproxil fumarate. In some
embodiments, a Compound of Formula 1 is co-administered with
tenofovir alafenamide. In still other embodiments, a Compound of
Formula 1 is co-administered with entecavir monohydrate.
[0086] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient a Compound of Formula 1, or
a pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and a transcription inhibitor.
[0087] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient a Compound of Formula 1, or
a pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and a nucleos(t)ide analogue.
[0088] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient a Compound of Formula 1, or
a pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and tenofovir, or a pharmaceutically
acceptable salt, or prodrug thereof, in an amount from 60 mg per
day to 600 mg per day.
[0089] In some embodiments, the present disclosure provides methods
of treating HBV infection in a patient in need thereof, comprising
administering to the patient a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and tenofovir alafenamide, or a
pharmaceutically acceptable salt thereof, in an amount from 60 mg
per day to 600 mg per day.
[0090] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient a Compound of Formula 1, or
a pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and entecavir, or a pharmaceutically
acceptable salt, in an amount from 0.1 mg per day to 1 mg per
day.
[0091] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient a Compound of Formula 1, or
a pharmaceutically acceptable salt thereof, in an amount from 75 mg
per day to 250 mg per day, and tenofovir, or a pharmaceutically
acceptable salt or prodrug thereof, in an amount of 300 mg per day.
In an embodiment, the co-administration of a Compound of Formula 1,
or a pharmaceutically acceptable salt thereof, and tenofovir, or a
pharmaceutically acceptable salt or prodrug thereof, produces a
synergistic effect.
[0092] In some embodiments, the present disclosure provides methods
of treating HBV infection in a patient in need thereof, comprising
administering to the patient a Compound of Formula 1 or a
pharmaceutically acceptable salt thereof in an amount from 75 mg
per day to 250 mg per day, and tenofovir alafenamide or a
pharmaceutically acceptable salt thereof in an amount of 300 mg per
day. In an embodiment, the co-administration of a Compound of
Formula 1 or a pharmaceutically acceptable salt thereof, and
tenofovir alafenamide or a pharmaceutically acceptable salt
thereof, produces a synergistic effect.
[0093] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient a Compound of Formula 1, or
a pharmaceutically acceptable salt thereof, in an amount from 75 mg
per day to 250 mg per day, and entecavir, or a pharmaceutically
acceptable salt, in an amount of 0.5 mg per day. In an embodiment,
the co-administration of a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, and entecavir, or a
pharmaceutically acceptable salt, produces a synergistic effect. In
another embodiment, the present disclosure provides methods of
treating HBV infection in a patient in need thereof, comprising
administering to the patient a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and tenofovir, or a pharmaceutically acceptable salt, or
prodrug thereof, in an amount of 300 mg per day.
[0094] In some embodiments, the present disclosure provides methods
of treating HBV infection in a patient in need thereof, comprising
administering to the patient a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount of 300 mg per day.
[0095] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient a Compound of Formula 1, or
a pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and entecavir, or a pharmaceutically acceptable salt, in
an amount of 0.5 mg per day.
[0096] Also provided herein are methods of treating HBV infection
in a patient in need thereof, comprising administering to the
patient Compound A, or a pharmaceutically acceptable salt thereof,
in an amount from 50 mg per day to 500 mg per day, wherein Compound
A is administered once per day. In embodiments, the patient is
administered Compound A for a duration of 28 days. In some
embodiments, the amount of Compound A administered to the patient
is from 75 mg per day to 250 mg per day. In some embodiments, the
amount of Compound A administered to the patient is 75 mg per day.
In some embodiments, the amount of Compound A, or a
pharmaceutically acceptable salt thereof, is 150 mg per day. In a
particular embodiment, the amount of Compound A administered to the
patient is 250 mg per day.
[0097] In an alternative embodiment, the present disclosure
provides methods of preventing HBV infection in a patient at risk
of being infected with HBV, comprising administering to the patient
Compound A, or a pharmaceutically acceptable salt thereof, in an
amount from 50 mg per day to 500 mg per day, wherein Compound A is
administered once per day. Thus, in a particular embodiment, the
present disclosure provides methods of preventing HBV infection in
a patient at risk of being infected with HBV, comprising
administering to the patient Compound A, or a pharmaceutically
acceptable salt thereof, in an amount of 250 mg per day.
[0098] In some embodiments of the methods, Compound A is
co-administered with a transcription inhibitor. In some
embodiments, the transcription inhibitor is a nucleos(t)ide
analogue. In some embodiments, the nucleos(t)ide inhibitor is
tenofovir or a pharmaceutically acceptable salt thereof or a
prodrug thereof (such as tenofovir disoproxil fumarate (TDF),
tenofovir alafenamide (TAF), or a pharmaceutically acceptable salt
thereof), or entecavir or a pharmaceutically acceptable salt
thereof. In some embodiments, Compound A is co-administered with
tenofovir disoproxil fumarate. In some embodiments, Compound A is
co-administered with tenofovir alafenamide. In other embodiments,
Compound A is co-administered with entecavir monohydrate.
[0099] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and a transcription inhibitor.
[0100] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and a nucleos(t)ide analogue.
[0101] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and tenofovir, or a pharmaceutically
acceptable salt, or prodrug thereof, in an amount from 60 mg per
day to 600 mg per day.
[0102] In some embodiments, the present disclosure provides methods
of treating HBV infection in a patient in need thereof, comprising
administering to the patient Compound A, or a pharmaceutically
acceptable salt thereof, in an amount from 50 mg per day to 500 mg
per day, and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount from 60 mg per day to 600 mg
per day.
[0103] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and entecavir, or a pharmaceutically
acceptable salt, in an amount from 0.1 mg per day to 1 mg per
day.
[0104] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
per day to 250 mg per day, and tenofovir, or a pharmaceutically
acceptable salt or prodrug thereof, in an amount of 300 mg per day.
In an embodiment, the co-administration of Compound A, or a
pharmaceutically acceptable salt thereof, and tenofovir, or a
pharmaceutically acceptable salt or prodrug thereof, produces a
synergistic effect.
[0105] In some embodiments, the present disclosure provides methods
of treating HBV infection in a patient in need thereof, comprising
administering to the patient Compound A, or a pharmaceutically
acceptable salt thereof, in an amount from 75 mg per day to 250 mg
per day, and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount of 300 mg per day. In an
embodiment, the co-administration of Compound A, or a
pharmaceutically acceptable salt thereof, and tenofovir
alafenamide, or a pharmaceutically acceptable salt thereof,
produces a synergistic effect.
[0106] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
per day to 250 mg per day, and entecavir, or a pharmaceutically
acceptable salt, in an amount of 0.5 mg per day. In an embodiment,
the co-administration of Compound A, or a pharmaceutically
acceptable salt thereof, and entecavir, or a pharmaceutically
acceptable salt, produces a synergistic effect.
[0107] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and tenofovir, or a pharmaceutically acceptable salt, or
prodrug thereof, in an amount of 300 mg per day.
[0108] In some embodiments, the present disclosure provides methods
of treating HBV infection in a patient in need thereof, comprising
administering to the patient Compound A, or a pharmaceutically
acceptable salt thereof, in an amount of 250 mg per day, and
tenofovir alafenamide, or a pharmaceutically acceptable salt
thereof, in an amount of 300 mg per day.
[0109] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound A, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and entecavir, or a pharmaceutically acceptable salt, in
an amount of 0.5 mg per day.
[0110] Also provided herein are methods of treating HBV infection
in a patient in need thereof, comprising administering to the
patient Compound B, or a pharmaceutically acceptable salt thereof,
in an amount from 50 mg per day to 500 mg per day, wherein Compound
B is administered once per day. In embodiments, the patient is
administered Compound B for a duration of 28 days. In some
embodiments, the amount of Compound B administered to the patient
is from 75 mg per day to 250 mg per day. In some embodiments, the
amount of Compound B administered to the patient is 75 mg per day.
In some embodiments, the amount of Compound B, or a
pharmaceutically acceptable salt thereof, is 150 mg per day. In a
particular embodiment, the amount of Compound B administered to the
patient is 250 mg per day.
[0111] In an alternative embodiment, the present disclosure
provides methods of preventing HBV infection in a patient at risk
of being infected with HBV, comprising administering to the patient
Compound B, or a pharmaceutically acceptable salt thereof, in an
amount from 50 mg per day to 500 mg per day, wherein Compound B is
administered once per day. Thus, in a particular embodiment, the
present disclosure provides methods of preventing HBV infection in
a patient at risk of being infected with HBV, comprising
administering to the patient Compound B, or a pharmaceutically
acceptable salt thereof, in an amount of 250 mg per day.
[0112] In some embodiments of the methods, Compound B is
co-administered with a transcription inhibitor. In some
embodiments, the transcription inhibitor is a nucleos(t)ide
analogue. In some embodiments, the nucleos(t)ide inhibitor is
tenofovir or a pharmaceutically acceptable salt thereof or a
prodrug thereof (such as tenofovir disoproxil fumarate (TDF),
tenofovir alafenamide (TAF), or a pharmaceutically acceptable salt
thereof), or entecavir, or a pharmaceutically acceptable salt
thereof. In some embodiments, Compound B is co-administered with
tenofovir disoproxil fumarate. In some embodiments, Compound B is
co-administered with tenofovir alafenamide. In other embodiments,
Compound B is co-administered with entecavir monohydrate.
[0113] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and a transcription inhibitor.
[0114] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and a nucleos(t)ide analogue.
[0115] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and tenofovir, or a pharmaceutically
acceptable salt, or prodrug thereof, in an amount from 60 mg per
day to 600 mg per day.
[0116] In some embodiments, the disclosure provides methods of
treating HBV infection in a patient in need thereof, comprising
administering to the patient Compound B, or a pharmaceutically
acceptable salt thereof, in an amount from 50 mg per day to 500 mg
per day, and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount from 60 mg per day to 600 mg
per day.
[0117] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
per day to 500 mg per day, and entecavir, or a pharmaceutically
acceptable salt, in an amount from 0.1 mg per day to 1 mg per
day.
[0118] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
per day to 250 mg per day, and tenofovir, or a pharmaceutically
acceptable salt or prodrug thereof, in an amount of 300 mg per day.
In an embodiment, the co-administration of Compound B, or a
pharmaceutically acceptable salt thereof, and tenofovir, or a
pharmaceutically acceptable salt or prodrug thereof, produces a
synergistic effect.
[0119] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
per day to 250 mg per day, and tenofovir alafenamide, or a
pharmaceutically acceptable salt thereof, in an amount of 300 mg
per day. In an embodiment, the co-administration of Compound B, or
a pharmaceutically acceptable salt thereof, and tenofovir
alafenamide, or a pharmaceutically acceptable salt thereof,
produces a synergistic effect.
[0120] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
per day to 250 mg per day, and entecavir, or a pharmaceutically
acceptable salt, in an amount of 0.5 mg per day. In an embodiment,
the co-administration of Compound B, or a pharmaceutically
acceptable salt thereof, and entecavir, or a pharmaceutically
acceptable salt, produces a synergistic effect.
[0121] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and tenofovir, or a pharmaceutically acceptable salt, or
prodrug thereof, in an amount of 300 mg per day.
[0122] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and tenofovir alafenamide, or a pharmaceutically
acceptable salt, in an amount of 300 mg per day.
[0123] In another embodiment, the present disclosure provides
methods of treating HBV infection in a patient in need thereof,
comprising administering to the patient Compound B, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day, and entecavir, or a pharmaceutically acceptable salt, in
an amount of 0.5 mg per day.
[0124] Patients who can be treated using the described methods are
in some embodiments human. Other warm-blooded animals can also be
treated.
[0125] In embodiments of the methods of treating HBV infection
provided herein, the patient in need thereof is a chronically
HBV-infected patient, with or without evidence of underlying liver
inflammation. In some embodiments, the patient has a chronic HBV
infection. In other embodiments, the patient is suffering from an
HBV-induced disease. In some embodiments, the HBV-induced disease
is cirrhosis, liver failure or hepatocellular carcinoma. In other
embodiments, the patient is a treatment-naive patient. More in
particular, the patient is a chronically HBV-infected
treatment-naive patient. In a further embodiment, the patient is
HBeAg-positive. In still a further embodiment, the patient is
treatment-naive and HBeAg-positive.
[0126] HBV infections that can be treated according to the
disclosed methods include HBV genotype A, B, C, and/or D
infections. However, in an embodiment, the methods disclosed can
treat any HBV genotype ("pan-genotypic treatment"). HBV genotyping
can be performed using methods known in the art, for example,
INNO-LIPA.RTM. HBV Genotyping, Innogenetics N.V., Ghent,
Belgium).
[0127] The methods of treating HBV infection as provided herein, in
particular, treat HBV infection by reducing serum HBV DNA in a
patient, by reducing serum HBV RNA in a patient, and/or by reducing
serum HBeAg in a patient.
[0128] Thus, in an additional embodiment, provided herein is a
method of reducing serum HBV DNA in a patient comprising
administering to the patient in need thereof a Compound of Formula
1, or a pharmaceutically acceptable salt thereof, in an amount from
50 mg to 500 mg per day.
[0129] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day.
[0130] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day.
[0131] In an additional embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and tenofovir, or a pharmaceutically acceptable
salt or prodrug thereof, in an amount from 60 mg to 600 mg per
day.
[0132] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and tenofovir, or a pharmaceutically acceptable
salt or prodrug thereof, in an amount of 300 mg per day.
[0133] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and tenofovir, or a pharmaceutically acceptable salt or
prodrug thereof, in an amount of 300 mg per day.
[0134] In an additional embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount from 60 mg to 600 mg per
day.
[0135] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount of 300 mg per day.
[0136] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and tenofovir alafenamide, or a pharmaceutically acceptable
salt thereof, in an amount of 300 mg per day.
[0137] In an additional embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and entecavir, or a pharmaceutically acceptable
salt thereof, in an amount from 0.1 mg to 1 mg per day.
[0138] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and entecavir, or a pharmaceutically acceptable
salt thereof, in an amount of 0.5 mg per day.
[0139] In another embodiment, provided herein is a method of
reducing serum HBV DNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and entecavir, or a pharmaceutically acceptable salt
thereof, in an amount of 0.5 mg per day.
[0140] In some embodiments of the method of reducing serum HBV DNA
provided herein, the Compound of Formula 1 is Compound A. In some
embodiments of the method of reducing serum HBV DNA provided
herein, the Compound of Formula 1 is Compound B.
[0141] In a further embodiment, the disclosure relates to a method
of reducing serum HBV RNA in a patient comprising administering to
the patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day.
[0142] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day.
[0143] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day.
[0144] In an additional embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, in an amount from 60 mg to 600 mg per
day.
[0145] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, in an amount of 300 mg per day.
[0146] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and tenofovir, or a pharmaceutically acceptable salt or
prodrug thereof, in an amount of 300 mg per day.
[0147] In an additional embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and tenofovir alafenamide, or a pharmaceutically
acceptable salt, in an amount from 60 mg to 600 mg per day.
[0148] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and tenofovir alfenamide, or a pharmaceutically
acceptable salt, in an amount of 300 mg per day.
[0149] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and tenofovir alefanimide, or a pharmaceutically acceptable
salt in an amount of 300 mg per day.
[0150] In an additional embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and entecavir, or a pharmaceutically acceptable
salt thereof, in an amount from 0.1 mg to 1 mg per day.
[0151] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and entecavir, or a pharmaceutically acceptable
salt thereof, in an amount of 0.5 mg per day.
[0152] In another embodiment, provided herein is a method of
reducing serum HBV RNA in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and entecavir, or a pharmaceutically acceptable salt
thereof, in an amount of 0.5 mg per day.
[0153] In some embodiments of the method of reducing serum HBV RNA
provided herein, the Compound of Formula 1 is Compound A. In some
embodiments of the method of reducing serum HBV RNA provided
herein, the Compound of Formula 1 is Compound B.
[0154] In an additional embodiment, the disclosure relates to a
method of reducing serum HBeAg in a patient comprising
administering to the patient in need thereof a Compound of Formula
1, or a pharmaceutically acceptable salt thereof, in an amount from
50 mg to 500 mg per day.
[0155] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day.
[0156] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day.
[0157] In an additional embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, in an amount from 60 mg to 600 mg per
day.
[0158] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, in an amount of 300 mg per day.
[0159] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and tenofovir, or a pharmaceutically acceptable salt, or
prodrug thereof, in an amount of 300 mg per day.
[0160] In an additional embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount from 60 mg to 600 mg per
day.
[0161] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, in an amount of 300 mg per day.
[0162] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and tenofovir aladenamide, or a pharmaceutically acceptable
salt thereof, in an amount of 300 mg per day.
[0163] In an additional embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg per day and entecavir, or a pharmaceutically acceptable
salt thereof, in an amount from 0.1 mg to 1 mg per day.
[0164] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 75 mg
to 250 mg per day and entecavir, or a pharmaceutically acceptable
salt thereof, in an amount of 0.5 mg per day.
[0165] In another embodiment, provided herein is a method of
reducing serum HBeAg in a patient comprising administering to the
patient in need thereof a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 250 mg
per day and entecavir, or a pharmaceutically acceptable salt
thereof, in an amount of 0.5 mg per day.
[0166] In some embodiments of the method of reducing serum HBeAg
provided herein, the Compound of Formula 1 is Compound A. In some
embodiments of the method of reducing serum HBeAg provided herein,
the Compound of Formula 1 is Compound B.
[0167] Serum HBV DNA quantitation can be performed according to
methods known in the art, for example, using the polymerase chain
reaction (PCR)-based assay COBAS.RTM. TAQMAN.RTM. HBV Test v2.0
(Roche Diagnostics), which has been validated to quantify HBV DNA
from serum samples for diverse HBV genotypes (A-H) including
pre-core mutant HBV strains, with a reported lower limit of
detection of 35 IU/mL and a linear dynamic range of quantitation of
1.7.times.10.sup.2 to 8.5.times.10.sup.8 IU/mL IU/mL, using the WHO
pooled serum reference standard for quantitation.
[0168] Serum HBsAg and HBeAg levels can be measured using for
example, the investigational Abbott ARCHITECT.TM. assays (Abbott
Laboratories; Abbott Park, Ill., USA).
[0169] In another aspect, provided herein is a method of decreasing
formation of HBV cccDNA in a subject infected with HBV or at risk
of being infected with HBV, said method comprising administering to
said subject a Compound of Formula 1 at a daily dose of 50-500
mg.
[0170] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg.
[0171] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 250 mg.
[0172] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 50-500 mg; and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, at a daily dose of 60-600 mg.
[0173] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg; and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, at a daily dose of 300 mg.
[0174] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 250 mg; and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, at a daily dose of 300 mg.
[0175] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 50-500 mg; and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, at a daily dose of 60-600 mg.
[0176] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg; and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, at a daily dose of 300 mg.
[0177] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 250 mg; and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, at a daily dose of 300 mg.
[0178] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 50-500 mg; and entecavir, or a pharmaceutically acceptable
salt thereof, at a daily dose of 0.1-1 mg.
[0179] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg; and entecavir, or a pharmaceutically acceptable
salt thereof, at a daily dose of 0.5 mg.
[0180] In another embodiment, provided herein is a method of
decreasing formation of HBV cccDNA in a subject infected with HBV
or at risk of being infected with HBV, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 250 mg; and entecavir, or a pharmaceutically acceptable
salt thereof, at a daily dose of 0.5 mg.
[0181] In an embodiment of the method of decreasing formation of
HBV cccDNA, a Compound of Formula 1 is formulated with stabilizer.
In an embodiment of method of decreasing formation of HBV cccDNA,
the stabilizer is HPMC (for example HPMC E5) or HPMC-AS. In an
embodiment of the method of decreasing formation of HBV cccDNA, the
stabilizer is HPMC (for example HPMC E5). In an embodiment of the
method of decreasing formation of HBV cccDNA, the stabilizer is
HPMC-AS.
[0182] In some embodiments of the method of decreasing formation of
HBV cccDNA provided herein, the Compound of Formula 1 is Compound
A. In some embodiments of the method of decreasing formation of HBV
cccDNA provided herein, the Compound of Formula 1 is Compound
B.
[0183] In another aspect, provided herein is a method of decreasing
HBsAg in a subject infected with HBV or at risk of being infected
with HBV, said method comprising administering to said subject a
Compound of Formula 1 at a daily dose of 50-500 mg.
[0184] In an embodiment, provided herein is a method of decreasing
HBsAg in a subject infected with HBV or at risk of being infected
with HBV, said method comprising administering to said subject a
Compound of Formula 1 at a daily dose of 75-250 mg.
[0185] In another embodiment, provided herein is a method of
decreasing HBsAg in a subject infected with HBV or at risk of being
infected with HBV, said method comprising administering to said
subject a Compound of Formula 1 at a daily dose 250 mg.
[0186] In another embodiment, provided herein is a method of
decreasing HBsAg in a subject infected with HBV or at risk of being
infected with HBV, said method comprising administering to said
subject a Compound of Formula 1 at a daily dose of 50-500 mg; and
tenofovir, or a pharmaceutically acceptable salt, or prodrug
thereof, at a daily dose of 60-600 mg.
[0187] In an embodiment, provided herein is a method of decreasing
HBsAg in a subject infected with HBV or at risk of being infected
with HBV, said method comprising administering to said subject a
Compound of Formula 1 at a daily dose of 75-250 mg; and tenofovir,
or a pharmaceutically acceptable salt, or prodrug thereof, at a
daily dose of 300 mg.
[0188] In another embodiment, provided herein is a method of
decreasing HBsAg in a subject infected with HBV or at risk of being
infected with HBV, said method comprising administering to said
subject a Compound of Formula 1 at a daily dose 250 mg; and
tenofovir, or a pharmaceutically acceptable salt, or prodrug
thereof, at a daily dose of 300 mg.
[0189] In another embodiment, provided herein is a method of
decreasing HBsAg in a subject infected with HBV or at risk of being
infected with HBV, said method comprising administering to said
subject a Compound of Formula 1 at a daily dose of 50-500 mg; and
tenofovir alafenamide, or a pharmaceutically acceptable salt
thereof, at a daily dose of 60-600 mg.
[0190] In an embodiment, provided herein is a method of decreasing
HBsAg in a subject infected with HBV or at risk of being infected
with HBV, said method comprising administering to said subject a
Compound of Formula 1 at a daily dose of 75-250 mg; and tenofovir
alafenamide, or a pharmaceutically acceptable salt thereof, at a
daily dose of 300 mg.
[0191] In another embodiment, provided herein is a method of
decreasing HBsAg in a subject infected with HBV or at risk of being
infected with HBV, said method comprising administering to said
subject a Compound of Formula 1 at a daily dose 250 mg; and
tenofovir alafenamide, or a pharmaceutically acceptable salt
thereof, at a daily dose of 300 mg.
[0192] In another embodiment, provided herein is a method of
decreasing HBsAg in a subject infected with HBV or at risk of being
infected with HBV, said method comprising administering to said
subject a Compound of Formula 1 at a daily dose of 50-500 mg; and
entecavir, or a pharmaceutically acceptable salt thereof, at a
daily dose of 0.1-1 mg.
[0193] In an embodiment, provided herein is a method of decreasing
HBsAg in a subject infected with HBV or at risk of being infected
with HBV, said method comprising administering to said subject a
Compound of Formula 1 at a daily dose of 75-250 mg; and entecavir,
or a pharmaceutically acceptable salt thereof, at a daily dose of
0.5 mg.
[0194] In another embodiment, provided herein is a method of
decreasing HBsAg in a subject infected with HBV or at risk of being
infected with HBV, said method comprising administering to said
subject a Compound of Formula 1 at a daily dose 250 mg; and
entecavir, or a pharmaceutically acceptable salt thereof, at a
daily dose of 0.5 mg.
[0195] In some embodiments of the method of decreasing HBsAg, a
Compound of Formula 1 is administered in a tablet formulation. In
an embodiment of the method of decreasing HBsAg, a Compound of
Formula 1 is formulated with stabilizer. In an embodiment of method
of decreasing HBsAg, the stabilizer is HPMC (for example HPMC E5)
or HPMC-AS. In an embodiment of the method of decreasing HBsAg, the
stabilizer is HPMC (for example HPMC E5). In an embodiment of the
method of decreasing HBsAg, the stabilizer is HPMC-AS.
[0196] In some embodiments of the method of decreasing HBsAg
provided herein, the Compound of Formula 1 is Compound A. In some
embodiments of the method of decreasing HBsAg provided herein, the
Compound of Formula 1 is Compound B.
[0197] In yet another aspect, provided herein is a method of
preventing HBV infection in a subject at risk of being infected
with HBV by decreasing formation of HBV cccDNA, said method
comprising administering to said subject a Compound of Formula 1 at
a daily dose of 50-500 mg (more particularly at the above-mentioned
doses or daily doses).
[0198] In an embodiment, provided herein is a method of preventing
HBV infection in a subject at risk of being infected with HBV by
decreasing formation of HBV cccDNA, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg (more particularly at the above-mentioned doses
or daily doses).
[0199] In another embodiment, provided herein is a method of
preventing HBV infection in a subject at risk of being infected
with HBV by decreasing formation of HBV cccDNA, said method
comprising administering to said subject a Compound of Formula 1 at
a daily dose of 250 mg.
[0200] In an embodiment, provided herein is a method of preventing
HBV infection in a subject at risk of being infected with HBV by
decreasing formation of HBV cccDNA, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 50-500 mg (more particularly at the above-mentioned doses
or daily doses); and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, at a daily dose of 60-600 mg.
[0201] In an embodiment, provided herein is a method of preventing
HBV infection in a subject at risk of being infected with HBV by
decreasing formation of HBV cccDNA, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg (more particularly at the above-mentioned doses
or daily doses); and tenofovir, or a pharmaceutically acceptable
salt, or prodrug thereof, at a daily dose of 300 mg.
[0202] In another embodiment, provided herein is a method of
preventing HBV infection in a subject at risk of being infected
with HBV by decreasing formation of HBV cccDNA, said method
comprising administering to said subject a Compound of Formula 1 at
a daily dose of 250 mg; and tenofovir, or a pharmaceutically
acceptable salt, or prodrug thereof, at a daily dose of 300 mg.
[0203] In an embodiment, provided herein is a method of preventing
HBV infection in a subject at risk of being infected with HBV by
decreasing formation of HBV cccDNA, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 50-500 mg (more particularly at the above-mentioned doses
or daily doses); and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, at a daily dose of 60-600 mg.
[0204] In an embodiment, provided herein is a method of preventing
HBV infection in a subject at risk of being infected with HBV by
decreasing formation of HBV cccDNA, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg (more particularly at the above-mentioned doses
or daily doses); and tenofovir alafenamide, or a pharmaceutically
acceptable salt thereof, at a daily dose of 300 mg.
[0205] In another embodiment, provided herein is a method of
preventing HBV infection in a subject at risk of being infected
with HBV by decreasing formation of HBV cccDNA, said method
comprising administering to said subject a Compound of Formula 1 at
a daily dose of 250 mg; and tenofovir alfenamide, or a
pharmaceutically acceptable salt, at a daily dose of 300 mg.
[0206] In an embodiment, provided herein is a method of preventing
HBV infection in a subject at risk of being infected with HBV by
decreasing formation of HBV cccDNA, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 50-500 mg (more particularly at the above-mentioned doses
or daily doses); and entecavir, or a pharmaceutically acceptable
salt thereof, at a daily dose of 0.1-1 mg.
[0207] In an embodiment, provided herein is a method of preventing
HBV infection in a subject at risk of being infected with HBV by
decreasing formation of HBV cccDNA, said method comprising
administering to said subject a Compound of Formula 1 at a daily
dose of 75-250 mg (more particularly at the above-mentioned doses
or daily doses); and entecavir, or a pharmaceutically acceptable
salt thereof, at a daily dose of 0.5 mg.
[0208] In another embodiment, provided herein is a method of
preventing HBV infection in a subject at risk of being infected
with HBV by decreasing formation of HBV cccDNA, said method
comprising administering to said subject a Compound of Formula 1 at
a daily dose of 250 mg; and entecavir, or a pharmaceutically
acceptable salt thereof, at a daily dose of 0.5 mg.
[0209] In some embodiments of the method of preventing HBV
infection by decreasing formation of HBV cccDNA, a Compound of
Formula 1 is administered in a tablet formulation. In an embodiment
of the method of preventing HBV infection by decreasing formation
of HBV cccDNA, a Compound of Formula 1 is formulated with
stabilizer. In an embodiment of the method of preventing HBV
infection by decreasing formation of HBV cccDNA, the stabilizer is
HPMC (for example HPMC E5) or HPMC-AS. In an embodiment of the
method of preventing HBV infection by decreasing formation of HBV
cccDNA, the stabilizer is HPMC (for example HPMC E5). In an
embodiment of the method of preventing HBV infection by decreasing
formation of HBV cccDNA, the stabilizer is HPMC-AS.
[0210] In some embodiments of the method of preventing HBV
infection by decreasing formation of HBV cccDNA provided herein,
the Compound of Formula 1 is Compound A. In some embodiments of the
method of preventing HBV infection by decreasing formation of HBV
cccDNA provided herein, the Compound of Formula 1 is Compound
B.
[0211] In an aspect of the methods provided herein, the particular
dosing strategy results in inhibition of DANE particles,
RNA-containing particles, and double-stranded DNA particles but
does not inhibit subviral particles containing HBsAg.
[0212] In another aspect of the methods provided herein, the
particular dosing strategy results in the inhibition of cccDNA,
which results in inhibition of subviral particles containing
HBsAg.
[0213] In some embodiments, a Compound of Formula 1 is administered
in a tablet formulation. In an embodiment, a Compound of Formula 1
is formulated with stabilizer. In an embodiment, the stabilizer is
HPMC (for example HPMC E5) or HPMC-AS. In an embodiment, the
stabilizer is HPMC (for example HPMC E5). In an embodiment, the
stabilizer is HPMC AS.
[0214] In an embodiment, the tablet comprises a Compound of Formula
1 and stabilizer at a ratio of 1:1, 1:2, 1:3, 1:4, or 1:5. In a
particular embodiment, the tablet comprises a Compound of Formula 1
and stabilizer at a ratio of 1:3.
[0215] In another embodiment, the tablet comprises 50-500 mg of a
Compound of Formula 1 (more particularly at the above-mentioned
doses or daily doses) and 150-1500 mg of stabilizer, more
particularly 50-1500 mg of stabilizer. In another embodiment, the
tablet comprises 75-250 mg of a Compound of Formula 1 (more
particularly at the above-mentioned doses or daily doses) and
225-750 mg of stabilizer, more particularly 75-750 mg of
stabilizer. In another embodiment, the tablet comprises 250 mg of a
Compound of Formula 1 and 750 mg of stabilizer.
[0216] A tablet of the application may further comprise one or
several agents selected from fillers, disintegrants, glidants and
lubricants. For example, a tablet of the application may further
comprise at least one filler selected from microcrystalline
cellulose, silicified microcrystalline cellulose and
pre-gelatinized maize starch, at least one disintegrant such as
croscarmellose sodium, at least one glidant such as colloidal
anhydrous silica, and at least one lubricant such as magnesium
stearate.
[0217] In some embodiments, the administration of a Compound of
Formula 1 is performed for an administration period of about 24
weeks. In another embodiment, the administration of a Compound of
Formula 1 is performed for an administration period of longer than
24 weeks. In yet another embodiment, the administration of a
Compound of Formula 1 is performed for an administration period
shorter than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks).
In embodiments, a Compound of Formula 1 is administered for a
duration of 28 days. In embodiments, a Compound of Formula 1 is
administered for a duration of about 48 weeks. In embodiments, a
Compound of Formula 1 is administered for a duration of longer than
48 weeks.
[0218] In some embodiments, the co-administration of a Compound of
Formula 1 and the transcription inhibitor is performed for an
administration period of about 24 weeks. In another embodiment, the
administration of a Compound of Formula 1 and the transcription
inhibitor is performed for an administration period of longer than
24 weeks. In yet another embodiment, the administration of a
Compound of Formula 1 and the transcription inhibitor is performed
for an administration period shorter than 24 weeks (e.g., 10, 12,
14, 16, 18, 20, or 22 weeks). In embodiments, a Compound of Formula
1 and the transcription inhibitor is administered for a duration of
28 days. In embodiments, a Compound of Formula 1 and the
transcription inhibitor is administered for a duration of about 48
weeks. In embodiments, a Compound of Formula 1 and the
transcription inhibitor is administered for a duration of longer
than 48 weeks.
[0219] In some embodiments, the co-administration of a Compound of
Formula 1 and the nucleos(t)ide analogue is performed for an
administration period of about 24 weeks. In another embodiment, the
administration of a Compound of Formula 1 and the nucleos(t)ide
analogue is performed for an administration period of longer than
24 weeks. In yet another embodiment, the administration of a
Compound of Formula 1 and the nucleos(t)ide analogue is performed
for an administration period shorter than 24 weeks (e.g., 10, 12,
14, 16, 18, 20, or 22 weeks). In embodiments, a Compound of Formula
1 and the nucleos(t)ide analogue is administered for a duration of
28 days. In embodiments, a Compound of Formula 1 and the
nucleos(t)ide analogue is administered for a duration of about 48
weeks. In embodiments, a Compound of Formula 1 and the
nucleos(t)ide analogue is administered for a duration of longer
than 48 weeks.
[0220] In some embodiments, the co-administration of a Compound of
Formula 1 and tenofovir is performed for an administration period
of about 24 weeks. In another embodiment, the administration of a
Compound of Formula 1 and tenofovir is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of a Compound of Formula 1 and
tenofovir is performed for an administration period shorter than 24
weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments,
a Compound of Formula 1 and tenofovir is administered for a
duration of 28 days. In embodiments, a Compound of Formula 1 and
tenofovir is administered for a duration of about 48 weeks. In
embodiments, a Compound of Formula 1 and tenofovir is administered
for a duration of longer than 48 weeks.
[0221] In some embodiments, the co-administration of a Compound of
Formula 1 and tenofovir alafenamide is performed for an
administration period of about 24 weeks. In another embodiment, the
administration of a Compound of Formula 1 and tenofovir alafenamide
is performed for an administration period of longer than 24 weeks.
In yet another embodiment, the administration of a Compound of
Formula 1 and tenofovir alafenamide is performed for an
administration period shorter than 24 weeks (e.g., 10, 12, 14, 16,
18, 20, or 22 weeks). In embodiments, a Compound of Formula 1 and
tenofovir alafenamide is administered for a duration of 28 days. In
embodiments, a Compound of Formula 1 and tenofovir alafenamide is
administered for a duration of about 48 weeks. In embodiments, a
Compound of Formula 1 and tenofovir alafenamide is administered for
a duration of longer than 48 weeks.
[0222] In some embodiments, the co-administration of a Compound of
Formula 1 and entecavir is performed for an administration period
of about 24 weeks. In another embodiment, the administration of a
Compound of Formula 1 and entecavir is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of a Compound of Formula 1 and
entecavir is performed for an administration period shorter than 24
weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments,
a Compound of Formula 1 and entecavir is administered for a
duration of 28 days. In embodiments, a Compound of Formula 1 and
entecavir is administered for a duration of about 48 weeks. In
embodiments, a Compound of Formula 1 and entecavir is administered
for a duration of longer than 48 weeks.
[0223] In some embodiments, the administration of Compound A is
performed for an administration period of about 24 weeks. In
another embodiment, the administration of Compound A is performed
for an administration period of longer than 24 weeks. In yet
another embodiment, the administration of Compound A is performed
for an administration period shorter than 24 weeks (e.g., 10, 12,
14, 16, 18, 20, or 22 weeks). In embodiments, Compound A is
administered for a duration of 28 days. In embodiments, Compound A
is administered for a duration of about 48 weeks. In embodiments,
Compound A is administered for a duration of longer than 48
weeks.
[0224] In some embodiments, the co-administration of Compound A and
the transcription inhibitor is performed for an administration
period of about 24 weeks. In another embodiment, the administration
of Compound A and the transcription inhibitor is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of Compound A and the transcription
inhibitor is performed for an administration period shorter than 24
weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments,
Compound A and the transcription inhibitor is administered for a
duration of 28 days. In embodiments, Compound A and the
transcription inhibitor is administered for a duration of about 48
weeks. In embodiments, Compound A and the transcription inhibitor
is administered for a duration of longer than 48 weeks.
[0225] In some embodiments, the co-administration of Compound A and
the nucleos(t)ide analogue is performed for an administration
period of about 24 weeks. In another embodiment, the administration
of Compound A and the nucleos(t)ide analogue is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of Compound A and the nucleos(t)ide
analogue is performed for an administration period shorter than 24
weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments,
Compound A and the nucleos(t)ide analogue is administered for a
duration of 28 days. In embodiments, Compound A and the
nucleos(t)ide analogue is administered for a duration of about 48
weeks. In embodiments, Compound A and the nucleos(t)ide analogue is
administered for a duration of longer than 48 weeks.
[0226] In some embodiments, the co-administration of Compound A and
tenofovir is performed for an administration period of about 24
weeks. In another embodiment, the administration of Compound A and
tenofovir is performed for an administration period of longer than
24 weeks. In yet another embodiment, the administration of Compound
A and tenofovir is performed for an administration period shorter
than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In
embodiments, Compound A and tenofovir is administered for a
duration of 28 days. In embodiments, Compound A and tenofovir is
administered for a duration of about 48 weeks. In embodiments,
Compound A and tenofovir is administered for a duration of longer
than 48 weeks.
[0227] In some embodiments, the co-administration of Compound A and
tenofovir alafenamide is performed for an administration period of
about 24 weeks. In another embodiment, the administration of
Compound A and tenofovir alafenamide is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of Compound A and tenofovir
alafenamide is performed for an administration period shorter than
24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In
embodiments, Compound A and tenofovir alafenamide is administered
for a duration of 28 days. In embodiments, Compound A and tenofovir
alafenamide is administered for a duration of about 48 weeks. In
embodiments, Compound A and tenofovir alafenamide is administered
for a duration of longer than 48 weeks.
[0228] In some embodiments, the co-administration of Compound A and
entecavir is performed for an administration period of about 24
weeks. In another embodiment, the administration of Compound A and
entecavir is performed for an administration period of longer than
24 weeks. In yet another embodiment, the administration of Compound
A and entecavir is performed for an administration period shorter
than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In
embodiments, Compound A and entecavir is administered for a
duration of 28 days. In embodiments, Compound A and entecavir is
administered for a duration of about 48 weeks. In embodiments,
Compound A and entecavir is administered for a duration of longer
than 48 weeks.
[0229] In some embodiments, the administration of Compound B is
performed for an administration period of about 24 weeks. In
another embodiment, the administration of Compound B is performed
for an administration period of longer than 24 weeks. In yet
another embodiment, the administration of Compound B is performed
for an administration period shorter than 24 weeks (e.g., 10, 12,
14, 16, 18, 20, or 22 weeks). In embodiments, Compound B is
administered for a duration of 28 days. In embodiments, Compound B
is administered for a duration of about 48 weeks. In embodiments,
Compound B is administered for a duration of longer than 48
weeks.
[0230] In some embodiments, the co-administration of Compound B and
the transcription inhibitor is performed for an administration
period of about 24 weeks. In another embodiment, the administration
of Compound B and the transcription inhibitor is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of Compound B and the transcription
inhibitor is performed for an administration period shorter than 24
weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments,
Compound B and the transcription inhibitor is administered for a
duration of 28 days. In embodiments, Compound B and the
transcription inhibitor is administered for a duration of about 48
weeks. In embodiments, Compound B and the transcription inhibitor
is administered for a duration of longer than 48 weeks.
[0231] In some embodiments, the co-administration of Compound B and
the nucleos(t)ide analogue is performed for an administration
period of about 24 weeks. In another embodiment, the administration
of Compound B and the nucleos(t)ide analogue is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of Compound B and the nucleos(t)ide
analogue is performed for an administration period shorter than 24
weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In embodiments,
Compound B and the nucleos(t)ide analogue is administered for a
duration of 28 days. In embodiments, Compound B and the
nucleos(t)ide analogue is administered for a duration of about 48
weeks. In embodiments, Compound B and the nucleos(t)ide analogue is
administered for a duration of longer than 48 weeks.
[0232] In some embodiments, the co-administration of Compound B and
tenofovir is performed for an administration period of about 24
weeks. In another embodiment, the administration of Compound B and
tenofovir is performed for an administration period of longer than
24 weeks. In yet another embodiment, the administration of Compound
B and tenofovir is performed for an administration period shorter
than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In
embodiments, Compound B and tenofovir is administered for a
duration of 28 days. In embodiments, Compound B and tenofovir is
administered for a duration of about 48 weeks. In embodiments,
Compound B and tenofovir is administered for a duration of longer
than 48 weeks.
[0233] In some embodiments, the co-administration of Compound B and
tenofovir alafenamide is performed for an administration period of
about 24 weeks. In another embodiment, the administration of
Compound B and tenofovir alafenamide is performed for an
administration period of longer than 24 weeks. In yet another
embodiment, the administration of Compound B and tenofovir
alafenamide is performed for an administration period shorter than
24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In
embodiments, Compound B and tenofovir is administered for a
duration of 28 days. In embodiments, Compound B and tenofovir
alafenamide is administered for a duration of about 48 weeks. In
embodiments, Compound B and tenofovir is administered for a
duration of longer than 48 weeks.
[0234] In some embodiments, the co-administration of Compound B and
entecavir is performed for an administration period of about 24
weeks. In another embodiment, the administration of Compound B and
entecavir is performed for an administration period of longer than
24 weeks. In yet another embodiment, the administration of Compound
B and entecavir is performed for an administration period shorter
than 24 weeks (e.g., 10, 12, 14, 16, 18, 20, or 22 weeks). In
embodiments, Compound B and entecavir is administered for a
duration of 28 days. In embodiments, Compound B and entecavir is
administered for a duration of about 48 weeks. In embodiments,
Compound B and entecavir is administered for a duration of longer
than 48 weeks.
[0235] In some embodiments of the methods provided herein, a
Compound of Formula 1 is in the form of a spray dried power. In
other embodiments of the methods provided herein, the spray dried
powder is formulated in a tablet, or in a capsule, or in a
suspension in water, or in a suspension in an aqueous buffer
solution. In other embodiments of the methods provided herein, each
of these formulations are for oral administration to the subject.
In particular embodiments of the methods provided herein, a
Compound of Formula 1 is administered orally as a 5 mg, 25 mg, or
100 mg tablet.
[0236] In embodiments of the methods provided herein, the Compound
of Formula 1 is administered to reach a maximal concentration
(Cmax) of at least 3,000 ng/mL (e.g., at steady state), in the
plasma of the patient and/or an AUC of at least 50,000 ngh/mL
(e.g., at steady state), in the plasma of the patient.
[0237] In embodiments of the methods provided herein, Compound A is
administered to reach a maximal concentration (Cmax) of at least
3,000 ng/mL, in the plasma of the patient and/or an AUC of at least
50,000 ngh/mL, in the plasma of the patient.
[0238] In embodiments of the methods provided herein, Compound B is
administered to reach a maximal concentration (Cmax) of at least
3,000 ng/mL, in the plasma of the patient and/or an AUC of at least
50,000 ngh/mL, in the plasma of the patient.
[0239] The daily doses described herein are calculated for an
average body weight of about 60 to about 70 kg and should be
recalculated in case of paediatric applications, or when used with
patients with a substantially diverting body weight.
Pharmaceutical Compositions and Kits
[0240] In an aspect, provided herein is a pharmaceutical
composition comprising a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount of 50-500
mg.
[0241] In another aspect, the present disclosure provides a
pharmaceutical product comprising a pharmaceutical composition
comprising a Compound of Formula 1, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier
or diluent. In some embodiments, the pharmaceutical composition
comprises a Compound of Formula 1, or a pharmaceutically acceptable
salt thereof, in an amount that is from about 50 mg to about 500 mg
(more particularly at the above-mentioned doses or daily doses),
and a pharmaceutically acceptable carrier or diluent. In certain
embodiments, the pharmaceutical composition comprises an amount of
a Compound of Formula 1 selected from 50, 75, 100, 150, 250, 300,
400, and 500 mg. In another embodiment, the pharmaceutical
composition comprises an amount of a Compound of Formula 1 is 250
mg.
[0242] In an embodiment of the pharmaceutical composition, the
composition further comprises at least one stabilizer. In some
embodiments of the pharmaceutical composition, the one or more
stabilizers are selected from HPMC (for example HPMC E5) and
HPMC-AS. In an embodiment, at least one of the stabilizers is HPMC
(for example HPMC E5). In an embodiment, at least one of the
stabilizers is HPMC-AS.
[0243] In an embodiment of the pharmaceutical composition, the
composition comprises a Compound of Formula 1 and stabilizer at a
ratio of 1:1, 1:2, 1:3, 1:4, or 1:5. In a particular embodiment,
the composition comprises a Compound of Formula 1 and stabilizer at
a ratio of 1:3.
[0244] In another embodiment of the pharmaceutical composition, the
composition comprises 50-500 mg of a Compound of Formula 1 and
150-1500 mg of stabilizer, more particularly 50-1500 mg of
stabilizer. In another embodiment of the pharmaceutical
composition, the composition comprises 75-250 mg of a Compound of
Formula 1 (more particularly at the above-mentioned doses or daily
doses) and 225-750 mg of stabilizer, more particularly 75-750 mg of
stabilizer. In another embodiment of the pharmaceutical
composition, the composition comprises 250 mg of a Compound of
Formula 1 and 750 mg of stabilizer.
[0245] The pharmaceutical composition can be formulated as a solid
formulation, such as a tablet, a pill or a capsule, or as a liquid
formulation such as a polyethylene glycol solution.
[0246] The pharmaceutical composition can be formulated for oral
administration.
[0247] In another aspect, the present disclosure provides a kit of
parts for treating HBV infections, comprising a Compound of Formula
1, or a pharmaceutically acceptable salt thereof, in an amount from
50 mg per day to 500 mg (more particularly at the above-mentioned
doses or daily doses), and a transcription inhibitor. In another
embodiment, the present disclosure provides a kit of parts for
treating HBV infections, comprising a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg (more particularly at the above-mentioned doses or daily
doses) and a nucleos(t)ide analogue. In another embodiment, the
present disclosure provides a kit of parts for treating HBV
infections, comprising a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg (more particularly at the above-mentioned doses or daily
doses) and tenofovir, or a pharmaceutically acceptable salt, or
prodrug thereof, in an amount of 60 mg to 600 mg. In another
embodiment, the present disclosure provides a kit of parts for
treating HBV infections, comprising a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof, in an amount from 50 mg
to 500 mg (more particularly at the above-mentioned daily doses)
and entecavir, or a pharmaceutically acceptable salt, in an amount
of 0.1 mg to 1 mg. In some embodiments, the kit of parts further
comprises packaging and instructions.
[0248] In some embodiments, the kit of parts comprises a
pharmaceutical composition comprising a Compound of Formula 1, or a
pharmaceutically acceptable salt thereof; an additional HBV
antiviral agent; and a pharmaceutically acceptable carrier or
diluent.
[0249] The additional HBV antiviral agent can e.g., be an immune
modulator (such as interferon), at least one Nucleic Acid Polymer
(more particularly at least one NAP which inhibits the release of
subviral particles from hepatocytes), or at least one small
interfering RNA (siRNA) or antisense oligonucleotide (more
particularly at least one siRNA or ASO selected from the group of
siRNAs and ASOs which inhibit the expression of one or more genes
that are necessary for replication or pathogenesis of HBV).
[0250] In another embodiment, the kit of parts comprises a
pharmaceutical product comprising:
[0251] a pharmaceutical composition comprising a Compound of
Formula 1:
##STR00007##
[0252] or a pharmaceutically acceptable salt thereof,
[0253] wherein:
[0254] A is N or CH;
[0255] R.sup.1 is, independently at each occurrence, selected from
halo, CF.sub.3, and CN;
[0256] R.sup.2 is C.sub.1-C.sub.3 alkyl;
[0257] R.sup.3 is, independently at each occurrence, selected from
C.sub.1-C.sub.3 alkyl and halo;
[0258] R.sup.4 is C.sub.1-C.sub.4 alkyl, which is independently
substituted 1 or 2 times with halo or CF.sub.3;
[0259] n is 0, 1, 2, or 3; and
[0260] m is 0, 1, or 2;
[0261] in an amount from 50 mg to 500 mg (more particularly at the
above-mentioned doses or daily doses), and a pharmaceutically
acceptable carrier or diluent; and
[0262] a nucleos(t)ide analogue;
[0263] a sealed container for housing the pharmaceutical
composition;
[0264] a sealed contained for housing the nucleos(t)ide analogue;
and
[0265] instructions for use.
[0266] In additional embodiments, pharmaceutical kits are provided.
The kit includes a sealed container approved for the storage of
pharmaceutical compositions, the container containing one of the
above-described pharmaceutical compositions. In some embodiments,
the sealed container minimizes the contact of air with the
ingredients, e.g. an airless bottle. In other embodiments, the
sealed container is a sealed tube. An instruction for the use of
the composition and the information about the composition are to be
included in the kit.
[0267] In some embodiments of the kit of parts provided herein, the
Compound of Formula 1 is Compound A:
##STR00008##
[0268] or a pharmaceutically acceptable salt thereof.
[0269] In other embodiments of the kit of parts provided herein,
the Compound of Formula 1 is Compound B:
##STR00009##
[0270] or a pharmaceutically acceptable salt thereof.
[0271] The following examples are merely illustrative and are not
intended to limit the disclosure to the materials, conditions, or
process parameters set forth therein.
Examples
Example 1: Safety, Pharmacokinetics and Antiviral Activity of
Compound a in Treatment Naive Patients with Chronic HBV
[0272] In part 1 of this study (FIG. 1, sessions 1-7), it was shown
that Compound A was well tolerated in healthy subjects at single
doses of up to 600 mg, and at multiple doses of 150 mg for two days
followed by 100 mg once a day for 10 days.
[0273] In part 2 of this study (FIG. 1, sessions 8-9), the
objective was to evaluate the safety, PK, and antiviral activity of
Compound A in treatment naive, chronic hepatitis B patients over a
28-day treatment period. The patient criteria were:
[0274] HBeAg-positive or negative
[0275] Plasma HBV DNA>2.0 log 10 IU/mL
[0276] ALT/AST<2.5.times.ULN
[0277] METAVIR stage<F3.
1.1 Patient Baseline Characteristics
[0278] The baseline characteristics of the patients in the study
are described in Table 1 below.
TABLE-US-00001 TABLE 1 Baseline Patient Characteristics Session 8
Session 9 Analysis set: Intent-to-treat (n = 12)* (n = 12)* Mean
age, years (SD) 39.5 (11.6) 36.5 (10.2) Sex - Male, n (%) 11 (92)
10 (83) Race - White, n (%) 6 (50) 12 (100) HBeAg positive, n (%) 6
(50) 3 (25) Mean HBV DNA log10 IU/mL (SD) 6.41 (1.99) 5.36 (1.54)
ALT Grade, n (%) Grade 0 9 (75) 9 (75) Grade 1 3 (25) 3 (25)
Fibrosis stage n, (%) F0 4 (33) 5 (42) F1 6 (50) 4 (33) F2 2 (17) 3
(25) HBV genotype, n (%) n = 10 n = 9 A 2 (20) 1 (11) C 2 (20) 0 D
5 (50) 8 (89) E 1 (10) 0
[0279] The study showed that there were no serious adverse events
(SAEs) or adverse events (AEs) of clinical concern and no treatment
discontinuations. Further, no patients showed clinically
significant ECG changes or persistent/worsening vital sign
abnormalities (see Table 2 below). Although no patients had Grade 3
or 4 AEs on treatment, one patient had Grade 1 & 2 ALT and
Grade 1 AST elevations on treatment that rose to Grade 3 & 4
ALT and Grade 3 AST elevations in follow up. No treatment-emergent
Grade 3 or 4 laboratory abnormalities were reported, with the
exception of the Grade 3 amylase increase.
TABLE-US-00002 TABLE 2 Evaluation of Adverse Events 25 mg Compound
A 75 mg Pooled (100 mg Day Compound A placebo 1; n = 8) (n = 8) (n
= 8) On-treatment AEs (28 days) At least one AE 5 (63) 4 (50) 5
(63) Worst Grade 1 AEs, n (%) 3 (38) 2 (25) 4 (50) Worst Grade 2
AEs, n (%) 1 (13) 1 (13) 1 (13) Worst Grade 3 AEs, n (%) 1 (13) 0
(0)* 0 (0) Most common AEs (.gtoreq.2 patients) Amylase Increased 2
(25)** 0 0 Headache 2 (25) 0 3 (38)
1.2 Pharmacokinetics
[0280] FIG. 2 shows that the pharmacokinetics were
dose-proportional and apparent clearance was low in both treatment
arms. The exposure (Cmax, AUC) increased in a dose-dependent manner
with time-linear PK. The pharmacokinetics of Compound A were not
markedly different between healthy volunteers and patients. Mean
Compound A exposures in patients with CHB could be predicted from
data in healthy volunteers. Mean (.+-.SD) exposure in the 75 mg arm
was within 90% prediction interval. Mean dose normalized Cmax at
steady state was 56.6 ng/mL (25 mg) and 53.2 ng/mL (75 mg). Mean
dose normalized AUC 0-24 h was 1109 ngh/mL for both the 25 mg and
75 mg groups. Apparent clearance was low and similar in the two
dosing groups (1 and 0.9 L/h at 25 mg and 75 mg, respectively).
1.3 HBV Reduction
[0281] HBV DNA was assessed for each patient weekly during this
study (see FIG. 3). A mean reduction in plasma HBV DNA levels of
2.16 (.+-.0.49 SD) log.sub.10 IU/mL (25 mg Compound A) and 2.89
(.+-.0.48 SD) log.sub.10 IU/mL (75 mg Compound A) from baseline was
observed after 28 days. Three patients dosed with 75 mg QD achieved
HBV DNA below the level of quantification of the HBV DNA assay
while none in the 25 mg Compound A group achieved this. A more
pronounced and consistent decline in HBV DNA was observed across
patients in the 75 mg group compared with the 25 mg group.
Consistent with HBV DNA, substantial reductions in HBV RNA levels
were observed with Compound A treatment, although baseline levels
were low (see Table 3 below).
TABLE-US-00003 TABLE 3 HBV DNA and RNA analysis HBV DNA HBV RNA Day
29 Day 29 Mean (SD) Mean (SD) Baseline Change from Baseline* Change
from Mean (SD) Baseline Mean (SD) Baseline Treatment log.sub.10
log.sub.10 log.sub.10 log.sub.10 Not arm N IU/mL IU/mL <LLOQ N
cp/mL cp/mL detected 25 mg QD 8 6.90 (1.91) -2.16 (0.49) 0 8 5.60
(2.37) -2.30 (0.59) 3 75 mg QD 8 5.26 (1.50) -2.89 (0.48) 3 8 3.39
(2.21) -1.85 (1.42) 6 Pooled 8 5.49 (1.77) -0.01 (0.31) 0 8 4.03
(2.64) -0.18 (0.72) 2 placebo
1.4 Conclusions
[0282] Across the two dose groups (n=24), patients had a median age
of 36 years (range: 21-58) with 88% males and 75% Caucasian.
Overall, 38% of patients were HBeAg-positive, and mean (.+-.SD)
baseline HBV DNA was 5.88 (.+-.1.82) log 10 IU/mL. AEs or
laboratory abnormalities Grade 3 were infrequent (2 patients/dose).
Of patients treated with Compound A, 56% (9/16) experienced at
least one adverse event (AE) during treatment (5 patients in the 25
mg arm, and 4 patients in the 75 mg arm) compared to 63% (5/8) in
the placebo arm. There were no serious AEs, no discontinuations due
to AEs, and no dose-limiting toxicities. After 28 days, mean
(.+-.SD) reductions in HBV DNA levels from baseline of 2.16
(.+-.0.49) log 10 IU/mL (25 mg QD) and 2.89 (.+-.0.48) log 10 IU/mL
(75 mg QD) were observed. Three patients dosed with 75 mg QD
achieved HBV DNA below the level of quantification of the HBV DNA
assay but no patients dosed with 25 mg QD reached HBV DNA below
quantification. In addition, a decline in HBV RNA levels was
observed in both Compound A treatment groups; while reduction in
HBV RNA was higher in the 25 mg group than the 75 mg group, more
patients in the 75 mg (n=6) than the 25 mg group (n=3) achieved HBV
RNA below the level of quantification of the HBV RNA assay.
Example 2: Safety, Tolerability and Pharmacokinetics of Single
Ascending Doses of Compound a in Healthy Subjects
[0283] A double-blind, placebo-controlled study was done to assess
the safety, tolerability, and pharmacokinetics (PK) of Compound A.
Thirty-two healthy adult Japanese volunteers were randomized into
four cohorts. The volunteers were randomized 3:1 to receive a
single dose of Compound A or placebo in a fasted state (see FIG.
4). The safety, tolerability and PK plasma profiles of Compound A
were assessed after each dose. Full plasma PK profiles were
determined up to 28 days after each single dose of Compound A.
Urinary elimination was assessed in Cohort C (see FIG. 4) for 7
day.
2.1 Healthy Volunteers Baseline Characteristics
[0284] The baseline characteristics of the subjects are summarized
in Table 4 below.
TABLE-US-00004 TABLE 4 Baseline Patient Characteristics Compound A
Placebo 25 mg 150 mg 300 mg 500 mg (n = 8) (n = 6) (n = 6) (n = 6)
(n = 6) Median 47.0 (32; 54) 34.0 (32; 51) 31.5 (26; 55) 40.0 (31;
55) 42.0 (28; 55) age (years [range]) Sex, n (%) 7 (88) 6 (100) 6
(100) 5 (83) 4 (67) Male Race 8 (100) 6 (100) 6 (100) 6 (100) 6
(100) Asian Median 22.90 23.29 21.74 24.40 22.25 BMI
(kg/m.sup.2)
[0285] Compound A was well tolerated. No volunteers experienced an
SAE or prematurely discontinued the study for an AE. The treatment
emergent adverse events (TEAEs) reported were hiccups, upper
respiratory tract infection, nasal congestion, and cough. All TEAEs
were mild and were resolved before the end of the study. The AEs
are summarized in Table 5 below.
TABLE-US-00005 TABLE 5 Adverse Events Compound A Placebo 25 mg 150
mg 300 mg 500 mg Total (n = 8) (0 = 6) (n = 6) (n = 6) (n = 6) (n =
32) Treatment-emergent AEs Volunteers with 0 0 2 (33) 0 2 (33) 4
(17) .gtoreq.1 AE Related to 0 0 0 0 0 0 Compound A SAEs 0 0 0 0 0
0 Deaths 0 0 0 0 0 0
[0286] No significant laboratory abnormalities were discovered,
most laboratory abnormalities were Grade 1. No Grade 3 or 4
abnormalities were reported. The laboratory abnormalities from the
study are summarized in Table 6 below.
TABLE-US-00006 TABLE 6 Laboratory Abnormalities Compound A Placebo
25 mg 150 mg 300 mg 500 mg Total (n = 8) (n = 6) (n = 6) (n = 6) (n
= 6) (n = 32) Grade 2 AEs Bilirubin 0 0 0 0 0 0 increased
Cholesterol 0 0 0 0 0 0 increased Triglycerides 1 (13) 1 (17) 0 1
(17) 0 2 (8) increased Leukocytes 0 0 0 0 0 0 decreased Fibrinogen
0 0 0 0 0 0 decreased
2.2 Pharmacokinetics
[0287] The PKs were dose-dependent in all four treatment cohorts.
The PK data is summarized in FIG. 5 and Table 7 below. Mean values
of CL/F, Vd/F and T1/2 term were comparable between dose levels.
The inter-subject variability, expressed as % CV, was low to
moderate and similar across dose levels. After single dose
administration of 300 mg of Compound A in Cohort C, 53.9 mg of the
unchanged drug was excreted in urine. Compound A is a low clearance
drug, with 18% of the administered dose excreted via the
kidneys.
TABLE-US-00007 TABLE 7 Pharmacokinetics Compound A 25 mg 150 mg 300
mg 500 mg Pharmacokinetics (n = 6)* (n = 6) (n = 6) (n = 6) Median
t.sub.max, h 1.75 (1.00-2.00) 3.00 (1.50-6.00) 3.00 (1.50-6.00)
1.75 (1.00-3.00) (range) Mean C.sub.max, 375 (89.8) 296 (88.8) 308
(131) 328 (88.1) ng/mL (SD).sup..dagger-dbl. Dose normalised
AUC.sub.24 h, ng h/mL 4627 (687) 4298 (739) 4012 (885) 4382 (792)
(SD).sup..dagger-dbl. Mean t.sub.1/2term, h 106.3 (35.9) 100.2
(31.1) 115.9 (27.2) 95.6 (36.5) (SD) Mean CL/F, L/h 1.03 (0.33)
0.929 (0.24) 0.852 (0.17) 0.919 (0.23) (SD) Mean V.sub.d/F, L (SD)
132 (17.8) 126 (12.9) 137 (16.3) 119 (20.7)
Example 3: Formulations of Compound A
[0288] The quantitative and qualitative composition of the Compound
A 250 mg/g spray dried powder (G001) is provided in Table 8
below.
TABLE-US-00008 TABLE 8 Quantitative and Qualitative Composition of
the Compound A 250 mg/g Spray Dried Powder (G001) Component Quality
Reference Function Quantity (mg) Compound A Company specification
Active 250 Hydroxypropyl methylcellulose Ph. Eur., NF Stabilizer
750 E5 .sup.b Methanol.sup.a Ph. Eur., NF Solvent -- Methylene
Chloride.sup.a Ph. Eur., NF Solvent -- Total 1,000 .sup.aRemoved
during processing .sup.b Hydroxypropyl methylcellulose (HPMC) is
also called Hypromellose
[0289] The qualitative and quantitative composition of the Compound
A 100-mg (G009) 25-mg (G008) and 5-mg (G007) oral tablets is
provided in Table 9 below.
TABLE-US-00009 TABLE 9 Qualitative and Quantitative Composition of
Compound A 100-mg oral tablets (G009), 25-mg tablets (G008) and
5-mg tablets (G007) Quantity Quantity Quantity per per per Tablet
Tablet Tablet Quality (mg) (mg) (mg) Component Reference Function
G009 G008 G007 250 mg/g spray dried Company Active 400.00 100.00
20.00 powder (G001) specifications Microcrystalline Ph. Eur., NF
Filler 477.70 119.42 177.66 cellulose Mannitol Ph. Eur., NF Filler
178.30 44.58 66.34 Croscarmellose Ph. Eur., NF Disintegrant 120.00
30.00 30.00 sodium Colloidal anhydrous Ph. Eur., NF Glidant 12.00
3.00 3.00 silica Magnesium stearate.sup.a Ph. Eur., NF Lubricant
12.00 3.00 3.00 Nominal Weight 1,200.00 300.00 300.00 .sup.aSourced
from vegetable origin.
[0290] The quantitative and qualitative composition of the Compound
A 250 mg/g spray dried powder (G021) is provided in Table 10
below.
TABLE-US-00010 TABLE 10 Quantitative and Qualitative Composition of
the Compound A 250 mg/g Spray Dried Powder (G021) Component Quality
Reference Function Quantity (mg) Compound A Company specification
Active 250 Hypromellose acetate NF Stabilizer 750 succinate
(HPMC-AS).sup.a Methanol.sup.b Ph. Eur. Solvent -- Methylene
Chloride.sup.b Ph. Eur. Solvent -- Total 1,000 .sup.aHypromellose
acetate succinate (HPMC-AS) is also called hydroxypropyl
methylcellulose acetate succinate .sup.bRemoved during
processing
[0291] The qualitative and quantitative composition of the Compound
A 100-mg (G022) oral tablets is provided in Table 11 below.
TABLE-US-00011 TABLE 11 Qualitative and Quantitative Composition of
Compound A 100-mg oral tablets (G022), 100-mg oral tablets (G024)
and 25-mg oral tablets (G025) Quantity Quantity Quantity per per
per Tablet Tablet Tablet Quality (mg) (mg) (mg) Component Reference
Function G022 G024 G025 Intragranular Phase 250 mg/g spray dried
Company Active 400.00 400.00 100.00 powder (G021) specifications
Microcrystalline Ph. Eur. Filler 400.00 256.00 64.00 cellulose
Croscarmellose Ph. Eur. Disintegrant 30.00 30.00 7.50 sodium
Colloidal anhydrous Ph. Eur. Glidant 6.00 6.00 1.50 silica
Magnesium stearate, Ph. Eur. Lubricant 3.00 3.00 0.75 NF.sup.a
Extragranular Phase Silicified NF Filler 316.00 394.00 98.50
Microcrystalline Cellulose Ph. Eur. Disintegrant 30.00 30.00 7.50
Croscarmellose sodium Colloidal anhydrous Ph. Eur. Glidant 6.00
6.00 1.50 silica Magnesium stearate, Ph. Eur. Lubricant 9.00 9.00
2.25 NF.sup.a Pre-gelatinized Maize Ph. Eur Filler -- 66.00 16.50
Starch Nominal Weight 1,200.00 1,200.00 300.00 .sup.aVegetable
grade
Example 4: Bioavailability of Tablets G009 and G022
[0292] A Phase 1, Open-label Study in Healthy Adult Subjects has
been conducted to assess the bioavailability of single doses of a
compound of formula (1) administered as oral tablets
(pharmacokinetic analysis). Tablets G009 or tablets G022 (cf.
Tables 10 and 11 of example 3 above) were administered as 300-mg
single oral doses in healthy adult subjects under fasted and fed
conditions. A total of 28 subjects was enrolled in the study,
equally divided over 2 cohorts (14 subjects per cohort). In Part I
of the study, all subjects in a cohort (n=14) received a single
oral 300-mg dose of compound of formula (1), formulated as
3.times.100-mg test tablets in Treatment Period 1 (tablet G022,
Treatment A), followed by a single oral 300 mg dose of compound of
formula (1), formulated as 3.times.100-mg tablets in Treatment
Period 2 (tablets G009, Treatment B). Both treatments were
administered under fasted conditions on Day 1. In Part I, study
drug intake in Treatment Periods 1 and 2 in an individual subject
were separated by a washout period of at least 37 days. In Part II,
all subjects in a cohort (n=14) received a single oral 300-mg dose
of compound of formula (1), formulated as 3.times.100-mg G022
tablets in Treatment Period 1 (Treatment C). Treatment C was
administered under fed conditions on Day 1. Full pharmacokinetic
(PK) profiles of compound of formula (A) were determined over
approximately 864 hours (37 days) after compound of formula (A)
drug administration on Day 1 of all treatments in Parts I and
II.
TABLE-US-00012 TABLE 12 Pharmacokinetics 300 mg API 300 mg API 300
mg API (mean [SD], tablets G022 tablets G009 tablets G022
t.sub.max: t.sub.last: median single dose, fasted single dose,
fasted single dose, fed [range]) Treatment A Treatment B Treatment
C n 14 12.sup.a 13.sup.b C.sub.max (ng/mL) 3105 (631) 2121 (615)
2522 (606) t.sub.max (h) 3.00 (0.99-8.00) 2.99 (1.00-12.01) 4.00
(1.50-12.00) C.sub.last (ng/mL) 58.3 (65.8) 54.8 (65.2) 41.1 (27.9)
t.sub.last (h) 815.91 (312.00-840.63) 816.00 (480.05-840.00) 480.00
(456.00-864.46) AUC.sub.72 h (ng h/mL) 107309 (17414) 93105 (18074)
108211 (23333) AUC.sub.last (ng h/mL) 331296 (123779) 326043
(119556) 296699 (87563) AUC.sub..infin. (ng h/mL) 345465 (148016)
343222 (151988) 302793 (90245) t.sub.1/2 (h) 124.6 (57.7) 142.2
(76.2) 95.7 (31.3) CL/F (L/h) 1.00 (0.419) 0.994 (0.342) 1.09
(0.367) V.sub.d/F (L) 156 (24.4) 177 (32.4) 141 (34.9) .sup.an = 13
for C.sub.max and t.sub.max .sup.bn = 14 for C.sub.max, t.sub.max,
and AUC.sub.72 h
TABLE-US-00013 TABLE 13 Effect of Formulation Geometric Mean
Treatment B Treatment A 300 mg API 300 mg API Geometric Intra-
tablets G009 tablets G022 Mean 90% subject Pharmacokinetic single
dose, single dose, Ratio, CI, CV, Parameter fasted fasted (%) (%)
(%) n 12.sup.a 14 C.sub.max (ng/mL) 2047 3043 148.70 127.46-173.48
22.8 AUC.sub.72 h (ng h/mL) 91062 106032 116.44 108.61-124.83 9.6
AUC.sub.last (ng h/mL) 290089 311608 107.42 100.76-114.52 8.8
AUC.sub..infin. (ng h/mL) 300237 321212 106.99 100.26-114.16 8.9
.sup.an = 13 for C.sub.max
TABLE-US-00014 TABLE 14 Effect of Food Geometric Mean Treatment A
Treatment C 300 mg API 300 mg API Geometric Inter- tablets G022
tablets G022 Mean 90% subject Pharmacokinetic single dose, single
dose, Ratio, CI, CV, Parameter fasted fed (%) (%) (%) n 14 13.sup.a
C.sub.max (ng/mL) 3043 2440 80.18 68.25-94.20 25.4 AUC.sub.72 h (ng
h/mL) 106032 105647 99.64 87.54-113.40 20.3 AUC.sub.last (ng h/mL)
311608 284160 91.19 72.81-114.22 35.2 AUC.sub..infin. (ng h/mL)
321212 289763 90.21 71.30-114.13 36.9 .sup.an = 14 for C.sub.max
and AUC.sub.72 h
TABLE-US-00015 TABLE 15 C.sub.max Maximum observed analyte
concentration; t.sub.max Actual sampling time to reach the maximum
observed analyte concentration; C.sub.last Last observed measurable
(non-below quantification limit [non- BQL]) plasma analyte
concentration; t.sub.last Actual sampling time of last measurable
(non-BQL) plasma analyte concentration; AUC.sub.72 h Area under the
analyte concentration-time curve (AUC) from time 0 to 72 hours
postdose, calculated by linear-linear trapezoidal summation;
AUC.sub.last Area under the analyte concentration vs time curve
from time 0 to time of the last measurable (non-BQL) concentration,
calculated by linear-linear trapezoidal summation; AUC.sub..infin.
Area under the analyte concentration-time curve from time 0 to
infinite time, calculated as AUC.sub.last +
C.sub.last/.lamda..sub.z, where C.sub.last is the last observed
measurable (non-BQL) concentration; extrapolations of more than
20.00% of the total AUC are reported as approximations; t.sub.1/2
Apparent terminal elimination half-life, calculated as
0.693/.lamda..sub.z; .lamda..sub.z Apparent terminal elimination
rate constant, estimated by linear regression using the terminal
log-linear phase of the log transformed concentration versus time
curve; CL/F Total apparent oral clearance, calculated as
dose/AUC.sub..infin.; Vd.sub.z/F Apparent volume of distribution,
calculated as dose/(.lamda..sub.z*AUC.sub..infin.).
Non-compartmental analysis (Model Type: Plasma [200-202], Dose
Type: Extravascular) was applied for the PK analysis. Furthermore,
SAS (version 9.3, SAS Institute Inc., Cary, N.C., USA) was used,
predominantly for the creation of PK tables. Effect of Formulation
(G022 versus G009) [0293] Based on the geometric mean ratios, of
tablets G022 provide a 1.49-fold higher Cmax than tablets G009,
both under fasted conditions at a 300 mg-dose. AUC72 h, AUClast,
and AUC.infin. were similar (90% CIs of the geometric mean ratios
within 80-125%) for both tablet formulations. [0294] Median tmax
was the same for tablets G022 (3.00 hours) and tablets G009 (2.99
hours) under fasted conditions. [0295] Under fasted conditions,
mean t1/2 was 124.6 hours for tablets G022 and 142.2 hours for
tablets G009.
Effect of Food
[0296] Based on the geometric mean ratios between intake of tablets
G022 under fed conditions and under fasted conditions, Cmax,
AUClast, and AUC.infin. were modestly lower (by 19.82%, 8.81% and
9.79%, respectively) after intake under fed conditions, while AUC72
h was similar for both treatments (300 mg-dose). The lower limits
of the 90% CIs of the geometric mean ratios of Cmax, AUClast, and
AUC.infin. fell below 80%. There was one subject in Part 1, who
showed relatively high AUC.sub.last and AUC.sub..infin. values as
compared to other subjects, due to slower elimination of compound
A. The AUC.sub.last and AUC.sub..infin. values for this subject may
explain the modestly lower geometric mean values in Treatment C
compared to Treatment A. [0297] For tablets G022, median tmax
occurred somewhat later under fed conditions compared to
administration under fasted conditions, respectively 4.00 hours and
3.00 hours postdose. [0298] Mean t1/2 was in the same range after
intake of tablets G022 under fasted and fed conditions, with values
of 124.6 hours (fasted) and 95.7 hours (fed).
Example 5: Bioavailability of Tablets G009 and G024
[0299] The protocol of bioavailability study that has been
described for tablets G009 and G022 (in example 4 above) can be
applied to tablets G009 and G024.
Example 6
[0300] The primary objectives were to evaluate the oral
bioavailability of Compound A when administered as single dose of
150 mg, composed of 6.times.25-mg oral tablets, under fasted and
fed conditions, and as single dose of 300 mg, composed of
3.times.100-mg oral tablets, under fasted conditions in healthy
adult subjects Part I was conducted to assess the bioavailability
of new 25 mg oral tablets of Compound A under fasted and fed
conditions, and of new 100 mg oral tablets of Compound A under
fasted conditions, in healthy adult subjects. In Treatment Period 1
of Part I, all 16 subjects received a single 150 mg dose
(6.times.25 mg oral tablets) under fed conditions (Treatment A).
Thereafter, subjects were randomly assigned to either Arm 1 or Arm
2 in a 1:1 ratio. In Arm 1, subjects received a single 150 mg dose
(6.times.25 mg oral tablets) under fasted conditions in Treatment
Period 2 (Treatment B). In Arm 2, subjects received a single 300 mg
dose (3.times.100 mg oral tablets) under fasted conditions in
Treatment Period 2 (Treatment C). Full pharmacokinetic (PK)
profiles of Compound A were determined over approximately 768 hours
(33 days) after Compound A administration on Day 1 of each
treatment period. Safety and tolerability were assessed throughout
the study. In Part I, 16 healthy adult subjects were included.
After Treatment A (150 mg Compound A, fed) in Treatment Period 1,
subjects were randomly assigned to either Arm 1 (n=8; Treatment B
[150 mg Compound A, fasted]) or Arm 2 (Treatment C [n=7; 300 mg
Compound A, fasted]) in a 1:1 ratio in Treatment Period 2. Fifteen
subjects completed study participation in Part I, but all 16
subjects were included in the PK and safety analyses. Healthy male
and female subjects between 18 and 55 years of age (inclusive), who
had a body mass index (BMI) between 18.0 and 30.0 kg/m2 (extremes
included), and a body weight of not less than 50.0 kg, were
eligible for enrollment into the study. Subjects had to be healthy
on the basis of medical and surgical history, physical examination,
12 lead electrocardiogram (ECG), vital signs, and clinical
laboratory tests performed at screening. Male and female subjects
had to adhere to the contraceptive requirements as specified in the
protocol.
TABLE-US-00016 TABLE 16 Treatment Dose (Formulation) A 150 mg (6
tablets of 25 mg) B 150 mg (6 tablets of 25 mg) C 300 mg (3 tablets
of 100 mg)
The study consisted of a screening phase, an admission phase, a
treatment phase, and a follow-up phase (posttreatment phase).
During the follow-up phase, subjects returned to the study site
10-14 days and 30-35 days after study drug administration in the
last treatment period for a follow-up visit. The duration of each
treatment phase was 33.+-.3 days and the study duration per
individual subject was at least 61 days (including admission and
follow-up period), screening period not included.
Study Population:
[0301] A total of 16 subjects were enrolled and received Treatment
A in Period 1. One subject prematurely terminated the study
(withdrawal of consent by subject) after having received Treatment
A in Period 1. Fifteen subjects were randomized to Treatment B
(N=8) or Treatment C (N=7) and completed treatment and the study as
planned.
TABLE-US-00017 TABLE 17 Summary of Demographics and Baseline
Characteristics: Part 1; Safety Analysis Set Analysis set: Safety,
N 16 Age, years Median 47.0 Range (19; 55) Sex Male 13 (81.3%)
Female 3 (18.8%) Race Asian 1 (6.3%) Black or African American 1
(6.3%) White 14 (87.5%) Body Mass Index, kg/m.sup.2 Median 25.75
Range (19.3; 29.7) Note: SD = Standard Deviation Screening values
have been considered as baseline characteristics for all the
parameters.
TABLE-US-00018 TABLE 18 PHARMACOKINETIC RESULTS: Pharmacokinetics
150 mg Compound A of 6x 25 mg 150 mg Compound A 300 mg Compound A
Compound A Fed (Standard 6x 25 mg 3x 100 mg (Mean [SD], Breakfast)
Fasting Fasting t.sub.max: Median [Range]) Treatment A Treatment B
Treatment C n 16 8 7 C.sub.max (ng/mL) 1543 (279) 1918 (458) 2773
(460) t.sub.max (h) 4.00 (1.00-4.05) 1.75 (1.00-3.00) 3.00
(1.00-4.02) AUC.sub.last (ng h/mL) 171012 (45636) 176800 (34478)
371406 (123728) AUC.sub..infin. (ng h/mL) 177482 (47313) 181907
(35169) 392969 (142342) Dose normalized PK parameters.sup.a
C.sub.max (ng/mL) 257 (46.5) 320 (76.3) 231 (38.3) AUC.sub.last (ng
h/mL) 28502 (7606) 29467 (5746) 30951 (10311) AUC.sub..infin. (ng
h/mL) 29580 (7886) 30318 (5861) 32747 (11862) .sup.adose normalized
to 25 mg.
Food Effect
[0302] The statistical results comparing the PK of Compound A
between Treatment A and Treatment B (food effect) are presented in
the table below.
TABLE-US-00019 TABLE 19 Geometric Mean 150 mg Compound A 150 mg
Compound A 6x 25 mg 6x 25 mg Fed (Standard Geometric
Pharmacokinetic Fasting Breakfast) Mean Parameters Treatment B
Treatment A Ratio, 90% CI, Compound A (Reference) (Test) (%) (%) n
8 16 C.sub.max (ng/mL) 1766 1516 85.84 77.01-95.68 AUC.sub.last (ng
h/mL) 163356 165071 101.05 96.86-105.42 AUC.sub..infin. (ng h/mL)
168064 171275 101.91 96.66-107.45
Based on the geometric mean ratios between Treatment A (fed, test,
n=16) and Treatment B (fasted, reference, n=8), Cmax was 14.2%
(GMR, 85.8%; 90% CI, 77.0-95.7%) lower under fed conditions, while
AUClast and AUC.infin. were similar under fasted or fed conditions.
The upper limit of the 90% CI of the geometric mean ratio of Cmax
fell below 100%.
Effect of Tablet Strength
[0303] The statistical results comparing the dose normalized PK
parameters of Compound A (effect of tablet strength) between
Treatments B and C are presented in the table below.
TABLE-US-00020 TABLE 20 Geometric Mean 150 mg Compound A 300 mg
Compound A 6x 25 mg 3x 100 mg Geometric Pharmacokinetic Fasting
Fasting Mean Parameters Treatment B Treatment C Ratio, 90% CI,
Compound A (Reference) (Test) (%) (%) n 8 7 C.sub.max, dose
normalized (ng/mL).sup.a 294 231 78.44 67.44-91.22 AUC.sub.last,
dose normalized (ng h/mL).sup.a 27226 30835 113.26 106.48-120.47
AUC.sub..infin., dose normalized (ng h/mL).sup.a 28011 32329 115.42
106.86-124.66 .sup.adose normalized to 25 mg.
Based on the geometric mean ratios between Treatment C and
Treatment B of the dose normalized PK parameters, Cmax was 21.6%
(GMR, 78.4%; 90% CI, 67.4-91.2%) lower for the 100 mg tablet
strength compared to the 25 mg tablet strength. The upper limit of
the 90% CI of the geometric mean ratio of Cmax fell below 100%. The
AUClast and AUC.infin. were similar under fasted or fed conditions.
Median (range) tmax was 1.75 (1.00-3.00) hours when 150 mg Compound
A was dosed as 6.times.25 mg oral tablets, and 3.00 (1.00-4.02)
hours when 300 mg Compound A was dosed as 3.times.100 mg oral
tablets. Mean (range) t1/2 term was similar between treatments.
Values ranged between subjects, namely 134.3 (65.7-221.6) hours,
123.9 (72.3-195.7) hours, and 161.1 (111.5-257.3) hours for
Treatment A, B, and C, respectively. Clearance (CL/F) ranged
between 0.47 and 1.55 L/h over all treatments and individuals.
Example 7: Therapeutic Exploratory Phase II Study on Compound A in
Patients with Chronic HBV Infection
[0304] A double-blind, placebo-controlled study is done to evaluate
efficacy of 24 weeks of Compound A treatment, either alone or in
combination with a nucleoside analogue, in terms of changes in
hepatitis B surface antigen (HBsAg) levels.
7.1 Patient Baseline Characteristics
[0305] Treatment naive, adult patients with chronic HBV infection
are randomized for the study.
7.2 Dosing and Combinations
[0306] Compound A is administered at 250 mg per day in a tablet
formulation by oral administration. Compound A is administered
either alone or in combination with a nucleoside analogue. The
nucleoside analogue is either tenofovir disoproxil fumarate
(Viread, Gilead Sciences International) administered at 300 mg per
day in a film-coated tablet by oral administration or entecavir
monohydrate (Baraclude, Bristol-Myers Squibb Pharma) administered
at 0.5 mg per day in a film-coated tablet by oral
administration.
7.3 Results
[0307] This study evaluates the safety and tolerability of 24 weeks
of study treatment. The efficacy is evaluated in terms of changes
in HBsAg levels, HBV DNA levels, changes in HBeAg levels (in HBeAg
positive subjects only), and HBsAg (in all subjects) or HBeAg (in
HBeAg-positive subjects only) seroclearance and/or seroconversion.
This study also evaluates the frequency of subjects with
biochemical response and HBV virological breakthrough. This study
also evaluates the potential effect of Compound A on the
pharmacokinetics of nucleos(t)ide analog (NA) when coadministered.
This study also evaluates the pharmacokinetics of Compound A when
administered as a monotherapy. This study also evaluates the
potential effect of NA on the pharmacokinetics of Compound A when
coadministered. This study assesses changes in the HBV genome
sequence following treatment with Compound A either alone or in
combination with a NA.
[0308] Finally, this study evaluates the synergistic effects of
Compound A and NAs. Synergy, additivity, and antagonism are
evaluated using the Pritchard and Shipman model. Synergy or
antagonism for a concentration combination is determined based on
the following 2 rules: First, the 95% CI of the mean difference
between observed and predicted fraction of inhibition at each
concentration combination is calculated. If the lower bound of 95%
CI is larger than zero, then the drug combination would be
considered having a synergistic effect; if the upper bound of 95%
CI is less than zero, then the drug combination would be considered
having an antagonistic effect; otherwise, no significant antagonism
or synergy at this concentration combination. Second, the
synergistic or antagonistic effect must have its relative mean
difference, the absolute mean difference divided by its
corresponding observed mean inhibition, greater than 1%. By doing
this, small differences of statistical significance caused by very
small variance could be excluded.
[0309] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
herein by reference in their entirety.
[0310] While the invention has been disclosed with reference to
specific embodiments, it is apparent that other embodiments and
variations of this invention can be devised by others skilled in
the art without departing from the true spirit and scope of the
invention. The appended claims are intended to be construed to
include all such embodiments and equivalent variations.
* * * * *