Gilead/Achillion Advance Back-Up Anti-HCV Molecule After Toxicity Problems With Lead Candidate

Companies plan IND filing for their next novel NS4A antagonist in the first or second quarter of 2008.

Gilead Sciences and Achillion Pharmaceuticals will turn to the next NS4A antagonist in their pipeline after their lead hepatitis C candidate demonstrated anti-viral activity but also elevated levels in a kidney function marker during a dose-escalation trial, the companies announced Feb. 8.

The fault in the failed compound (GS 9132/ACH-806) lies in its molecular structure and not in its mechanism of action, Achillion CEO Michael Kishbauch said during a same-day conference call. The companies will look at preclinical data and choose from other compounds with "potency like ... 9132, but differing chemotypes and/or metabolic profiles." The likely nominee is called ACH-1095.

"Based on all we've learned through the 9132/806 program, and our increasing integration with Gilead's development capabilities ... we believe we can achieve an IND filing in the first quarter to the second quarter of next year," Kishbauch said, acknowledging that the setback could have cost the partnership as much as a year in development time. "We may even discuss a different trial strategy for Phase I, such as the possibility of going directly into patients," he said.

Six of eight subjects in the first cohort of the Phase Ib/II dosing trial for 9132 had "small elevations of serum creatinine ... which were reversible upon discontinuation" of dosing, the chief executive officer said.

However, he added, "even at the lowest entry dose studies, right at the cusp of where we expected to see activity, we observed reductions in hepatitis C viral load that were significant."

After further analysis, data from the double-blind, randomized, placebo-controlled dose-escalation study will be submitted for presentation in a scientific forum, Kishbauch said.

The two companies plan to work more closely going forward, he said. "By mutual agreement, and frankly because we're in a catch-up mode ... we're going to collaborate with Gilead on a far more integrated basis, tapping into their development resources to a far greater degree."

Under a 2005 deal between New Haven, Conn.-based Achillion and Gilead, headquartered in Foster City, Calif., Achillion is to develop the antivirals through proof of concept then hand them off to Gilead. That formal arrangement has not changed, Kishbauch said.

As part of the agreement, Gilead paid Achillion $5 million upfront and made a $5 million equity investment in the company, as well as providing some research funding. Achillion also could earn milestone payments in excess of $100 million and has the option to participate in U.S. commercialization efforts of products from the collaboration. Gilead has exclusive worldwide license rights and will pay royalties to Achillion on net sales of products from the collaboration.

NS4A antagonism is a novel mechanism of action for HCV treatment, distinct from that of protease or polymerase inhibitors in development, Kishbauch said. "As far as we know there is no one else out there with an advanced program against this target." NS4A binds to a portion of HCV-1 protease, and is intended to disrupt replication of the virus.

Competition to develop improved hepatitis C therapies is heating up. On Feb. 1, AstraZeneca announced plans to acquire Arrow Therapeutics, whose assets include two anti-HCV compounds targeting the NS5A protein (¹ (Also see "AstraZeneca Hits Anti-Infective Target With Arrow Acquisition" - Pink Sheet, 1 Feb, 2007.)).

Other companies developing compounds in the space include Johnson & Johnson/Vertex and Schering-Plough, both in Phase II with protease inhibitors (² (Also see "Vertex Hopes To PROVE Telaprevir’s Promise With Final Installment Of Phase II Program" - Pink Sheet, 2 Feb, 2007.)). Novartis/Human Genome Sciences recently advanced their hepatitis C candidate, Albuferon (albumin interferon afa-2b), into Phase III (³ (Also see "Novartis/HGS’ Albuferon May Offer Dosing Advantages Over Roche’s Pegasys" - Pink Sheet, 6 Oct, 2006.)).

-Shirley Haley ([email protected])