Since there is a whole lot we don’t know about human biology, disease pathogenesis, and pharmacodynamics, a common idea in the biotech/pharma world is to think of drug discovery and development process statistically: the more shots (unique proto-drug molecules) fired at the more goals (disease-related cellular-level targets), the greater chance of success. Hence, there are multi-million-member compound libraries, ultra-high-throughput screening methods, hundreds of research methods to dissect in vivo bio-activity, and, of course, billions of dollars spent on drug r and d. For people with diseases whose treatments are reimbursable and have strong lobbies, this has worked pretty well (e.g., there are 3078 industry-sponsored trials for cancer that are recruiting patients now), and not so well for others (24 new industry-sponsored trials for parasitic diseases) (Clintrials). Of course, to remain innovative and profitable, companies have searched for ways to reduce r and d costs, and over the past several years the concept of “accelerated proof of concept” (APOC) has gained currency. Simply put, the idea is to move drug candidates through preclinical studies (in which efficacy and safety in animal models is shown) and into early-stage human trials as quickly as possible to “prove the concept” of the candidate compound working as a drug.
A pioneer of APOC has been Eli Lilly and Co. which started its Chorus group as an alternative R and D pilot project in 2002 and, due to a 3-10x productivity enhancement, established it as an in house unit that now manages a significant part of Lilly’s preclinical pipeline (Chorus). Novartis embarked on a similar effort called Exploratory Clinical Development Groups, which, as was reported in In Vivo’s blog, has been too successful (In Vivo blog). Not to miss a promising trend, VCs and Chorus’s founders started Flexion Therapeutics (Flexion) in 2007; it “in-licenses clinically enabled drug candidates with high-value specialty potential and develops these to proof of concept (PoC) and beyond.” Although knowing which decisions and how to decide for APOC to succeed is still more art than science (c.f., Derek Lowe’s comments, In the Pipeline), many pharma drug developers are generating and trying ideas to accelerate the process (e.g., two conferences: American Association of Pharmaceutical Scientists, AAPS meeting and Healthtech, Healthtech meeting, and Wendy Hill’s presentation, Hill presentation). The theme is to make better decisions about which candidates to push forward in what studies and to demonstrate value faster or to pull the plug before the project gets too expensive.
APOC holds promise for the community of academic, government, company, and PDP scientists who are developing drugs for the unreimbursed diseases. They need to get more compounds in the pipeline (e.g., Medicines for Malaria Venture, one of the larger PDPs, has only three compounds in preclinical testing and seven in trials, MMV pipeline), coordinate research contracts across the globe, and avoid pouring too many resources into academic groups that don’t know how to do drug development. Note that I am distinguishing here between “collaborative research” in which there is a primary organization coordinating and funding disparate groups vs. “open innovation” in which the research is unguided and the results shared without obligation (or commitment). Examples of the latter are the India-based, Open Source Drug Discovery (OSDD), the still-maturing CA-based, Synaptic Leap (Synaptic), and the Tropical Disease Initiative (TDI).
One APOC approach to speed the identification and selection of promising candidate compounds is to use a web-based platform to aggregate and analyze data on structure/activity relationships (SAR). A leader in this field is Collaborative Drug Discovery (CDD) which has a commercial focus but also provides server space and tools for public data it has gleaned from, or was submitted by, government and academic groups, a chunk of which is relevant to malaria and tuberculosis SAR. In early 2009, CDD also received a Gates grant of $1.9 million “to create a cheminformatics database and expand its software functionalities for scientists developing therapies for tuberculosis” and integrate it with an existing database of genomics data (TBDB). Although most of CDD’s tools and customers are oriented toward in vitro screening data (the earliest stage in drug development), their intent is build out the platform to handle the full range of preclinical data, according to Navin Kadaba, one of CDD’s Community Advocates.
One may even imagine a global health drug development company based on the Flexion model that is:
-funded by donors willing to try a different approach and investors with patience and wanting to sleep well;
-in-licensing proto-drugs from academia or companies at highly favorable terms in exchange for diligence and geographical limits;
-contracting preclinical work globally to get the best price;
-using no/low cost platforms like CDD’s to coordinate and analyze the results;
-using government resources to conduct clinical trials or contracting with PDPs with experience in conducting trials;
-registering products through a (currently non-existent) expedited process at the USFDA and through (currently non-existent) reciprocity agreements with other countries; and
-manufacturing locally to keep prices as low as possible.
Voila: more shots on goal and more scores.