The FDA smacked Alkermes plc with a complete response letter (CRL) for ALKS-3831, its oral therapy for schizophrenia and bipolar I disorder in adults. Regulators reviewed manufacturing records and said the Dublin-based firm needs to supply documents related to making the tablet’s coating at the Wilmington, Ohio, facility.
No clinical or non-clinical concerns were raised, and observations in the CRL had to do with certain development batches of the drug, which consist of new molecular entity samidorphan – an opioid antagonist – formulated in a two-layer pill with the antipsychotic agent olanzapine, sold under the brand name Zyprexa by Eli Lilly and Co., of Indianapolis. Alkermes designed ALKS-3831 to provide olanzapine’s efficacy while pushing back weight gain.
Per the FDA's August 2020 guidance for manufacturing inspections during the COVID-19 pandemic, the agency did not conduct an on-site pre-approval inspection, making do with a remote review of records instead. Alkermes provided those records in September and didn’t hear anything until the CRL was delivered.
The NDA for ALKS-3831 was based on data from 27 studies, including 18 that tested the combo drug and nine trials with samidorphan alone, as well as pharmacokinetic bridging data comparing ALKS-3831 and Zyprexa. Experiments turned up a consistent antipsychotic efficacy, safety and tolerability profile in patients with schizophrenia.
Specifically, Zyprexa is labeled for schizophrenia, acute mixed or manic episodes associated with bipolar I disorder (as monotherapy or in combination with lithium or valproate), and for maintenance monotherapy of bipolar patients. Samidorphan, also known as 3-carboxamido-4-hydroxynaltrexone, preferentially acts as an antagonist of the μ-opioid receptor. Alkermes has proposed Lybalvi as the brand name for the combo product, meant for adult schizophrenia and adult bipolar I as an acute therapy for manic and mixed episodes, as maintenance treatment, and as an adjunct to valproate or lithium in manic or mixed episodes.
In October, the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee appointed by the FDA jointly voted that samidorphan mitigates olanzapine-associated weight gain (16 yes, 1 no) and that the safety profile of ALKS-3831 has been adequately characterized (13 yes, 3 no, 1 abstention). The committees also said labeling is sufficient to mitigate the risks related to the opioid antagonist action of samidorphan (11 yes, 6 no). The drug’s PDUFA date was Nov. 15.
Alkermes is no stranger to regulatory trouble. At the start of last year, the FDA dealt the company a CRL for ALKS-5461, designed as an adjunctive treatment of major depressive disorder. Gatekeepers said they were unable to clear the NDA without more clinical data. In early 2016, the compound – made up of samidorphan plus the opioid buprenorphine – failed in two phase III studies.
Wainwright analyst Douglas Tsao said in an Oct. 30 report that he expected approval of ALKS-3831 on its PDUFA date. “We’re still in wait-and-see mode on the commercial opportunity based on questions regarding the clinical relevance of the weight-loss benefit provided by the product, and potential for interactions with patients on opioids,” he wrote in a report. Wall Street, though, seemed to take the CRL in stride, as shares (NASDAQ:ALKS) were trading premarket at $18.25, down 41 cents.