Alkermes plc announced preliminary results, including initial proof-of-concept data, from a phase 1 study evaluating ALKS 2680, the company’s novel, investigational orexin-2 receptor agonist in development for the treatment of narcolepsy. 

The ongoing phase 1 study is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALKS 2680 in healthy volunteers and patients with narcolepsy or idiopathic hypersomnia via once-daily oral administration. Initial data from the single- and multiple-ascending dose evaluations in healthy volunteers and the first cohort of four patients with narcolepsy type 1 will be presented at the 2023 World Sleep Congress.

The patients with narcolepsy type 1 were randomized to a crossover study in which each received 1 mg, 3 mg, and 8 mg of ALKS 2680 and placebo, with washout periods between each treatment. Single administration of each dose strength of ALKS 2680 achieved statistically significant, clinically meaningful improvements compared to placebo in wakefulness, as measured by the maintenance of wakefulness test (MTW).

In the four patients with narcolepsy type 1, treatment with ALKS 2680 demonstrated improved sleep latency compared to placebo at all doses tested, with a clear dose-response. Following treatment with ALKS 2680, mean sleep latency in patients improved by 18 minutes, 30 minutes, and 37 minutes from mean pre-treatment baseline sleep latency of three minutes at the 1 mg, 3 mg, and 8 mg doses, respectively. Placebo treatment resulted in a one-minute reduction in mean sleep latency. The differences between ALKS 2680 and placebo were statistically significant for all doses: 1 mg (p<0.01), 3 mg (p<0.001), and 8 mg (p<0.001).

Treatment with ALKS 2680 resulted in clinically meaningful improvements in MWT from baseline at all doses tested. At the 8 mg dose of ALKS 2680, patients maintained wakefulness for the full 40-minute MWT duration, up to 10 hours post-dose. MWT scores at 3 mg were comparable to the 8 mg scores for the first six hours post-dose, and treatment with both the 1 mg and 3 mg doses of ALKS 2680 resulted in improved MWT scores up to eight hours post-dose. 

ALKS 2680 was generally well tolerated across all doses tested in the patients with narcolepsy type 1.

Drug-related adverse events were seen only at the 8 mg dose and were mild in severity. The adverse advents observed in >1 participant and deemed to be treatment-emergent at the 8 mg dose were insomnia (n=3), pollakiuria (urinary urgency or frequency) (n=2), and salivary hypersecretion (n=2). There were no serious adverse events or adverse events leading to discontinuation. Additionally, there were 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,” says Brendon Yee, PhD, professor of respiratory and sleep physician at the Woolcock Institute of Medical Research, in a release. “Orexin-2 receptor agonists such as ALKS 2680 represent an exciting new class of potential treatments for narcolepsy, with the opportunity to transform the treatment paradigm for people living with this disease.”

In healthy volunteers, ALKS 2680 was evaluated at single- and multiple-ascending doses. In the single-dose evaluation, ALKS 2680 was dosed from 1 mg to 50 mg. In the multiple-dose evaluation, participants received single daily doses of ALKS 2680 at 3 mg, 8 mg, 15 mg, and 25 mg strengths for up to 10 days. 

ALKS 2680 was generally well tolerated across all doses tested, and the maximum tolerated dose was not reached. Most adverse events were mild, transient, and resolved without intervention or treatment interruption. In the single-ascending dose evaluation, adverse events observed in >1 participant and deemed related to the study drug were dizziness, pollakiuria, nausea, and blurred vision, and most occurred at or above the 15 mg dose level. 

In the multiple-ascending dose evaluation, adverse events observed in >1 participant and deemed related to the study drug were insomnia, dizziness, pollakiuria, and visual disturbances described as blurred or distorted vision, and most occurred at or above the 8 mg dose. No safety signals were identified in vital signs, laboratory parameters, or electrocardiogram.

In healthy volunteers, ALKS 2680 was observed to be centrally active and to have a pharmacokinetic and pharmacodynamic profile that supports once-daily oral dosing.

“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,” says Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes, in a release. “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.”

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