NM283: a Novel Nucleoside Analog That Specifically Inhibits the HCV RNA Polymerase

There are at least six basic genotypes of HCV, with more than 100 subtypes, which vary in prevalence in different regions of the world. In the U.S., Western Europe and Japan the genotype 1 strain of HCV is the predominant genotype, responsible for more than 70% of the reported cases of hepatitis C.

The genotype 1 strain of HCV is significantly less responsive than genotypes 2 or 3, the two other most common genotypes of HCV, to the current standard therapy of interferon in combination with ribavirin.

Large-scale clinical trials have shown that fewer than half of hepatitis C patients infected with the genotype 1 strain of HCV will experience successful responses to the current standard of therapy, while over 70% of patients with the genotype 2 or genotype 3 strain of HCV are likely to experience successful responses to current therapy.

Therefore, an important goal for new HCV therapies is improved effectiveness against the genotype 1 strain of HCV.

NM283: a Novel Nucleoside That Specifically Inhibits the HCV RNA Polymerase

NM283 is an investigational new drug for the treatment of chronic hepatitis C. This agent is a specific and selective inhibitor of HCV replication, and specifically targets the HCV RNA polymerase.

NM283, a prodrug of the active molecule NM107, is converted into biologically active NM107 after oral absorption, and was developed to optimize oral bioavailability. In the studies described below, in vitro work was done with NM107; studies in animals and man with oral dosing were done with NM283.

Preclinical Evidence

The parent compound of NM283, NM107 was tested in a panel of in vitro antiviral and toxicity assays. NM107 potently inhibits flavi- and pesti-virus replication, exhibiting an EC50 of 0.67 µM against bovine viral diarrhea virus (BVDV) replication.

After 8-10 weeks, NM107 eradicated persistent BVDV infection at nontoxic concentrations. Other in vitro studies showed that NM107 exhibits synergistic antiviral activity when tested in combination with interferon in the BVDV model system.

Preclinical Toxicology

NM107 was not incorporated into cellular DNA and RNA, and had a favorable profile with respect to in vitro mitochondrial and bone marrow toxicity.

NM283 is a prodrug of NM107 developed to improve bioavailability. In subsequent animal toxicological studies, NM283 exhibited a favorable sub-chronic toxicology profile in rats and monkeys.

In vitro Resistance

In laboratory studies that assessed the potential for viral resistance to NM283, NM283-resistant viral strains emerged relatively slowly. Such viral mutants appeared to have impaired replication capacity, and were about 30-fold more sensitive to inhibition by interferon.

These findings suggest that combination treatment with NM283 + interferon has the potential to provide enhanced antiviral effects while minimizing the development of viral resistance to NM283.

Activity in Animal Model

The antiviral efficacy of NM283 was examined in chimpanzees that carry chronic human HCV-1 infections. Animals were treated orally once daily for seven days with NM283 at doses of 8.3 or 16.6 mg/kg/day (2 animals/dose group) and compared to placebo (1 animal).

NM283 demonstrated antiviral activity in this primate model, achieving reductions in serum HCV RNA on day 7 of 0.90 log10 and 1.15 log10 at the 8.3 and 16.6 mg/kg/day doses respectively, compared with an increase of 0.30 log10 with placebo.

Both doses of NM283 were well tolerated, with no significant safety issues or dose limiting side effects.

Clinical Efficacy and Safety of NM283

Results of a phase I/II dose-escalation study of NM283 were presented recently at DDW 2004 (Godofsky et al. Abstract 407. May 15-20, 2004. New Orleans, LA).

To date, based on experience with more than 50 patients receiving NM283, the overall safety profile of NM283 has been satisfactory, with no serious adverse side effects and no dose-limiting toxicities. Initial results demonstrated dose-related increases in the antiviral activity of NM283 and dose-proportional increases in blood levels of NM283.

After cessation of treatment, patients’ serum HCV levels rebounded nearly to pre-treatment baseline, confirming that NM283 suppressed HCV viral replication during treatment.

A phase IIb clinical trial of NM283 in patients with chronic HCV-1 infections, designed to evaluate the long-term safety and antiviral efficacy of NM283 alone and in combination with interferon, will begin in mid-2004.

Conclusions

• NM283 is a nucleoside analog that specifically and selectively inhibits HCV replication by interfering with HCV RNA synthesis.

• NM283 exhibited a satisfactory safety profile in pre-clinical studies, with no serious side effects and no dose limiting toxicities.

• NM283 demonstrated good antiviral activity in the chimpanzee model of HCV infection.

• NM283 is being developed as a single-agent therapy for use by patients, including liver transplant patients, for whom interferon based treatment is not appropriate. NM283 is also being developed as a potentially more effective alternative to ribavirin in an interferon-based treatment combination.

• Results of a phase I/II dose-escalation study were presented at DDW 2004.

• A phase IIb clinical trial evaluating the long term safety and efficacy of NM283 alone and in combination with interferon will be initiated in mid-2004.

05/26/04

Sources
E Godofsky and others. [powerpoint] Phase I/II Dose Escalation Trial Assessing Tolerance, Pharmacokinetics, and Antiviral Activity of NM283, a Novel Antiviral Treatment for Hepatitis C. Abstract 407 (plenary). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

Idenix Pharmaceuticals. Viral Hepatitis Therapeutic Development Programs. 2004.

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