Along with HIV/AIDS and malaria, tuberculosis (TB) is one of the Big Three of global health diseases, which due to their prevalence, consequence, and predilection for developing resistance to drugs are the focus of international prevention and treatment efforts. TB is caused by a hardy type of bacteria, Mycobacterium tuberculosis, which can infect and kill especially in those weakened by malnutrition or other infections like HIV/AIDS or infect and colonize without symptoms with the possibility of becoming active later (CDC TB Basics). According to the WHO, TB is highly contagious, infects one-third of the worlds’ population, kills about 1.8 million people each year, and is resistant to standard therapy in about 5% of all cases (Stop TB Fact Sheet).
Last week, a new deal was announced by three of the major TB players: the Global Alliance for TB Drug Development, the Bill & Melinda Gates Foundation, and the USFDA. Called the Critical Path to TB Drug Regimens (CPTR), this initiative “will test promising combinations of individual TB drug candidates from different companies early in the development pipeline- and identify the best new treatment regimens.” It will have as active participants the Alliance, FDA, Johnson & Johnson, sanofi-aventis, Pfizer, AstraZeneca, GlaxoSmithKline, Bayer, Otsuka, Novartis, Sequella and Anacor Pharmaceuticals, Inc., and will be coordinated by staff of the Critical Path Institute of Tuscon, AZ (Institute press release, CPI Press Release, and TB Alliance press release, TB Alliance Press Release). The overarching theme is that therapies that combine two or more drugs have been demonstrated to be the better treatments for infectious disease (examples are HARRT for HIV/AIDS, Wikipedia Article, and ACT for malaria, Shoklo FAQ) but that their traditional method of development (clinical trials that combine two already-approved mono-therapy agents) takes way too long (FDA article, FDA Article). The goal of the initiative is to reduce this time by both developing preclinical combination testing methods (so-called “regulatory science tools”) and to conduct the preclinical testing (and possibly the phase I human testing?). The result will be treatments that are more potent, faster-acting, and less-prone to evasion.
The creation of the CPTR is the result of the confluence of a number of efforts that have been years in the making:
-the several-billion dollar investment in TB research, drug and vaccine development, and treatment by the Gates Foundation (well-summarized in their recent strategy document, Gates TB Strategy) and the perseverance and abilities of Peter Small (Small Info);
-the USFDA’s Critical Path Initiative which, since 2004 has funded a number of programs to improve regulatory science through improved use of biomarkers, clinical trial design, and bioinformatics (FDA Critical Path Initiative);
-the availability of nine (or more) TB proto-drugs in development at companies and at the TB Alliance (TB Alliance Press Release); and
-the investment in TB drug development by the major pharma companies, an investment made because of the dual- and emerging-market profit potential.
The CPTR is great deal but here are some of the wild cards I see in the deck.
Is the Critical Path Institute (CPI) up to the organizational and operational task? The CPI has significant experience in running consortia (e.g., in preclinical testing and adverse event reporting, CPI Consortia) but CPTR has a lot of high-powered players whose diverse aims need to be aligned. Also the knowledge base of regulatory science (the science of testing) is limited since it has not been an NIH funding priority (or even an interest) until recently. Also the CPI’s actual drug development experience seems nil, so I assume the actual work will be out-sourced, a challenge in itself. I’m hoping that they are able to utilize methods to accelerate the testing like the archiving and analysis tools developed by Collaborative Drug Discovery, Inc., which is already doing a Gates-funded TB project (TBDB) (c.f. my posting of March 11).
Will the participants provide their best drugs, be willing to share their exiting data, and accept the data on the combos? In a Wall Street Journal article on the CPTR, it was reported that at a March 2009 meeting of Bill Gates and executives of 14 drug companies “all [CPTR] partners agree to share data and test new drugs in combination treatments early in the development process” (WSJ Article). I did not find a similar statement in the CPTR documents (e.g., CPI CPTR). Also I found no commitment on which drugs, although at last year’s Pacific Health Summit, Dr. Robert Sebagg, vice president of Access to Medicines at Sanofi-Aventis, was quoted as saying his company will allow its most promising TB drug to be tested in combination (Seattle Times Article). As for acknowledging and publicizing the combo results, the stakes are high for a company in that adverse results (e.g., toxicity) may raise concerns about their drug (rightly or wrongly, it may be hard to tell) that could affect its approval.
What is the source and level of funding for the preclinical testing? Always a sticky question and unanswered in the announcements, although it is stated that “To facilitate clinical research of combination TB therapies, collaboration partners are also exploring creative funding mechanisms and potential trial site support for Phase IIB and Phase III clinical trials” (TB Alliance Press Release). Presumably the Gates Foundation will pony up and maybe the companies, too, which would be great. It is not likely the CPI will add to the pot. Although they do a good job fund-raising, including from local businesses like AAA Landscape and Jim Click Automotive (CPI Funding), they are not likely to have extra money for the CTPR, and I am guessing many millions are needed.
Finally, a wild card not in this deck is whether the combination drugs will be competitive in cost/benefit against the existing therapies. The current standard of care of an active infection is four drugs administered over 6 to 9 months with observation to assure compliance at a cost of under $60 per patient (TB Alliance). Well-designed clinical trials will be needed to generate the data required to convince the TB public health industry of the value of a new therapeutic standard, and creative pricing and marketing will be needed to sell an affordable, yet profitable, therapy.
“All in” on this deal?