The US Food and Drug Administration (FDA) is expected to make its final decision on tetrabenazine in the next few months. Despite rumors that the FDA was planning to hold a public hearing on tetrabenazine in early November, we have learned that the hearing is not yet on the official FDA calendar and is unlikely to occur before the end of the year. This follows an FDA announcement in March that found tetrabenazine "approvable" if specified conditions were met. Prestwick has not publicized the details of the FDA's letter, but anyone who followed clinical trials for this drug knows that there are two questions that need to be addressed: Should chorea be treated? And if so, is tetrabenazine safe enough?
The Hereditary Disease Foundation (HDF), led by Dr. Nancy Wexler, is collecting letters from Huntington's people that will be forwarded to the FDA. If you wish to write, the instructions are here.
The Chorea QuestionShould chorea be treated? It seems that the answer depends on who, and how the question is asked. Based on a 1998 study by Snowden et al, many Huntington's doctors believe that chorea causes relatively little disability. And they think that because damaged neural circuits prevent the sensation or awareness of chorea in those who experience it, it is a symptom that need not be treated at all. Some further suggest that it is patient families, not patients themselves who wish treatment.
While it is true that patients lack of awareness of chorea, some in the healthcare and research communities seem to lack an awareness of the suffering it causes. Chorea impacts the lives of many with Huntington's. Mistaken for drunk, one of my independent young male Huntington's patients with chorea is routinely thrown out of shops just trying to buy lunch; chorea bothers him. Another, who very capably maintains a sales job, fears he will lose it because coworkers and customers are distracted by his symptoms; chorea bothers him too. Chorea limits the social interactions of most of my patients and their families. Many stop traveling: one won't leave her home due to the stigma. Chorea promotes imbalance that leads to falls. One is regularly thrown from her chair by it, another bruises her head on the bathroom wall just sitting on the toilet.
Chorea causes suffering and impairs quality of life for those with Huntington's and their families. This feature of Huntington's absolutely should be treated when it impairs usual life functions. For a more accurate evaluation of the limitations imposed by chorea, Snowden, et al. should conduct a study of HD people "before and after" chorea treatment.
Tetrabenazine Benefits Those treated with tetrabenazine have noted improvements including increased comfort and desire for socialization. Some have returned to international travel. My patient who wouldn't leave home now gets out several times a week. They report better balance and fewer falls. They describe improved ability to talk and read, improved mechanics of eating, a return to gardening, even riding a bike again. Some find falling asleep easier, and several happily report that they can lie in bed to hug and sleep with their partners again. Treating chorea is important for many.
Tetrabenazine RisksDrug approval hinges on whether the FDA views the symptoms of chorea as debilitating enough to risk the side effects of this drug. TETRA-HD, the recent placebo-controlled clinical trial conducted by the Huntington Study Group (HSG) to obtain FDA approval was well designed to test for efficacy. While this trial addressed swallowing and other potential side effects, it was not designed to directly deal with the most serious side effect of this drug: severe depression leading to increased rates of suicide. I suspect this is the safety concern the FDA wants addressed.
Fortunately Jankovic and colleagues from Baylor School of Medicine, who have decades-long history with the use of this drug, have recently reported a retrospective review that addresses tetrabenazine and depression. They give compelling evidence that tetrabenazine depression can be treated and controlled in the vast majority of patients, causing only 3% of 518 patients to stop the drug. While another 15% stopped tetrabenazine due to fatigue or other side effects, more than 80% of patients chose to remain on tetrabenazine long term. This rate of drug acceptance is comparable to many approved drugs. Because it is unethical to perform a placebo controlled trial to study suicide risk, I hope the FDA strongly considers this evidence in this extensive review.
Minimizing RiskDepression is especially dangerous and potentially life threatening for people with Huntington's. Because there are several reports of suicide while on this drug, the FDA will take this potential side effect very seriously. They can minimize this risk by several FDA mechanisms already in use. They could grant approval of tetrabenazine with "black box" warnings, as is done for ADHD drugs, and require frequent physician follow-up, as is done for antidepressant use in adolescence. They could recommend the co-administration of antidepressants, as is already done in a hepatitis C treatment known to induce depression.
To be sure, tetrabenazine is not a perfect drug, and better ones may come along. But for now, it is the only one. Because so many with Huntington's want access to this drug that can presently be obtained only outside of the U.S. at substantial financial cost, we support its FDA approval. We believe that it should be the right of anyone with Huntington's to decide, with their treating physician, the personal benefits and risks. Withholding FDA approval is not the best choice for Huntington's people.
The Reports Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006 Feb 14;66(3):366-72. PubMed abstract
Kenney C, Hunter C, Mejia N, Jankovic J. Is history of
depression a contraindication to treatment with tetrabenazine?
Clin Neuropharmacol. 2006 Sep-Oct;29(5):259-64. PubMed abstract
Snowden JS, Craufurd D, Griffiths HL, Neary D. Awareness of involuntary movements in Huntington disease. Arch Neurol. 1998 Jun;55(6):801-5. PubMed abstract