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New HCV Drug, NM283, polymerase inhibitor: first data in patient: 1 log viral load decline in highest dose
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Reported by Jules Levin
Today's final oral session at EASL captured the imagination of viewers and was the most exciting of the conference to me. There were several very interesting presentations including the first clinical data on a new drug for HCV: NM283, a polymerase inhibitor administered orally. Norbert Brau from the Bronx VA reported a very interesting study which found that HCV disease progression in coinfectedpatients was the same as for HCV monoinfected if their HIV viral load was <400 copies/ml. Brau's study is I think the first to break down HCV disease progression in coinfected patients by CD4 count and viral load. My next report will provide the details from this study. Mangia from Italy reported the first study data on 12 weeks therapy with PegIntron plus ribavirin for genotype 2/3 who had a viral response at week 4. She found that the viral response rate for 12 weeks therapy was equal to 24 weeks. I'll report details on this as well. The other interesting study was a registration study for Pegasys in HBV and found Pegasys monotherapy was more effective than lamivudine for HBV, and again I'll report more details.
But first to what might be the biggest news to come out of EASL: the first clinical data in HCV-infected patients for a new HCV drug.
FIRST CLINICAL RESULTS FOR A NOVEL ANTIVIRAL TREATMENT FOR HEPATITIS C: A PHASE I/II DOSE ESCALATION TRIAL ASSESSING TOLERANCE, PHARMACOKINETICS, AND ANTIVIRAL ACTIVITY OF NM283
Nat Brown from Idenix Pharmaceuticals reported the exciting study results that captured the imagination of the audience. The conference saved this presentation until the last, unfortunately the room was half empty as many conference attendees had already left the conference.
NM283 is a novel candidate HCV RNA polymerase inhibitor, has anti-flavivirus activity that is highly synergistic with interferon-alpha in vitro, and suppresses viremia in chimpanzees chronically infected with human-derived HCV-1 (Standring, EASL2003).
NM283 is a prodrug for NM107. NM107 was not very bioavailable but NM283 is much more bioavailable. NM107 has submicromolar activity (at low doses) in the BVDV assay. It has no activity against HIV or DNA viruses. In a surrogate virus model (BVDV) NM107 reduced BVDV virus titer by almost 4 logs within 4 days when used as monotherapy, and interferon reduced virus titer by less than 1 log, but the combination of interferon 200 units/mL plus NM107 was synergistic in reducing virus titer by 8 logs at day 6 in thiscell-based persistent BVDV infection model.
NM283 inhibited HCV-1 replication in chronically infected chimpanzees. 5 chimps chronically infected with HCV received 2 different oral once daily doses (NM283 8.3 mg/kg/day or NM283 16.6 mg/kg/day) of NM283 and 1 chimp received placebo. Serum HCV RNA was quantified by Roche Amplicor PCR. HCV RNA was reduced by 0.83 log (low dose) and 1.05 log (high dose) at day 7 on treatment and there was no change in the placebo chimp.
Brown reported the first data in HCV+ patients, a dose escalation study. The study evaluates safety, antiviral activity, and PK during 15 days treatment and 2 weeks followup. Adult patients were all genotype 1, and treatment-naïve or interferon failures. Serum HCV RNA was >5 log copies/ml and ALT was <5 x ULN. All had compensated liver disease, no cirrhosis. Dosing levels were 50, 100, 200, 400, and 800 mg once daily. Each dosing patient group had 12 eligible patients randomized 10:2to NM283 or placebo. Patients were mostly male Caucasians; 86% had prior IFN experience; they had high HCV viral load- 6.7 log copies/ml. Average ALT was 64.
Brown showed PK data demonstrating the drug is well absorbed. There was no accumulation of the drug, day 15 steady state levels were the same as on day 1. There was a dose proportionality to observed drug levels.
RESULTS
MEAN LOG REDUCTIONS. At day 15, the lowest dose reduced viral load by .15 log, the middle doses reduced viral load by 0.4 log. The 400mg dose reduced viral load by 0.7 at day 15. They saw GI side effects in some patients on the 400mg dose. The dose titration group dosed up from 100 to 800mg and had a 0.7 log viral load reduction at day 15. A patient group dose escalate from 400 to 800 and reached 800 mg by the second week. They took antiemetic for the first two days. The average viral load reduction for this group was 1 log by day 15. After stopping the drug viral loads rebounded. The rate of decline in viral load appearsto exceed that seen with interferon.
SAFETY & TOLERANCE
Brown said the overall clinical safety was satisfactory. There were no serious adverse events or dose limiting toxicities. All 49 compliant patients completed treatment. 1 patient discontinued for non-compliance. No patients discontinued treatment for adverse event.
There was no grade 3 or 4 lab abnormalities during treatment; no pattern of lab abnormalities. GI side effects seen in some patients was transient; 3 patients had vomiting. 15 of 18 patients who had nausea said it was mild, 3 moderate. The GI effects tend to onset in the first 2 days and tend to be transient as they last <1 day in 64% of affected patients. N one changed or discontinued treatment. Brown commented that side effects compare favorably to interferon/ribavirin.
Brown summarized: we see consistent antiviral activity in HCV+ patients including previous IFN experience. The viral load reductions seen corresponds to 80-90% reductions in 2 weeks. Overall safety issatisfactory with no dose-limiting toxicities, transient nausea, and vomiting in some patients. All patients were compliant with treatment. The next study is a 4 week combination trial of NM283 and pegIFN.
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