"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.