hsg logo white

HD InsightsMeet the Investigator

Dr. Kathleen Clarence-Smith
Dr. Kathleen Clarence-Smith


NAME: Kathleen (Kitty) Clarence-Smith, MD, PhD

CURRENT POSITION: Chairman of the Board of Chase Pharmaceuticals; Partner, KM Pharmaceuticals Consulting (clients include Lundbeck).

EDUCATION: MD and PhD in Neurosciences, Université de Tours, France; Residency in Neurology, Salpêtrière, Paris, France; post-doctoral fellowship at Johns Hopkins University School of Medicine, Department of Pharmacology and Experimental Therapeutics.

HOBBIES: Reading, currently Walter Isaacson’s Steve Jobs.

Dr. Kathleen Clarence-Smith has dedicated her career to developing novel pharmaceuticals and bringing them to market. As the founder and CEO of Prestwick Pharmaceuticals, she helped bring tetrabenazine, the first FDA approved treatment for HD, to the US. She has held senior positions in major pharmaceutical companies (Roche, Sanofi, and Otsuka) and authored over 100 peer-reviewed publications. Dr. Clarence-Smith discussed the history and future of HD therapies with HD Insights. The following is an edited transcript of the conversation.

HD INSIGHTS: How did you first become interested in HD?

CLARENCE-SMITH: I read a Victorian novel when I was nine years old, the diary of somebody who knew that one of his parents had a disease that he would also have. The book ends with, “This is where I stop; I now have the shakes.” I thought it was a horrible disease, since you knew exactly what was going to happen to you, and then it happened. And of course, as I read the diary as a child, I kept hoping that it would turn out that he didn’t have the un-named disease. Much later, when I studied medicine, I realized that the disease I had read about in my childhood must have been HD. When I was 20, I knew a family who had HD, and was again confronted with the sadness and concerns about the children faced by families affected by this disease. I had absolute faith that biochemistry could find a drug that would stop or slow the disease.

HD INSIGHTS: As founder and CEO of Prestwick Pharmaceuticals, you were instrumental in bringing tetrabenazine to market in the United States. Did you ever think that your interest in finding a biochemical treatment for HD would lead to an approved drug?

CLARENCE-SMITH: No, I never thought of that in those days. I just knew that I wanted to find a cure, and I kept hoping that I would either read something in the literature which would point to the cure, or that I would be able to do real research into finding the cure.

HD INSIGHTS: How did you become interested in tetrabenazine?

CLARENCE-SMITH: I met Dr. Joseph Jankovic at a meeting, and he knew that I was working on trying to get drugs approved by the FDA. He wanted more than anything to see tetrabenazine approved in this country. I called the company who manufactured tetrabenazine in Europe and managed to convince them that it was possible to get this drug approved in the United States, and I was able to raise money to do it.

HD INSIGHTS: What are the current limitations of tetrabenazine?

CLARENCE-SMITH: It seems to only treat chorea, and clearly we also need treatments for the cognitive impairment and behavioral symptoms seen in HD. It remains to be seen whether we need three different treatments, or one yet-to-be-discovered therapy for all the disease symptoms. A lot more work needs to be done to understand the physiopathology of the cognitive impairment. For behavioral symptoms, I think that tetrabenazine has not been completely studied. I would have expected that a drug such as tetrabenazine that acts on the dopamine axis would also improve behavioral symptoms. Today, I’m leaning towards a need for three treatments, but sometimes you get surprised in drug discovery and development.

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.


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.

About HD Insights

Our mission is to promote, disseminate, and facilitate research on Huntington’s disease. To fulfill this mission, we are guided by an outstanding editorial board that includes representatives from three continents, academia, industry, and the HD community.

More from this Issue