Even as Alkermes plc works to resolve the complete response letter (CRL) sent by the FDA regarding ALKS-3831, labeling talks are underway for the compound, an oral therapy for schizophrenia and bipolar I disorder in adults.

“Unfortunately, it’s not unusual at all to be in label negotiations right up until the very last moments of the action date,” CEO Richard Pops noted, adding that the company will “go as fast as we possibly can. We activated right away and we’re going like hell. The fact is, we think this is a problem we’ve already solved.”

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, the firm said, and shares (NASDAQ:ALKS) hardly moved, closing Nov. 17 at $18.30, up 45 cents. “We’re going to continue to proceed in anticipation of the launch of the drug, because we think that’s going to happen in the first quarter of next year,” Pops said during a conference call with investors.

Observations in the CRL had to do with certain development batches of the drug, which consists 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.

“There’s not a need to generate new data so it’s just a matter of assembling documentation and getting the submission out the door,” said Heather Faulds, senior vice president of regulatory affairs and knowledge management services. Per the FDA's August guidance for manufacturing inspections during the COVID-19 pandemic, the agency did not conduct an on-site pre-approval inspection (PAI), making do with a remote review of records instead. Alkermes provided those records in September. “We were surprised it was an issue in the FDA’s mind and we didn’t hear about it or learn about it until the CRL,” she said, noting that Alkermes already had fixed any would-be glitches in manufacturing. “There was really no need to reach out to the FDA [regarding the matter] because it’s just part of normal drug development.”

Pops said that, with a normal PAI in normal times, Alkermes would have gotten immediate feedback from the agency. Simply sending in paperwork and then waiting changes the picture. “I don’t think anybody in the industry thinks that’s a good plan but that’s the current plan” with COVID-19, he said.

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.

CRL ‘the better scenario’

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 for 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.

Meanwhile, company watchers remained calm about the slight delay. SVB Leerink analyst Marc Goodman in a report called the latest news “a minor bump in the road to approval,” calling the CRL “basically a COVID issue due to the agency’s limited capability for [PAIs], and it should be resolved fairly quickly without much, if any, impact on the launch timing.” J.P. Morgan’s Cory Kasimov agreed, even deploying the same metaphor. The CRL, he said in a report, “really isn’t thesis-changing for the company.”

Mizuho’s Vamil Divan was optimistic. “In the context of the pandemic, the FDA is conducting limited [PAIs] and, based on the FDA guidelines, the agency may choose to issue a CRL or push out the action date for a drug until it is able to conduct an inspection,” he pointed out in a report. “In that context, a CRL is actually the better scenario, with the company likely able to submit the necessary information in the coming weeks, setting up a class 1 review that could allow for approval two months later.” He moved his launch date for ALKS-3831 from the first half of 2021 to the third quarter of 2021 “to be conservative, but this has no impact on our blended price target of $24 and our buy rating on Alkermes shares.”

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