NS4A Antagonists: Superior Potency Against Other Clinical Stage HCV Inhibitors
Collaboration with Gilead Sciences, Inc.
In 2004, Achillion entered into a research collaboration and license agreement with Gilead Sciences, Inc. for the development and commercialization of compounds for the treatment of chronic hepatitis which inhibit HCV replication through a novel mechanism of action targeting the NS4A protein. Under the collaboration, research and development activities prior to proof-of-concept are overseen by a research committee comprised of equal numbers of Achillion and Gilead representatives. The joint research committee assigns research and development tasks and agrees upon a budget for the research program.
Achillion received $10.0 million from Gilead Sciences upon the execution of the agreement, consisting of license fees and an equity investment, and could receive up to $157.5 million in development, regulatory and sales milestone payments, assuming the successful simultaneous development of a lead and back-up compound, as well as royalties on net sales of products.
Achillion believes its portfolio of antagonists to NS4A have the following benefits:
Novel Mechanism of Action. Based upon extensive virology and biochemistry studies, the mechanism of action of these compounds appears to be novel and involves targeting the NS4A protein of HCV. Inhibiting this target prevents the formation of a functional replicase complex, a necessary step in viral replication that occurs before copying the viral RNA genome. Achillion believes this unique mechanism may contribute to the lack of cross resistance between its compounds and other HCV inhibitors.
Potency. Data obtained in the standard laboratory assays used to determine anti-HCV activity against the genotype 1 virus demonstrate that the Achillion compounds have potency in vitro in a range similar to the published data on Boehringer Ingelheims protease inhibitor under clinical development, and 14 to 21 times more potent in vitro than either the Schering-Plough or Vertex HCV protease inhibitors under clinical development.
Lack of Cross Resistance. In laboratory studies, Achillions compounds have not demonstrated cross resistance to any of the polymerase inhibitors or protease inhibitors of which the Company is aware and has tested.
Ease of Administration. Based on current animal studies, compounds in this series appear to be orally bioavailable.
Potential for Combination Treatment. Because of the lack of cross resistance in in vitro tests with all other known classes of HCV inhibitors, Achillion believes that NS4A antagonists are well positioned for evaluation as a treatment for chronic HCV in combination with the current standard of care and/or in combination with other direct-acting antivirals.
Until February 2007, Achillion was pursuing clinical development of its first NS4A antagonist, ACH-806. Unfortunately, while significant reductions in HCV viral load were observed even at the lowest doses studied in a human proof-of-concept trial, unacceptable levels of serum creatinine, a key marker of kidney function, were also observed. As a result, Achillion, along with its partner Gilead Sciences, made the decision to discontinue development of the compound and focus efforts on a new series of NS4A antagonists, including ACH-1095.
