Orexin Receptor ALKS 2680 Demonstrates Positive Phase 1 Findings

Brendon Yee, PhD

Newly announced preliminary data from a proof-of-concept phase 1 study showed that treatment with ALKS 2680 (Alkermes), an investigational orexin 2 receptor (OX2R) agonist, was safe to use among healthy volunteers and patients with narcolepsy, with observed dose-dependent improvements in sleep latency. Based on these positive findings, Alkermes is expected to begin a phase 2 study of ALKS 2680 in the first half of 2024.

Presented at the 2023 World Sleep Congress, held October 20-25, in Rio de Janeiro, Brazil, the data was from single- and multiple-ascending dose evaluations in healthy participants and the first cohort of 4 patients with narcolepsy type 1 (NT1). Following treatment with ALKS 2680, investigators observed mean improvements of 18, 30, and 37 minutes, in the 1, 3, and 8 mg dosed groups, respectively. The between group differences for all 3 doses (1 mg; P <.01; 3 mg; P <.001, and 8 mg; P <.001) were all statistically significant, as those on placebo demonstrated a 1-minute reduction in mean sleep latency.

Following an initial 2-week washout period of all existing medications, patients received single doses of 3 active dose levels of ALKS 2680 and placebo in a randomized sequence in a 4-way crossover design, with washout periods between each treatment in the sequence. In all doses tested, treatment with the OX2R agonist resulted in clinically meaningful improvements in maintenance of wakefulness test (MWT) for the full 40-minute duration, up to 10 hours post-dose. Scores on MWT at 3 mg were comparable to the 8 mg scores for the first 6 hours post-dose, while treatment with both the 1 mg and 3 mg doses of the agent resulted in improved MWT scores up to 8 hours post-dose.

The study’s main goal was to assess safety and tolerability of the agent. At the conclusion of the treatment period, drug-related adverse events (AEs) were documented only at the 8 mg dose, and were mild in severity. Insomnia (n = 3), pollakiuria (n = 2), and salivary hypersecretion (n = 2) were the only treatment-emergent AEs observed in at least 1 treated participant. Investigators observed no serious AEs or AEs that led to discontinuation, as well as no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.

"The early proof-of-concept and safety data we've seen in this ongoing phase 1 study of ALKS 2680 in both healthy volunteers and four patients with narcolepsy type 1 are compelling. These data support further evaluation of ALKS 2680 as a potential treatment for narcolepsy," Brendon Yee, PhD, respiratory and sleep physician, Woolcock Institute of Medical Research, said in a statement.

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In the healthy volunteer phase of the study, each cohort included 8 participants, 6 of whom were randomized to either ALKS 2680 and 2 of whom received placebo. In the single-dose portion (n = 48), ALKS 2680 was dosed from 1 mg to 50 mg whereas in the multiple-dose portion (n = 32), patients received single daily doses of the agent at 3 mg, 8 mg, 15 mg, and 25 mg strengths for up to 10 days. In healthy individuals, ALKS 2680 was orally absorbed and showed biphasic distribution/elimination, with a terminal half-life suitable for maintaining daytime wakefulness with once-daily administration.

Preliminary analysis of the qualitative electroencephalogram data suggests central activity consistent with the mechanism of action. Similar to patients with narcolepsy, healthy volunteers who received the agent did not show any safety signals in vital signs, safety laboratory tests, ECGs at any dose level. There were no serious or severe AEs; however, 1 participant in the multiple-ascending dose portion discontinued after the first dose because of non-serious, non-severe AE that resolved without treatment. In single-dose escalation, pollakiuria, nausea, and blurred vision were the most reported AEs whereas insomnia, dizziness, pollakiuria, and visual disturbance were mostly observed in the multiple-ascending dose portion.

"Narcolepsy is a serious, chronic, neurological disease that impairs regulation of the sleep-wake cycle and negatively impacts daily life. There is significant unmet need for people with narcolepsy, as no currently available treatments address the underlying biology of the disease: orexin deficiency or dysfunction,” Craig Hopkinson, MD, chief medical officer and executive vice president of Research & Development at Alkermes, said in a statement.¹ "These initial data support our design rationale for ALKS 2680 as a highly potent, orally bioavailable, selective orexin 2 receptor agonist designed to address the underlying pathology of narcolepsy. The consistent and dose-dependent effects observed in the initial proof-of-concept data enable dose selection for evaluation in phase 2. We look forward to sharing additional updates from the phase 1 study, and plan to initiate our phase 2 study of ALKS 2680, in the first half of 2024."

REFERENCES
1. Alkermes presents first clinical data for orexin 2 receptor agonist ALKS 2680 at World Sleep Congress. News release. October 23, 2023. Accessed November 3, 2023. https://www.prnewswire.com/news-releases/alkermes-presents-first-clinical-data-for-orexin-2-receptor-agonist-alks-2680-at-world-sleep-congress-301963945.html
2. Yee B. Preliminary results from a phase 1 study of ALKS 2680, an orexin-2 receptor agonist, in healthy participants and patients with narcolepsy or idiopathic hypersomnia. Presented at: World Sleep 2023; October 20-25; Rio de Janeiro, Brazil. POSTER 1599