Teva's Deutetrabenazine Nears Approval in China as First Deuterated Drug

Text | Dopine

On April 30, the marketing application for Teva’s deutetrabenazine tablets (acceptance numbers: JXHS1900175, 176, 177, 178, 179, and 180) had its status updated to “Under Review” by the National Medical Products Administration (NMPA), signaling that China’s first deuterated drug is poised for imminent approval and launch.

Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor. VMAT2 (vesicular monoamine transporter 2) is a protein predominantly located in the human brain, primarily responsible for the repackaging and transport of monoamine molecules (dopamine, norepinephrine, serotonin, and histamine) in presynaptic neurons.

This drug was initially developed by Auspex Pharmaceuticals and later acquired by Teva. In April 2017, the FDA approved this drug for the treatment of Huntington's disease under the brand name Austedo™, making it the first deuterated drug approved by the FDA for market release. It was subsequently also approved by the FDA for the treatment of tardive dyskinesia.

Compared with tetrabenazine (Xenazine), deutetrabenazine is a deuterated derivative in which the hydrogen atoms (H) of the two methoxy groups (-OCH3) of tetrabenazine are replaced by their isotope, deuterium (D) (-OCD3). This structural modification slows its metabolic rate relative to tetrabenazine and improves its efficacy and safety profile.

Since its market launch, deutetrabenazine has experienced rapid sales growth, with global sales reaching $204 million in 2018 and $412 million in 2019. It is anticipated that sales of deutetrabenazine will reach new heights as new indications are developed, such as primary dystonia (Phase I/II), dyskinetic cerebral palsy (Phase III), and Tourette syndrome (Phase III). Regrettably, this February, Teva announced that deutetrabenazine failed to meet the primary endpoints in both the Phase 2/3 ARTISTS 1 trial and the Phase 3 ARTISTS 2 trial for the treatment of children with moderate-to-severe Tourette syndrome.

In China, deutetrabenazine was included in the “First Batch of Clinically Urgent Overseas New Drugs List” in November 2018, with indications for tardive dyskinesia and Huntington’s chorea. In December 2019, the marketing application for deutetrabenazine was accepted by the Center for Drug Evaluation (CDE), and it was included in the priority review pathway in March 2020.

Notably, the marketing application for deuterated tetrabenazine was submitted directly in accordance with the “Procedures for the Review and Approval of Urgently Needed Overseas New Drugs.” Under these procedures, technical review for drugs treating rare diseases is to be completed within three months of acceptance, while for other overseas new drugs, it is to be completed within six months. The author anticipates that, likely due to the COVID-19 pandemic, the technical review for this drug was completed only after more than four months following acceptance, and expects that formal approval in China will be granted imminently.

Huntington’s disease is a rare autosomal dominant genetic disorder, primarily manifested by abnormalities in motor, cognitive, and psychiatric functions. Tardive dyskinesia is a central nervous system disorder characterized by involuntary, rhythmic, and repetitive movements of the face, trunk, or limbs, including lip smacking, grimacing, tongue protrusion, facial movements, blinking, and puckering. A shared feature of both conditions is dopaminergic hyperactivity; modulating neuronal dopamine levels in these disorders can provide clinical benefit to patients.

Currently, there are very few approved drugs for the treatment of these two diseases. In addition to tetrabenazine and deutetrabenazine, the FDA has also approved Neurocrine Biosciences' Ingrezza (valbenazine) for the treatment of tardive dyskinesia in adults. Ingrezza is also a selective VMAT2 inhibitor. Although it was approved later than deutetrabenazine, it has a better safety profile and does not carry the black box warning for depression and suicidal ideation associated with deutetrabenazine (the first approved indications for these two drugs differ). In China, no drugs have yet been approved for market launch for these two conditions, highlighting an urgent need for effective therapeutic options.

Deuterium is a naturally occurring hydrogen isotope. Replacing hydrogen with deuterium can block metabolic sites, prolong the drug’s half-life, and not affect pharmacological activity (due to the minimal difference in size between H and D). In addition to deutetrabenazine, Teva is also developing SD-1077, a deuterated derivative of levodopa; SD-254, a deuterated derivative of venlafaxine; and SD-560, a deuterated derivative of pirfenidone, all of which are currently in Phase I clinical trials.

In addition to Teva, numerous companies both domestically and internationally have established a presence in the field of deuterated drugs, including foreign enterprises such as BMS, Concert Pharma, Aclaris Therapeutics, Alkeus Pharma, DeuteRx, Euclises, and Vertex.

In China, companies such as Zeltgen Biopharma, Chengdu Haichuang Pharmaceutical, Tongyuan Kang, and Chia Tai Tianqing are also developing deuterated drugs. Among them, Zeltgen’s donafenib mesylate is a deuterated analog of Bayer’s first-in-class sorafenib, developed for the treatment of various tumors. Currently, its Phase III clinical trials for advanced/metastatic thyroid cancer and colorectal cancer are underway. According to the company’s website, Zeltgen has submitted a marketing application for this drug. In addition, Zeltgen’s ruxolitinib (the prototype drug is Gilead’s JAK inhibitor momelotinib) and ocaftinib (the prototype drug is AstraZeneca’s EGFR T790M inhibitor osimertinib) are also deuterated compounds. Ruxolitinib is in Phase II clinical trials for the treatment of alopecia areata and myelofibrosis, while ocaftinib is in Phase I/II clinical trials for the treatment of advanced NSCLC and ALK-positive advanced NSCLC. Haichuang Pharmaceutical’s first compound, HC-1119, is a novel androgen receptor (AR) antagonist and a deuterated version of enzalutamide. It is currently undergoing global multicenter Phase III clinical trials for patients with mCRPC.

References:

[1] NMPA Official Website

[2] Official websites of Zeltigen Biopharmaceuticals and Chengdu Haichuang