Tackling a family of proteins linked to cancer but long considered undruggable, Infinity Pharmaceuticals Inc. and Novartis AG signed a global development and commercialization deal potentially worth more than $400 million.

The companies intend to leverage Infinity’s small-molecule chemistry, Diversity Oriented Synthesis (DOS), to create natural compounds that modulate the Bcl-2 family of proteins, which includes Bcl-2 and Bcl-xL.

The protein family is known to mediate cancer cell survival through protein-protein interactions, marking themselves as clear drug targets.

Finding drugs that work with traditional small-molecule chemistries has proved challenging, but Novartis, of Basel, Switzerland, sees something promising in the DOS chemistry, which already has developed selective Bcl-2 inhibitors and dual Bcl-2/Bcl-xL inhibitors that have potential in treating a range of solid tumors and hematologic malignancies.

Terms call for Infinity to receive $30 million through an up-front license fee, an equity investment and two years of committed research funding. On top of that, the Cambridge, Mass.-based company is entitled to success-based milestone payments, which push the deal’s total potential value to more than $400 million. Infinity also would receive royalties, and Novartis has said it will invest in an Infinity public offering if it occurs within the next two years.

"Historically, Infinity has entered into significant alliances with Amgen, Novartis and Johnson & Johnson, but in all instances, these were for access on a nonexclusive basis to our technologies for use in their own drug discovery efforts," said Steven Holtzman, president and CEO of Infinity. "This is the first alliance in which we have entered into a partnership around one of our cancer candidates."

Together, Infinity and Novartis will work to identify molecules for clinical development, hoping to name a lead candidate by the end of this year, or early next year, and starting trials in 2007 or 2008.

While Novartis will take the lead, Infinity may opt to participate in clinical development, and it also retains an option to co-commercialize any Bcl-2 family inhibitors that reach the U.S. market.

"That’s a reflection of Novartis’ appreciation that Infinity has a lot to offer," said Adelene Perkins, Infinity’s chief business officer, who added that the company’s existing relationship with Novartis helped in the negotiation of the new deal.

The two parties entered an alliance in January 2005 for Infinity to use its DOS chemistry technologies to create a compound collection for use in each company’s independent drug development efforts.

It concurrently signed its deal with a unit of New Brunswick, N.J.-based J&J to provide nonexclusive access to its compound collection. (See BioWorld Today, Jan. 6, 2005.)

The company’s first partnership was signed in January 2004 and granted Thousand Oaks, Calif.-based Amgen Inc. nonexclusive access to Infinity’s collection of small molecules. The three deals together have provided Infinity with more than $60 million in up-front and committed funds, as well as potential milestone and royalty payments. (See BioWorld Today, Jan. 9, 2004.)

The Bcl-2 family of proteins was discovered almost two decades ago and was identified in the context of B-cell lymphoma, for which it is named. It is essentially the "Holy Grail" of how cancer cells survive and are able to express or produce guards against apoptosis, said Julian Adams, Infinity’s chief scientific officer.

"This has been a long sought-after target in the pharmaceutical industry, but because of the nature of the complexity of the protein-protein interaction, which is how it works in the cell," Adams told BioWorld Today, "it has been very difficult to find small-molecule drugs."

Researchers have learned that cancer does not kill as a result of hyper-proliferation, as previously thought. While it has been viewed as a disease of uncontrolled cell division, only 1 percent of cells are dividing at any given time, Adams said.

"So 99 percent of cells are sitting there, quiescent," he added. "Cancer is winning by simply not dying."

An attractive feature of going after Bcl-2 as a target is "getting at the Achilles’ heel of cancer cell survival," Adams said. It could change the way cancer patients are treated, considering traditional chemotherapy induces the production of Bcl-2.

"While you would expect the cytotoxic agents to be able to kill the tumor cells," Adams said, "they, in fact, induce the survival mechanism induced by Bcl-2," making chemotherapy ineffective in much the same way antibiotics develop resistance.

But what is Infinity doing different from other research companies in developing Bcl-2 inhibitors?

Adams uses the analogy of the princess and the pea, but instead of mattresses, the idea is to stick a drug between two large proteins.

Traditional pharmaceutical companies have tried to slip a flat molecule between the proteins, like a credit card between the mattresses, but the princess doesn’t feel it.

Infinity uses a "more 3-dimensional-type of molecule," Adams said, "that will enable disrupting the association of these two proteins," and therefore affect cancer cell survival.

The molecules are 100 percent synthetic but are inspired by molecules found in nature that are 3-dimensional, he added.

Founded in mid-2001, Infinity has raised $140 million in equity capital since inception.

Its lead compound, an Hsp 90 inhibitor called IPI-504, is in two Phase I trials in multiple myeloma and in gastrointestinal stromal tumors.

The product should be ready to enter Phase II trials in the second half of this year.

Infinity also intends to file an investigational new drug application in the second half of the year for IPI-609, an inhibitor of the hedgehog pathway that had demonstrated efficacy in preclinical models of pancreatic and prostate cancers.

The Bcl-2 inhibitor is third in line for reaching the clinic, but the only one partnered.

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