18 February 2013. In the AD field, most readers can count on one hand the companies that are widely known to have at least two drugs in sufficiently advanced stages to test combinations; Roche and Eli Lilly and Company come to mind, for example. These companies can go ahead on their own with some combination trials, but on a broader scale, single-company trials limit what could be done scientifically. Indeed, at an ACT-AD/C-Path conference held last November in Rockville, Maryland (see Part 1 of this series), part of the day was devoted to discussing how multiple companies could be brought to the table for combination trials in AD. Will companies work together on a topic that goes well beyond the accepted notion of precompetitive space? Their compounds, their clinical trials, and enrolling into those trials rapidly—that is where companies compete intensely, after all.
Will legal concerns trump the scientific rationale? “Based on our experience, the scientists at companies typically say yes, the lawyers may initially say no,” said Diane Stephenson of those types of out-of-the-box ideas. Stephenson heads the Coalition Against Major Diseases initiative of the Tucson, Arizona-based C-Path Institute, which co-sponsored the meeting with the Washington-based ACT-AD coalition of Alzheimer’s organizations. Stephenson works toward expanding the accepted definition of precompetitive space to also include a complete understanding of drugs to be used in combination. Intellectual property and data sharing hurdles may seem daunting, but in fact, examples for how to clear them already exist in other indications and even AD itself.
One example in Alzheimer’s research is the Dominantly Inherited Alzheimer Network (DIAN). It developed a legal agreement whereby companies jointly support, with money and expertise, the work necessary to get preclinical treatment trials off the ground, regardless of whether a given company’s drug was chosen. DIAN offered companies a model to join or be left behind. In the end, more than a dozen biopharma companies signed on to this Pharma Consortium (see ARF related news story), and more have requested entry since then. Drugs by Eli Lilly and Roche went into the initial trial, which started in December 2012. More trials are being planned.
The best-known example in oncology is perhaps the I-SPY 2 adaptive Phase 2 trial platform. It tests the effects of four to five different cancer drugs against a common control on biomarkers that are then correlated with the endpoint. A well-performing drug "graduates" into its own small Phase 3 trial, which the company then conducts on its own while a new drug enters the joint Phase 2 trial. Participating companies sign a unified intellectual property agreement for this arrangement. This was drawn up by the Foundation of the National Institutes of Health, in Bethesda, Maryland, which also holds the IND and interacts with the FDA. I-SPY 2 accommodates drug combinations by embedding them in a factorial design, and drops ineffective arms as Phase 2 proceeds.
“This is essentially an adaptively randomized Phase 2 screening process for multiple drugs,” said I-SPY 2’s co-developer, Don Berry of the University of Texas, Houston. “Pfizer, Abbott, Amgen, Merck, Genentech are playing in the same sandbox to participate in it.” Developed originally for breast cancer, this model is being applied as well to colorectal cancer, melanoma, lymphoma, HIV, and other diseases.
For Alzheimer’s combination trials, Reisa Sperling of Brigham and Women’s Hospital, Boston, envisioned a consortium that supports a translational mouse core where drug combinations from several companies can be tested simultaneously in multiple model systems. Successful ones would advance into an I-SPY-like system for early human testing. “If a company said I would be willing to test my BACE inhibitor with your antibody on a neutral platform in several mouse strains, then they might come to the table,” Sperling said.
An existing example comes from tuberculosis. The C-Path Institute drives the Critical Path to TB Drug Regimens (CPTR) initiative to develop new drugs for multidrug-resistant tuberculosis. In 2010, CPTR started with the Bill and Melinda Gates Foundation and the TB Alliance. Its express goal is to develop combination therapy right from the beginning as a way of addressing the worldwide problem of rising multidrug resistance to tuberculosis, said Debra Hanna of C-Path. No new tuberculosis drugs were developed for 40 years after the first drugs had come on the market. At present, four old drugs developed individually are given together in a complex regimen that takes up to nine months to clear the infection and causes many people to drop out because the drug-drug interactions make them sick.
CPTR decided to start fresh by developing multi-target combinations of investigational drugs supplied by different companies. The combination is to be developed in parallel, not sequentially, i.e., using unapproved new chemical agents with new mechanisms of action.
The CPTR is a public-private consortium. Its 24-member groups include government, regulatory, advocacy, and other groups, as well as every major company that is developing new TB drugs. Ten working groups advance separate scientific, legal, regulatory, and policy problems in parallel. “We have one very clear but massive mission, which is to accelerate the development of a new, safer, more effective regimen that can be taken for shorter periods of time, by enabling the early testing of combinations,” Hanna said.
Much like C-Path’s CAMD project does for Alzheimer’s, CPTR so far has built drug development tools such as a common CDISC data standard (see ARF related news story). It is also building a disease model to simulate potential drug combinations that can help companies assess early on if a given combination would likely fail. As does CAMD in Alzheimer’s, CPTR works with international regulatory agencies to push forward the qualification process for tuberculosis biomarkers for use in drug trials.
A critical component of CPTR's work is a legal framework that enables companies to share clinical trial data in a precompetitive environment. This helps them understand better what is going on in their trials, Hanna said.
Yet another example of a successful legal framework for data sharing can be found in the work of the National Center for Advancing Translational Science. NCATS started up in December 2011 after initial controversy around the appropriate role of the NIH in translational biomedical research. John McKew of NCATS cited drug repurposing programs to fund the search for new uses for drugs that were proven safe but were then axed because they failed efficacy in their intended indication. In one program, NCATS persuaded eight companies to contribute such molecules, for a total of 58. The companies include some that are active in Alzheimer’s as well, such as Lilly, Janssen Pharmaceuticals, and Pfizer. This program is different from the kind of precompetitive cooperation needed for AD combination trials in that the molecules are ones the companies are no longer intending to develop. All the same, certain aspects are relevant to the challenge of multi-company Alzheimer’s combination trials.
One lies in McKew’s experience building the cooperation. “It was very challenging to get the first couple of companies to sign on. Once we had that, it dominoed, and when we closed the process we had companies waiting at the door,” McKew said. A similar dynamic occurred during the building of DIAN’s Pharma Consortium. Negotiating a model agreement that these first few companies could sign was the most time-consuming component of setting up the repurposing program, McKew said. It was worth the effort because it pre-empted the need to renegotiate intellectual property and other issues with subsequent companies. NCATS' template agreements for collaborative research and confidential disclosure are freely available online. In discussion, Rusty Katz of the FDA noted that the agency encourages such agreements.—Gabrielle Strobel.
- Combination Drug Trials: Time to Open a New Front in AD?
- Combination Trials: FDA Puts Flesh on Bones of Draft Guidance
- DIAN Grows, Gets Ready for Therapeutic Trials
- New AD Data Standard: FDA Wants It; Will Trial Groups Use It?