NIH NCATS Drug Repurposing

In his latest Forbes column, John LaMattina makes a number of very good points over the NIH plan to take existing drug candidates and use their resources to look for new applications that they may treat.

As LaMattina says, this would be great if it worked, but is it really likely and is there a better way that NIH could be spending its precious resources? Is this sort of sifting through the dusty shelves of the pharmaceutical industry panning for gold really what the NIH should be doing? I see this as the sort of activity a small start-up forms around, takes a chance on their find and then lives or dies. It is more than a little risky.

Curious Wavefunction makes the point (while broadly agreeing with LaMattina) that the pharma industry is not really doing all it can to discover new drugs, putting next quarter’s revenue forecast over a more long term outlook and it is hard to deny that the pharmaceutical industry has been rather self-destructive lately.

However, re-examining old drug candidates can’t be the best use of NIH funds. It is there to spur the research, the basic research, that will eventually lead to a practical impact upon society in the form of new treatments, new prevention, or things we can’t yet imagine. The old Molecular Libraries Program – now being phased out in favor of NCATS – made a stuttering start but my impression was that it was doing the right things, making high-through-put screening, modeling and some medicinal chemistry available to academia. Indeed, folks at Vanderbilt had praised its importance to their academic drug discovery program. The screening sites set up under this initiative now need to find their own funding which may be difficult in the current climate, but there has been some collaborative work with industry as industry also needs innovation in order to feed their dwindling pipeline. Pfizer has its Centers for Therapeutic Innovation, as well as a number of academic collaborations. Eli Lilly has its Open Innovation program. Other companies have made efforts in this area too.

However, it has to be said that the main player in starting the basic research programs that result in such innovation has historically been NIH and it seems to me that even a scaled back version should concentrate on its core function.

Pharma 2.0

This piece has taken me longer to write than I expected, but hopefully a few people are still interested.

I am sure most people have by now heard about the Morgan Stanley analysis that buying drugs gives a much better return on investment that developing them yourself. Looking at the lay-offs and closing of research sites, it appears that Big Pharma is listening to the Wall Street analysis with interest, despite some rejecting the idea as dangerous. After all, if Big Pharma doesn’t develop any of its own drugs any more, how are they all going to keep fed?

I tried to imagine what this remoulding of the pharmaceutical industry would look like, what the drug discovery cycle would look like.

It all starts with the initial lead. A lot of these have previously come from screening the compound libraries of the big pharma companies, with some coming from biotech companies developing interesting targets and from academic labs (with funding from the government as a major source). Those latter two will clearly still contribute to the initial leads in pharma 2.0. I can also imagine big pharma still using their screening to find leads – but then who develops them? Biotech companies often are pure biology (or at least only a limited chemistry staff) and use contract research to effectively be their chemistry departments. Big Pharma might do this (they already use contract companies for projects they don’t have the resources to work on internally) or the lead of GSK might be followed, as they allow companies to screen their libraries and then if they get a hit, negotiations begin.

Once a lead is identified, the lead optimization begins, the meat and potatoes of the medicinal chemistry department. If we assume that Big Pharma will not be doing this part, we will likely have a mix of companies doing this type of work, some being the archetypal biotech companies, focused on one pathway, the reason the company was formed. They will have their small chemistry department (possibly sub-contracted) working on the project, with biology resources using their compounds to expand their knowledge of their target. They will take the compound into preclinical evaluation – beyond that depends on their financing.

The other type of company I can imagine is one that is more diverse, more chemistry-based. They may do contract work for other companies and may pursue one or two internal lead optimization programs. Again, they will be able to do preclinical evaluation (either outsourcing the biological analysis, PK, toxicity, etc. or perhaps a limited amount themselves).

To take these compounds through clinical trials is where things start to get a lot more expensive. Pure biotech companies may be able to ride their great white hope through the minefield, though many will fall. The ones that succeed will get their return on investment and everyone gets rich. The chemistry-based companies will not be able to go all the way through – some biotechs may not either. However, this is where Big Pharma come back into the picture – looking for the most promising compounds, so they can take on some of the risk in exchange for their expertise and financial muscle to take the compound through clinical evaluation. The further the small company takes it alone, the greater the potential reward for them. If they have a preclinical candidate, which has just passed the initial (and most likely preliminary) toxicity screens is much less valuable then something that has proof of concept in real patients in phase II.

So what big pharma is hoping is to improve their return on investment by having more in-licensed drug candidates and thus transferring the burden of the early drug discovery onto small companies and their venture capital backers. Right now, VC is hard to find so it seems hard to believe that there is enough to keep the mighty pharmaceutical giants happy. They might help that along by passing along some of their abandoned internal projects to start up companies (possibly made up of old employees), seeding the pool as it were. You can’t help but feel, though, that small companies with promising compounds will be highly sought after, possibly prompting bidding wars and certainly elevating the price for acquiring that piece of the pie. Smart execs might seek to have in place agreements with the biotechs to avoid such stand-offs with their competitors. They may end up more involved in early phase drug discovery than they planned to be. Though since these investments won’t be direct employees, lay-offs won’t be such an issue any more.

I’m not sure if this could all work – I have many doubts. We may get to find out. These will continue to be Interesting Times.