Although Wyeth, Novartis and other drug makers have experienced setbacks in the development of their non-nucleoside polymerase inhibitors for the treatment of hepatitis C, Pfizer is proceeding nonetheless with its candidate, PF-868,554.

"Early, but promising, findings have encouraged us to pursue additional Phase II studies at longer dosing durations in the coming year," VP/Development Head, Infectious Disease Global R&D Michael Dunne said Sept. 18. Dunne's comments were part of an update on Pfizer's infectious disease pipeline during the Interscience Conference on Antimicrobial Agents and Chemotherapy meeting in Chicago.

Polymerase inhibitors are a new class of medicines under development for the treatment of hepatitis C virus that have shown early promise due to their antiviral activity. However, since the start of the year, emerging data on side effects has led several drug makers to discontinue their programs and others to halt dosing in clinical trials.

"As recently as last month, the development of many of the more advanced compounds has been discontinued," Dunne said. "The compound that appears to be furthest along is 868,554."

The Pfizer compound has shown in vitro activity against the genotype 1a and 1b strains of the virus. A single-dose study in normal volunteers was completed in the third quarter of 2006, showing the compound was well tolerated at doses up to 1,600 mg, with mild gastrointestinal side effects, according to Dunne.

A multi-dose Phase Ib/IIa study in HCV patients is ongoing, but preliminary data has confirmed tolerability after seven days of dosing at 300 mg bid. That dose also resulted in a viral load reduction of greater than 1.5 logs, he said.

Gastrointestinal side effects were among the reasons that Idenix and its partner, Novartis, announced they were suspending development of their non-nucleoside polymerase inhibitor valopicitabine in July, shortly after FDA put a clinical hold on the drug (¹ Also see "Idenix Focusing On HIV Program, Tyzeka Launch Following Clinical Hold On Hep C Candidate" - Pink Sheet, 13 July, 2007.).

At the time, Idenix said it held no hope for the future development of the drug, which had generated concerns over nausea, vomiting and diarrhea even after dosing had been reduced to 200 mg/day and 400 mg/day. Valopicitabine had been in Phase IIb development.

In August, ViroPharma and Wyeth discontinued dosing of their polymerase inhibitor HCV-796 in a Phase II study in hepatitis C patients in combination with pegylated interferon and ribavirin after elevated liver enzymes were seen in some patients following eight weeks of treatment (² Also see "Wyeth/ViroPharma Discontinue Study Of Hep C Drug Due To Elevated Liver Enzymes" - Pink Sheet, 10 August, 2007.).

While those were two of the highest profile setbacks in the class, other companies also announced they were discontinuing their programs, including XTL Biopharmaceuticals, which announced in June that it had decided to halt development of its polymerase inhibitor XTL-2125 based upon a lack of efficacy.

Gilead is another company continuing with development of its polymerase candidate, GS-9190, despite increased safety events surrounding the class. The company told "The Pink Sheet" DAILY that it is continuing to evaluate GS-9190 in a two-part Phase I trial. The single-dose Phase Ia data is scheduled to be presented during the American Association for the Study of Liver Diseases meeting in November, while the Phase Ib study is ongoing.

Despite its optimism on '554, Pfizer did say it was discontinuing development of an earlier-stage polymerase inhibitor, AG-121541, which was in Phase I.

Discovery and development of antivirals to treat HCV and HIV is a core part of Pfizer's strategy in infectious disease, Senior Director/Commercial Head-Infectious Disease Worldwide Pharmaceutical Operations Andrew Schmeltz said.

"Our infectious disease portfolio has transformed from a primary care focus with Diflucan and Zithromax to a specialty focus targeting immuno-compromised patients with high unmet medical need."

-Jessica Merrill (j.merrill@elsevier.com)

Pfizer Moving Ahead With Polymerase Inhibitors For Hep C As Competitors Fall

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