Pharmasset this week released new data from a
Phase 1 ascending dose trial of R7128
(aka RO5024048), the experimental oral nucleoside analog HCV polymerase inhibitor
the company is developing in collaboration with Roche.
Data from several
studies of R7128 (and its related compounds PSI-6130 and PSI-6206) were presented
at the 14th International Symposium on Hepatitis C Virus and Related Viruses (HCV
2007), taking place this week in Glasgow, UK (September 9-13, 2007).
Phase
1 (Part 1): R7128 Single Ascending Dose Study
in Healthy Volunteers [1]
R7128
is a prodrug of PSI-6130, an oral nucleoside polymerase inhibitor currently in
development for the treatment of chronic HCV infection. Researchers from Pharmasset
and Roche presented data from a Phase 1 study of the properties, clinical safety,
tolerability, and pharmacokinetics of R7128 and its metabolites in healthy volunteers
after single ascending doses.
In Phase 1 (Part 1), single oral doses of
R7128 (500-9000 mg) were administered to 46 healthy subjects without HCV. Pharmacokinetic
(PK) and safety assessments were conducted. Subjects were enrolled in 5 sequential
dose groups (500 mg, 1500 mg, 4500 mg, 6000 mg, and 9000 mg); there were 6 subjects
taking the active drug and 2 taking placebo in each group, and 1 food effect group
(1500 mg) with 6 active subjects.
Results
•
19 adverse
events (AEs) were reported, including headache (3), sunburn (2), sore throat (2),
and nasal congestion (2); all were mild to moderate, none were dose dependent,
and no gastrointestinal AEs were observed.
•
No
clinically significant changes in vital signs, electrocardiograms (ECGs), hematology,
or other laboratory parameters were noted.
•
Plasma
exposure to the prodrug R7128 was negligible.
•
Exposure
to PSI-6130 and PSI-6206 (RO2433), a metabolite of PSI-6130, rose with increasing
doses of R7128.
•
Terminal
half-life was approximately 5 hours for PSI-6130 and 19 hours for PSI-6206.
•
Food
increased exposure of PSI-6130 by approximately 20%.
In
conclusion, the authors observed, "Single ascending doses of R7128 were well-tolerated
in this study. The PK profile indicates good exposure to the active moiety, PSI-6130,
and no dose-related adverse events or laboratory abnormalities were observed."
Based
upon these results, a multiple dose study of R7128 was initiated in patients with
genotype 1 hepatitis C who did not achieve sustained response to prior interferon-based
therapy.
Phase
1 (Part 2): Multiple Ascending Dose Study of
R7128 in HCV Patients [2]
On
September 10, Pharmasset reported safety and antiviral activity results for the
monotherapy component of the Phase 1 study of R7128 among 40 patients chronically
infected with genotype 1 HCV who had failed prior interferon-based therapy. The
Phase 1 (Part 2) multiple ascending dose study was designed to evaluate safety,
tolerability, pharmacokinetics, and preliminary antiviral activity.
More
data from this study will be presented in November 2007 as a late-breaker abstract
at the 58th annual meeting of the American Association for the Study of Liver
Diseases (AASLD) in Boston, MA. In accordance with the conference press embargo
guidelines, no additional data will be available for this study until the scientific
abstracts are published by AASLD on October 1, 2007.
R7128 demonstrated
potent, dose-dependent antiviral activity across the 4 patient cohorts (n=10 per
cohort; 8 active, 2 placebo) receiving 750 mg or 1500 mg administered either once-daily
or twice-daily as monotherapy for 14 days.
The greatest mean decrease
in HCV RNA from baseline was observed in the patient cohort that received 1500
mg twice-daily, the highest dose of R7128 administered in this study. These patients
demonstrated a mean 2.7 log10 IU/mL (> 99%) decrease in HCV RNA. There was
no evidence of viral rebound in any dose cohort during the 14 days of dosing.
R7128 was generally safe and well tolerated in this Phase 1 study. There
were no serious adverse events, no AEs requiring dose modification, no dose-related
gastrointestinal AEs and no clinically significant changes in vital signs, ECGs,
hematologic, renal, or other laboratory parameters.
"The R7128 results
are exciting based on the combination of potency, safety and tolerability,"
said Dr. Rajender Reddy, Professor of Medicine and Surgery in the Division of
Gastroenterology at the University of Pennsylvania and a clinical investigator
in the R7128 multiple ascending dose study. "There were no major organ or
other acute toxicities observed during the 14-day dosing period, which is encouraging
for future studies with longer exposures to R7128 in combination with the standard
of care."
Dr. Reddy added that, "Leading clinicians believe that
HCV therapy will evolve to include direct-acting antiviral drug combinations,
and nucleoside polymerase inhibitors such as R7128 could improve sustained virologic
response (SVR) rates for the treatment of chronic HCV."
"R7128
has demonstrated the most potent antiviral activity of any investigational nucleoside
HCV polymerase inhibitor to date in doses suitable for progression into future
combination studies," stated Dr. Michelle Berrey, Pharmasset's Vice President,
Clinical Development and Chief Medical Officer. "Nucleosides are the cornerstone
of antiviral therapeutic regimens due to their potency and safety profile. In
addition, nucleosides have a significantly higher genetic barrier than non-nucleosides
and protease inhibitors, which protects against drug-resistant mutations of HCV."
Planned
Phase 1 (Part 3): Study of R7128 in Combination
with Peginterferon Alfa-2a (Pegasys) plus Ribavirin
[3]
Based
on the results of the multiple ascending dose study, Pharmasset and Roche plan
to initiate a Phase 1 (Part 3) 28-day study of R7128 in combination with pegylated
interferon alfa-2a (Pegasys) plus ribavirin (Copegus) in 75 treatment-naive
patients chronically infected with HCV genotype 1.
The primary purpose
of Part 3 (COMBO) is to evaluate the safety, tolerability, and pharmacokinetics
of R7128 in treatment-naive genotype 1 patients in the clinically relevant setting
of combination therapy with the current standard of care, consisting of pegylated
interferon plus ribavirin. The secondary objective is to evaluate the short-term
decrease in viral load in this population with once or twice daily dosing of R7128
in combination with pegylated interferon plus ribavirin for 28 days.
Participants
initially will receive once or twice daily oral R7128 in combination with pegylated
interferon plus ribavirin for 28 days on an outpatient basis. Following 28 days
of combination dosing, they will be treated for an additional 28 days (through
Day 56 of the study) with just pegylated interferon plus ribavirin.
After
completing 56 days, patients who participate in Part 3 will have the option to
enroll into a standard of care protocol with pegylated interferon plus ribavirin,
to be conducted by Roche. Patients who opt to enroll into the standard of care
protocol will be pegylated interferon plus ribavirin for up to 40 weeks.
Beta-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine
Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication
[4]
Even as R7128
proceeds through the clinical trial pipeline, Pharmasset researchers are exploring
other potential anti-HCV candidates.
The
R7128 active moiety PSI-6130 has been shown to be a potent and non-cytotoxic inhibitor
of HCV in the subgenomic replicon assay, and it has been demonstrated that the
triphosphate of PSI-6130 is a potent inhibitor of the HCV NS5B polymerase.
Cell
metabolism studies have shown that PSI-6130 is converted to its uridine metabolite
(PSI-6206) via cytidine deaminase. It has also been demonstrated that PSI-6206
is not an inhibitor of HCV in the replicon assay and is not metabolized to its
monophosphate derivative, however, its triphosphate is a potent inhibitor of the
HCV NS5B polymerase.
Further
metabolism studies have shown that the monophosphate of PSI-6130 is partially
metabolized to the uridine monophosphate and that this PSI-6206 monophosphate
can be converted to the triphosphate derivative via YMPK and NDPK.
To
investigate the potential for utilizing PSI-6206 as an inhibitor of HCV replication
required that the investigators bypass the first phosphorylation step. This was
accomplished by the preparation of phosphoramidate derivatives at the 5'-position.
Such a strategy has produced potent and safe inhibitors of HCV replication.
Conclusions
•
5'-Phosphoramidate
derivatives of PSI-6206 are potent inhibitors of HCV in the subgenomic replicon
assay.
•
Selected
phosphoramidates of PSI-6206 are as much as 100 x more potent than the cytidine
analog PSI-6130.
•
Selected
PSI-6206 phosphoramidate derivatives show no cytotoxicity across several different
cell lines.
•
PSI-6206
phosphoramidates show good stability under simulated gastrointestinal conditions
and have the potential to be rapidly released at the target organ, the liver.
•
Clear
SAR was demonstrated for PSI-6206 phosphoramidates with a 1000 x range in potency.
•
Several
PSI-6206 phosphoramidates have demonstrated stability profiles that are attractive
for further development.
•
Beta-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine
phosphoramidates have potential as therapeutic agents for the treatment of HCV
infection.
Pharmasset,
Inc., Princeton, NJ, USA
09/14/07
References
1. M J Otto,
R Robson, C A Rodriguez, and others. Pharmacokinetics, Safety, and Tolerability
of R7128, a Novel Nucleoside Polymerase Inhibitor for HCV Following Single, Ascending
Oral Doses in Healthy Volunteers. 14th International Symposium on Hepatitis C
Virus and Related Viruses. September 9-13, 2007. Glasgow, UK. Abstract (poster)
P-268.
2. Pharmasset Pharmaceuticals. R7128 Demonstrates Safety and Potent
Antiviral Activity in HCV-infected Patients. Press Release. September 10, 2007.
[Editor's Note: This study will be presented as a late breaker abstract at the
58th AASLD meeting in Boston, November 2-6, 2007.]
4. M J Sofia, P Wang, J Du, and others. Beta-D-2'-Deoxy-2'-fluoro-2'-C-methyluridine
Phosphoramidates: Potent and Selective Inhibitors of HCV RNA Replication.14th
International Symposium on Hepatitis C Virus and Related Viruses. September 9-13,
2007. Glasgow, UK. Abstract (poster) P-259.
