The U.S. Food and Drug Agency has approved deutetrabenazine, marketed under the name Austedo by the Israel company Teva Pharmaceutical Industries, for the treatment of Huntington’s disease. Tetrabenazine was the only approved treatment until now. Its deuterated version works the same way, binding to vesicular monoamine transporter type 2 and blocking neurotransmitters such as dopamine and serotonin from being loaded into synaptic vesicles. Both drugs improve chorea, the random and uncontrollable movements that mark Huntington’s, a disease that attacks primarily striatal neurons in the mid brain. This is the first deuterated compound approved by the FDA, according to the company press release.
U.S. approval follows a Phase 3 clinical trial run by the Huntington Study Group. Results showed that among 90 patients, half randomized to deutetrabenazine and half to placebo, those on drug had better motor control (see Frank et al., 2016). Patients on drug improved by 4.4 points on the primary outcome measure, chorea assessed by the Unified Huntington Disease Rating Scale Total Maximal Chorea score. People on placebo also improved slightly, by 1.9 points. The difference, 2.5 points, was significant.
The trial did not test deutetrabenazine and tetrabenazine head to head. In fact, the dose of these drugs must be optimized for each individual patient. In the deutetrabenazine trial, patients were initially given 6 mg/day. The dose was then increased by 6 mg/day weekly until chorea was controlled, or a predetermined maximal dose of 48 mg/day was reached, or the patient showed adverse effects. At the end of the trial, patients were taking 39.7 mg/day on average. Deutetrabenazine seemed well tolerated, with only one person dropping out by the end of the 13-week trial. In the pivotal tetrabenazine trial, patients were titrated up to 100 mg per day.
Both drugs are broken down by CYP2D6, a member of the cytochrome P450 family of liver metabolic enzymes. However, the half-lives of deutetrabenazine and its active metabolites are almost twice as long as those of the undeuterated compounds, meaning the heavier drug can be given less often and in lower doses yet still be effective. Data suggest deutetrabenazine has a better safety and tolerability profile (see Claassen et al., 2017). For detailed prescribing information on this drug, marketed as AustedoTM, see FDA website.—Tom Fagan.
- Huntington Study Group, Frank S, Testa CM, Stamler D, Kayson E, Davis C, Edmondson MC, Kinel S, Leavitt B, Oakes D, O'Neill C, Vaughan C, Goldstein J, Herzog M, Snively V, Whaley J, Wong C, Suter G, Jankovic J, Jimenez-Shahed J, Hunter C, Claassen DO, Roman OC, Sung V, Smith J, Janicki S, Clouse R, Saint-Hilaire M, Hohler A, Turpin D, James RC, Rodriguez R, Rizer K, Anderson KE, Heller H, Carlson A, Criswell S, Racette BA, Revilla FJ, Nucifora F Jr, Margolis RL, Ong M, Mendis T, Mendis N, Singer C, Quesada M, Paulsen JS, Brashers-Krug T, Miller A, Kerr J, Dubinsky RM, Gray C, Factor SA, Sperin E, Molho E, Eglow M, Evans S, Kumar R, Reeves C, Samii A, Chouinard S, Beland M, Scott BL, Hickey PT, Esmail S, Fung WL, Gibbons C, Qi L, Colcher A, Hackmyer C, McGarry A, Klos K, Gudesblatt M, Fafard L, Graffitti L, Schneider DP, Dhall R, Wojcieszek JM, LaFaver K, Duker A, Neefus E, Wilson-Perez H, Shprecher D, Wall P, Blindauer KA, Wheeler L, Boyd JT, Houston E, Farbman ES, Agarwal P, Eberly SW, Watts A, Tariot PN, Feigin A, Evans S, Beck C, Orme C, Edicola J, Christopher E. Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial. JAMA. 2016 Jul 5;316(1):40-50. PubMed.
- Claassen DO, Carroll B, De Boer LM, Wu E, Ayyagari R, Gandhi S, Stamler D. Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease. J Clin Mov Disord. 2017;4:3. Epub 2017 Mar 1 PubMed.
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