Avila Therapeutics is reporting the advancement of a cancer drug candidate under its agreement with Clovis Oncology as well as a new deal with the NIAID in HCV. The company entered into a nonclinical evaluation agreement that allows it to access the NIAID’s preclinical services program to further evaluate AVL-192, a targeted, irreversible covalent inhibitor of the HCV protease (NS3).
“NS3 protease is now recognized as a key target of therapeutic intervention in HCV infection, and the ability of AVL-192 to strike at known drug-resistant mutations will be a critical feature of next-generation protease inhibitors,” notes Juswinder Singh, Ph.D., Avila CSO.
AVL-192 forms an irreversible bond with Cys159, a non-catalytic amino acid that is present in all variants of HCV protease, thus creating the potential for inhibition across all known HCV genotypes, Avila explains. In addition, the compound has shown unusually high potency by demonstrating the ability to clear replicon cells as a monotherapy in vitro, the firm adds.
Separately, Avila reported that its partnership with Clovis Oncology for epidermal growth factor receptor mutant-selective inhibitor (EMSI) has resulted in the selection of a candidate to advance into clinical development. Clovis is now advancing the drug candidate into preclinical development for the treatment of non-small cell lung cancer (NSCLC).
An IND application is planned for the first half of 2012. In parallel, Clovis will develop a companion diagnostic with Roche Molecular Diagnostics. Under terms of their deal, inked in May 2010, Avila is eligible to receive development, regulatory, and sales-based milestone payments totaling $209 million as well as tiered royalties.
The selected compound, called CO-1686 (AVL-301), has demonstrated tumor regression activity in animal models carrying both the activating mutation of EGFR and the T790M mutation that is resistant to approved drug therapies. It did not show significant inhibition of normal EGFR, which is a source of dose-limiting toxicities for current EGFR-targeted therapies, the companies point out.
T790M drives roughly 50% of NSCLC cases that are resistant to existing EGFR therapy, according to Clovis and Avila. They say that patients with tumors containing this secondary mutation are also resistant to second-generation pan-ErbB inhibitors currently in clinical development.
By inhibiting both T790M and the initial activating mutations, the EMSI program offers the prospect of effective drug treatment for first- and second-line NSCLC patients with activating EGFR mutations, the firms point out. With sparing of the wild-type EGFR, the EMSI program could also offer an improved therapeutic window compared to current therapies in a first-line setting.
“We have made excellent progress in advancing this EGFR mutant-selective inhibitor program, further validating the robustness of Avila’s platform and our ability to design targeted covalent drugs,” says Katrine S. Bosley, CEO of Avila Therapeutics. “This partnered program with Clovis, along with Avila’s proprietary clinical program targeting bruton’s tyrosine kinase (Btk), show our advancement of drug candidates and exemplify the range of important problems that can be solved with targeted covalent drugs.”
Covalent drugs are able to establish a strong and enduring bond that exceeds the more temporary binding of conventional drugs. They may thus provide prolonged duration of action through this silencing of the disease target.
Avila currently has three covalent drug programs that were developed on its Avilomics platform. The most advanced candidate is AVL-292, a potential treatment for cancer and autoimmune diseases. It is currently in Phase I testing. Besides Clovis, the company also has collaborations with Sanofi and Novartis.