TB DD Needy

Last month the third annual Global Funding of Innovation for Neglected Diseases (“G-Finder”) report was released by Policy Cures, a grant-funded policy research operation in Sydney (G-Finder page).   Through a survey of more than 800 organizations, the G-Finder team compiles and sorts the amounts of money spent in the previous year (2009) on neglected disease research and product development to provide “governments, funders and civil society organisations with the information they need to make optimal research and development (R&D) policy and funding decisions for diseases of the developing world.”  While some advocacy groups use the report to argue that the overall amounts are too low (true but not the point) and some that the relative amounts are wrong (everyone has her/his cause), I am concerned that the data reflect a bias on the part of the funders toward the status quo (the funding basic research) at the expense of preclinical and clinical studies, i.e., funders are not optimizing their decisions to meet the goal getting effective and safe drugs into the people that need them.

For example, as noted in the report, tuberculosis (TB) is the disease receiving the third largest portion of the funding (17.6%), after HIV (36.7%) and malaria (18.6%), which is appropriate since, according to WHO, TB is highly contagious, infects one-third of the worlds’ population, and kills about 1.8 million people each year (Stop TB Fact Sheet).  The report also notes, of the $560 million in TB R&D, of 35.6% went to basic research and 51.5% into product discovery/invention and development (drugs, 32.1%, and preventative vaccines, 19.4%) (diagnostics and unspecified got the rest).  This seems like a healthy balance, but unfortunately the report doesn’t note where in the product development process the money was spent, how much at the early stages of discovering candidate drugs/vaccines and how much on turning those candidates into products (it looks to me as if the team collected data on preclinical vs. clinical research but these are not reported).  Ideally a drug development pipeline should look like a pyramid in terms of the number of candidate drugs (lots to start with that get winnowed down as the most promising move forward) and that what TB looks like, e.g., as in the pipeline described by the New Drugs for TB Working Group (NDTBWG chart).  But if the pipeline is scaled in dollars spent per stage, it should look like a tower at least, i.e., just as much money being spent on finding promising candidates as on testing and approval.  But that doesn’t seem to the be case, in fact, one may say the TB pipeline is plugged up.

In my closer look at the NDTBWG pipeline, I found six compounds at the preclinical stage, but also an apparent lack of investment in conducting the GLP (Good Laboratory Practices) tox and metabolism studies needed for approval and in having back-up compounds in case the lead compound drops out (good drug development practice).  My summary:

Drug Candidate Developer Entered GLP? Backup Compound?
Benzothiazinone NM4TB* No No
CPZEN45 Lilly TB Drug Discovery Program et al. No No
DC159a Japan Anti-tuberculosis Society, Daiichi-Sankyo Pharma No No
SQ609 Sequella No No
SQ641 Sequella No No
Q201 Quron Sciences No No

* NM4TB- New Medicines for TB, see below.

I also found that of the eight NMEs (new molecular entities or novel, new drugs) listed in human testing, only one, PA-824 by the TB Alliance that is in Phase I, seemed barely adequately funded at $5-10 M per year (my ballpark guessimate of the “average” clinical testing cost is $30-50 million per year).  Of the rest, one had an annual budget of $1-3 M, three less than $1 M, and three no data.  And six have pharma/biotech company involvement so you think that those programs would be adequately funded if diligence was important (and it should be).  Also there are no NMEs in Phase III.  At the base of the pyramid/start of the pipeline, one group, the TB Alliance (TB Alliance) is carrying most of the load being responsible for 6 of 14 hit-to-lead and 3 of 9 lead optimization drug discovery programs listed by the NDTBWG.  Although the NDTBWG doesn’t report how long these drug candidates have been in development (a helpful metric), I poked around and found that it has been ten years since one (SQ109) was identified in a NIH screening program (Sequella docs), a long time to get to Phase I.  Overall, the participation, funding, and diligence are not what I would expect from a healthy pipeline.

I’m not the only one who has expressed concern about the basic/development funding imbalance as shown in G-Finder.  A Lancet editor noted, “Public funders might, understandably, want to invest in their own academic institutes and universities as their national economies try to recover from the global financial crisis. But basic research is being done whether it is needed or not; for many neglected diseases product development is a more urgent priority.” (Lancet commentary).  And in the director’s summary accompanying this year’s G-Finder, Mary Moran noted that the share of funding going to PDPs, which are grant-funded programs aimed at finding and developing drugs for neglected disease, dropped from 26 to 23% of all funding and that the overall increase in funding was welcome but only if it is aimed at creating new medicines and vaccines.  And to further the imbalance toward early-stage TB drug candidate discovery, an academically-based and -lead, European Union-funded consortium, More Medicines for TB, was launched this month (Pharmalive article).  MM4TB is the successor to NM4TB and is focused on screening compound libraries against new targets and doing lead optimization but apparently not preclinical and clinical testing (MM4TB).  Interestingly, the consortium has two big pharma company partners, Sanofi-Aventis and AstraZeneca, which will provide libraries and expertise, but apparently will not conduct the (more expensive) later-stage studies.  Unfortunately, governments, foundations, and big companies seems to have an attraction to funding  new and shiny “basic research” and early-stage TB drug discovery programs (and probably those that are located in the funder’s own country or company) as opposed to putting money into the more boring testing and approval stages.  But without adequate funding of the latter, the TB drug pipeline will remain sluggish.

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