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NM283, HCV Polymerase Inhibitor in Non-Responders
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Reported by Jules Levin
42nd EASL
Barcelona, April 11-15, 2007
Two studies were presented today on NM283, one in treatment-naives in which patients responded well, and a second study in treatment-experienced where the response was considered by observers not to be so good.
Ned Afdahl reported the results from this study: "Valopicitabine (NM283), Alone or with Peg-Interferon, Compared to Peg-Interferon/Ribavirin (Peg-IFN/RBV) Retreatment in Patients with HCV-1 Infection and Prior Non-Response to Peg-IFN/RBV: Final Results"
190 study patients were peg/RBV non-responders genotype 1. Patients received NM283 800 mg monotherapy or 1 of 3 peginterferon plus NM283 regimens, and these were compared to peginterferon+ribavirin.
AUTHOR CONCLUSIONS
There was lack of efficacy of valopicitabine in null responders (prior nonresponders to peg/RBV), where Peg-IFN / RBV provides modest antiviral activity, and it is likely that combinations of novel HCV agents will be needed to improve response rates
Partial responders had better 48 week ETR responses but will need RBV to maximize SVR rates
GI side effects with 400 mg valopicitabine + Peg-IFN less frequent / severe - 800 mg dose will not be developed further
An Ammendment to the Study Design (dosing) was made part way through the study.
Patients responding to treatment were allowed treatment up to a maximum of 72 weeks or until PCR-nondetectable for 36 weeks
As a result of severe GI side effects in some patients at 800 mg
valopicitabine dosing, dose was reduced to 400 mg
-- active patients had been on treatment >40 weeks
-- all patients on the 800 mg monotherapy arm had already discontinued
-- 13 patients with HCV RNA >1000 IU/mL were discontinued
-- For analyses, 800 mg valopicitabine / Peg-IFN arms pooled as patients in these arms received the same dose
Patient Disposition
Valopicitabine (NM283) Phase IIb Trial in Non-Responders
--All 800 mg mono Rx pts discontinued prior to Week 28, 18 / 21 for lack of efficacy
Mean Reduction HCV RNA to Week 48
Valopicitabine (NM283) Phase IIb Trial in Non-Responders
-- In the NM283 800mg monotherapy arm the viral load reduction was about .75 log at week 12 and then started to return towards baseline.
Antiviral Activity
Valopicitabine (NM283) Phase IIb Trial in Non-Responders: 15-24% achieved PCR-negative in the 3 peg arms.
Week 48 Response - Prior Null vs Partial Responders
Valopicitabine (NM283) Phase IIb Trial in Non-Responders
Adverse Events (>20%) to Week 48
Valopicitabine (NM283) Phase IIb Trial in Non-Responders
GI adverse events nausea (66-80%), vomiting (48-65%)and diarrhea (3-48%) were much higher in the NM283 arms than in the peg/RBV arm.
Safety Summary
Valopicitabine (NM283) Phase IIb Trial in Non-Responders
Most frequent AEs were GI-related (nausea, vomiting, diarrhea) and typically occurred with initiation of treatment
GI AEs less frequent and less severe with 400 mg/day
31 / 178 (17%) patients discontinued for AEs,12 / 178 (7%) patients discontinued for GI-related AEs
36 SAEs reported, 24 on-treatment and 12 during
follow-up
7 attributed to valopicitabine or valopicitabine + Peg-IFN
-- 1 in 400 mg arm (gram-negative bacteremia)
-- no GI-related SAEs attributed to valopicitabine since dose reduction
Lab abnormalities
decreases in WBC, ANC and platelets in combination arms consistent with Peg-IFN
-- no grade 3 / 4 hemoglobin decreases in any treatment arm
Sporadic grade 3 / 4 elevations in amylase, lipase, AST in 800 mg arms
In the 400 mg arm
-- no grade 3 / 4 amylase, lipase, AST elevations
-- no grade 3 / 4 hemoglobin decreases
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