U.S. patent application number 13/203334 was filed with the patent office on 2012-05-24 for combination of a nucleoside polymerase inhibitor with a macrocyclic protease inhibitor and use thereof in the treatment of hepatitis c, liver fibrosis and impaired liver function (as amended).
Invention is credited to Williamson Ziegler Bradford, Abel De La Rosa, Steven B. Porter, Michael D. Rogers, Patrick F. Smith, William T. Symonds, Ellen S. Yetzer.
Application Number | 20120128628 13/203334 |
Document ID | / |
Family ID | 42111299 |
Filed Date | 2012-05-24 |
United States Patent
Application |
20120128628 |
Kind Code |
A1 |
Porter; Steven B. ; et
al. |
May 24, 2012 |
COMBINATION OF A NUCLEOSIDE POLYMERASE INHIBITOR WITH A MACROCYCLIC
PROTEASE INHIBITOR AND USE THEREOF IN THE TREATMENT OF HEPATITIS C,
LIVER FIBROSIS AND IMPAIRED LIVER FUNCTION (as amended)
Abstract
Embodiments disclosed in the present application relate to a
composition that can include a hepatitis C viral polymerase
inhibitor, or pharmaceutically acceptable salt or prodrug thereof
and a hepatitis C viral protease inhibitor, or pharmaceutically
acceptable salt or prodrug thereof. Additional embodiments
disclosed relate to methods for treating a disease condition such
as a hepatitis C virus infection, liver fibrosis and/or impaired
liver function with a hepatitis C viral polymerase inhibitor, or
pharmaceutically acceptable salt or prodrug thereof and a hepatitis
C viral protease inhibitor, or pharmaceutically acceptable salt or
prodrug thereof.
Inventors: |
Porter; Steven B.; (Mill
Valley, NJ) ; Bradford; Williamson Ziegler; (Wilson,
WY) ; Smith; Patrick F.; (Pleasanton, CA) ;
Yetzer; Ellen S.; (San Francisco, CA) ; De La Rosa;
Abel; (Alpharetta, GA) ; Rogers; Michael D.;
(Chaoel Hill, NC) ; Symonds; William T.; (Cary,
NC) |
Family ID: |
42111299 |
Appl. No.: |
13/203334 |
Filed: |
February 26, 2010 |
PCT Filed: |
February 26, 2010 |
PCT NO: |
PCT/US10/25611 |
371 Date: |
February 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61156414 |
Feb 27, 2009 |
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61257367 |
Nov 2, 2009 |
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Current U.S.
Class: |
424/85.4 ;
424/85.5; 424/85.7; 514/1.1; 514/49 |
Current CPC
Class: |
A61K 31/395 20130101;
A61P 31/12 20180101; A61K 31/4709 20130101; A61P 31/14 20180101;
A61K 31/7068 20130101; A61K 2300/00 20130101; A61P 37/00 20180101;
A61K 31/395 20130101; A61P 43/00 20180101; A61P 1/16 20180101; A61K
31/7068 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/4709 20130101 |
Class at
Publication: |
424/85.4 ;
424/85.5; 424/85.7; 514/1.1; 514/49 |
International
Class: |
A61K 38/21 20060101
A61K038/21; A61P 1/16 20060101 A61P001/16; A61P 31/12 20060101
A61P031/12; A61K 38/22 20060101 A61K038/22; A61K 31/7068 20060101
A61K031/7068 |
Claims
1. A composition comprising a first compound, or a pharmaceutically
acceptable salt or prodrug thereof, wherein the first compound is
##STR00001## and a second compound, or a pharmaceutically
acceptable salt or prodrug thereof, wherein the second compound is
##STR00002##
2. A composition consisting essentially of a first compound, or a
pharmaceutically acceptable salt or prodrug thereof, wherein the
first compound is ##STR00003## and a second compound, or a
pharmaceutically acceptable salt or prodrug thereof, wherein the
second compound is ##STR00004##
3. The composition of claim 1, wherein the prodrug of the first
compound has the structure: ##STR00005##
4. The composition of claim 1, further comprising a
pharmaceutically acceptable excipient, diluent or carrier.
5. The composition of claim 1, wherein the composition comprises an
amount of the first compound, or a pharmaceutically acceptable salt
or prodrug thereof, in the range of about 9000 mg to about 50
mg.
6. The composition of claim 1, wherein the composition comprises an
amount of the first compound, or a pharmaceutically acceptable salt
or prodrug thereof, in the range of about 5000 mg to about 150
mg.
7. The composition of claim 1, wherein the composition comprises an
amount of the first compound, or a pharmaceutically acceptable salt
or prodrug thereof, in the range of about 2000 mg to about 300
mg.
8. The composition of claim 1, wherein the composition comprises an
amount of the first compound, or a pharmaceutically acceptable salt
or prodrug thereof, in the range of about 1000 mg to about 450
mg.
9. The composition of claim 1, wherein the composition comprises an
amount of the first compound, or a pharmaceutically acceptable salt
or prodrug thereof, in the range of about 1000 mg to about 500
mg.
10. The composition of claim 1, wherein the composition comprises
an amount of the second compound, or a pharmaceutically acceptable
salt or prodrug thereof, in the range of about 2000 mg to about 2
mg.
11. The composition of claim 1, wherein the composition comprises
an amount of the second compound, or a pharmaceutically acceptable
salt or prodrug thereof, in the range of about 1600 mg to about 25
mg.
12. The composition of claim 1, wherein the composition comprises
an amount of the second compound, or a pharmaceutically acceptable
salt or prodrug thereof, in the range of about 500 mg to about 50
mg.
13. The composition of claim 1, wherein the composition comprises
an amount of the second compound, or a pharmaceutically acceptable
salt or prodrug thereof, in the range of about 200 mg to about 100
mg.
14. The composition of claim 1, wherein the composition comprises a
total amount of the first compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 1% to
about 99% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
15. The composition of claim 1, wherein the composition comprises a
total amount of the first compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 5% to
about 90% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
16. The composition of claim 1, wherein the composition comprises a
total amount of the first compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 10% to
about 80% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
17. The composition of claim 1, wherein the composition comprises a
total amount of the first compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 20% to
about 70% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
18. The composition of claim 1, wherein the composition comprises a
total amount of the first compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 30% to
about 60% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
19. The composition of claim 1, wherein the composition comprises a
total amount of the first compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 40% to
about 50% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
20. The composition of claim 14 wherein the composition comprises a
total amount of the second compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 1% to
about 99% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
21. The composition of claim 14, wherein the composition comprises
a total amount of the second compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 5% to
about 90% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
22. The composition of claim 14, wherein the composition comprises
a total amount of the second compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 10% to
about 80% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
23. The composition of claim 14, wherein the composition comprises
a total amount of the second compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 20% to
about 70% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
24. The composition of claim 14, wherein the composition comprises
a total amount of the second compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 30% to
about 60% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
25. The composition of claim 14, wherein the composition comprises
a total amount of the second compound, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 40% to
about 50% (weight/weight) based on the sum of the total amount of
the first compound, or a pharmaceutically acceptable salt or
prodrug thereof, and the total amount of the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition.
26. The composition of claim 1, wherein the amount of the first
compound, or a pharmaceutically acceptable salt or prodrug thereof,
in the composition is less than the amount of the first compound,
or a pharmaceutically acceptable salt or prodrug thereof, needed to
achieve substantially the same viral load reduction as when the
first compound, or a pharmaceutically acceptable salt or prodrug
thereof, is administered as monotherapy.
27. The composition of claim 1, wherein the amount of the second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
in the composition is less than the amount of the second compound,
or a pharmaceutically acceptable salt or prodrug thereof, needed to
achieve substantially the same viral load reduction as when the
second compound, or a pharmaceutically acceptable salt or prodrug
thereof, is administered as monotherapy.
28. The composition of claim 1, wherein the composition further
comprises one or more additional therapeutic agents.
29. The composition of claim 28, wherein the one or more additional
therapeutic agents are selected from the group consisting of a
nucleoside analog, pirfenidone, a pirfenidone analog, an NS5B
RNA-dependent RNA polymerase inhibitor, a tumor necrosis factor
antagonist, thymosin-.alpha., interferon-gamma (IFN-.gamma.),
interferon-alpha (IFN-.alpha.), 3'-azidothymidine,
2',3'-dideoxyinosine, 2',3'-dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir
dipivoxil, cidofovir, ritonavir, an inosine monophosphate
dehydrogenase inhibitor, an interferon, an additional NS3 protease
inhibitor, an NS5B polymerase inhibitor, and an NS3 helicase
inhibitor.
30. The composition of claim 29, wherein the nucleoside analog is
selected from the group consisting of ribavirin, levovirin,
viramidine, an L-nucleoside, and isatoribine.
31. The composition of claim 29, wherein the tumor necrosis factor
antagonist is selected from the group consisting of etanercept,
infliximab, and adalimumab.
32. The composition of claim 29, wherein the thymosin-.alpha. is in
an amount in the range of from about 1.0 mg to about 1.6 mg.
33. The composition of claim 29, wherein the IFN-.gamma. is in an
amount in the range of from about 10 .mu.g to about 300 .mu.g.
34. The composition of claim 29, wherein the IFN-.alpha. is monoPEG
(30 kD, linear)-ylate consensus.
35. The composition of claim 29, wherein the IFN-.alpha. is
selected from the group consisting of a 40 kD branched mono-methoxy
PEG conjugate of interferon .alpha.-2b and a 12 kD mono-methoxy PEG
conjugate of interferon .alpha.-2b.
36. The composition of claim 29, wherein the IFN-.alpha. is
INFERGEN consensus IFN-.alpha..
37. The composition of claim 29, wherein the additional NS3
protease inhibitor is selected from ##STR00006##
38. The composition of claim 1, wherein the composition does not
comprise ribavirin.
39. The composition of claim 1, wherein the composition does not
comprise an interferon.
40. The composition of claim 39, wherein the interferon is a
pegylated interferon.
41. A method for ameliorating or treating a disease condition in a
patient population comprising administering a therapeutically
effective amount of the composition claim 1 to a subject suffering
from the disease condition, wherein the disease condition is
selected from the group consisting of a hepatitis C virus
infection, liver fibrosis, and impaired liver function.
42. A method for ameliorating or treating a disease condition in a
patient population comprising administering a therapeutically
effective amount of a first compound, or a pharmaceutically
acceptable salt or prodrug thereof, wherein the first compound is
##STR00007## and a therapeutically effective amount of a second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
wherein the second compound is ##STR00008## to a subject suffering
from the disease condition, wherein the disease condition is
selected from the group consisting of a hepatitis C virus
infection, liver fibrosis, and impaired liver function.
43. The method of claim 42, wherein the prodrug of the first
compound has the structure: ##STR00009##
44. The method of claim 42, wherein the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, is
administered before the second compound, or a pharmaceutically
acceptable salt or prodrug thereof.
45. The method of claim 42, wherein the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, is
administered after the second compound, or a pharmaceutically
acceptable salt or prodrug thereof.
46. The method of claim 42, wherein the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, is
administered at approximately the same time as the second compound,
or a pharmaceutically acceptable salt or prodrug thereof.
47. The method of claim 42 wherein the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, and the second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
are together in one dosage form.
48. The method of claim 42, wherein the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, and the second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
are in separate dosage forms.
49. The method of claim 41, wherein the disease condition is a
hepatitis C viral infection.
50. The method of claim 41, wherein the patient population
experiences a decreased average viral load compared to an average
viral load experienced by an otherwise comparable patient
population being administered the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, alone at
substantially the same amount.
51. The method of claim 41, wherein the patient population
experiences a decreased average viral load compared to an average
viral load experienced by an otherwise comparable patient
population being administered the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, alone at
substantially the same amount.
52. The method of claim 41, wherein the patient population
experiences a decrease in the average number of side effects
compared to an average number of side effects experienced by an
otherwise comparable population being administered the first
compound, or a pharmaceutically acceptable salt or prodrug thereof,
alone at substantially the same amount.
53. The method of claim 41, wherein the patient population
experiences a decrease in the average number of side effects
compared to an average number or side effects experienced by an
otherwise comparable population being administered the second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
alone at substantially the same amount.
54. The method of claim 41, wherein the patient population
experiences a decrease in the average severity of a side effect
compared to an average severity of the same side effect experienced
by an otherwise comparable population being administered the first
compound, or a pharmaceutically acceptable salt or prodrug thereof,
alone at substantially the same amount.
55. The method of claim 41, wherein the patient population
experiences a decrease in the average severity of a side effect
compared to an average severity of the same side effect experienced
by an otherwise comparable population being administered the second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
alone at substantially the same amount.
56. The method of claim 41, wherein the patient population contains
a decreased average number of subjects experiencing viral load
rebound as compared to an average number of subjects experiencing
viral load rebound contained in an otherwise comparable population
being administered the first compound, or a pharmaceutically
acceptable salt or prodrug thereof, alone at substantially the same
amount.
57. The method of claim 41, wherein the patient population contains
a decreased average number of subjects experiencing viral load
rebound as compared to an average number of subjects experiencing
viral load rebound contained in an otherwise comparable population
being administered the second compound, or a pharmaceutically
acceptable salt or prodrug thereof, alone at substantially the same
amount.
58. The method of claim 41, wherein the patient population contains
a decreased average number of non-responders as compared to an
average number of non-responders contained in an otherwise
comparable population being administered the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, alone at
substantially the same amount.
59. The method of claim 41, wherein the patient population contains
a decreased average number of non-responders as compared to an
average number of non-responders contained in an otherwise
comparable population being administered the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, alone at
substantially the same amount.
60. The method of claim 41, wherein the patient population
experiences an onset of resistance at an average time later than an
average time an onset of resistance is experienced by an otherwise
comparable population being administered the first compound, or a
pharmaceutically acceptable salt or prodrug thereof, alone at
substantially the same amount.
61. The method of claim 41, wherein the patient population
experiences an onset of resistance at an average time later than an
average time an onset of resistance is experienced by an otherwise
comparable population being administered the second compound, or a
pharmaceutically acceptable salt or prodrug thereof, alone at
substantially the same amount.
62. The method of claim 41, wherein the patient population
experiences a decrease in the average level of resistance to the
first compound, or a pharmaceutically acceptable salt or prodrug
thereof, compared to an average level of resistance to the first
compound, or a pharmaceutically acceptable salt or prodrug thereof,
experienced by the population being administered the first
compound, or a pharmaceutically acceptable salt or prodrug thereof,
alone at substantially the same amount.
63. The method of claim 41, wherein the patient population
experiences a decrease in the average level of resistance to the
second compound, or a pharmaceutically acceptable salt or prodrug
thereof, compared to an average level of resistance to the second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
experienced by an otherwise comparable population being
administered the second compound, or a pharmaceutically acceptable
salt or prodrug thereof, alone at substantially the same
amount.
64. The method of claim 41, wherein the method further comprises
administering an effective amount of an additional nucleoside
analog.
65. The method of claim 64, wherein the additional nucleoside
analog is selected from the group consisting of ribavirin,
levovirin, viramidine, an L-nucleoside, and isatoribine.
66. The method of claim 41, wherein the method further comprises
administering an effective amount of pirfenidone or a pirfenidone
analog.
67. The method of claim 41, wherein the method further comprises
administering an effective amount of an NS5B RNA-dependent RNA
polymerase inhibitor.
68. The method of claim 41, wherein the method further comprises
administering an effective amount of a tumor necrosis factor
antagonist selected from the group consisting of etanercept,
infliximab, and adalimumab.
69. The method of claim 41, wherein the method further comprises
administering an effective amount of thymosin-.alpha..
70. The method of claim 69, wherein the thymosin-.alpha. is in an
amount in the range of from about 1.0 mg to about 1.6 mg.
71. The method of claim 41, wherein the method further comprises
administering an effective amount of interferon-gamma
(IFN-.gamma.).
72. The method of claim 71, wherein the IFN-.gamma. is administered
subcutaneously in an amount in the range of from about 10 .mu.g to
about 300 .mu.g.
73. The method of claim 41, wherein the method further comprises
administering an effective amount of interferon-alpha
(IFN-.alpha.).
74. The method of claim 73, wherein the IFN-.alpha. is monoPEG (30
kD, linear)-ylate consensus administered at a dosing interval in
the range of every 8 days to every 14 days.
75. The method of claim 73, wherein the IFN-.alpha. is monoPEG (30
kD, linear)-ylated consensus IFN-.alpha. administered at a dosing
interval of once every 7 days.
76. The method of claim 73, wherein the IFN-.alpha. is selected
from the group consisting of a 40 kD branched mono-methoxy PEG
conjugate of interferon .alpha.-2b and a 12 kD mono-methoxy PEG
conjugate of interferon .alpha.-2b.
77. The method of claim 73, wherein the IFN-.alpha. is INFERGEN
consensus IFN-.alpha..
78. The method of claim 41, wherein the method further comprises
administering an effective amount of an agent selected from
3'-azidothymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine,
2-,3-didehydro-2',3'-dideoxythymidine, combivir, abacavir, adefovir
dipivoxil, cidofovir, ritonavir, and an inosine monophosphate
dehydrogenase inhibitor.
79. The method of claim 41, wherein the method further comprises
administering an effective amount of an interferon, an additional
NS3 protease inhibitor, an NS5B polymerase inhibitor, or an NS3
helicase inhibitor.
80. The method of claim 79, wherein the additional NS3 protease
inhibitor is selected from ##STR00010##
81. The method of claim 41, wherein the patient population is
administered pegylated interferon after administration of the first
compound, or a pharmaceutically acceptable salt or prodrug thereof,
and the second compound, or a pharmaceutically acceptable salt or
prodrug thereof, is complete.
82. The method of claim 41, wherein the patient population is
administered ribavirin after administration of the first compound,
or a pharmaceutically acceptable salt or prodrug thereof, and the
second compound, or a pharmaceutically acceptable salt or prodrug
thereof, is complete.
83. The method of claim 41, wherein the method does not include
administering an additional agent.
84. The method of claim 83, wherein the additional agent is
ribavirin.
85. The method of claim 83, wherein the additional agent is an
interferon.
86. The method of claim 85, wherein the interferon is a pegylated
interferon.
87-133. (canceled)
Description
BACKGROUND
[0001] 1. Field
[0002] The present application relates to compositions and methods
for the treatment of a disease condition such as a hepatitis C
virus infection, liver fibrosis, and impaired liver function.
[0003] 2. Description
[0004] Hepatitis C virus (HCV) infection is the most common chronic
blood borne infection in the United States. Although the numbers of
new infections have declined, the burden of chronic infection is
substantial, with Centers for Disease Control estimates of 3.9
million (1.8%) infected persons in the United States. Chronic liver
disease is the tenth leading cause of death among adults in the
United States, and accounts for approximately 25,000 deaths
annually, or approximately 1% of all deaths. Studies indicate that
40% of chronic liver disease is HCV-related, resulting in an
estimated 8,000-10,000 deaths each year. HCV-associated end-stage
liver disease is the most frequent indication for liver
transplantation among adults.
[0005] Antiviral therapy of chronic hepatitis C has evolved rapidly
over the last decade, with significant improvements seen in the
efficacy of treatment. Nevertheless, even with using the standard
of care (SOC) combination therapy of pegylated IFN-.alpha. plus
ribavirin, 40% to 50% of patients fail therapy, i.e., are
nonresponders or relapsers. These patients currently have no
effective therapeutic alternative. In particular, patients who have
advanced fibrosis or cirrhosis on liver biopsy are at significant
risk of developing complications of advanced liver disease,
including ascites, jaundice, variceal bleeding, encephalopathy, and
progressive liver failure, as well as a markedly increased risk of
hepatocellular carcinoma.
[0006] The high prevalence of chronic HCV infection has important
public health implications for the future burden of chronic liver
disease in the United States. Data derived from the National Health
and Nutrition Examination Survey (NHANES III) indicate that a large
increase in the rate of new HCV infections occurred from the late
1960s to the early 1980s, particularly among persons between 20 to
40 years of age. It is estimated that the number of persons with
long-standing HCV infection of 20 years or longer could more than
quadruple from 1990 to 2015, from 750,000 to over 3 million. The
proportional increase in persons infected for 30 or 40 years would
be even greater. Since the risk of HCV-related chronic liver
disease is related to the duration of infection, with the risk of
cirrhosis progressively increasing for persons infected for longer
than 20 years, a substantial increase in cirrhosis-related
morbidity and mortality is likely to result among patients infected
between the years of 1965-1985.
[0007] HCV is an enveloped positive strand RNA virus in the
Flaviviridae family. The single strand HCV RNA genome is
approximately 9500 nucleotides in length and has a single open
reading frame (ORF) encoding a single large polyprotein of about
3000 amino acids. In infected cells, this polyprotein is cleaved at
multiple sites by cellular and viral proteases to produce the
structural and non-structural (NS) proteins of the virus (NS2, NS3,
NS4, NS4A, NS4B, NS5A, and NS5B).
SUMMARY
[0008] Some embodiments described herein relate to a composition
that can include a first compound, or a pharmaceutically acceptable
salt or prodrug thereof, wherein the first compound is
.beta.-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (Compound 1); and a
second compound, or a pharmaceutically acceptable salt or prodrug
thereof, wherein the second compound is
(1S,4R,6S,14S,18R)-4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid
14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-diox-
o-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-18-yl ester
(Compound 2).
[0009] Other embodiments described herein relate to a composition
that consists essentially of a first compound, or a
pharmaceutically acceptable salt or prodrug thereof, wherein the
first compound is Compound 1; and a second compound, or a
pharmaceutically acceptable salt or prodrug thereof, wherein the
second compound is Compound 2.
[0010] Embodiments described herein relate to the use of such
compositions for ameliorating or treating a disease condition in a
patient population, and/or for the preparation of a medicament for
ameliorating or treating such a disease condition. For example, the
disease condition can be selected from a hepatitis C virus
infection, liver fibrosis, and impaired liver function. In an
embodiment, the prodrug of the first compound can be the diisobutyl
ester prodrug of .beta.-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine
(Compound 1a). In some embodiments, the salt of the second compound
can be the sodium salt of
1S,4R,6S,14S,18R)-4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid
14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-diox-
o-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-18-yl ester (sodium
salt of Compound 2).
[0011] Other embodiments described herein relate to the use of
Compound 1 or a pharmaceutically acceptable salt or prodrug thereof
for ameliorating or treating a disease condition in a patient
population, and/or for the preparation of a medicament for
ameliorating or treating such a disease condition, wherein Compound
1 or a pharmaceutically acceptable salt or prodrug thereof is for
use, and/or is manufactured for use, in combination with Compound 2
or a pharmaceutically acceptable salt or prodrug thereof. Another
embodiment described herein relates to the use of Compound 2 or a
pharmaceutically acceptable salt or prodrug thereof for
ameliorating or treating a disease condition in a patient
population, and/or for the preparation of a medicament for
ameliorating or treating such a disease condition, wherein Compound
2 or a pharmaceutically acceptable salt or prodrug thereof is for
use, and/or is manufactured for use, in combination with Compound 1
or a pharmaceutically acceptable salt or prodrug thereof. For
example, the disease condition can be selected from a hepatitis C
virus infection, liver fibrosis, and impaired liver function.
[0012] Other embodiments described herein relate to methods for
ameliorating or treating a disease condition in a patient
population that can include administering a therapeutically
effective amount of a first compound, or a pharmaceutically
acceptable salt or prodrug thereof, wherein the first compound is
Compound 1; and a therapeutically effective amount of a second
compound, or a pharmaceutically acceptable salt or prodrug thereof,
wherein the second compound is Compound 2 to a subject suffering
from the disease condition. In some embodiments, the disease
condition can be selected from a hepatitis C virus infection, liver
fibrosis, and impaired liver function. In an embodiment, the
prodrug of the first compound can be the diisobutyl ester prodrug
of .beta.-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (Compound 1a).
In some embodiments, the salt of the second compound can be the
sodium salt of
1S,4R,6S,14S,18R)-4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid
14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-diox-
o-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-18-yl ester (sodium
salt of Compound 2).
[0013] These and other embodiments are described in greater detail
below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows the structures of
.beta.-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (Compound 1), the
diisobutyl ester prodrug of
.beta.-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (Compound 1a) and
(1S,4R,6S,14S,18R)-4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid
14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-diox-
o-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-18-yl ester
(Compound 2).
[0015] FIGS. 2 and 3 show a pictorial representation of seven
treatment regimes using the compounds shown in FIG. 1.
[0016] FIG. 4 is a graph showing the changes in the level of serum
alanine aminotransferase (ALT) over 14 days of treatment with
Compound 1a and Compound 2.
DETAILED DESCRIPTION
[0017] Embodiments include, but are not limited to, therapeutic
compositions and their use in the treatment and/or amelioration of
a disease condition. In some embodiments, the disease condition can
be selected from a hepatitis C virus infection, liver fibrosis,
and/or impaired liver function.
[0018] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the embodiments belong. All
publications mentioned herein are incorporated herein by reference
to disclose and describe the methods and/or materials in connection
with which the publications are cited.
[0019] As used herein and in the appended claims, the singular
forms "a," "and," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"a method" includes a plurality of such methods and reference to "a
dose" includes reference to one or more doses and equivalents
thereof known to those skilled in the art, and so forth.
[0020] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range is encompassed within the embodiments.
The upper and lower limits of these smaller ranges, which may
independently be included in the smaller ranges, are also
encompassed within the invention, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those
included limits are also included in the embodiments.
[0021] The term "pharmaceutically acceptable salt" refers to a salt
of a compound that does not cause significant irritation to an
organism to which it is administered and does not abrogate the
biological activity and properties of the compound. In some
embodiments, the salt is an acid addition salt of the compound.
Pharmaceutical salts can be obtained by reacting a compound with
inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or
hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and
the like. Pharmaceutical salts can also be obtained by reacting a
compound with an organic acid such as aliphatic or aromatic
carboxylic or sulfonic acids, for example acetic, succinic, lactic,
malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,
ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic
acid. Pharmaceutical salts can also be obtained by reacting a
compound with a base to form a salt such as an ammonium salt, an
alkali metal salt, such as a sodium or a potassium salt, an
alkaline earth metal salt, such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
C.sub.1-C.sub.7 alkylamine, cyclohexylamine, triethanolamine,
ethylenediamine, and salts with amino acids such as arginine,
lysine, and the like. The sodium salt of Compound 2 is a
non-limiting example of a pharmaceutically acceptable salt.
[0022] A "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug. An
example, without limitation, of a prodrug would be a compound which
is administered as an ester (the "prodrug") to facilitate
transmittal across a cell membrane where water solubility is
detrimental to mobility but which then is metabolically hydrolyzed
to the carboxylic acid, the active entity, once inside the cell
where water-solubility is beneficial. A further example of a
prodrug might be a short peptide (polyaminoacid) bonded to an acid
group where the peptide is metabolized to reveal the active moiety.
Compound 1a is a non-limiting example of a prodrug (in this case a
prodrug of Compound 1). Conventional procedures for the selection
and preparation of suitable prodrug derivatives are described, for
example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985),
which is hereby incorporated herein by reference for the purpose of
describing procedures and preparation of suitable prodrug
derivatives.
[0023] The term "effective amount" is used to indicate an amount of
an active compound, or pharmaceutical agent, that elicits the
biological or medicinal response indicated. For example, an
effective amount of compound can be the amount needed to prevent,
alleviate or ameliorate symptoms of disease or prolong the survival
of the subject being treated This response may occur in a tissue,
system, animal or human and includes alleviation of the symptoms of
the disease being treated. Determination of an effective amount is
well within the capability of those skilled in the art, especially
in light of the detailed disclosure provided herein. The effective
amount of the compounds disclosed herein required as a dose will
depend on the route of administration, the type of animal,
including human, being treated, and the physical characteristics of
the specific animal under consideration. The dose can be tailored
to achieve a desired effect, but will depend on such factors as
weight, diet, concurrent medication and other factors which those
skilled in the medical arts will recognize. In general, an
effective amount of the compositions described herein, and
optionally one or more additional antiviral agents, is an amount
that is effective to reduce viral load or achieve a sustained viral
response to therapy.
[0024] As used herein, the terms "treatment," "treating," and the
like, refer to obtaining a desired pharmacologic and/or physiologic
effect. The effect may be prophylactic in terms of completely or
partially preventing a disease or symptom thereof and/or may be
therapeutic in terms of a partial or complete cure for a disease
and/or adverse affect attributable to the disease. "Treatment," as
used herein, covers any treatment of a disease in a mammal,
particularly in a human, and includes: (a) preventing the disease
from occurring in a subject which may be predisposed to the disease
but has not yet been diagnosed as having it; (b) inhibiting the
disease, i.e., arresting its development; and (c) relieving the
disease, i.e., causing regression of the disease.
[0025] The terms "individual," "host," "subject," and "patient" are
used interchangeably herein, and refer to a mammal, including, but
not limited to, murines, simians, humans, mammalian farm animals,
mammalian sport animals, and mammalian pets.
[0026] As used herein, the term "hepatic fibrosis," used
interchangeably herein with "liver fibrosis," refers to the growth
of scar tissue in the liver that can occur in the context of a
chronic hepatitis infection.
[0027] As used herein, the term "liver function" refers to a normal
function of the liver, including, but not limited to, a synthetic
function, including, but not limited to, synthesis of proteins such
as serum proteins (e.g., albumin, clotting factors, alkaline
phosphatase, aminotransferases (e.g., alanine transaminase,
aspartate transaminase), 5'-nucleosidase,
.gamma.-glutaminyltranspeptidase, etc.), synthesis of bilirubin,
synthesis of cholesterol, and synthesis of bile acids; a liver
metabolic function, including, but not limited to, carbohydrate
metabolism, amino acid and ammonia metabolism, hormone metabolism,
and lipid metabolism; detoxification of exogenous drugs; a
hemodynamic function, including splanchnic and portal hemodynamics;
and the like.
[0028] The term "sustained viral response" (SVR; also referred to
as a "sustained response" or a "durable response"), as used herein,
refers to the response of an individual to a treatment regimen for
HCV infection, in terms of serum HCV titer. For example, a
"sustained viral response" refers to no detectable HCV RNA (e.g.,
less than about 500, less than about 200, or less than about 100
genome copies per milliliter serum) found in the patient's serum
for a period of at least about one month, at least about two
months, at least about three months, at least about four months, at
least about five months, and/or at least about six months following
cessation of treatment.
[0029] The compound,
.beta.-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (hereinafter
"Compound 1") has been demonstrated to be effective in inhibiting
HCV replication. Although this invention is not limited by any
particular theory, it is believed that Compound 1 inhibits HCV
replication by inhibiting the HCV RNA polymerase, an enzyme
involved in the replication of the hepatitis C virus. Compound 1
can be obtained using methods known to those skilled in the art,
such as those methods described in U.S. Pat. No. 7,419,572, which
is hereby incorporated by reference in its entirety.
Pharmaceutically acceptable salts and prodrugs of Compound 1 can be
utilized in the compositions described herein. For example, the
diisobutyl ester prodrug of
.beta.-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (Compound 1a),
shown in FIG. 1, has been shown to have increased permeability that
led to increased plasma exposure, and thereby improved anti-viral
efficacy.
[0030] The compound,
(1S,4R,6S,14S,18R)-4-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid
14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-diox-
o-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-18-yl ester
(hereinafter "Compound 2") has shown to be effective in inhibiting
HCV replication. The aforementioned compound can be obtained using
methods known to those skilled in the art, including, for example,
those methods disclosed in U.S. Pat. No. 7,491,794, which is hereby
incorporated by reference in its entirety. Although this invention
is not limited by any particular theory, Compound 2 is believed to
inhibit the HCV protease, in particular the NS3/4A protease.
Pharmaceutically acceptable salts and prodrugs of Compound 2 can be
utilized in the compositions described herein. For example, the
sodium salt of Compound 2 can be included in compositions described
herein. The structure and methods for producing the sodium salt are
described in U.S. Publication No. 2007-0054842, filed on Jul. 21,
2006, which is hereby incorporated by reference in its
entirety.
[0031] For the compounds described herein, each stereogenic carbon
can be of R or S configuration. Although the specific compounds
exemplified in this application can be depicted in a particular
configuration, compounds having either the opposite stereochemistry
at any given chiral center or mixtures thereof are also envisioned
unless otherwise specified. When chiral centers are found in the
salts or prodrugs of the compounds, it is to be understood that the
compounds encompasses all possible stereoisomers unless otherwise
indicated. In addition it is understood that, in any compound
described herein having one or more double bond(s) generating
geometrical isomers that can be defined as E or Z, each double bond
may independently be E or Z a mixture thereof. Likewise, all
tautomeric forms are also intended to be included.
[0032] Some embodiments described herein relate to a composition
that can include Compound 1, or a pharmaceutically acceptable salt
or prodrug thereof; and Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof. In an embodiment, the prodrug
of Compound 1 can be Compound 1a. In some embodiments, the salt of
Compound 2 can be the sodium salt.
[0033] An embodiment described herein relates to a composition
consisting essentially of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof; and Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof. In some
embodiments, the prodrug of Compound 1 can be Compound 1a. In an
embodiment, the salt of Compound 2 can be the sodium salt.
[0034] In some embodiments, the composition can further include a
pharmaceutically acceptable excipient, diluent and/or carrier, such
as those described herein.
[0035] Various amounts of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, can be included in the
compositions described herein. In some embodiments, the composition
can include an amount of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 9000 mg
to about 50 mg. In other embodiments, the composition can include
an amount of Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, in the range of about 5000 mg to about 150 mg. In
still other embodiments, the composition can include an amount of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, in the range of about 2000 mg to about 300 mg. In yet
still other embodiments, the composition can include an amount of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, in the range of about 1000 mg to about 450 mg. In an
embodiment, the composition can include an amount of Compound 1, or
a pharmaceutically acceptable salt or prodrug thereof, in the range
of about 1000 mg to about 500 mg.
[0036] Similarly, various amounts of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, can be
included in the compositions. In some embodiments, the composition
can include an amount of Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 2000 mg
to about 2 mg. In other embodiments, the composition can include an
amount of Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof, in the range of about 1600 mg to about 25 mg. In
still other embodiments, the composition can include an amount of
Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof, in the range of about 500 mg to about 50 mg. In an
embodiment, the composition can include an amount of Compound 2, or
a pharmaceutically acceptable salt or prodrug thereof, in the range
of about 200 mg to about 100 mg.
[0037] A potential advantage of utilizing a combination of
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, may be a reduction in the required amounts of one or more
compounds that are effective in treating a disease condition
disclosed herein (for example, HCV), as compared to monotherapy
treatment of an otherwise comparable patient population using
either Compound 1 or 2, or pharmaceutically acceptable salts or
prodrugs thereof, alone. In some embodiments, the amount of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, in the composition can be less compared to the amount of
Compound 1 or a pharmaceutically acceptable salt or prodrug
thereof, needed to achieve the same viral load reduction when
administered as a monotherapy. In some embodiments, the amount of
Compound 2 or a pharmaceutically acceptable salt or prodrug
thereof, in the composition can be less compared to the amount of
Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof, needed to achieve the same viral load reduction when
administered as a monotherapy. In an embodiment, the sum of the
amount of Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, and the amount of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, is less than
expected or predicted based on the additive combination of Compound
1, or a pharmaceutically acceptable salt or prodrug thereof, alone
and Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof, alone for treating the disease condition such as HCV.
[0038] Additional advantages of utilizing a combination of
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, may include little to no cross resistance between
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof; different routes for elimination of Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof; little to no
overlapping toxicities between Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof; little to no
significant effects on cytochrome P450; and/or little to no
pharmacokinetic interactions between Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof.
[0039] The percentages of Compounds 1 and 2, or pharmaceutically
acceptable salts or prodrugs thereof, present in the composition
can also vary. For example, in some embodiments, the composition
can include an amount of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 1% to
about 99% (weight/weight) based on the sum of the amount of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, and the amount of Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof, in the composition. Additional
embodiments include, but are not limited to, an amount of Compound
1, or a pharmaceutically acceptable salt or prodrug thereof, in the
range of about 5% to about 90%, about 10% to about 80%, about 20%
to about 70%, about 30% to about 60% and about 40% to about 50%
(weight/weight) based on the sum of the amount of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, and the amount
of Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof, in the composition. As to Compound 2, in an embodiment,
the composition can include an amount of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, in the range
of about 1% to about 99% (weight/weight) based on the sum of the
amount of Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, and the amount of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, in the
composition. Examples of additional embodiments, include, but are
not limited to, an amount of Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof, in the range of about 5% to
about 90%, about 10% to about 80%, about 20% to about 70%, about
30% to about 60% and about 40% to about 50% (weight/weight) based
on the sum of the amount of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, and the amount of Compound 2,
or a pharmaceutically acceptable salt or prodrug thereof, in the
composition.
[0040] Additional therapeutic agents can also be included in a
composition that includes Compounds 1 and 2, or pharmaceutically
acceptable salts or prodrugs thereof. In some embodiments, the
additional therapeutic agent can be an anti-viral agent. In an
embodiment, the anti-viral agent can be a HCV anti-viral agent. A
non-limiting list of examples of suitable therapeutic agents
include nucleotides and nucleoside analogs (such as azidothymidine
(AZT) (zidovudine), and analogs and derivatives thereof;
2',3'-dideoxyinosine (DDI) (didanosine), and analogs and
derivatives thereof; 2',3'-dideoxycytidine (DDC) (dideoxycytidine),
and analogs and derivatives thereof;
2',3'-didehydro-2',3'-dideoxythymidine (D4T) (stavudine), and
analogs and derivatives thereof; combivir; abacavir; adefovir
dipivoxil; cidofovir; ribavirin; ribavirin analogs; levovirin,
viramidine, isatoribine and the like), pirfenidone or a pirfenidone
analogs, NS5B RNA-dependent RNA polymerase inhibitors, tumor
necrosis factor antagonists (such as etanercept, infliximab and
adalimumab), thymosin-.alpha. (Zadaxin.TM.), an interferon receptor
agonist(s), .alpha.-glucosidase inhibitors, TNF-.alpha.
antagonists, NS3 helicase inhibitors, NS5B polymerase inhibitors,
NS3 protease inhibitors (for example, (VX-950) and (SCH 503034)),
Ritonavir
(10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]--
3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic
acid, 5-thiazolylmethyl ester[5S-(5R*,8R*,10R*,11R*)], available
from Abbott Laboratories), and ribozymes such as Heptazyme.TM. and
phosphorothioate oligonucleotides which are complementary to HCV
protein sequences and which inhibit the expression of viral core
proteins.
[0041] One limitation of early interferon (IFN) therapy was rapid
clearance of the protein from the blood. Chemical derivatization of
IFN with polyethyleneglycol (PEG) has resulted in proteins with
substantially improved pharmacokinetic properties. PEGASYS.RTM. is
a conjugate of .alpha.-2a and a 40 kD branched mono-methoxy PEG and
PEG-INTRON.RTM. is a conjugate of .alpha.-2b and a 12 kD
mono-methoxy PEG. B. A. Luxon et al., Clin. Therapy. 2002, 24(9):
13631-1383; and A. Kozlowski and J. M Harris, J. Control. Release,
2001, 72: 217-224. However, some patients are unable or unwilling
to subject themselves to interferon therapy for one or more
reasons, for example, having to give themselves self-injections
and/or one or more side effects related to interferon therapy.
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, further can include an interferon receptor agonist, such
as a Type I interferon agonist and/or a Type II interferon agonist.
In an embodiment, the Type II interferon agonist can be
interferon-.gamma. (IFN-.gamma.). In an embodiment, the Type 1
interferon agonist can be interferon-.alpha. (IFN-.alpha.), for
example, monoPEG (30 kD, linear)-ylate consensus, INFERGEN
consensus IFN-.alpha., a 40 kD branched mono-methoxy PEG conjugate
of interferon .alpha.-2b and/or a 12 kD mono-methoxy PEG conjugate
of interferon .alpha.-2b. In some embodiments, ribavirin can be
also included in a composition that includes Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof. In other
embodiments, a composition that includes Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof, does not
include an interferon agonist. For example, the interferon agonist
can be a Type I interferon agonist. In an embodiment, the Type I
interferon agonist is a pegylated Type I interferon agonist such as
those described herein. In still other embodiments, a composition
that includes Compounds 1 and 2, or pharmaceutically acceptable
salts or prodrugs thereof, does not include ribavirin.
[0042] As used herein, the term "interferon receptor agonist"
refers to any Type I interferon receptor agonist, Type II
interferon receptor agonist, or Type III interferon receptor
agonist. As used herein, the term "a Type I interferon receptor
agonist" refers to any naturally occurring or non-naturally
occurring ligand of human Type I interferon receptor, which binds
to and causes signal transduction via the receptor. Type I
interferon receptor agonists include interferons, including
naturally-occurring interferons, modified interferons, synthetic
interferons, pegylated interferons, fusion proteins comprising an
interferon and a heterologous protein, shuffled interferons;
antibody specific for an interferon receptor; non-peptide chemical
agonists; and the like. As used herein, the term "Type II
interferon receptor agonist" refers to any naturally occurring or
non-naturally occurring ligand of human Type II interferon receptor
that binds to and causes signal transduction via the receptor. Type
II interferon receptor agonists include native human
interferon-.gamma., recombinant IFN-.gamma. species, glycosylated
IFN-.gamma. species, pegylated IFN-.gamma. species, modified or
variant IFN-.gamma. species, IFN-.gamma. fusion proteins, antibody
agonists specific for the receptor, non-peptide agonists, and the
like. As used herein, the term "a Type III interferon receptor
agonist" refers to any naturally occurring or non-naturally
occurring ligand of humanIL-28 receptor .alpha. ("IL-28R"), the
amino acid sequence of which is described by Sheppard, et al.,
infra., that binds to and causes signal transduction via the
receptor.
[0043] Suitable .alpha.-glucosidase inhibitors include any of the
above-described imino-sugars, including long-alkyl chain
derivatives of imino sugars as disclosed in U.S. Patent Publication
No. 2004/0110795; inhibitors of endoplasmic reticulum-associated
.alpha.-glucosidases; inhibitors of membrane bound
.alpha.-glucosidase; miglitol (Glyset.RTM.), and active
derivatives, and analogs thereof; and acarbose (Precose.RTM.), and
active derivatives, and analogs thereof.
[0044] The compositions described herein can be administered to a
human patient per se, or in compositions where they are mixed with
other active ingredients, as in combination therapy, or carriers,
diluents, excipients or combinations thereof, and may be formulated
into preparations in solid, semi-solid, liquid or gaseous forms,
such as tablets, capsules, powders, granules, ointments, solutions,
suppositories, injections, inhalants and aerosols. Proper
formulation is dependent upon the route of administration chosen.
Techniques for formulation and administration of the compositions
described herein are known to those skilled in the art.
Pharmaceutically acceptable excipients are known to those skilled
in the art, and are described in a variety of publications,
including, for example, A. Gennaro (2000) "Remington: The Science
and Practice of Pharmacy," 20th edition, Lippincott, Williams,
& Wilkins; Pharmaceutical Dosage Forms and Drug Delivery
Systems (1999) H. C. Ansel et al., eds., 7.sup.th ed., Lippincott,
Williams, & Wilkins; and Handbook of Pharmaceutical Excipients
(2000) A. H. Kibbe et al., eds., 3.sup.rd ed. Amer. Pharmaceutical
Assoc.
[0045] The compositions disclosed herein may be manufactured in a
manner that is itself known, e.g., by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or tableting processes. Additionally, the
active ingredients are contained in an amount effective to achieve
its intended purpose. Many of the compounds used in the
compositions disclosed herein may be provided as salts with
pharmaceutically compatible counterions.
[0046] In some embodiments, the compounds, or pharmaceutically
acceptable salts or prodrugs thereof, (e.g., Compounds 1, 1a and 2)
are formulated in an aqueous buffer. Suitable aqueous buffers
include, but are not limited to, acetate, succinate, citrate, and
phosphate buffers varying in strengths from about 5 mM to about 100
mM. In some embodiments, the aqueous buffer includes reagents that
provide for an isotonic solution. Such reagents include, but are
not limited to, sodium chloride; and sugars e.g., mannitol,
dextrose, sucrose, and the like. In some embodiments, the aqueous
buffer further includes a non-ionic surfactant such as polysorbate
20 or 80. Optionally the formulations may further include a
preservative. Suitable preservatives include, but are not limited
to, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride,
and the like. In many cases, the formulation is stored at about
4.degree. C. Formulations may also be lyophilized, in which case
they generally include cryoprotectants such as sucrose, trehalose,
lactose, maltose, mannitol, and the like. Lyophilized formulations
can be stored over extended periods of time, even at ambient
temperatures.
[0047] Suitable routes of administration may, for example, include
oral, rectal, topical transmucosal, or intestinal administration;
parenteral delivery, including intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intranasal, intraocular
injections or as an aerosol inhalant. The compositions will
generally be tailored to the specific intended route of
administration. In an embodiment, the compositions described herein
can be administered orally.
[0048] Subcutaneous administration can be accomplished using
standard methods and devices, e.g., needle and syringe, a
subcutaneous injection port delivery system, and the like. See,
e.g., U.S. Pat. Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137;
and 6,017,328. A combination of a subcutaneous injection port and a
device for administration of a pharmaceutical composition of the
embodiments to a patient through the port is referred to herein as
"a subcutaneous injection port delivery system." In many
embodiments, subcutaneous administration is achieved by bolus
delivery by needle and syringe.
[0049] For oral preparations, the compounds can be used alone or in
combination with appropriate additives to make tablets, powders,
granules or capsules, for example, with conventional additives,
such as lactose, mannitol, corn starch or potato starch; with
binders, such as crystalline cellulose, cellulose derivatives,
acacia, corn starch or gelatins; with disintegrators, such as corn
starch, potato starch or sodium carboxymethylcellulose; with
lubricants, such as talc or magnesium stearate; and if desired,
with diluents, buffering agents, moistening agents, preservatives
and flavoring agents.
[0050] The compounds can be formulated into preparations for
injection by dissolving, suspending or emulsifying them in an
aqueous or nonaqueous solvent, such as vegetable or other similar
oils, synthetic aliphatic acid glycerides, esters of higher
aliphatic acids or propylene glycol; and if desired, with
conventional additives such as solubilizers, isotonic agents,
suspending agents, emulsifying agents, stabilizers and
preservatives.
[0051] Furthermore, the compounds can be made into suppositories by
mixing with a variety of bases such as emulsifying bases or
water-soluble bases. The compounds of the embodiments can be
administered rectally via a suppository. The suppository can
include vehicles such as cocoa butter, carbowaxes and polyethylene
glycols, which melt at body temperature, yet are solidified at room
temperature.
[0052] Unit dosage forms for oral or rectal administration such as
syrups, elixirs, and suspensions may be provided wherein each
dosage unit, for example, teaspoonful, tablespoonful, tablet or
suppository, contains a predetermined amount of the composition
containing one or more inhibitors. Similarly, unit dosage forms for
injection or intravenous administration may comprise the
inhibitor(s) in a composition as a solution in sterile water,
normal saline or another pharmaceutically acceptable carrier.
[0053] The term "unit dosage form," as used herein, refers to
physically discrete units suitable as unitary dosages for human and
animal subjects, each unit containing a predetermined quantity of
compounds of the embodiments calculated in an amount sufficient to
produce the desired effect in association with a pharmaceutically
acceptable diluent, carrier or vehicle. The specifications for the
novel unit dosage forms of the embodiments depend on the particular
compound employed and the effect to be achieved, and the
pharmacodynamics associated with each compound in the host.
[0054] The compositions described herein can be administered
orally, parenterally or via an implanted reservoir. In an
embodiment, the composition can be orally administered or
administered by injection.
[0055] One may also administer the composition in a local rather
than systemic manner, for example, via injection of the composition
directly into the infected area, often in a depot or sustained
release formulation. Furthermore, one may administer the
composition in a targeted drug delivery system, for example, in a
liposome coated with a tissue-specific antibody. The liposomes will
be targeted to and taken up selectively by the organ.
[0056] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions comprising a
compound disclosed herein formulated in a compatible pharmaceutical
carrier may also be prepared, placed in an appropriate container,
and labeled for treatment of an indicated condition.
[0057] Some embodiments described herein relate to a method for
ameliorating or treating a disease condition that can include
administering an amount of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, and an amount of Compound 2, or
a pharmaceutically acceptable salt or prodrug thereof, wherein the
disease condition can be a hepatitis C virus infection, liver
fibrosis, and/or impaired liver function. In an embodiment, the
prodrug of Compound 1 can be Compound 1a.
[0058] Various dosages forms of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, and/or Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, can be used to
ameliorate and/or treat a disease condition. In some instances,
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, can be present in the same dosage form such as the
compositions described herein. In other instances, Compounds 1 and
2, or pharmaceutically acceptable salts or prodrugs thereof, can be
administered as separate dosage forms. For example, Compound 1, or
a pharmaceutically acceptable salt or prodrug thereof, can be
administered in one tablet and Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof, can be administered in a second
tablet. When Compounds 1 and 2, or pharmaceutically acceptable
salts or prodrugs thereof, are contained in separate dosage forms,
the dosage forms can be the same (e.g., as both pills) or different
(e.g., one compound can be formulated in a pill and the other
compound can be formulated as an injectable).
[0059] Administration of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, and Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, can vary. When
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, are contained in separate dosage forms, the dosage forms
can be administered simultaneously or sequentially. In some
embodiments, the dosage form that contains Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, can be
administered before the dosage form that contains Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof. In other
embodiments, the dosage form that contains Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, can be
administered after the dosage form that contains Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof. In still other
embodiments, the dosage form that contains Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, can be
administered at approximately the same time as the dosage form that
contains Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof.
[0060] In some embodiments, Compounds 1 and 2, or pharmaceutically
acceptable salts or prodrugs thereof, can be administered
concurrently. As used, the term "concurrently" means effective
concentrations of both compounds are present in a subject. When
being administered concurrently, Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof, can be
administered in the same dosage form or separate dosage forms. In
other embodiments, Compounds 1 and 2, or pharmaceutically
acceptable salts or prodrugs thereof, can be administered
sequentially. As used herein, the term "sequentially" means
administering one compound for a first time period and then
administering a second compound for a second time period in which
the first and second time periods do not overlap.
[0061] Additional therapeutic agents can also be administered to
the subject having the disease condition. A non-limiting list of
additional therapeutic agents includes those previously described
herein. When one or more additional therapeutic agents are
utilized, the additional agent(s) can be administered in the same
dosage form as Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, and/or Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof. For example, the additional
therapeutic agent(s) can be included in a composition that includes
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, without Compound 2, or a pharmaceutically acceptable salt
or prodrug thereof; or a composition that includes Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, without
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof; or a composition described herein (for example, a
composition that includes Compounds 1 and 2, or pharmaceutically
acceptable salts or prodrugs thereof). Alternatively, the
additional therapeutic agent(s) can be administered in one or more
separate dosage forms. If administered as one or more separate
dosage forms, each dosage form with one or more additional
therapeutic agents can be the same as the dosage form containing
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, and/or the dosage form containing Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, or different
from the dosage form containing Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, and/or the dosage form
containing Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof.
[0062] When one or more additional therapeutic agents are in one or
more separate dosage forms, the dosage forms with one or more
additional therapeutic agents can be administered before, after,
in-between, concurrently or sequentially with Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, and/or
Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof. In some embodiments, the additional therapeutic agent can
be an interferon receptor agonist, for example, a Type I interferon
receptor agonist and/or a Type II interferon receptor agonist. In
an embodiment, the Type II interferon agonist can be
interferon-.gamma. (IFN-.gamma.). In an embodiment, the Type 1
interferon agonist can be interferon-.alpha. (IFN-.alpha.). In some
embodiments, the Type I interferon agonist can be selected from
monoPEG (30 kD, linear)-ylate consensus, INFERGEN consensus
IFN-.alpha., a 40 kD branched mono-methoxy PEG conjugate of
interferon .alpha.-2b and a 12 kD mono-methoxy PEG conjugate of
interferon .alpha.-2b. In an embodiment, the additional therapeutic
agent can be ribavirin. In some embodiments, Compounds 1 and 2 can
be administered without administering one or more additional
therapeutic agents such as an interferon receptor agonist and/or
ribavirin. In an embodiment, the interferon receptor agonist can be
a Type 1 interferon receptor agonist, such as a pegylated Type 1
interferon receptor agonist.
[0063] One or more additional therapeutic agents can be
administered after administration of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, and Compound
2, or a pharmaceutically acceptable salt or prodrug thereof. For
example, one or more additional therapeutic agents can be
administered after completion of a treatment regimen with Compound
1, or a pharmaceutically acceptable salt or prodrug thereof, and
Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof. In some embodiments, the additional therapeutic agent can
be an interferon receptor agonist such as a Type I interferon
receptor agonist. In an embodiment, the Type I interferon receptor
agonist can be a pegylated Type I interferon receptor agonist. In
some embodiments, the additional therapeutic agent can be
ribavirin.
[0064] Whether a subject method is effective in treating an HCV
infection can be determined in various ways, for example, by a
reduction in viral load, a reduction in time to seroconversion
(virus undetectable in patient serum), an increase in the rate of
sustained viral response to therapy, a reduction of morbidity or
mortality in clinical outcomes, or other indicator of disease
response. Thus, whether a subject method is effective in treating
an HCV infection can be determined by measuring viral load, or by
measuring a parameter associated with HCV infection, including, but
not limited to, liver fibrosis, elevations in serum transaminase
levels, and necroinflammatory activity in the liver.
[0065] In some embodiments, administration and/or use of Compounds
1 and 2, or pharmaceutically acceptable salts or prodrugs thereof,
in combination can reduce the viral load more than the viral load
reduction achieved by administration of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, alone at
substantially the same amount. For example, the combination of
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, may reduce the viral load by at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about
30%, at least about 40%, at least about 50%, at least about 60%, at
least about 70%, at least about 80%, or at least about 90%, or
more, as compared to the reduction of HCV viral load achieved by
substantially the same amount of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, administered as a monotherapy.
In some embodiments, administration and/or use of Compounds 1 and
2, or pharmaceutically acceptable salts or prodrugs thereof, in
combination can reduce the viral load more than the viral load
reduction achieved by the administration of substantially the same
amount of Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof, alone. As examples, the combination of Compounds 1
and 2, or pharmaceutically acceptable salts or prodrugs thereof,
may reduce the viral load by at least about 10%, at least about
15%, at least about 20%, at least about 25%, at least about 30%, at
least about 40%, at least about 50%, at least about 60%, at least
about 70%, at least about 80%, or at least about 90%, or more, as
compared to the reduction of HCV viral load achieved by
substantially the same amount of Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof, administered as a
monotherapy.
[0066] In some embodiments, an amount of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, and an amount
of Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof, is a synergistic amount. As used herein, a "synergistic
combination" or a "synergistic amount" is a combined dosage that is
more effective in the therapeutic or prophylactic treatment of an
HCV infection than the incremental improvement in treatment outcome
that could be predicted or expected from a merely additive
combination of (i) the therapeutic or prophylactic benefit of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, when administered at that same dosage as a monotherapy and
(ii) the therapeutic or prophylactic benefit of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, when
administered at the same dosage as a monotherapy. The term
"synergistic combination" or a "synergistic amount" may also be
used to refer to a combined dosage that is more effective in the
therapeutic or prophylactic treatment of an HCV infection than
could be predicted or expected, based on the rule of mixtures, from
a combination of (i) the therapeutic or prophylactic benefit of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, and (ii) the therapeutic or prophylactic benefit of
Compound 2, or a pharmaceutically acceptable salt or prodrug
thereof. Accordingly, in some embodiments, the combination of
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, may reduce the viral load by at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about
30%, at least about 40%, at least about 50%, at least about 60%, at
least about 70%, at least about 80%, or at least about 90%, or
more, as compared to the reduction in HCV viral load predicted or
expected from the rule of mixtures or additive combination of the
viral load reductions from administration of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, and Compound
2, or a pharmaceutically acceptable salt or prodrug thereof. In
some embodiments, the foregoing levels of viral load reduction are
averages based on a population of subjects. HCV viral load and
viral load reduction can be determined by methods known in the art.
For example, HCV viral load may be determined by measuring HCV RNA
levels using a suitable assay such as a reverse transcriptase PCR
assay. In one embodiment, the assay is the COBAS.RTM.
AmpilPrep/COBAS.RTM. Taqman.RTM. HCV Test RUO.
[0067] The combination of Compounds 1 and 2, or pharmaceutically
acceptable salts or prodrugs thereof, may shorten the time period
it takes a subject to achieve a sustained viral response to
therapy. For example, the combination of Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof, may shorten
the time period it takes a subject to achieve a sustained viral
response to therapy compared to the time period it takes the
subject to achieve a sustained viral response being administered
substantially the same amount of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, as a monotherapy. Likewise or
in the alternative, the combination of Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof, may shorten
the time period it takes a subject to achieve a sustained viral
response to therapy compared to the time period it takes the
subject to achieve a sustained viral response to therapy being
administered substantially the same amount of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, as a
monotherapy. In an embodiment, the combination of Compounds 1 and
2, or pharmaceutically acceptable salts or prodrugs thereof, may
shorten the time period it takes a subject to achieve a sustained
viral response to therapy by at least about 10%, at least about
15%, at least about 20%, at least about 25%, at least about 30%, at
least about 40%, at least about 50%, at least about 60%, at least
about 70%, at least about 80%, or at least about 90%, or more, as
compared to that expected based on the rule of mixtures or additive
combination expected or predicted from the time period it takes the
subject to achieve a sustained viral response to therapy being
administered substantially the same amount of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, as monotherapy
and the time period it takes the subject to achieve a sustained
viral response to therapy being administered substantially the same
amount of Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof, as monotherapy. In some embodiments, the time
periods for achieving a sustained viral response are averages based
on a population of subjects.
[0068] As noted above, whether a subject method is effective in
treating an HCV infection can be determined by measuring a
parameter associated with HCV infection, such as liver fibrosis.
Methods of determining the extent of liver fibrosis are known to
those skilled in the art. In some embodiments, the level of a serum
marker of liver fibrosis indicates the degree of liver
fibrosis.
[0069] As a non-limiting example, levels of serum alanine
aminotransferase (ALT) are measured, using standard assays. In
general, an ALT level of less than about 45 international units is
considered normal. In some embodiments, the combination of
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, reduces a serum level of a marker of liver fibrosis by at
least about 10%, at least about 20%, at least about 25%, at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%, at
least about 65%, at least about 70%, at least about 75%, or at
least about 80%, or more, compared to the level of the marker in a
subject undergoing monotherapy (such as being administered
substantially the same amount of Compound 1 or 2, or a
pharmaceutically acceptable salt or prodrug thereof, alone). In
other embodiments, the combination of Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof, reduces a
serum level of a marker of liver fibrosis by at least about 10%, at
least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 55%, at least about 60%, at least about 65%, at
least about 70%, at least about 75%, or at least about 80%, or
more, as compared to that expected based on the rule of mixtures or
the additive combination of the levels of reduction of a serum
level of a marker of liver fibrosis using substantially the same
amounts of Compounds 1 and 2, or pharmaceutically acceptable salts
or prodrugs thereof. In some embodiments, the reduction of serum
levels of a marker of liver fibrosis are averages based on a
population of subjects.
[0070] A subject being treated for a disease condition can
experience resistance to one or more of the therapeutic agents (for
example, Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, and/or Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof). The term "resistance" as used
herein refers to a subject displaying a delayed, lessened and/or
absent response to the therapeutic agent(s). For example, the viral
load of a subject with HCV who has become resistant to an
anti-viral or combination thereof may be reduced to a lesser degree
compared to the amount in viral load reduction exhibited by the
subject before becoming resistant to the anti-viral or combination
thereof and/or the determined normal mean viral load reduction. In
some embodiments, the level of resistance of the disease condition
to therapy can be decreased compared to the level of resistance
measured in a subject being administered substantially the same
amount of Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, as a monotherapy. In some embodiments, the level
of resistance of the disease condition to therapy can be decreased
compared to the level of resistance measured in a subject being
administered substantially the same amount of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, as a
monotherapy. In other embodiments, the combination of Compounds 1
and 2, or pharmaceutically acceptable salts or prodrugs thereof,
reduces the level of resistance of the disease condition to therapy
by at least about 10%, at least about 20%, at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, at least about 55%, at least about
60%, at least about 65%, at least about 70%, at least about 75%, or
at least about 80%, or more, as compared to that expected based on
the rule of mixtures or additive combination of the levels of
resistance using substantially the same amounts of Compounds 1 and
2, or pharmaceutically acceptable salts or prodrugs thereof. In
some embodiments, the levels of resistance are averages based on a
population of subjects.
[0071] Some subjects being treated for HCV who develop or have
resistance for one or more therapies experience a viral load
rebound. The term "viral load rebound" as used herein refers to a
sustained .gtoreq.0.5 log IU/ml increase of viral load above nadir
before the end of treatment, where nadir is a .gtoreq.0.5 log IU/ml
decrease from baseline. In some embodiments, co-administration of
Compound 1, or pharmaceutically acceptable salts or prodrugs
thereof, and Compound 2, or pharmaceutically acceptable salts or
prodrugs thereof, results in less subjects experiencing a viral
load rebound as compared to monotherapy with Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, or Compound 2,
or a pharmaceutically acceptable salt or prodrug thereof. In some
embodiments, the co-administration of Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof, results in
at least about 10%, at least about 20%, at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, at least about 55%, at least about
60%, at least about 65%, at least about 70%, at least about 75%, or
at least about 80%, or more, reduction in number of subjects
experiencing a viral load rebound as compared to monotherapy, for
example monotherapy with Compound 1, or pharmaceutically acceptable
salts or prodrugs thereof, and Compound 2, or pharmaceutically
acceptable salts or prodrugs thereof. In some embodiments, the
co-administration of Compounds 1 and 2, or pharmaceutically
acceptable salts or prodrugs thereof, results in less than about
75%, less than about 50%, less than about 40%, less than about 30%,
less than about 20%, less than about 10%, or less than about 5% of
the patient population who experiences a viral load rebound. In
other embodiments, the combination of Compounds 1 and 2, or
pharmaceutically acceptable salts or prodrugs thereof, reduces the
percentage of the patient population who experiences a viral load
rebound by at least about 10%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, at least about 55%, at least
about 60%, at least about 65%, at least about 70%, at least about
75%, or at least about 80%, or more, as compared to that expected
based on the rule of mixtures.
[0072] Some subjects being treated for HCV who develop or have
resistance for one or more therapies are or become non-responders.
The term "non-responder" as used herein refers to a viral load
decrease .ltoreq.0.5 log IU/ml during treatment. In some
embodiments, co-administration of Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, and Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, results in
less subjects who are non-responders as compared to monotherapy of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, or Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof. In some embodiments, the co-administration of
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, results in at least about 10%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 60%, at least about 65%, at least about 70%, at
least about 75%, or at least about 80%, or more, reduction in
number of patients who are non-responders as compared to
monotherapy. In some embodiments, the co-administration of
Compounds 1 and 2, or pharmaceutically acceptable salts or prodrugs
thereof, results in less than about 75%, less than about 50%, less
than about 40%, less than about 30%, less than about 20%, less than
about 10%, or less than about 5% of the patient population who are
non-responders. In other embodiments, the combination of Compounds
1 and 2, or pharmaceutically acceptable salts or prodrugs thereof,
reduces the percentage of the patient population who are
non-responders by at least about 10%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, at least about 55%, at
least about 60%, at least about 65%, at least about 70%, at least
about 75%, or at least about 80%, or more, as compared to that
expected based on the rule of mixtures.
[0073] In addition or in the alternative, in some embodiments, the
onset of resistance of the disease condition to therapy can be
delayed compared to when the onset of resistance occurs in a
subject being administered substantially the same amount of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, as a monotherapy. In some embodiments, the onset of
resistance of the disease condition to therapy can be delayed
compared to when the onset of resistance occurs in a subject being
administered substantially the same amount of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, as a
monotherapy. In an embodiment, Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, can delay the onset of
resistance to Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof. For example, Compound 1, or a pharmaceutically
acceptable salt or prodrug thereof, can delay the onset of HCV
resistance to Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof, as indicated by an HCV replicon assay. As used
herein, the phrase "onset of resistance" is the point in time when
the subject shows resistance to one or more therapeutic compounds.
In an embodiment, the disease can be HCV. In some embodiments, the
combination of Compounds 1 and 2, or of pharmaceutically acceptable
salts or prodrugs thereof, may be a synergistic combination in that
the onset of resistance may be delayed by at least about 10%, at
least about 15%, at least about 20%, at least about 25%, at least
about 30%, at least about 40%, at least about 50%, at least about
60%, at least about 70%, at least about 80%, or at least about 90%,
or more, as compared to when the onset of resistance is predicted
or expected based on the rule of mixtures or the additive
combination of substantially the same amounts of Compounds 1 and 2,
or pharmaceutically acceptable salts or prodrugs thereof. In some
embodiments, the time of the onset of resistance is an average
based on a population of subjects.
[0074] Often one or more side effects are experienced by subjects
being treated with therapeutic agents such as anti-viral compounds.
In some instances, the side effects may be to such a degree that
treatment with the agent may not be feasible or recommended such
that treatment is not an option for some subjects or treatment has
to be stopped. By lessening or decreasing the number and/or
severity of the side effects, subject compliance with the treatment
may be increased. In some embodiments, the number of side effects
associated with co-administration of Compound 1, or a
pharmaceutically salt or prodrug thereof; and Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, can be less
than the number of side effects exhibited by the subject being
administered substantially the same amount of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, as the only
active agent. In some embodiments, the number of side effects
associated with co-administration of Compound 1, or a
pharmaceutically salt or prodrug thereof, and Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof can be less
than the number of side effects exhibited by the subject being
administered substantially the same amount of Compound 2, or a
pharmaceutically acceptable salt or prodrug thereof, as the only
active agent. In other embodiments, the subject being administered
a combination of Compounds 1 and 2, or pharmaceutically acceptable
salts or prodrugs thereof, may exhibit less side effects than
predicted or expected based on the rule of mixtures or the additive
combination of side effects experienced by a subject being
administered substantially the same amounts of Compounds 1 and 2,
or pharmaceutically acceptable salts or prodrugs thereof, by at
least about 10%, at least about 20%, at least about 25%, at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, at least about 55%, at least about 60%, at
least about 65%, at least about 70%, at least about 75%, or at
least about 80%. In some embodiments, the number of side effects is
an average based on a population of subjects.
[0075] As previously stated, compliance by subjects to the
anti-viral treatment may also be increased by decreasing the
severity of one or more side effects that is associated with
monotherapy with the active compounds. In some embodiments, the
severity of a side effect associated with the combination of
Compound 1, or a pharmaceutically acceptable salt or prodrug
thereof, and Compound 2, or a pharmaceutically acceptable salt or
prodrug thereof, is decreased compared to the severity of the side
effect experienced by the subject being administered Compound 1, or
a pharmaceutically acceptable salt or prodrug thereof, as a
monotherapy. In an embodiment, the severity of a side effect
associated with the combination of Compound 1, or a
pharmaceutically acceptable salt or prodrug thereof, and Compound
2, or a pharmaceutically acceptable salt or prodrug thereof, is
decreased compared to the severity of the side effect experienced
by the subject being administered Compound 2, or a pharmaceutically
acceptable salt or prodrug thereof, as a monotherapy. In some
embodiments, the severity of a side effect associated with the
combination of Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, and Compound 2, or a pharmaceutically acceptable
salt or prodrug thereof, may be decreased by at least about 10%, at
least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 55%, at least about 60%, at least about 65%, at
least about 70%, at least about 75%, or at least about 80%, as
compared to the severity of the side effect predicted or expected
based on the rule of mixtures or the additive combination of the
severities of the side effect associated with substantially the
same amount of Compound 1, or a pharmaceutically acceptable salt or
prodrug thereof, and substantially the same amount of Compound 2,
or a pharmaceutically acceptable salt or prodrug thereof. In some
embodiments, the severity of a side effect is an average based on a
population of subjects.
[0076] As will be readily apparent to one skilled in the art, the
useful in vivo dosage to be administered and the particular mode of
administration will vary depending upon the age, weight, the
severity of the affliction, and mammalian species treated, the
particular compounds employed, and the specific use for which these
compounds are employed. (See e.g., Fingl et al. 1975, in "The
Pharmacological Basis of Therapeutics", which is hereby
incorporated herein by reference in its entirety, with particular
reference to Ch. 1, p. 1). The determination of effective dosage
levels, that is the dosage levels necessary to achieve the desired
result, can be accomplished by one skilled in the art using routine
pharmacological methods. Typically, human clinical applications of
products are commenced at lower dosage levels, with dosage level
being increased until the desired effect is achieved.
Alternatively, acceptable in vitro studies can be used to establish
useful doses and routes of administration of the compositions
identified by the present methods using established pharmacological
methods.
[0077] Although the exact dosage will be determined on a
drug-by-drug basis, in most cases, some generalizations regarding
the dosage can be made. The dosage may be a single one or a series
of two or more given in the course of one or more days, as is
needed by the subject. In some embodiments, the compounds will be
administered for a period of continuous therapy, for example for a
week or more, or for months or years.
[0078] In instances where human dosages for compounds have been
established for at least some condition, those same dosages, or
dosages that are between about 0.1% and 500%, more preferably
between about 25% and 250% of the established human dosage will be
used. Where no human dosage is established, as will be the case for
newly-discovered pharmaceutical compositions, a suitable human
dosage can be inferred from ED.sub.50 or ID.sub.50 values, or other
appropriate values derived from in vitro or in vivo studies, as
qualified by toxicity studies and efficacy studies in animals.
[0079] In cases of administration of a pharmaceutically acceptable
salt, dosages may be calculated as the free base. As will be
understood by those of skill in the art, in certain situations it
may be necessary to administer the compounds disclosed herein in
amounts that exceed, or even far exceed, the above-stated,
preferred dosage range in order to effectively and aggressively
treat particularly aggressive diseases or infections.
[0080] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety which are sufficient to
maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will
depend on individual characteristics and route of administration.
However, HPLC assays or bioassays can be used to determine plasma
concentrations.
[0081] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, preferably
between 30-90% and most preferably between 50-90%. In cases of
local administration or selective uptake, the effective local
concentration of the drug may not be related to plasma
concentration.
[0082] It should be noted that the attending physician would know
how to and when to terminate, interrupt, or adjust administration
due to toxicity or organ dysfunctions. Conversely, the attending
physician would also know to adjust treatment to higher levels if
the clinical response was not adequate (precluding toxicity). The
magnitude of an administrated dose in the management of the
disorder of interest will vary with the severity of the condition
to be treated and the route of administration. The severity of the
condition may, for example, be evaluated, in part, by standard
prognostic evaluation methods. Further, the dose and perhaps dose
frequency will also vary according to the age, body weight, and
response of the individual patient. A program comparable to that
discussed above may be used in veterinary medicine.
[0083] In non-human animal studies, applications of potential
products are commenced at higher dosage levels, with dosage being
decreased until the desired effect is no longer achieved or adverse
side effects disappear. The dosage may range broadly, depending
upon the desired effects and the therapeutic indication.
Alternatively dosages may be based and calculated upon the surface
area of the patient, as understood by those of skill in the
art.
[0084] Compounds disclosed herein can be evaluated for efficacy and
toxicity using known methods. For example, the toxicology of a
particular compound, or of a subset of the compounds, sharing
certain chemical moieties, may be established by determining in
vitro toxicity towards a cell line, such as a mammalian, and
preferably human, cell line. The results of such studies are often
predictive of toxicity in animals, such as mammals, or more
specifically, humans. Alternatively, the toxicity of particular
compounds in an animal model, such as mice, rats, rabbits, or
monkeys, may be determined using known methods. The efficacy of a
particular compound may be established using several recognized
methods, such as in vitro methods, animal models, or human clinical
trials. Similarly, acceptable animal models may be used to
establish efficacy of chemicals to treat such conditions. When
selecting a model to determine efficacy, the skilled artisan can be
guided by the state of the art to choose an appropriate model,
dose, and route of administration, and regime. Of course, human
clinical trials can also be used to determine the efficacy of a
compound or composition in humans.
[0085] Any of the compositions and methods described herein can be
administered to individuals who have been diagnosed with an HCV
infection. Any of the compositions and methods described herein can
be administered to individuals who have failed previous treatment
for HCV infection ("treatment failure patients," including
non-responders and relapsers).
[0086] Individuals who have been clinically diagnosed as infected
with HCV are of particular interest in many embodiments.
Individuals who are infected with HCV are identified as having HCV
RNA in their blood, and/or having anti-HCV antibody in their serum.
Such individuals include anti-HCV ELISA-positive individuals, and
individuals with a positive recombinant immunoblot assay (RIBA).
Such individuals may also, but need not, have elevated serum ALT
levels.
[0087] Individuals who are clinically diagnosed as infected with
HCV include naive individuals (e.g., individuals not previously
treated for HCV, particularly those who have not previously
received IFN-.alpha.-based and/or ribavirin-based therapy) and
individuals who have failed prior treatment for HCV ("treatment
failure" patients). Treatment failure patients include
non-responders (i.e., individuals in whom the HCV titer was not
significantly or sufficiently reduced by a previous treatment for
HCV, e.g., a previous IFN-.alpha. monotherapy, a previous
IFN-.alpha. and ribavirin combination therapy, or a previous
pegylated IFN-.alpha. and ribavirin combination therapy); and
relapsers (i.e., individuals who were previously treated for HCV,
e.g., who received a previous IFN-.alpha. monotherapy, a previous
IFN-.alpha. and ribavirin combination therapy, or a previous
pegylated IFN-.alpha. and ribavirin combination therapy, whose HCV
titer decreased, and subsequently increased).
[0088] In an embodiment, HCV-positive individuals have an HCV titer
of at least about 10.sup.5, at least about 5.times.10.sup.5, or at
least about 10.sup.6, or at least about 2.times.10.sup.6, genome
copies of HCV per milliliter of serum. The patient may be infected
with any HCV genotype (genotype 1, including 1a and 1b, 2, 3, 4, 6,
etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), particularly a
difficult to treat genotype such as HCV genotype 1 and particular
HCV subtypes and quasispecies.
[0089] In some embodiments, the HCV-positive individuals (as
described above) are those who exhibit severe fibrosis or early
cirrhosis (non-decompensated, Child's-Pugh class A or less), or
more advanced cirrhosis (decompensated, Child's-Pugh class B or C)
due to chronic HCV infection and who are viremic despite prior
anti-viral treatment with IFN-.alpha.-based therapies or who cannot
tolerate IFN-.alpha.-based therapies, or who have a
contraindication to such therapies. In an embodiment, HCV-positive
individuals with stage 3 or 4 liver fibrosis according to the
METAVIR scoring system are suitable for treatment with the
compositions and methods described herein. In other embodiments,
individuals suitable for treatment with the compositions and
methods described herein are patients with decompensated cirrhosis
with clinical manifestations, including patients with far-advanced
liver cirrhosis, including those awaiting liver transplantation. In
still other embodiments, individuals suitable for treatment with
the compositions and methods described herein include patients with
milder degrees of fibrosis including those with early fibrosis
(stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring
systems; or stages 1, 2, or 3 in the Ishak scoring system).
EXAMPLES
[0090] Embodiments are disclosed in further detail in the following
examples, which are not in any way intended to limit the scope of
the claims.
Example 1
Treatment Protocols
[0091] A randomized, double-blind, placebo controlled, dose ranging
study of Compound 1a and Compound 2 in adult patients with chronic
hepatitis C genotype 1 was conducted. Approximately 54 treatment
naive males and females between 18 and 65 years of age (inclusive)
with genotype 1 HCV infection who had not previously been treated
with an interferon or investigational HCV therapeutic agent were
enrolled. Approximately an additional 20 treatment patients who had
failed treatment with the current standard of care (null, partial
responders and relapsers) were enrolled. Subjects had a liver
biopsy or non-invasive (e.g., Fibroscan) procedure within 24
calendar months of first dose consistent with chronic hepatitis C
without cirrhosis. Liver biopsies within 5 years demonstrating F0
or F1 disease were also acceptable. Subjects with liver cirrhosis
or incomplete/transition to cirrhosis, or other forms of liver
disease, anemia, HIV or HBV infection, hepatocellular carcinoma,
cardiac disease or renal disease were excluded from this particular
protocol, as well as pregnant or lactating women, women of
childbearing potential, and male partners of women who are pregnant
or lactating. Women of non-child bearing potential is defined as
postmenopausal (not had a spontaneous menstrual period for at least
1 year and confirmation by FSH and LH laboratory results); surgical
sterile (status post hysterectomy or tubal ligation for at least 6
months); and/or, natural sterile (amenorrheic for at least 1
year).
[0092] Seven groups, Groups I, II, III, IV, V, VI and VII, of
subjects were studied. Blood samples were collected at time points
to determine pharmacokinetics parameters, including T.sub.max,
C.sub.max, K.sub.el, T.sub.1/2, AUC, CL/F, Vd/F and accumulation
ratio.
[0093] The specifics of Groups I, II, III, IV, V, VI and VII are
shown in Table 1 below and pictorially in FIGS. 2 and 3. Group I
included two arms with 8 subjects in Arm 1 and 8 subjects in Arm 2.
In Arm 1, Compound 1a was administered for the full 7 days and
Compound 2 was administered for the last half of the seven days. In
Arm 2, Compound 2 was administered the full seven days and Compound
1a was administered the last half of the seven days. For Group II,
a total of 10 subjects were enrolled. The subjects were either
receiving Compounds 1a and 2, or placebos for the full fourteen
days. Group I and Group II were completed sequentially.
[0094] For Groups III and IV, subjects received Compounds 1a and 2,
or placebos for the full fourteen days. Group III enrolled 18
subjects which were administered either 500 mg (Compound 1a) and
200 mg (Compound 2), 1000 mg (Compound 1a) and 100 mg (Compound 2),
or placebos of Compounds 1a and 2. Group IV enrolled 12 subjects. 8
subjects in Group IV took 1000 mg (Compound 1a) and 200 mg
(Compound 2), and 4 subjects took placebos. Groups III and IV were
completed sequentially after the safety data for Groups I and II
was obtained.
[0095] For Groups V, VI and VII, subjects received Compounds 1a and
2 or placebos for the full fourteen days. Group V enrolled 10
subjects who were classified as treatment failure non-null. Eight
subjects in Group V took 1000 mg (Compound 1a) and 600 mg (Compound
2), and 2 subjects in Group V took placebos of Compounds 1a and 2.
Group VI enrolled 10 subjects classified as treatment null. Eight
subjects in Group VI were administered 1000 mg (Compound 1a) and
900 mg (Compound 2), and 2 subjects were administered placebos of
Compounds 1a and 2. Group VII enrolled 10 subjects. Eight subjects
in Group VII took 1000 mg (Compound 1a) and 900 mg (Compound 2),
and 2 subjects in Group VII took placebos of Compounds 1a and
2.
TABLE-US-00001 TABLE 1 Group Compound Amount Frequency Regime I 1a
500 mg bid Days 1 to 7 Arm 1 2 placebo NA q8h Days 1 to 3 (n = 8) 2
100 mg q8h Days 4 to 7 I 2 100 mg q8h Days 1 to 7 Arm 2 1a placebo
NA bid Days 1 to 3 (n = 8) 1a 500 mg bid Days 4 to 7 II 1a 500 mg
bid Days 1 to 14 Arm 1 2 100 mg q8h Days 1 to 14 (n = 8) II 1a
placebo NA bid Days 1 to 14 Arm 2 2 placebo NA q8h Days 1 to 14 (n
= 2) III 1a 500 mg bid Days 1 to 14 Arm 1 2 200 mg q8h Days 1 to 14
(n = 8) III 1a 1000 mg bid Days 1 to 14 Arm 2 2 100 mg q8h Days 1
to 14 (n = 8) III 1a placebo NA bid Days 1 to 14 Arm 3 2 placebo NA
q8h Days 1 to 14 (n = 2) IV 1a 1000 mg bid Days 1 to 14 Arm 1 2 200
mg q8h Days 1 to 14 (n = 8) IV 1a placebo NA bid Days 1 to 14 Arm 2
2 placebo NA q8h Days 1 to 14 (n = 4) V 1a 1000 mg bid Days 1 to 14
TF (non-null) 2 600 mg bid Days 1 to 14 Arm 1 (n = 8) V 1a placebo
NA bid Days 1 to 14 TF (non-null) 2 placebo NA bid Days 1 to 14 Arm
2 (n = 2) VI 1a 1000 mg bid Days 1 to 14 TF (null) 2 900 mg bid
Days 1 to 14 Arm 1 (n = 8) VI 1a placebo NA bid Days 1 to 14 TF
(null) 2 placebo NA bid Days 1 to 14 Arm 2 (n = 2) VII 1a 1000 mg
bid Days 1 to 14 Naive 2 900 mg bid Days 1 to 14 Arm 1 (n = 8) VII
1a placebo NA bid Days 1 to 14 Naive 2 placebo NA bid Days 1 to 14
Arm 2 (n = 2) * bid--twice daily * q8h--every 8 hours * NA--not
applicable * TF = subjects who failed the current standard of care
(null, partial responders and relapsers)
Pharmacokinetic Assessments
[0096] Four mL blood samples were collected as follows:
Group I
[0097] Compound 1a [0098] Day 1 predose prior to first dose of
study drugs and just prior to dosing of Compound 1a at 12 hours
[0099] Day 3 at predose and 0.5, 1, 2, 3, 4, 8 and 12 hours
postdose [0100] Day 4 pre-morning dose [0101] Day 7 at predose and
0.5, 1, 2, 3, 4, 8 and 12 hours postdose
[0102] Compound 2 [0103] Day 1 predose prior to first dose of study
drugs and just prior to dosing of Compound 2 at 8 hours [0104] Day
3 at predose and 0.5, 1, 1.5, 2, 3, 4 and 8 hours postdose [0105]
Day 4 pre-morning dose [0106] Day 7 at predose and 0.5, 1, 1.5, 2,
3, 4 and 8 hours postdose
Groups II, III and IV
[0107] Compound 1a [0108] Day 1 predose prior to first dose of
study drugs and just prior to dosing of Compound 1a at 12 hours
[0109] Day 4 pre-morning dose [0110] Day 7 at predose and 0.5, 1,
2, 3, 4, 8 and 12 hours postdose [0111] Day 14 at predose
[0112] Compound 2 [0113] Day 1 predose prior to first dose of study
drugs and just prior to dosing of Compound 2 at 8 hours [0114] Day
4 pre-morning dose [0115] Day 7 at predose and 0.5, 1, 1.5, 2, 3, 4
and 8 hours postdose [0116] Day 14 at predose
Groups V, VI and VII
[0117] Compound 1a [0118] Day 1 predose prior to first dose of
study drugs and just prior to dosing of Compound 1a at 12 hours
[0119] Day 4 pre-morning dose [0120] Day 7 at predose and 0.5, 1,
2, 3, 4, 8 and 12 hours postdose [0121] Day 10 at predose [0122]
Day 14 at predose
[0123] Compound 2 [0124] Day 1 predose prior to first dose of study
drugs and just prior to dosing of Compound 1a at 12 hours [0125]
Day 4 pre-morning dose [0126] Day 7 at predose and 0.5, 1, 2, 3, 4,
8 and 12 hours postdose [0127] Day 10 at predose [0128] Day 14 at
predose
[0129] Plasma concentrations of Compound 1 (and, if applicable, its
metabolites) and Compound 2 were measured by validated liquid
chromatography/tandem mass spectrometry (LC-MS/MS) methods. The
pharmacokinetic parameters for each compound were estimated using
standard non-compartmental methods using WinNonlin (Version 5.2,
Pharsight Co.) using standard methods.
HCV RNA Viral Load Determination and Viral Resistance
Assessment
[0130] Blood samples for HCV RNA assessments (anti-viral
activity.+-.resistance) were collected throughout the treatment and
follow-up period as follows:
Group I
[0131] Screening [0132] Day 1 within 1 hour prior to morning doses
and at 4 and 12 hours after morning doses [0133] Days 5, 6, and 7
within 1 hour prior to morning doses [0134] Days 8, 14, 35 and
91
Groups II, III and IV
[0134] [0135] Screening [0136] Day 1 within 1 hour prior to morning
doses and at 4 and 12 hours after morning doses [0137] Days 2, 3,
and 4 within 1 hour prior to morning doses and 12 hours after
morning doses [0138] Days 5, 6, 7, 10, 13 and 14 within 1 hour
prior to morning doses [0139] Days 15, 21, 42 and 98
Groups V, VI and VII
[0139] [0140] Screening [0141] Day 1 within 1 hour prior to morning
doses and at 4, 12 and 16 hours after morning doses [0142] Days 2
and 14 within 1 hour prior to morning doses and 12 hours after
morning doses [0143] Days 3 and 4 within 1 hour prior to morning
doses and at 12 and 16 hours after morning doses [0144] Days 5, 6,
7, 10, and 13 within 1 hour prior to morning doses [0145] Days 21,
42 and 98
[0146] Predose samples were taken within 1 hour of dosing.
Approximately 10 mL of blood was used for both the HCV RNA viral
load determination and the viral resistance assessment. The HCV RNA
levels were determined by COBAS.RTM. AmpilPrep/COBAS.RTM.
Taqman.RTM. HCV Test RUO. This is a real-time PCR method. HCV and
RNA measurements were taken at designated time points. Mean and
individual plots of viral load data (absolute and change from
baseline) were provided from each arm in each group. A listing of
individual change from baseline was determined. Summaries of HCV
RNA measurements at each nominal time point are provided by
treatment arm.
[0147] Selected blood samples collected for viral load
determinations were utilized for phenotypic and sequence analyses
to monitor for development of resistance to Compound 1 and Compound
2 in subjects, who experience either viral load rebound or
non-response while on treatment with Compound 1 and/or Compound
2.
[0148] Population sequencing of the complete coding sequence of the
HCV NS5B polymerase and/or NS3/4A of all baseline samples was
performed using standard sequencing technology. For subjects
experiencing viral load rebound, attempts were made to determine
the population NS5B coding sequence at (a) baseline and (b) at the
first sample after viral load rebound. Amino acid substitutions in
the samples after viral load rebound were determined as compared to
the respective baseline sequence for each selected subject.
Secondary analyses included sequencing the entire HCV genome,
sequencing of samples derived from subjects having a virological
response, and determining sequences of minority quasispecies.
Phenotype studies to monitor for resistance to Compound 1 and to
Compound 2 of the samples outlined in (a) and (b) were performed,
and included analysis of samples derived from subjects having a
virological response. Assessment of cross resistance to other HCV
inhibitors and sequences analyses were performed on selected
samples and may require amplification and subcloning of sequences
from the HCV genome.
[0149] Table 2 provides the viral kinetic results for Group I, Arms
1 and 2, and monotherapy treatment with Compound 1a or Compound 2
after 7 days of treatment. The results show the mean log change
from baseline of HCV RNA polymerase (IU/mL).
TABLE-US-00002 TABLE 2 Arm 1 -2.9 Arm 2 -3.2 Compound 2 -1.7
monotherapy 100 mg, q8h Compound 1a -1.3 monotherapy 750 mg,
bid
[0150] As shown from the results in Table 2, subjects treated with
the combination of Compounds 1a and 2 showed a decrease in viral
load compared to subjects treated with Compound 1a or Compound 2 as
monotherapy.
[0151] Tables 3 and 4 provide the virological results for Groups
I-VII. Subjects treated with the combination of Compounds 1a and 2,
without pegylated interferon or ribavin, experienced a median
reduction in viral levels of -4.8 to -4.6 log.sub.10 IU/mL in all
regimens and patient populations tested. Furthermore, patient's
viral load became undetectable when switched to the standard of
care.
TABLE-US-00003 TABLE 3 NCV RNA change from HCV RNA < HCV RNA
< baseline LLOQ LLOD Regimen Patient (Log.sub.10 IU/mL) (<43
IU/mL) (<15 IU/mL) 1a mg/2 mg Group n Population median (range)
N (%) N (%) 500/100 II 8 Naive -3.9 1/8 1/8 (-5.0 to -2.9) (13)
(13) 500/200 III 8 Naive -5.2 5/8 2/8 (-5.5 to -3.1) (63) (25)
1000/100 III 7 Naive -4.8 5/7 2/7 (-5.7 to -4.5) (71) (29) 1000/200
IV 8 Naive -4.8 5/8 2/8 (-5.5 to -2.7) (63) (25) * LLOQ = lower
limit of quantification by Roche TaqMan Assay (<43 IU/mL) * LLOD
= lower limit of detection by Roche TaqMan Assay (<15 IU/mL)
TABLE-US-00004 TABLE 4 NCV RNA change from HCV RNA < HCV RNA
< baseline LLOQ LLOD Regimen Patient (Log.sub.10 IU/mL) (<43
IU/mL) (<15 IU/mL) 1a mg/2 mg Group n Population median (range)
N (%) N (%) 1000/600 V 8 TF -4.0 4/8 1/8 non-null (-6.0 to -2.5)
(50) (13) 1000/900 VI 8 TF-null -4.9 4/8 2/8 (-5.3 to -3.5) (50)
(25) 1000/900 VII 8 Naive -5.1 7/8 5/8 (-5.9 to -3.0) (88) (63) *
LLOQ = lower limit of quantification by Roche TaqMan Assay (<43
IU/mL) * LLOD = lower limit of detection by Roche TaqMan Assay
(<15 IU/mL)
Determination of Serum ALT
[0152] Serum ALT activity was measured using a standard routine
blood work test(s). The baseline value was obtained prior to the
first dose. Values outside the normal ranges and marked
abnormalities were flagged according to the standard definitions of
Roche. The values and changes from baseline were plotted by
individual subjects to aid with data evaluation. A transformation
of the data was performed. The mean change from baseline of serum
ALT for Group II is shown in FIG. 4. As shown in FIG. 4, the
combination of Compounds 1a and 2 reduces serum ALT activity.
Safety and Tolerability
[0153] Provided in Table 5 are the safety and tolerability results
for the combination treatment using Compounds 1a and 2, with and
without pegylated interferon and/or ribavirin. As shown by the
results in Table 5, the combination treatment of Compounds 1a and 2
is safe and well tolerated.
TABLE-US-00005 TABLE 5 Group Group Group Group Group Group Group
Group I II III IV V VI VII* Serious Adverse 0 0 0 0 0 0 0 Events
Discontinuations 0 0 0 0 0 0 0 Grade 3/4 0 0 0 0 0 0 0 Laboratory
Abnormalities Total Adverse 16/17 15/12 18/18 14/12 13/10 12/10
4/10 Events Headache 6 1 5 5 5 4 1 Disturbance in 0 0 0 1 1 0 0
Attention Dysgeusia 0 0 1 0 1 0 0 Nausea 1 1 0 0 0 4 0 Diarrhea 1 1
1 0 0 2 0 Dry Mouth 0 2 0 1 0 0 0 Abdominal 1 0 1 1 2 0 0
pain/Discomfort Dyspepsia 0 0 1 1 0 0 0 Rash 2 0 0 0 1 0 0 Dry Eyes
0 1 2 0 0 0 0 Fatigue 1 0 1 0 0 0 0 Chest Pain 0 1 0 0 0 0 1
Palpitations 1 0 1 0 1 0 0 Uncoded 0 1 0 2 1 0 2 Adverse Events
*Group VII - one subject in treatment
[0154] It will be understood by those of skill in the art that
numerous and various modifications can be made without departing
from the spirit of the present application. Therefore, it should be
clearly understood that the forms of the present application are
illustrative only and not intended to limit the scope of the
present application.
* * * * *