NATURE REVIEWS | DRUG DISCOVERY – VOLUME 16 | MAY 2017 | 305

The FDA approved Teva Pharmaceuticals’ deutetrabenazine for chorea associated with Huntington disease, providing the first approval of a drug that contains the heavy hydrogen isotope deuterium. Early adopters first started tinkering with the use of deuterium in drug candidates more than 50 years ago. Because deuterium–carbon bonds are stronger than hydrogen–carbon bonds, a few researchers hoped that the isotope would help drugs better withstand drug-metabolizing enzymes such as the cytochrome P450s. Renewed interest in this approach in recent years led to a few deuterated candidates entering the clinic (Nat. Rev. Drug Discov. 15, 219–221; 2016).  Deutetrabenazine, like other candidates in the first wave of deuterated drugs, uses heavy hydrogen to improve the dosing and safety profiles of an already approved agent. Deutetrabenazine is a deuterated version of tetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor that the FDA approved for the treatment of chorea associated with Huntington disease in 2008. The new contender seems to offer a lower risk of depression, somnolence and akathisia than the established competition. It still carries a black box warning, however, citing the risk of depression and suicidality. Teva, which gained the drug through the 2015 acquisition of Auspex, initially submitted deutetrabenazine for FDA approval in 2015. In 2016 it received a complete response letter citing the need for deeper analysis of the drug’s metabolites. Concert Pharmaceuticals, whose
discovery focus is wholly on deuterated drugs, has also developed candidates to compete with nearly identical approved agents. Concert’s phase II candidate CTP-656, for example, is a deuterated version of Vertex Pharmaceuticals’ cystic fibrosis transmembrane conductance regulator (CFTR) potentiator ivacaftor for cystic fibrosis. CTP-656 seems to offer a longer half-life and a slower clearance profile than the approved small molecule. In March, Vertex acquired CTP-656 for US$160 million upfront and $90 million in potential milestones. Companies have started using deuterium in novel drugs as well. Vertex incorporated the isotope into its DNA-dependent protein kinase (DNA-PK) inhibitor VX-984, one of three DNA-PK inhibitors in phase I trials. In January, Merck KGaA licensed the drugfrom Vertex.
Teva’s deutetrabenazine is also currently under FDA review for tardive dyskinesia, with a PDUFA decision due by the end of August. In April, the agency approved the first ever tardive dyskinesia drug, giving the green light to Neurocrine Biosciences’ VMAT2 inhibitor valbenazine.

Asher Mullard

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