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NM283: new oral HCV drug, polymerase inhibitor
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"Phase I/II Dose Escalation Trial Assessing Tolerance, Pharmacokinetics and Antiviral Activity of NM283, a novel Antiviral Treatment for Hepatitis C"
Reported by Jules Levin
E Godofsky reported on NM283, a new HCV drug (polymerase inhibitor), and the initial clinical study results at the final hepatitis oral session on May 18 at DDW May 2004 in New Orleans.
Summary: NM283 is orally administered new HCV drug. This is the first study conducted in HCV-infected patients. About 80 patients were studied with various doses. Using the highest dose regimen HCV viral load was reduced by a mean 1.1 log after 15 days of dosing. Patients were all genotype 1 and interferon failures. Overall the drug appeared safe and tolerable. GI side effects were seen but were transient. The next planned study is a 4 week combination study with peginterferon.
Godofsky said in his talk that >800,000 cases of end-stage hepatitis C are expected in the USA in the coming decade; similar trend in Europe. We need high SVR rates with limited treatment duration, particularly in genotype 1 with >70% in the USA being genotype 1 and 60% in Europe. We need oral, safe and well-tolerated medicines with treatment for patients with decompensated cirrhosis.
NM283, a novel candidate HCV RNA polymerase inhibitor, has anti-flavivirus activity that is highly synergistic with interferon-_ in vitro, and suppresses viremia in chimpanzees chronically infected with human-derived HCV-1 (Standring, EASL2003). Here we report the first clinical data for NM283 in humans.
NM283 has EC50 vs BVDV=0.67 ± 0.22 uM; 2'-methyl substituent key to anti-HCV activity; inhibits virus encoded RNA polymerase- probable mechanism of action- viral RNA chain-terminator; no activity against HIV or DNA viruses; valyl ester prodrug provides high oral bioavailability.
NM107 is the precursor to NM283 and is active in a surrogate mouse virus model and is synergistic in combination with IFN-a in a cell based persistent BVDV infection model. In this model BVDV titer log units/mL was reduced about 1 log by IFN 200 units/mL, about 4 logs by NM107 8uM, and by 8 logs with IFN 200 units/mL plus NM107 8uM in 12 day experiment (Standring et al EASL 2003).
NM283 inhibited HCV-1 replication in chronically infected chimpamzees by mean 1.05 log. 5 chimpanzees who were chronically infected with HCV-1 received oral treatment for 7 days once daily, 3 treatment arms: placebo (1 animal); NM283 8.3 mg/kg/day (7 animals); higher dose NM283 16.6 mg/kg/day (2 animals). 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); no change in placebo chimp (Standring et al EASL 2003).
NM283 for Hepatitis C: Dose Escalation Trial
--first in man dose escalation trial
--objective is to evaluate safety, antiviral activity and PK during 15 day treatment and 2 week post-treatment follow-up. The patients were adults with chronic HCV; HCV genotype 1; IFN failures & treatment-naïve. Serum HCV RNA >5 log IU/mL; ALT <5 x ULN; no IFN in preceding 6 months; compensated liver disease, no cirrhosis.
Dosing levels: 50-800 mg/day. Each dosing cohort of 12 eligible patients randomized 10:2 to NM283 vs placebo. The study was held at 6 US sites. All patienys confirmed non-cirrhotic by liver biopsy.
Characteristics of patients: age 47-52; 60-70% men; 90% Caucasian; 90% IFN failures; serum HCV RNA -- 6.6 mean log IU/mL; serum ALT -- 64 mean units/mL; cohrt 6 was dose escalated from 100 to 800 mg; cohort 7 was escalated from 400 to 800 mg + antiematic.
VIRAL LOAD REDUCTIONS AT DAY 15
The placebo group had no reduction.
The dose escalation group 400 to 800 mg + antiematic had mean viral load reduction of 1.1 log.
The group escalated from 100 to 400 had reduction of 0.8 log.
In cohort 7 individual patient HCV RNA reductions ranged from 0.68 to 1.94 log. One patient had reduction of 1.94 log; 2nd patient's viral load declined by 1.37 log; three patients had 1 to 1.2 log reductions.
SAFETY & TOLERANCE
Godofsky reported clinical safety satisfactory overall: no serious adverse events or dose limiting toxicities; all 68 compliant patients completed treatment; 1 patient (400 mg group) discontinued for non-compliance. No grade 3 or 4 lab abnormalities during treatment; no pattern of lab abnormalities.
GI side effects in some patients (typically transient nausea; total of 5 patients with vomiting): seen primarily at doses >=400 mg/day; 23 of 26 nausea events rated "mild", 3 "moderate"; most with onset in first 2 days; <1 day duration in 62% of affected patients; 5/14 (36%) placebo patients with miscellaneous GI complaints. Godofsky said overall side effects favorable compared to current treatment.
Godofsky concluded: there was consistent antiviral activity in patients, 87% of whom previously failed IFN; increased antiviral activity with each higher dose: HCV RNA reductions after 15 days treatment was --0.15 to 1.1 log IU/mL in completed cohorts; 1.1 log viral load reduction equals 92% viral load reduction in 2 weeks; in highest dose cohort, 9/9 previous IFN failures exhibited HCV RNA responses (0.7-1.9 log: 79-99% HCV RNA reductions in individual patients over 2 weeks); 800 mg/day cohort ongoing, will be highest dose tested; overall safety satisfactory: no dose limiting toxicities, transient nausea & vomiting in some patients, all compliant patients completed treatment.
The next planned study is a 4-week combination trial of NM283 and peginterferon.
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