West Coast Editor

Inotek Pharmaceuticals Corp.'s Phase II poly-ADP polymerase (PARP) inhibitor program bagged the firm a potential $600 million-plus deal with Genentech Inc., which is paying the privately held company $20 million up front.

Signing with "arguably the top oncology company in the world" gives Inotek leverage to take its next-generation PARP inhibitors forward into fields not covered by the pact, said Jeff Walsh, business development officer for Inotek, of Beverly, Mass.

The 130-employee firm, which has raised $55 million since its inception a decade ago and operates also at two sites in Israel, now has "enough money to move this mission forward, without any question," said Andrew Salzman, president and CEO.

Under the terms of the global discovery, development, manufacture and commercialization deal, South San Francisco-based Genentech will provide up to $405 million in milestone payments related to PARP inhibitors against cancer, and possibly as much as $200 million more in milestones related to progress with the compounds in acute cardiovascular conditions, for which Genentech has an option.

Salzman said Genentech's taking the option is "based on various considerations" with "a variety of factors," though he declined to be more specific, adding that Genentech will decide "in the not too distant future" about the second therapeutic area.

"They're very serious about cardiovascular [indications], and they have an excellent franchise," he said, adding that the preclinical data "are as exciting in cancer as they are in the non-cancer indications. They are riveting across the board."

PARP inhibitors block necrosis and blunt the expression of pro-inflammatory molecules, which might make them useful in such settings as cardiopulmonary bypass and myocardial infarction with angioplasty. Inotek has retained an option to co-promote PARP inhibitors in the cardiovascular field in the U.S., as well as rights to develop and commercialize the compounds outside of cancer and outside of the cardiovascular diseases that Genentech might work on.

PARP is a nuclear enzyme that mediates the repair of DNA single-strand breaks, and inhibitors could block one of the key defense mechanisms of cancer cells against chemotherapy. As stand-alone agents, PARP inhibitors also might help against familial and sporadic cancers that are genetically deficient in DNA repair. (See BioWorld Today, Jan. 26, 2005.)

In cancer generally, the compounds not only can reverse tumor resistance to chemo, but may increase sensitivity to it, in cases where "there may not be frank resistance," Salzman said. Also, with certain breast and ovarian cancers (i.e., those deficient in BRCA1 and BRCA2) may be particularly susceptible to the approach.

"If you treat them with a PARP inhibitor, the cells die," even though the compound is not cytotoxic per se, and therefore does not harm the surrounding normal cells, he said.

The BRCA-deficient tumors number "somewhere between 5 percent to 15 percent" of the total, Salzman estimated, "but there's a much more significant [patient] population that are defective or deficient in expression," who might also benefit.

PARP inhibitors also have shown promise in various inflammatory and ischemia/reperfusion diseases, and Inotek's lead compound, INO-1001, has entered Phase Ib/IIa trials in the cancer and cardiovascular areas, including advanced metastatic melanoma - "a horrible condition, with a very poor outcome," Salzman noted - as well as glioma and breast cancer.

As part of a multi-year collaborative research program, Genentech will pay all development costs for INO-1001 and other PARP inhibitors against cancer, plus royalties on eventual sales.

Other Inotek candidates take aim at different mechanisms of inflammation and DNA damage and repair. IMS is Inotek's Phase Ib therapy for ulcerative colitis, and PJ875 is entering Phase I trials for atrial fibrillation. Three more programs are preclinical.

Salzman said the firm is open to more partnering areas such as inflammatory bowel disease. PARP inhibitors may have efficacy against arthritis and some neurologic conditions, he added, and "the [Genentech] deal allows us the freedom to operate in these spaces."

Inotek is not entirely alone in PARP research. BiPar Sciences Inc., of Brisbane, Calif., in March entered the clinic with its first product, BSI-201, a PARP inhibitor for cancer, though Salzman said Inotek - which did all its PARP work in house, and had a patent issued for INO-1001 last year - "clearly [has] staked out a position as the leader in the PARP field."

With a bundle of other intellectual property related to PARP inhibitors, Inotek was the first to take such a compound into humans in 2003, and the only company to advance its PARP program clinically beyond cancer, he said.

Genentech's stock (NYSE:DNA) closed Monday at $80.37, up $2.44.