Beyond The Guidance: The Business Of Co-Development Combinations

FDA put together its well-received draft guidance on co-development of experimental drugs to be used in combination in less than a year, but even with regulators on board and the science burgeoning, the timeline for finding predictable ways for companies to actually collaborate on combining investigative cancer therapies looks to be much longer.

The draft guidance, which FDA published in December 2010, is not specifically for cancer drugs, but it is limited to combinations of novel drugs to treat serious diseases or conditions (Also see "FDA Issues Co-Development Guidance, But Only For Products Treating "Serious" Diseases" - Pink Sheet, 14 Dec, 2010.). It has been interpreted as a green light to industry to follow the emerging science to logical combinations of targeted cancer drugs, a pathway some drug makers are already following internally.

But, the possibility of co-developing two or more therapies owned by different companies raises business, legal, liability and intellectual property issues, any one of which can be a roadblock to getting those combinations into the lab and eventually to market.

A group of representatives from government, academia, advocacy groups and industry met May 4 in Columbus, Ohio, to discuss possible solutions to those problems at a roundtable convened by Friends of Cancer Research and The Ohio State University Comprehensive Cancer Center. Industry representatives attended from Pfizer Inc., Sanofi SA, Merck & Co. Inc. and Eli Lilly & Co.

"There could be a synergistic effect among the players and the researchers, as well as among the products they are researching," FOCR's Allen said.

After a one-hour public session, roundtable participants retired for discussions that by all reports were fruitful in terms of cooperative spirit and framing next steps. A report from the closed-door session of the meeting is due in the coming weeks.

"There was not a clear template as far as saying, 'Here's how your lawyers work out your intellectual property,' but what was very evident in talking toward what the solutions could be was that the different sectors should capitalize on each others' strengths," Jeff Allen, FOCR's executive director, said in an interview.

"There was discussion of how a consortia approach … could speed this along by developing kind of a precompetitive space that would foster some early needs," such as validated assays and biomarkers, he said. "There could be a synergistic effect among the players and the researchers, as well as among the products they are researching."

Focusing on the pre-competitive side has eased cooperation among companies involved in other efforts to accelerate drug development, such as the Predictive Safety Testing Consortium (which has an extensive intellectual property agreement) and the Foundation for the National Institutes of Health's public/private Biomarkers Consortium, which is running the I-SPY 2 trial of breast cancer drugs from multiple companies. FNIH is serving as a neutral party to manage the data and intellectual property coming from the trial (Also see "Biomarkers Consortium Launches Adaptive Trial To Test Targeted Breast Cancer Drugs" - Pink Sheet, 1 Mar, 2010.).

The Regulatory Uncertainty Barrier

FDA has been proactive: putting together the proposed policy shows the agency recognized the need for modification of drug development pathways to exploit the promise of molecularly targeted therapies. However, there is still much ground to cover. "The guidance is a start, but it's really just a first step," Janet Woodcock, head of FDA's Center for Drug Evaluation and Research, said in remarks during the Ohio meeting’s public session.

Woodcock listed barriers that must be overcome in order to put the guidance to good use, among them regulatory uncertainty, which the CDER chief acknowledged "can be a very big barrier to, say, investment."

Regulatory uncertainty shouldn't be at the top of anyone's list of concerns, CDER's Woodcock said.

She argued, however, that regulatory uncertainty "really shouldn't be" at the top of anyone's list of concerns. Woodcock said she recognizes that some drug makers are afraid a toxicity that arises from a drug being tested in an experimental combination could derail development of that drug as a single agent. On the contrary, she stressed, "I think most of you know that if, in combination, you found a really highly effective, ground-breaking treatment effect in cancer, in that circumstance, the toxicity is not the limiting factor in getting a drug approved."

Nonetheless, she said, "developers fear loss of control if they go into a combination program, and perhaps the regulatory consequences of that," and that raises an uncertainty barrier to entering into a co-development arrangement. It's not clear to some whether these programs will work out to the benefit of the developers because none have been done yet, Woodcock said. Once there are some successes, everybody will rush to embrace this concept, but "we need some early adopters here to get this on the road," she said.

"We need some early adopters here to get this on the road," Woodcock said.

Merck And AstraZeneca: "Early Adopters"

A June 2009 tie-up between Merck and AstraZeneca PLC may give Woodcock the proof of concept she's looking for. Together they are developing a combination of Merck's AKT inhibitor MK-2206 and AstraZeneca's AZD6244, a mitogens-activated protein kinase 1 (Mek) inhibitor, both first-in-class candidates.

The direct collaboration is the first example of two companies working together in this way with two agents, Eric Rubin, Merck VP-Oncology Clinical Research, said, adding that he found working with AstraZeneca "surprisingly easy."

The combination is headed into Phase II studies as an arm in the biomarker-driven BATTLE trial being conducted by the M.D. Anderson Cancer Center in Houston to test targeted therapies in lung cancer. Phase I data are to be presented in early June at the American Society of Clinical Oncology meeting in Chicago ("BATTLE Trial: Biopsy-Driven Therapies Feasible, Can Benefit Lung Cancer Patients," Health News Daily, April 20, 2010).

Merck is also testing an insulin-like growth factor-1 receptor/mTOR combination it matched using agnostic whole genome search techniques that led to a biologic rationale for the combination, Rubin explained. That combination is being tested in Phase II against breast cancer, using one of the study designs suggested in the draft guidance ( (Also see "FDA Draft Co-Development Guidance Emphasizes Phase II Studies" - Pink Sheet, 20 Dec, 2010.).

"It's a two-step trial where the first step is comparison to a standard of care agent, exemestane [Pfizer's Aromasin], and if we pass an efficacy bar there, it moves to a second part where we're looking at the combinations versus each individual arm," Rubin said.

"To our knowledge this is among the first [combinations] to be in Phase II for this setting."

Roche's Genentech division also is working on an internally devised combination. Phase Ib data on the MIK/PI3K inhibitor combo was presented recently at the American Association for Cancer Research meeting in Orlando (Also see "Roche Co-Developed Drugs Deliver Early Synergistic Results Without Added Toxicities" - Pink Sheet, 4 Apr, 2011.).

Serendipity: A Bad Business Development Plan

Anecdotally, Merck and AstraZeneca are said to owe the deal that brought the AKT/Mek molecules together to a long security line at the Dublin airport, where two scientists bided time by discussing their work (Also see "In A First, Merck And AstraZeneca Team Up For Oncology Study" - Pink Sheet, 1 Jun, 2009.). But serendipity isn't a viable development strategy, and roundtable members hoped to work out a more reliable way of putting companies together.

The Merck/AstraZeneca story makes an important point that a lot of what happens in industry and academia depends on relationships, Michael Caligiuri, director of the NCI comprehensive cancer center at Ohio State and CEO of the James Cancer Hospital, said in an interview.

It's nice when you're friends, but we're trying to put something together for when those ties don't exist. – OSU's Caligiuri

"It's nice when you're friends, or even better when your bosses are friends, but we're trying to put something together for when that doesn't exist," Caligiuri said. "In most instances that kind of pre-existing relationship is not there," and "we hope to provide an existing pathway to formally approach the idea."

Caligiuri said he thinks the timing of the co-development guidance is good for both business and scientific reasons. "We've got a better understanding of the signaling pathways and the targets, so you've got a better understanding of what needs to be hit. As we discover more about the molecular heterogeneity of tumors, relatively small markets are going to be available. And, therefore, companies are going to need to save money on R&D, so it makes sense that there be a pathway to seek these combinations outside their walls," he said.

At the end of the day, Dr. Woodcock asked to be included in any future meetings, which Caligiuri said he takes as an important sign that she thinks resolving these issues is important.

Indeed, active participation from FDA at this point "makes people feel like all stakeholders are dedicated to working toward the same goal," said Friends' Allen. The meeting itself was nice because "it took a step forward to say there are unique challenges in oncology that we can work together on," he said.

By Shirley Haley