HD Insights™

Clarence-Smith, cont... Copyright © Huntington Study Group 2014. All rights reserved. 1 Kenney C, Hunter C, Davidson A, Jankovic J. Short-term effects of tetrabenazine on chorea associated with Huntington's disease. Mov. Disord. 2007;22(1):10–13. doi: 10.1002/mds.21161. MOLECULAR FORMULA: C 19 H 21 D 6 NO 3 MOLECULAR WEIGHT: 324 g/mol MECHANISM OF ACTION: Tetrabenazine reversibly inhibits monoamine re-uptake, which depletes monoamines and reduces involuntary movements. 1 Auspex Pharmaceuticals, developer of SD-809, has shown that deuteration of tetrabenazine may slow its metabolism and decrease the need for large repeated doses. 2,3 MEET THE COMPOUND: SD-809 (dutetrabenazine) Image source: Auspex Pharmaceuticals, Inc. United States Securities and Exchange Commission Form S-1: Registration Statement. Filed December 20, 2013. www.nasdaq.com/markets/ipos/filing.ashx?filingid=9241956 Accessed January 21, 2014. HD INSIGHTS: Tetrabenazine is usually prescribed three times daily and has some side effects. Are there ways that the drug can be improved? CLARENCE-SMITH: Yes. I am a consultant to Lundbeck, who markets the drug in the USA, and I have been examining this problem for the past two months. I think that some of the side effects are related to the very interesting pharmacokinetic profile of tetrabenazine. It has a very sharp peak, and a short half-life. Some of the side effects – sedation in particular – are likely linked to this sharp peak, so if it were possible to blunt the peak with a novel formulation, you might ameliorate some of the side effects. It would also be nice to extend the duration of action. If you look at the pharmacokinetics, patients are rapidly getting on, and then rapidly getting off. 1 That fluctuation seems very uncomfortable for patients. A formulation that could both blunt the peak and prolong the duration of action would improve patient experiences with tetrabenazine. HD INSIGHTS: Do you have any advice for innovators who are looking to develop new pharmaceutical treatments for HD? CLARENCE-SMITH: I think one of the most difficult obstacles to getting innovative drugs from bench to market is the transition between the lab bench and the clinic. Preclinical people work on new drugs in the lab, in rats and mice and primates, and then the drug passes to the clinic to be tested in patients. That transition is often not well negotiated. Usually, not enough work is done on the animal model, leading to an incomplete understanding of what may be expected in humans. You must completely and critically understand the animal model information to know what to do in patients. For example, humans sometimes have different enzymes and different ways of metabolizing drugs than animal models. I remember a drug developed about 40 years ago that was a miracle drug for treatment of myocardial infarct in dogs, but when it was used in humans, it was absolutely inactive. It turned out that the drug's effectiveness depended on an enzyme present in dogs, but not in humans. The other thing is that while patients participate in clinical trials at all stages of the disease, animal models are usually treated at the same stage of the disease. You really should study your drug in many stages of the disease in animals first, to measure the stage beyond which it is not going to help. For example, if the animal models were to show that the drug always slows the disease whenever you start treatment, why would you not also enroll individuals with more advanced disease in your studies? But if the animal model were to show that it only works if you give it early, then you do not want to enroll patients at an advanced stage in your trials because you will get a negative result. And it will be unfair to the patients – this drug could have worked if it had been studied properly. HD INSIGHTS: Dr. Clarence-Smith, thank you for bringing the first FDA-approved treatment for HD to market, and for your continued efforts in developing new therapeutics for HD and other conditions. H D I N S I G H T S HD Insights, Vol. 7 3

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