Deuterated drug is an entirely old idea which was first proposed in 1961. There have been no major advances in the last 50 years. Recently, Auspex Pharmaceuticals (NASDAQ: ASPX) announced surprise promising results from the First-HD trial of SD-809. Shares of Auspex soared about 100% on December 16, 2014.
The differences in physical chemical properties between H and D are small:
D is slightly less lipophilic than H, ΔlogP=-0.006;
the molar volume of D is smaller than H by 0.140 cm3/mol per atom;
and C-D bonds are shorter than C-H bonds by 0.005 Å.
The small differences in physical chemical properties make it hard to generate significant improvement in clinical outcomes. It was even argued whether the use of deuterium is novel and non-obvious and whether the deuterated effects are not predictable.
Auspex’s SD-809 is the most advanced deuterated compound in clinical trials. The drug is a deuterated version of VMAT-2 inhibitor tetrabenzine for the treatment of Huntington’s disease (HD), tardive dyskinesia (TD) and Tourette syndrome (TS).
SD-809 has the same shape, size, charge, potency and target pharmacology of tetrabenazine. The difference is that the C-D bond requires about eight times more energy to break than the C-H bond.
The substitution of deuterium attenuates the breakdown of active metabolites resulting in a differentiated PK profile compared to tetrabenazine. In the Phase I trial, 15 mg of SD-809 provided similar systemic exposure to active metabolites as 25 mg of tetrabenazine, while substantially reducing Cmax.
In the First-HD trial, SD-809 achieved similar benefits to tetrabenazine and significantly reduced side effects.
|SD809 (n=45)||Placebo (n=45)||Xenazine (n=54)||Placebo (n=30)|
Lundbeck’s Xenaxine (tetrabenazine) brought in about DKK 1,420 million in 2013. It is believed Auspex will take nearly all the market away from Xenazine, as well as bring in a new 25% of the population.
Neurocrine Bioscience (NASDAQ: NBIX) is testing valbenazine (NBI-98854), an active metabolite prodrug of tetrabenazine, in Phase II trials in TD. Valbenazine showed a similar PK profile to SD-809 and is expected to compete with SD-809.
Another main player in the field of deuterated drug is Concert Pharmaceuticals (NASDAQ: CNCE). The company is joining up several Big Pharmas such as GlaxoSmithKline and Celgene to develop a robust pipeline of deuterated candidates.
Zelgen Biosciences (苏州泽璟生物制药) is developing deuterated sorafenib called多纳非尼 (Patent: WO2011113203). I’d like to see the drug significantly reduced side effects compared to sorafenib.
Auspex’s success should be attributed to the in-depth understanding of the metabolism of tetrabenazine. Using deuterium to improve PK profile may not work well all the time, but it provides a new approach to discover me-better candidates.
 Science. 1961, 133(3446), 102-104.
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 Auspex Pharmaceuticals. FORM S-1/A. 2014-01-17.
 Auspex Pharmaceuticals. Press Release. 2014-12-16.
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