Investors clipped shares of Avadel Pharmaceuticals plc recently as anxieties rose over the application by Jazz Pharmaceuticals plc for a patent that relates to a once-nightly oxybate product that could threaten the prospects for Avadel’s FT-218.

Dublin-based Jazz gained approval this summer for Xywav (calcium, magnesium, potassium and sodium oxybates) for cataplexy and excessive daytime sleepiness (EDS) in patients ages 7 and older with narcolepsy. Xyrem (sodium oxybate), also from Jazz, was the first medicine approved for the indication, but it carries a warning because of its high sodium content. Xywav, known as JZP-258 during its development, is meant to provide a reduced-sodium alternative to Xyrem, with 92% less per nightly dose.

Xywav, however, also bears a boxed warning as a central nervous system depressant, and because of its potential for abuse. The drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS), and is listed as a Schedule III medicine under the Controlled Substances Act. An oral solution, it’s given at night in two doses: the first at bedtime at least two hours after eating, and the second two-and-a-half to four hours later.

Regarding his firm’s FT-218, a form of sodium oxybate given by way of Micropump technology for extended release, Avadel CEO Gregory Divis cited during an Aug. 10 conference call with investors “a high level of interest” in a once-nightly treatment. “We certainly are aware of the [Xywav] product that's been approved as expected from that standpoint. With regards to the flexible dosing – positioning that's been taken in the marketplace to date relative to [its] label – is that their way of trying to make it a once-nightly product? In other words, give a little bit more at bedtime and a little less in the middle of the night? It sounds a lot like trying to emulate our once-nightly pharmacokinetic curve.”

FT-218 was tested in the pivotal experiment called REST-ON (a rough acronym for “Randomized study Evaluating the efficacy and SafeTy of a Once Nightly formulation of sodium oxybate”), a double-blind, randomized, placebo-controlled phase III trial against EDS and cataplexy in narcolepsy. The REST-ON study completed patient enrollment (212 patients) in December 2019. Top-line results rolled out in April of this year, and Avadel recently provided more details.

At the 9-g dose, FT-218 turned up a highly statistically significant (p<0.001) and clinically meaningful improvement across all three co-primary endpoints (Maintenance of Wakefulness Test, Clinical Global Impression-Improvement and Mean Weekly Cataplexy Attacks) compared to placebo. The dose was generally well-tolerated, with commonly known sodium oxybate adverse reactions occurring at low rates (nausea 1.3%, vomiting 5.2%, decreased appetite 2.6%, dizziness 5.2%, somnolence 3.9%, tremor 1.3%, enuresis 9%; discontinuation rate due to adverse reactions 3.9%). FT-218 at the 7.5-g and 6-g dose levels also achieved highly statistically significant (p<0.001), clinically meaningful improvements across all three co-primary endpoints compared to placebo, as soon as three weeks after starting treatment.

All three doses were highly significant compared to placebo on secondary endpoints, too, evaluating daytime sleepiness, sleep architecture and other narcolepsy symptoms. Results were satisfying compared to placebo for all sensitivity analyses of the three co-primary endpoints at all three doses. Avadel, of Dublin, plans to offer detailed data for the secondary endpoints and sensitivity analyses at a scientific conference or in a peer-reviewed scientific publication.

The company has started an open-label extension/switch study with FT-218, and completed its pre-NDA meeting with the FDA. Jordan Dubow, chief medical officer, said during the call that officials feel “very comfortable” with the meeting’s outcome. “We showed them the data from the phase III trial [and] we got confirmation that the data from this trial is sufficient for us to file with. We asked about certain things in terms of what we need to integrate, what we don't need to integrate. I think the meeting was very straightforward. We felt very confident with all the answers we've gotten,” he said, though most had been answered before going in.

H.C. Wainwright’s Oren Livnat noted in an Aug. 11 report that Avadel has “declined to guide to a specific NDA filing timing range, presumably not to give Jazz any help in timing potential roadblocks it might try to throw up, such as a citizen’s petition or even lawsuit. The company asserts there is no change to its expectation that it can pursue a 505(b)(2) filing without having to certify to Xyrem Orange Book-listed drug-drug interactions or REMS intellectual property, thus no potential 30-month stay of approval,” he noted. “We understand that investors are nervous about the filing strategy in light of Jazz’s successful IP strategies to date,” a problem that “isn’t assuaged when Avadel management won’t provide more specific NDA guidance.” SVB Leerink analyst Ami Fadia sought to quell jitters about the once-nightly Jazz candidate’s patent application. She said Avadel’s stock weakness represented a buying opportunity, since Jazz likely won’t win approval of its candidate until 2024 “at the earliest.”

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