West Coast Editor

Genentech Inc. is acting the pharma part in a deal with Abbott to advance the latter's Phase I-stage compounds ABT-263 and ABT-869, a Bcl-2 protein antagonist and VEGF receptor kinase inhibitor, respectively.

"This is a perfect match for us," said Catherine Bryan, director of external communications for Abbott Park, Ill.-based Abbott.

Under the terms of the global research, development and commercialization pact, the two firms will work together on all aspects of pushing the compounds to market, and would co-promote in the U.S., with Abbott solely handling promotion outside the country. Financial terms were not disclosed.

ABT-263 is thought to restore apoptosis, or programmed cell death, in a variety of cancer cells, and recently entered Phase I clinical trials for lymphomas, chronic lymphocytic leukemia and solid tumors, including small-cell lung cancer. ABT-869 works through suppressing tumor growth by preventing the growth of new blood vessels, and is undergoing Phase I trials, with Phase II expected to start later this year.

Genentech has a strong interest in both areas, and spokeswoman Caroline Pequet said the multiyear deal is "focused on these two compounds, but we will be looking to conduct additional follow-on research" into the areas where the drugs appear to be active. The Bcl-2 space is particularly tricky, she acknowledged. Targeting protein-protein interactions has been a challenge because interacting protein surfaces can be large and lack deep pockets in which small molecules can readily bind.

Stephen Fesik, divisional vice president of oncology research for Abbott, said the firm's biggest hurdle - finding initial leads - was overcome by a fragment-based approach developed more than 10 years ago. "You find these small fragments that bind to subpockets on the protein and eventually link them together, so that you're essentially tailoring molecules to bind to a site on the protein," he said.

"Since then, we've had to go up against a number of other hurdles," such as finding ways to boost potency while designing out of a compound its tendency to bind to serum albumin, he said. In 2005, Abbott scientists published a paper in Nature showing that an earlier candidate, ABT-737, was "very potent, didn't bind as tightly [as previous compounds] to albumin and showed fantastic preclinical activity."

The problem with ABT-737, though, was that it had to be given intravenously. Abbott wanted an oral drug that could be given to cancer patients along with other therapies such as chemo. "We had to use medicinal chemistry tricks to modify [ABT-737] and get to ABT-263," he said.

Among the start-up firms with compounds in the Bcl-2 class recently to make news are Cambridge, Mass.-based Aileron Therapeutics Inc., which raised $7 million this month for its stapled peptide technology platform, and Coronado Biosciences Inc., of San Diego, which in late May licensed its first compound, a Bcl-2 inhibitor in development against multiple cancer types. Both firms' drugs are preclinical. (See BioWorld Today, June 7, 2007, and May 30, 2007.)

Also in May, Montreal-based Gemin X Biotechnologies Inc. published preclinical data in the journal Blood on obatoclax (GX15-070), a pan-Bcl-2 inhibitor, which induced cell death in vitro in mantle cell lymphoma cell lines and in primary cells from 11 MCL patients, while also sensitizing MCL cell lines to Velcade (bortezomib, Millennium Pharmaceuticals Inc.). Obatoclax is undergoing several Phase I and Phase II trials.

Genta Inc., of Berkeley Heights, N.J., is starting a new randomized Phase III study with Genasense (oblimersen sodium) in 300 advanced melanoma patients. The compound previously was rejected by the FDA's Oncologic Drugs Advisory Committee, which in 2004 issued a negative opinion against the drug's use in melanoma. Earlier this year, Europe's Committee for Medicinal Products for Human Use also gave a negative opinion for the compound in that indication. (See BioWorld Today, May 4, 2004, and Dec. 18, 2006.)

Abbott, Bryan said, is "always looking for opportunities" like the one that brought the company together with South San Francisco-based Genentech. Late last year, Abbott entered a deal worth as much as $307 million to Enanta Pharmaceuticals Inc., of Watertown, Mass., with $57 million up front. The deal centers on Enanta's preclinical NS3 and NS3/4A protease inhibitors for hepatitis C virus. (See BioWorld Today, Dec. 13, 2006.)

Also in Abbott's cancer pipeline, though not part of the Genentech deal, are ABT-751, an oral anti-mitotic in Phase II studies for non-small-cell lung cancer and neuroblastoma; ABT-888, a PARP inhibitor that can prevent DNA damage repair in cancer; and ABT-828, described as "a biologic anti-tumor agent with a novel mechanism of action."

Genentech's stock (NYSE:DNA) closed Tuesday at $72.60, down $1.35. Abbott's shares (NYSE:ABT) ended the day at $53.97, up 8 cents.