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FDA Grants Fast Track
Designation to VX-950, an Experimental Oral Hepatitis C Virus Protease
Inhibitor from Vertex
Vertex
Pharmaceuticals announced that the US Food and Drug Administration (FDA) has
granted Fast Track designation to
VX-950, an experimental oral hepatitis C virus (HCV) protease inhibitor
for the treatment of chronic HCV infection.
Fast Track designation indicates
that FDA will speed up the development and expedite the review of promising
experimental drugs for the treatment of a serious or life-threatening
condition if it shows the potential to address an unmet medical need for
such a condition.
VX-950 has the potential to
shorten the duration of therapy compared to the standard of care (peginterferon
alfa plus ribavirin),
which may result in improved
sustained
virologic response (SVR) rates
and a more favorable
adverse
event profile.
Vertex is currently
conducting a clinical development program to assess whether VX-950 will
address these unmet medical needs in HCV therapy.
VX-950 Clinical
Status
Earlier in 2005, Vertex
concluded a 14-day,
Phase Ib study of
VX-950 that
showed a rapid and dramatic reduction in HCV RNA in HCV patients when VX-950
was administered as a single agent.
Overall in the Phase
Ib study, adverse events observed in patients
receiving VX-950 that were considered possibly related to the drug were
mild, and generally similar in frequency to events in the placebo group. The
most common adverse events reported in both placebo and VX-950 patients were
headache, frequent urination and gastrointestinal symptoms.
Based on
these encouraging Phase Ib clinical
results, Vertex recently initiated two additional clinical studies with
VX-950. In October 2005 in
Europe, Vertex began a 20-patient Phase
Ib study of
VX-950 dosed in combination with pegylated
interferon.
In December 2005, Vertex
initiated in the
United States the
first Phase II study of VX-950, which will evaluate the safety, tolerability
and pharmacodynamics of VX-950 when dosed with
pegylated interferon and
ribavirin.
Vertex expects to obtain results
from both these Phase Ib and Phase II studies of
VX-950 in early 2006. Vertex also expects to initiate multiple additional
Phase II studies in the
United States in 2006,
including a three-month study in more than 200 treatment-naive patients.
Other
HIV and Hepatitis.com Articles on VX-950
12/09/05
Source
Vertex
Pharmaceuticals. FDA Grants Fast
Track Designation to Vertex’s Investigational Oral Hepatitis C Virus
Protease Inhibitor VX-950. Press Release.
December 8, 2005.
http://www.hivandhepatitis.com/hep_c/news/2005/ad/120905_a.html
VX-950 Hep C Protease Inhibitor
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"Final results of a phase 1b Multiple
Dose Study of VX-950, a Hepatitis C Virus Protease Inhibitor"
Reported by Jules Levin
http://www.natap.org
from AASLD
Nov 14, 2005, San Francisco
Viral load reduction at day 14 was mean -4.4 log with the 750 mg every 8
hours dose.
HW Reesnik reported these data today at AASLD oral session. VX950 Ki=7nM.
Dose escalation study. Primary objective: assessment of safety.
Secondary objective: assessment of PK and viral kinetics.
PART A: 24 healthy subjects. First study reported previously.
PART B: 36 subjects with genotype 1. These data were reported today.
DOSING: 450 mg or 750 mg every 8 hours, 1250 mg every 12 hours, or
placebo for 14 days. In each cohort 2 placebo & 10 patients receiving
VX-950.
Baseline Characteristics
Median weight 70-77 kg. Mostly treatment-experienced patients. Median
HCV RNA: 6.38-6.48 log. Males & females.
Reesnik reported VX-950 was well tolerated. No serious adverse events.
No treatment discontinuations. Most common AEs considered possibly
related to study drug (all mild in severity): placebo n=6; VX-950 n=28
Headache: 33% placebo; 39% VX-950
Diarrhea: 17% placebo; 21% VX-950
Abdominal pain: 0% placebo; 14% VX-950
Nausea: 0% placebo; 14% VX-950
Dry mouth: 33% placebo; 11% VX-950
Flatulence: 33% placebo; 11% VX-950
Frequent urination: 33% placebo; 11% VX-950
Viral Load Reductions
All patients on VX-950 had at least a 2 log drop in HCV RNA. The dose
group of 750 mg every 8 hours had the best results: (n=8): 3 patients
had -3 to -4 log HCV RNA reductions; 3 patients had -4 to -5 log
reductions. 2 patients had 5 log or more in viral load reductions.
Placebo (n=6): 6 patients had 0 to -1 log reduction.
450 mg every 8 hours (n=10): 1 patient had -2 to -3 log drop. 7 patients
had -3 to -4 log drop. 2 patients had 5 log or more drop.
1250 mg every 12 hours (n=10); 1 patient had -2 to -3 log drop. 9
patients had -3 to -4 log drop.
By week 3 all three dose groups had 3 log viral load reduction, study
authors called it " rapid & dramatic decreases". At week 3 the 750 mg
dose group continued decrease in viral load with a steady decline to
about a -4.4 log decrease at day 14. Phase 2 viral load decline was slow
but steady & at day 14 the slope was still declining. But for the other
two dose groups viral load started to increase at week 3.
The mean trough concentrations of VX-950 was 1054 ng/mL at day 14 for
patients taking the 750 mg dose, 781 ng/mL for patients taking 1250 mg
dose, and 676 ng/mL for patients taking the 450 mg dose.
Pharmacokinetic/Pharmacodynamic Analysis
VX-950 induced a biphasic decline in viral load.
VX-950 AUC during early dosing, and trough concentrations at steady
state, were the key determinants of the first & second slope of viral
load decline, respectively.
Viral kinetic modeling with extrapolation of antiviral responses
indicates that viral eradication with VX-950 monotherapy could
potentially occur in 12 weeks of dosing, the presenter said.
Viral Sequencing Analysis
The error prone RNA polymerase of HCV creates a variety of quasispecies,
some of which may have decreased sensitivity to direct antivirals and
can be selected during dosing.
A state-of-the-art viral sequencing approach suggests that suboptimal
responses observed in some patients can be explained by selection of
viral variants that contain 1 or 2 sequence changes at 4 specific
locations in the protease region. While exhibiting varying levels of
reduced sensitivity to VX-950, these variants also demonstrated
decreased replicative capacity. |
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The Era
of Protease Inhibitors for the Treatment of HCV: An Overview of SCH 503034
By Marina Nunez, MD
SCH 503034
is a new, orally administered HCV protease inhibitor that has shown potent
activity against HCV in earlier laboratory testing.
In a phase 1
study (randomized, single rising dose, double blind), the
pharamcokinetics
and safety of SCH 503034 oral capsules were evaluated in healthy subjects
[1]. SCH 503034 was administered to 36 subjects (50 mg, 100 mg, 200 mg, 400
mg, 600 mg, 800 mg), and placebo to 18 subjects.
The drug was
rapidly absorbed, and after attaining Tmax
(1-2.25 h), plasma SCH 503034 concentrations declined in a biphasic manner,
with a mean terminal phase half-life (T1/2) of 7.0 to 15 h.
Cmax and AUC increased in a dose-related manner.
The safety profiles were similar in subjects receiving SCH 503034 and
placebo.
In a double-blind
placebo-controlled 14-day dosing study performed in adult patients with
HCV-1 infection who had failed pegylated
interferon (pegIFN)-a therapy, SCH 503034
exhibited dose-dependent HCV antiviral activity [2].
In a phase
Ib study comparing SCH 503034 alone (200 mg or
400 mg for 7 days) versus pegIFN-a-2b
alone (for 14 days) versus
SCH 503034 with pegIFN-a-2b
(for 14 days), the combined therapy showed greater log reductions of HCV RNA
(mean, 2.4 log for 200 mg and 2.9 log for 400 mg) than
pegIFN-a-2b
monotherapy (1.1 log) [3]. The adverse event
profile for combination treatment was similar to PEG-Intron
alone, except for a slight increase in the incidence of headache.
In a study
applying viral dynamic modeling to analysis of
data from the previous clinical trial, results indicated that the decay of
HCV RNA under the effect of pegIFN is
substantially augmented in the presence of SCH 503034, compared to its value
for IFN monotherapy in IFN
nonresponders
[3,4]. This suggests that SCH 503034 may act to
enhance IFN antiviral activity.
The molecular
activity of SCH 503034 was examined by Malcolm and colleagues [5]. The drug
binds the NS3 protease inhibiting its activity. Viral propagation is
interrupted as a consequence, since the cleavage of the HCV
polyprotein by the NS3 protease is essential.
Given that the NS3-mediated cleavage of host factors involved in IFN
response, inhibition of the NS3 protease might also increase the activity of
IFN.
The SCH
503034 NS3 binding activity was determined by
spectophotometry. Antiviral potency was assayed in
replicon cells exposed to increasing amounts of
SCH 503034. The effect of SCH 503034 on response to IFN was evaluated by
incubating cells with SCH 503034 and IFN.
SCH 503034
exhibited potent antiviral activity both alone and in combination with IFN
in the HCV replicon assay. SCH 503034 combined
with IFN was more effective than the line of additivity,
though the difference was non-significant. Nevertheless, the combination of
SCH 503034 with IFN may lead to enhanced clinical efficacy.
With the
available data, there is great expectation about the prospects of this new
drug. Belonging to a new family of drugs, it is awaited with the hope that
it may improve the efficacy of the treatment of HCV infection.
11/23/05
References
-
J Zhang and others. Single dose
pharamcokinetics of a novel hepatitis C
protease inhibitor, SCH 503034, in an oral capsule formulation. Abstract
862. 56th annual meeting of the American Association for the
Study of Liver Diseases (56th AASLD).
November 11-15, 2005.
San Francisco,
CA.
-
S
Zeuzem
and others.
Anti-viral Activity of SCH 503034, a HCV Protease Inhibitor, Administered
as Monotherapy in
Hepatitis C Genotype-1 (HCV-1) Patients Refractory to
Pegylated Interferon (Peg-IFN-a).
Abstract 94. 56th annual meeting of
the American Association for the Study of Liver Diseases (56th
AASLD). November 11-15, 2005.
San Francisco,
CA.
-
S
Zeuzem
and others.
Combination therapy with the HCV protease inhibitor, SCH 503034, plus Peg-Intron
in hepatitis C Genotype-1 Peg-Intron
non-responders: phase Ib
results. Abstract 201. 56th annual
meeting of the American Association for the Study of Liver Diseases (56th
AASLD). November 11-15, 2005.
San Francisco,
CA.
-
B A
Malcolm and others. Modeling of HCV dynamics
during combination therapy with peginterferon
alfa-2b and the NS3 protease inhibitor SCH 503034.
Abstract 1266. 56th annual meeting of the American
Association for the Study of Liver Diseases (56th AASLD).
November 11-15, 2005.
San Francisco,
CA.
-
SCH 503034, a mechanism-based
inhibitor of hepattis C virus (HCV) NS3
suppresses polyprotein
maduration and enhances the antiviral activity of
interferon-alfa-2b (INF). Abstract 864. 56th
annual meeting of the American Association for the Study of Liver Diseases
(56th AASLD). November
11-15, 2005.
San Francisco,
CA.
http://www.hivandhepatitis.com/2005icr/aasld/docs/112305_b.html |
