Ten months after an FDA complete response letter (CRL) set back efforts by Teva Pharmaceutical Industries Ltd. to gain its first approval for Austedo (deutetrabenazine), an agency review has finally led to approval for the orphan-designated drug, a treatment for chorea – involuntary, random and sudden, twisting and/or writhing movements – associated with Huntington's disease (HD).
FDA concerns about blood levels of certain metabolites in the candidate, the subject of the June 2016 CRL, were addressed with no further trials, leading to an October 2016 resubmission of the company's new drug application. Now, Austedo is expected to be available in the U.S. within the next three weeks, the company said. (See BioWorld Today, June 1, 2016.)
A Cortellis forecast suggests sales of the drug could reach $56 million this year, though Teva has modeled more conservative revenue of $29.4 million, according to Mizuho Securities USA LLC analyst Irina Koffler. The annual wholesale acquisition cost (WAC) for the drug is expected to be about $60,000 per year, below the list price of the standard-of-care chorea drug, Xenazine (tetrabenazine, H. Lundbeck A/S), with its $152,000 annual WAC, and generic tetrabenazine, which has a WAC of about $96,000 annually.
But Austedo's approved label includes a box warning that it increases the risk of depression and suicidal thoughts and behavior in patients with HD. Those warnings are mostly in line with a similar warning on Xenazine's label. However, depression was reported by only 4 percent of patients in Austedo's pivotal trial vs. 19 percent in the 12-week pivotal trial for Xenazine, noted Evercore ISI analyst Umer Raffat. Furthermore, sedation, a common dose-limiting effect for both drugs, occurred in just 11 percent of Austedo-treated patients during its pivotal trial vs. 31 percent of patients enrolled in the separate pivotal trial of Xenazine.
In addition to the box warning, Austedo's label also lists it as contraindicated for patients with hepatic impairment or those taking monoamine oxidase inhibitors (typically used to treat depression), the antipsychotic reserpine, and Xenazine.
Formerly known as SD-809, the drug is a vesicular monoamine transporter 2 (VMAT2) inhibitor that Jerusalem-based Teva picked up as the star asset in its $3.2 billion acquisition of La Jolla, Calif.-based Auspex Pharmaceuticals Inc. in 2015. It is the first deuterated product approved by the FDA, referencing a process in which metabolically sensitive hydrogen atoms are replaced with the non-radioactive isotope deuterium in order to provide a pharmacokinetic profile that allows for lower doses and, thus, a better safety profile. (See BioWorld Today, Dec. 18, 2014, and March 31, 2015.)
Teva said the approval was based on results from First-HD, a phase III randomized, placebo-controlled study that assessed the safety and efficacy of Austedo in reducing chorea in patients with HD. Patients enrolled in the study were randomized to either deutetrabenazine or placebo. There was improvement of 4.4 points in the total maximal chorea (TMC) score in deutetrabenazine-treated patients vs. a 1.9-point change in placebo-treated patients (p < 0.0001). At the end of maintenance therapy, the treatment effect increased by 2.5 points when compared to baseline. Total motor score in deutetrabenazine patients increased by 7.4 vs. 3.4 with placebo (p = 0.0023). At the end of week 12, there was also significant improvement in the Patient Global Impression of Change (51 percent, p = 0.0020) and Clinical Global Impression of Change scores (42 percent, p = 0.0022) in patients receiving deutetrabenazine.
In parallel with its rollout of Austedo, Teva will continue to move toward an Aug. 30 PDUFA date for the drug in tardive dyskinesia, a bigger and more commercially important indication, according to Credit Suisse analyst Vamil Divan. The company is also expected to start a phase III trial in Tourette's syndrome this year. It could compete in both indications with Neurocrine Biosciences Inc., which is advancing its own VMAT2 inhibitor, Ingrezza (valbenazine).
Shares of Teva (NYSE:TEVA) fell 19 cents on Tuesday to close at $32, significantly lower than the $51.54 price they commanded when Austedo drew its CRL last summer. Since then, Teva has embarked on a significant review of the company's business, operations, areas of therapeutic focus and pipeline under the leadership of interim President and CEO Yitzhak Peterburg, its fifth chief executive since 2012. Peterburg, and whomever is chosen to succeed him, will oversee a transformation of Teva's business as a result of the company's acquisition of Allergan plc's worldwide generic pharmaceuticals business, which it calls Actavis Generics. (See BioWorld Today, July 28, 2015.)