A deuterium-driven breakthrough in the push for a safer, better therapy in Huntington’s disease (HD) may have come in the form of Auspex Pharmaceuticals Inc.’s SD-809 (deutetrabenazine), an altered form of black-boxed, standard-of-care Xenazine (tetrabenazine, H. Lundbeck A/S).

La Jolla, Calif.-based Auspex said top-line data from its phase III trial called First-HD with SD-809 met its primary efficacy endpoint in HD chorea, or uncontrolled movements, and hit secondary goals as well – news that propelled the stock (NASDAQ:ASPX) to a 99.8 percent rise, closing Wednesday at $50.14, up $25.05.

SD-809, a small molecule invented by Auspex, is a formulation of the vesicular monoamine transporter 2 inhibitor Xenazine that has been modified, with “heavy” hydrogen isotope deuterium – a naturally occurring substance in humans, first isolated from sea water – replacing the usual hydrogen molecule, which has about half the mass. The result is a compound designed to enable less frequent dosing, with improved tolerability, reduced drug interactions and a reduced need for genotyping for drug-metabolizing enzymes. (See BioWorld Today, Nov. 9, 2012.)

“We have a strong sense of urgency, having seen these data, to put together a [new drug application (NDA)] to the FDA,” CEO Pratik Shah told BioWorld Today. “Normally, industry timelines from top-line data to submission have been about six or eight months. We’ve said we intend to file such an application by mid-next year, and we will do everything we can to [file] as soon as possible.”

The company is continuing development of SD-809 in other movement disorders, with two ongoing pivotal trials in tardive dyskinesia, while pursuing work in Tourette’s syndrome, an indication that has not seen an approved drug in more than 30 years.

First-HD was a one-to-one randomized, double-blind, placebo-controlled, parallel-group trial evaluating the efficacy, safety and tolerability of SD-809 in chorea associated with HD, and the primary efficacy endpoint for the study was the change from baseline to maintenance therapy in the Total Maximal Chorea (TMC) score of the Unified Huntington’s Disease Rating Scale.

Patients taking SD-809 achieved a meaningful improvement of 2.5 points on the TMC score from baseline to maintenance therapy compared to placebo (p < 0.0001).

The study turned up a favorable safety and tolerability profile, including low rates of depression, somnolence, akathisia/restlessness and anxiety. Piper Jaffray analyst Charles Duncan wrote in a research report that the safety data stand out especially, “with adverse event levels comparable and in many cases better than placebo, clearly differentiating the candidate from [Xenazine] at 12 weeks.”

Shah said the safety outcomes are “indeed striking and very important,” and drawbacks with Xenazine have meant “such a need for new options, and I think the data are clear with SD-809. The world is starting to appreciate that.”

Four pre-specified key secondary endpoints were tested on a hierarchical basis, Auspex said: treatment success based on patient global impression of change and clinical global impression of change, quality of life and balance. Other pre-specified motor endpoints were also analyzed. A total of 90 patients (45 in each group) were enrolled for evaluation over 13 weeks, with patients titrated weekly to an optimal dose up to weeks eight. They were on maintenance therapy for four weeks, and were taken off study medication in the final week of the study. A total of 87 patients completed the experiment, with one patient in the SD-809 group and two in the placebo group discontinuing.

Auspex also unveiled results from an analysis of the completed four-week “switch” portion of the ARC-HD study, which also has an ongoing long-term safety component. Data from the study show that patients who switched from Xenazine to SD-809 maintained control of their chorea at week one and week four.

PIRFENIDONE NEXT IN LINE

Chorea affects about 90 percent of the 300,000 HD patients in the U.S. Xenazine, cleared for marketing in 2008, has been hampered by its adverse events, including suicidality and depression, along with short half-life.

The latest outcome for Auspex’s drug “enhances conviction” with regard to the company’s deuterium-based orphan disease pipeline, in the view of Duncan, who recommended buying shares despite the run-up. He cited “several 2015 milestones including additional data from ARC-HD,” and a meeting with the FDA ahead of the NDA filing.

“We’ve just gotten these, and of course we intend to gather the rest of the data and put them together,” Shah said, noting that a pair of upcoming medical meetings – the American Academy of Neurology in April and the International Congress of Parkinson’s Disease and Movement Disorders in June – could be appropriate venues for the full data set.

Duncan said his firm “look[s] forward to the additional data which may, with a limited set of physicians to influence use patterns vs. Xenazine, be an excellent venue to gauge interest in adoption and ultimate market potential.” But most prescribing decisions, he predicted, would be based on the label, in terms of tolerability and dosing guidance, as well as clinical experience and relative cost. “Based on the data presented for First-HD, with very few central nervous system adverse events, most notable being somnolence at 11 percent vs. 4.4 percent for placebo, we feel there is a strong likelihood for a more lenient black box warning and maybe no risk evaluation and mitigation strategies requirement,” Duncan wrote.

Other firms are advancing deuterium-based compounds, including Avanir Pharmaceuticals Inc., of Aliso Viejo, Calif., Jazz Pharmaceuticals plc, of Dublin, and Celgene Corp., of Summit, N.J., but Auspex is the farthest along. Tokyo-based Otsuka Pharmaceutical Co. Ltd. recently disclosed a plan to buy Avanir for $3.5 billion. (See BioWorld Today, Dec. 3, 2014.)

“We’re intending to bring SD-809 to patients on our own,” Shah said. “We’ve been investing in being able to effectively do that without a large-company partner.”

Behind SD-809 in the pipeline is deuterated pirfenidone (Esbriet, Intermune Inc.), a drug for idiopathic pulmonary fibrosis. In mid-2015, Auspex likely will have data on blood-level comparisons that will show whether SD-560 has a better half-life than the non-deuterated form.