Refusal Reversal: Alkermes Review Back On Track, But Could Still Be Bumpy

US FDA accepts Alkermes' NDA for depression drug after issuing refuse-to-file letter just two weeks ago; unusual move falls outside agency's guidance on RTFs because no changes were made to submission and it wasn't filed over protest.

In a surprising turn of events, the US FDA reversed its refuse-to-file decision on Alkermes PLC's depression drug ALKS 5461, but the quick change of course could mean the agency's questions will need to be addressed in the standard review process instead.

Alkermes announced April 16 that FDA has accepted an NDA for ALKS 5461 as an adjunctive therapy for the treatment of major depressive disorder after initially issuing a refuse-to-file (RTF) letter. The agency rescinded the RTF just two weeks after Alkermes announced it received it April 2.

The move is highly unusual as FDA does not usually reverse RTFs without substantial changes to the NDA, and in this case, there have been no changes, and the application also wasn't filed under protest. A RTF generally means the sponsor has omitted essential information.

As CEO Richard Pops explained the development to investors in a same-day conference call, the company quickly met with FDA – in this instance the division of psychiatric products – after receiving the letter and essentially cleared up FDA's two main questions, with the agency ultimately agreeing they should not be the basis for an RTF. Nonetheless, that doesn't mean the uncertainties won't still have to be addressed in the standard review process.

Pops confirmed that they would be in fact. "Both of these issues will be addressed within the context of the review," he told investors.

The two main issues in the RTF were "facial deficiencies" in the application, meaning missing information or clear inadequacies: insufficient evidence of overall effectiveness and inadequate bridging data between ALKS 5461 and the reference drug buprenorphine.

At the time, the expectation was that the RTF would result in a lengthy delay for the product. (Also see "Keeping Track Of Bad News: Alkermes' Depression Candidate Gets Refuse To File; Teva/Celltrion Biosimilars Land CRLs" - Pink Sheet, 8 Apr, 2018.)

But Pops said FDA was misguided on both accounts. The question on insufficient evidence of effectiveness did not reflect the complete understanding of the NDA submission, he said. "We directed FDA to the relevant information in the NDA," he said. As for the bridging issue, he said that was raised in a pre-NDA meeting with FDA and addressed in the submission.

Decision Falls Outside FDA's RTF Guidance

The challenge for investors is that they only get to hear the company's perspective on the reversal. FDA doesn't comment on the decision, so it's unclear how much uncertainty the agency may still have.

FDA's guidance on RTFs, issued in December 2017, says that after an informal conference, the FDA review division will file the application over protest and review it as filed if the sponsor requests the review division to file it. Alternatively, FDA says the applicant can amend the NDA and resubmit it and the review division will make a separate determination whether the resubmitted NDA may be filed. (Also see "Refuse-to-File Turns 25: New Guidance Changes In Style, But Not Substance" - Pink Sheet, 11 Jan, 2018.)

In this case, ALKS 5461 appears to fall somewhere else, as Alkermes confirmed that it did not file the application over protest.

Last July, FDA rescinded its decision on Amicus Therapeutics Inc.'s migalastat, an oral drug for Fabry disease, after originally saying the application required a new 12-month gastrointestinal study.  However, in that instance, there were eight months between when the RTF was announced and reversed, and a new FDA commissioner. (Also see "FDA Reversal Gives Amicus Renewed Hope For US Oral Fabry Launch" - Pink Sheet, 11 Jul, 2017.)

Pops said the timeline for FDA action remains on target because the filing was accepted by Day 74 and therefore the original PDUFA date of Jan. 31, 2019 stands.

ALKS 5461 is expected to face an FDA advisory committee review in the fourth quarter, which will inevitably bring any concerns, particularly about lack of efficacy, to the forefront. 

Jefferies analyst Biren Amin speculated that the review could pose challenges in a same-day research note. "Given the short time interval, there were no material revisions to the NDA and this is an unexpected an unusual move by the agency," he said. "However, we remain cautious on approvability of '5461 given there are still outstanding questions around efficacy, which will undoubtedly be raised during the review process."

While Alkermes management and some investors were surprised by the RTF, the regulatory strategy has also been considered high risk, because the NDA is based on a single positive Phase III trial after two prior studies failed. Another Phase III trial is ongoing, and there is the possibility FDA may want to see the results before approving the drug.

The third Phase III, FORWARD-5, met the prespecified primary endpoint of significantly reducing depressions cores compared to placebo as measured by the 6-item Montgomery-Asberg Depression Rating Scale (MADRS-6) and significant reductions in the 10-item MADRS (MADRS-10) scores compared to placebo. But the endpoint relied on a novel time-weighted average to measure efficacy rather than a single time point. The two prior studies, FORWARD-3 and FORWARD-4 showed a trend toward efficacy in the treatment arm but also had a higher than expected placebo response.

Jefferies Amin pointed out that the data package for '5461 remains controversial. "There are issues that are likely to be flagged by FDA as it conducts its review," he said.

Alkermes initiated a rolling NDA submission for '5461 in August 2017 under a Fast Track designation. ALKS 5461 is a novel oral medicine that acts as an opioid system modulator. It is a fixed-dose combination of the partial mu-opioid receptor agonist and kappa-opioid receptor antagonist buprenorphine and a mu-opioid receptor antagonist samidorphan.