Reported by Jules Levin
EASL, April 11-15, 2007
Barcelona
On the other hand Eric Lawitz reported results from a study of NM283 in treatment-naive patients and the drug had antiviral efficacy: "Valopicitabine (NM283) plus Peg-Interferon in Treatment-Naive Hepatitis C Patients with HCV Genotype-1 Infection: HCV RNA Clearance
During 48 Weeks of Treatment"
STUDY OBJECTIVES
-- Identify optimal valopicitabine dose for use in combination with Peg-IFN
-- antiviral efficacy vs Peg-IFN alone at Week 4
-- clearance to non-detectable HCV RNA during treatment with valopicitabine + Peg-IFN regimens
-- SVR rates
-- safety / tolerability objectives
-- safety / tolerability for valopicitabine + Peg-IFN regimens
AUTHOR CONCLUSIONS
Initial rate of HCV RNA decline is valopicitabine dose-dependent
Current EOT data indicate that valopicitabine has maintained antiviral activity up to 48 weeks when combined with Peg-IFN (viral load reduction 1 to 1.7 log at week 4)
Valopicitabine 200 mg has better GI tolerability profile than the 800 mg dose
Valopicitabine 200 mg + Peg-IFN combination has improved safety profile with favorable HCV RNA reduction rates through Week 48 (EOT)
NEXT STEPS
Resistance: HCV RNA sequencing in process for all patients with viral breakthrough
NV-08A-008 trial using 200 mg dose of valopicitabine is fully enrolled and ongoing
to assess potential drug-drug interactions between valopicitabine and RBV
to evaluate safety and antiviral activity of triple combination regimen vs double regimens
-- valopicitabine + Peg-IFN + RBV
-- Peg-IFN + RBV
-- valopicitabine + Peg-IFN
STUDY DESIGN
Patients were genotype 1, treatment-naive and were randomized to 1 of several study arms: arm A; peg only for 4 weeks then peg+NM283 800mg; arm B: NM284 200mg QD for 1 week then peg+NM283 200mg; arm C: NM283 400mg then up t0 800mg QD for 1 week then peg+NM283 800mg; arm D: NM283 800mg QD for 1 week then peg+NM283 800mg; arm E: peg+NM283 800mg.
STUDY AMMENDMENT: DOSE MODIFICATION
A dose reduction was implemented in late March 2006
Patients receiving valopicitabine 800 mg + Peg-IFN continued treatment at reduced dose, randomly assigned (1:1) to
-- valopicitabine 200 mg + Peg-IFN or
-- valopicitabine 400 mg + Peg-IFN
At time of protocol amendment
-- 12 patients with HCV RNA >600 IU/mL were discontinued
-- 68% of patients had completed study Week 12
Patients in Group B (valopicitabine 200 mg + Peg-IFN) continued study treatment unchanged
Data displayed according to original treatment assignment.
Patient Disposition
In the 800MG NM283+peg (pooled data from several arms) groups 24% discontinued due to adverse event/lab abnormality/dose-limiting toxicity compared to 9% in the NM283 200mg+peg arm. 24% discontinued for lack of efficacy in the 200mg NM283+peg arm.
It looks like there was a 1 to 1.8 log reduction in viral load due to NM283 by week 4.. The peg alone arm had -1.87 log reduction; the 200mg NM283+peg arm showed -2.84 log reduction; arms C & D had -3.11 to -3.17 reduction; arm D which was the only arm in which patients started at the same time 800mg NM283+peg and reduction was -3.69.
Absolute HCV RNA 200 mg vs 800 mg* to Week 48 (LOCF)
This graph shows similar viral load reductions after 48 weeks in 200mg NM283+peg arm (-4.02) as in the 800mg NM283+peg arm (-3.94).
End of Treatment Efficacy Summary
Dose-related antiviral efficacy for valopicitabine + Peg-IFN at
Week 4 suggests an enhanced antiviral effect vs Peg-IFN alone
Favorable EOT responses in the valopicitabine 200 mg + Peg-IFN arm: HCV RNA reductions and PCR-negativity rates
Valopicitabine 200 mg + Peg-IFN showed an overall greater
HCV RNA reduction than the 800 mg + Peg-IFN arms, most likely due to GI tolerability
Current EOT data indicate that valopicitabine 200 mg shows durable antiviral activity up to 48 weeks when combined with Peg-IFN
SAFETY SUMMARY
Valopicitabine 200 mg + Peg-IFN regimens have demonstrated improved GI tolerability profile through Week 48 (EOT)
GI adverse events are valopicitabine dose-related
--less severe in patients receiving valopicitabine 200 mg or 400 mg + Peg-IFN vs valopicitabine 800 mg + Peg-IFN regimens
-- early onset, usually within 24 hours of dosing
-- resolve with continued therapy in many patients
27 SAEs have been reported
-- 7 attributed to valopicitabine or valopicitabine + Peg-IFN
Lab abnormalities
800 mg arms
-- decreases in WBC, ANC and platelets in all treatment arms consistent with Peg-IFN and 1 grade 3 / 4 hemoglobin decrease
-- sporadic grade 3 / 4 elevations in AST, amylase, lipase
200 mg arm
-- no grade 1-4 hemoglobin decreases
-- no grade 3 / 4 amylase / lipase elevations
-- only 1 patient had a grade 3 ALT and AST elevation and 1 patient had a grade 3 AST elevation
