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NM283 HCV Polymerase Inhibitor in Previous Nonresponders to PegIFN/RBV
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Reported by Jules Levin
EASL April 2006, Vienna, Austria
Recently, due to GI side effects and toxicities dosing was required to be reduced by the FDA. Dosing in studies was up to 800 mg once daily. "Future studies in naives" will be examining 200 and 400 mg once daily. The phase III study for NM283 will be presumably delayed to address these modifications. An interaction study of NM283 with ribavirin is planned and if there is no interaction a triple regimen of NM283+pegIFN+RBV will be clinically investigated. Studies of high dosing in animal model underway, to evaluate mechanism and prevention of GI toxicity.
At EASL (April 2006), Doug Dieterich Doug Dieterich reported the study results for the Valopicitabine 006 Study Group:
"Early Clearance of HCV RNA with Valopicitabine (NM283) plus Peg-Interferon in Treatment-Naive Patients with HCV-1 infection: First Results from a Phase IIb Trial"
12 weeks results were reported including an arm that treated patients with NM283 200 mg QD plus Pegasys added at day 8. There were 3 arms in this 5 arm study in which patients were receiving 800 mg QD, but patients in this study are switched to 400 or 200 mg QD.
At EASL Nezam Afdahl reported results from this study in nonresponders, which only examined the higher doses of NM283.
"Randomized Trial of Valopicitabine (NM283) Alone and in Combination with Peg-Interferon vs. Retreatment with Peg-Interferon plus Ribavirin (PegIFN/RBV) in Hepatitis C Patients with Previous Non-Response to PegIFN/RBV: Second Interim Results"
N. Afdhal, C. O'Brien, E. Godofsky, M. Rodriguez-Torres, S. Pappas, P. Pockros, E. Lawitz, N. Bzowej, V. Rustgi, M. Sulkowski, K. Sherman,I. Jacobson, G. Chao, S. Knox, K. Pietropaolo, and N. Brown
Protocol Amendments
Valopicitabine (NM283) Phase IIb Trial in Non-responders
First amendment: Goal to allow consolidation of treatment responses; so treatment period amended to allow Rx up to maximum 72 weeks or until PCR-nondetectable x 36 weeks.
Second amendment: Severe GI side effects in some patients at NM283 dosing 800 mg/d, more in naive study than non-responder study
- Hence a dose reduction has been implemented in both studies to a maximal dose of 400mg (see also: Dieterich et al, EASL 2006):
- All 13 patients with HCV RNA >1000 IU/mL discontinued
SEE SAFETY SUMMARY BELOW.
Conclusions by Authors
Week 24 data continue to demonstrate statistically superior antiviral efficacy as evaluated by HCV RNA & EVR Rate for NM283 800mg + pegIFN dose groups. NM283 + pegIFN is satisfactorily tolerated by most nonresponders: 3% of NM283+pegIFN recipients discontinued for GI side effects in this nonresponder study. Final end-of-treatment response and SVR data available in 2nd half 2007.
Note: in the naive-study presented at EASL by Dieterich, 18% discontinued by week 12, 14% for adverse events, mostly GI side effects, only 2 patients discontinued in the 200mg cohort. 9 patients had grade _ AST and 2 patients with grade _ lipase elevations, all in the 800 mg groups.
Current Status and Patient Disposition
Valopicitabine (NM283) Phase IIb Trial in Non-responders
190 patients randomized (fully enrolled in 2005)
- 12 patients withdrew prior to receiving study medications
178 patients received study medications (ITT population)
-- 60 patients discontinued by Week 24
- 34 (19 %) failed viral response criteria at 4 or 12 weeks
- 14 (8 %) discontinued for adverse events; only 1 on 400mg
- 12 (7 %) withdrew consent or discontinued for other reasons
118 patients past week 24
Trial ongoing, today's presentation: final 24 week interval analysis
Baseline Parameters
Valopicitabine (NM283) Phase IIb Trial in Non-responders
Mean HCV RNA: 6.9 to 7.0 log10 IU/mL; 81% did not have 2 log drop in previous therapy. 50-70% Caucasian; of note: 10-23% Hispanic and 10-23% African-American.
Safety Summary to Week 24
Valopicitabine (NM283) Phase IIb Trial in Non-responders
Nausea (with/without vomiting) common with initiation of NM283 + pegIFN treatment; diarrhea is less common; usually transient or intermittent
- 4 patients (3%) discontinued for GI side effects
24 serious adverse events (SAEs) through Week 24
- 6 reported possibly attributed to NM283 (anemia, colitis, dehydration, fatigue, pancreatitis, gram-negative bacteremia 2 to UTI)
Sporadic elevations of amylase, lipase, AST, ALT rarely treatment-limiting
Adverse events (>10%):
Valopicitabine (NM283) Phase IIb Trial in Non-responders
GI side effects nausea, vomiting, and diarrhea were much greater in the arms containing NM283 (66-80%, 47-78%, & 33-61%, respectively) than the control arm of PegIFN/RBV (32%, 8.8%, and 14.7%, respectively). The vomiting appeared to perhaps be dose related: 48.8% in NM283 400mg arm+PegIFN; 78% in the NM283 800mg+PegIFN arm).
Adverse events (>10%) reported were those associated with PegIFN and were equal between arms: depression, insomnia, myalgia, neutropenia, irritability etc. However, in the 400 mg NM283 the rates of these typical IFN side effects were often less than in patients receiving the 800 NM283.
Valopicitabine (NM283)
First Nucleoside-type HCV Polymerase Inhibitor
NS5b polymerase inhibitor
- Ribonucleoside; cytidine analogue
- NM107-triphosphate inhibits viral polymerase and causes viral RNA chain termination
Oral agent
- Valyl ester pro-drug provides high oral bioavailability
- Plasma half life (4-6 hrs) & intracellular half life (15 hrs) support once-daily dosing
- 200 - 800mg demonstrates
anti-viral efficacy
Study Objectives
Valopicitabine (NM283) Phase IIb Trial in Non-responders
Compare antiviral efficacy and safety/tolerability of:
- 3 different dosing regimens of valopicitabine + peg-IFN_-2a vs. re-treatment with peg-IFN_-2a + ribavirin
- also included: valopicitabine monoRx arm
Patient population: patients with genotype 1 chronic hepatitis C who were non-responders to pegIFN_/RBV
- relapsers to pegIFN+RBV excluded
Key Eligibility Criteria
Valopicitabine (NM283) Phase IIb Trial in Non-responders
18-65 years of age, male or female
HCV genotype 1
Non-responders to previous adequate treatment course
- At least 12 weeks of pegIFN + RBV
- At least 75% of the prescribed doses pegIFN/RBV
- Failed to clear HCV RNA to non-detectable levels
- Patients must have previously failed for efficacy, not safety
Screen/Baseline
- HCV RNA >/= 105 IU/mL
- ALT < 5 x ULN
Compensated liver disease
Study Design
Valopicitabine (NM283) Phase IIb Trial in Non-responders
- Multicenter (22), randomized, active control design
- HCV RNA response criteria for failure and discontinuation - reductions from baseline
- Week 4 >/= 0.5 log
- Week 12 >/= 1.0 log
- Week 24 > 2.0 log
- Primary efficacy endpoint: SVR by HCV RNA: COBAS TaqMan PCR assay (20 IU/mL)
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