Thursday, July 3, 2008

Metabolic Disease Drug Development Anxieties Highlight Benefit of Diversified RNAi Therapeutics Pipeline

Like the commodity bubble, it seems that the regulatory hurdles to drug development are mounting just when we thought we had reached the top. This is the impression one gets from the vote taken by an FDA advisory panel this week that can be essentially boiled down to the presumption that lowering blood sugar increases the risk of heart attack. The prospect of longer and more expensive clinical trials has certainly caused a few mini heart attacks to a number of drug companies developing medicines for diabetes and other metabolic diseases thinking that the obesity epidemic in the prosperous half of the world was bad enough such that regulatory agencies, politicians, and certain clinicians involved in drug development would have a keen interest in new treatment options. Don’t get me wrong here, I see very well the problem of millions of real patients and maybe not-so-needy folks taking drugs from which they do not derive any benefit, but there certainly are other ways of ensuring drug safety and efficacy without rendering drug development, and eventually the cost of drugs just unaffordable to anybody, and often without good reason.

Now that I got this off my chest, what does the broad attack on metabolic disease drug development mean for RNAi Therapeutics?

Metabolic disease, because of the ability of current systemic delivery methods to effectively knock down genes in the liver which is critically involved in regulating blood sugar and lipid levels, is one of the main therapeutic focus areas of current RNAi Therapeutics development. It shares this position with cancer, followed by respiratory, ocular and CNS-related disease. It may therefore be tempting, if you have the ability to target a range of hot metabolic disease targets, to create a development pipeline based on metabolic disease and little else. ISIS Pharmaceuticals from the related field of antisense therapeutics is probably the best example here as it has very much limited their internal drug development activities on metabolic disease, while handing off some of the more challenging targets such as for cancer to one of their many satellite companies.

Of course, if you don’t have the capability to diversify, concentrating on building a franchise around a single, but potentially very lucrative market may be the most efficient way of maximizing shareholder value given the many synergies derived from largely having only to exchange the siRNA inside and comparatively few other changes. However, if you can afford it and you are interested in establishing RNAi Therapeutics as a broadly applicable drug development platform, you probably would want to spread your risk more widely even if all the programs added up individually would yield a higher valuation. The fact that the regulatory environment may change overnight while drug development is a 12-15 year effort being one reason.

Next to insuring from regulatory risk, diversification also means that failure of one drug candidate such as for a given organ does not necessarily have to impact the perceived probability of success for candidates aimed at other organs. In the same vein, it may also be wise not to be too dogmatic about delivery technologies, siRNA modification or DNA-directed RNAi methods and structures. For example, if your entire IP claim depends on just one siRNA modification pattern even without so much as functional validation in a non-human primate, you may have ended up totally reliant on clinically non-viable chemistries. Related technologies have shown that developing chemistries in generations rather than multiple chemistries in parallel may mean that if your chosen chemistry generation turns out to be either inefficient or unsafe, it may take another 7 years to get a shot with the next generation.
Meanwhile, all bets are off what steps the FDA will take next.


Anonymous said...

Dirk, a question for you or anyone else readig this who is familiar with the regulatory environment:

To what extent can the FDA be circumvented by applying first (or simultaneously) for the approval of a metabolic disease drug in Europe and/or Asia. Although this would presumably not accelearate the ability to sell the drug in the US, it could accelerate the ability to sell in Europe and/or Asia (assuming the drug regulatory agencies there do not take the same conservative view as the FDA) thus bringing forward revenues as compared to the scenario where the drug is first approved in the US and only after that and on that basis in the other major markets. If viable, this approach could actually put pressure on the FDA if it is too unreasonable.

Another and unrelated thought on this is that this FDA position could actually help someone who has metabollic drug in late stage clinical trials, such as ISIS' mipomersen, in that once they get approved (if they get approved), it will take longer for competing drugs (e.g., ALNY's or TKM's hypercholesterolemia RNAi drugs) to hit the market.


Dirk Haussecker said...

Martin- Yes, the regulatory agencies outside of the US do not have to follow the FDA and is nothing unusual. Kind of like the Fed and the European Central Bank. However, to a certain degree their philosophies should also influence each other. Also imagine the pressure if a drug that had been rejected in the US shows safety issues in Europe.

The other issue for US-based pure-play RNAi Therapeutics companies is that they would most likely want to build US sales forces first, and an approval in Europe would likely benefit them less than an approval in the US.

It looks like mipomersen and all the other cholesterol-lowering drug candidates would have to jump through the same hoops, so I do not believe that the new regulatory environment will change any of the competitive time-lines. Of course, there is a benefit once your drug has been approved and your competitors fail, but the prolonged clinical studies also mean that your period of exclusivity and therefore pricing power will be reduced quite a bit, and nobody really wins if it does not pay from the outset to develop metabolic drugs.

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