Alixorexton

Early data for Alkermes' oral orexin 2 receptor (OX2R) agonist throws weight behind the theory that the modality can benefit patients with a range of neurological conditions, not just narcolepsy. The drugmaker said Monday that ALKS 7290 is the first in its class to meaningfully improve symptoms of attention-deficit hyperactivity disorder (ADHD) in adults. The data were disclosed as the company's more advanced OX2R agonist, alixorexton, is nearing Phase III readouts in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Even if the candidate succeeds in NT1, however, it still lags behind Takeda's own oral OX2R agonist Orzeyful (oveporexton), approved by the FDA in August for the indication (see – Physician Views Results: Clinician feedback strongly suggests Takeda's Orzeyful is a game-changer for narcolepsy and Spotlight On: Takeda breaks new ground with narcolepsy approval as Alkermes and Eli Lilly wait in slipstream).While alixorexton might not be first to market in narcolepsy, it helped lay the groundwork for exploring OX2R agonism in ADHD. The candidate met its primary endpoints in a pair of Phase II trials for narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). As part of a detailed June readout from the NT2 trial that included findings on exploratory measures beyond wakefulness, Alkermes said alixorexton achieved a meaningful improvement on patient-reported outcomes focused on cognition and fatigue. That result, Evercore ISI analyst Umer Raffat said at the time, "bodes very well for the big indications beyond narcolepsy," including ADHD, Alzheimer's disease and other dementias (see – Spotlight On: Alkermes' NT2 data boost case for broad potential of orexins and KOL Views Q&A: Solid but unspectacular data for Alkermes’ alixorexton set NT2 benchmark for orexins).From moderate to mild illness The latest data backing a broader exploration of orexin in neurological conditions were generated in a Phase I trial of ALKS 7290 that enrolled 88 healthy volunteers and 50 adults with ADHD. The safety portion of the study established that ALKS 7290 was generally well tolerated, with the maximum tolerated dose not reached. The most common treatment-emergent adverse events were insomnia, pollakiuria, dizziness, change in sustained attention, micturition urgency and constipation, and the candidate avoided any "clinically significant" hepatic, renal or cardio safety signals.The oral OX2R agonist also demonstrated clinically meaningful results on a pair of exploratory ADHD measures, the Adult ADHD Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression-Severity Scale (CGI-S). Participants with ADHD were randomised to receive a two-week in-patient treatment course of 20 mg or 50 mg ALKS 7290 daily, or placebo, following a two-week washout of existing ADHD medications.At day 14, patients receiving low- and high-dose ALKS 7290 achieved median reductions from baseline in AISRS total scores of 14 points and 19 points, respectively. According to Alkermes, improvements were seen as early as day 6, when the first post-baseline AISRS assessment was conducted. The same quick-response timeline was true when symptoms were measured with CGI-S, which also showed improvements as early as day 6. By day 14, the 20-mg and 50-mg dose groups saw median reductions from baseline in CGI-S scores of 1 and 2, respectively, which represent "a shift in disease severity from markedly or moderately ill to mildly ill," Alkermes said. The data "support our strategy to explore the potential of orexin biology beyond hypersomnolence disorders," said Craig Hopkinson, the company's chief medical officer and EVP of R&D. "This exploratory, first-in-patient study was designed to provide early insights into the potential of orexin 2 receptor agonism as a novel treatment for adults with ADHD, and we are excited to see the emerging clinical profile of ALKS 7290."Alkermes already has a Phase II trial underway of ALKS 7290 in patients with ADHD, expected to enrol 312 participants.