Alkermes Initiates Phase 2 Study of Orexin Receptor Agent ALKS 2680 in Narcolepsy Type 2

Craig Hopkinson, MD

According to a recent announcement, Alkermes has initiated a new phase 2 study, dubbed Vibrance-2 (NCT06555783) that will assess the therapeutic potential of ALKS 2680, an investigational, selective orexin 2 receptor (OX2R) agonist, as a treatment for patients with narcolepsy type 2 (NT2). This is the second phase 2 study in its development program, behind Vibrance-1, which includes those with narcolepsy type 1 (NT1).

Vibrance-2, a double-blind, dose-range-finding, placebo-controlled study, will evaluate the efficacy and safety of 3 doses of ALKS 2680 (10 mg, 14 mg, or 18 mg) in comparison with placebo over an 8-week treatment period. The trial is expected to include 80 participants with a diagnosis of NT2, defined as narcolepsy without cataplexy, who will receive once-daily treatment. All patients who complete the double-blind portion of the study will have a chance to opt into an open-label safety extension, where additional monitoring will continue.

The study will primarily assess ALKS 2680 on the primary end point of change in mean sleep latency on the Maintenance Wakefulness Test (MWT) over the 8-week period. Additional secondary outcomes include change in the Epworth Sleepiness Scale, as well as the incidence of adverse events (AEs). For eligibility, patients must be between 18-70 years of age, have a body mass index between 18 and 35 kg/m2, and meet the diagnostic criteria of NT2 according to the ICSD-3-TR guidelines.

"We are pleased to initiate Vibrance-2, a phase 2 clinical study for adults with narcolepsy type 2, based on the data from our phase 1, proof-of-concept study in this patient population. ALKS 2680 is the most advanced investigational orexin 2 receptor agonist currently in development for narcolepsy type 2," Craig Hopkinson, MD, chief medical officer and executive vice president of Research and Development at Alkermes, said in a statement.¹ "Across narcolepsy type 1 and narcolepsy type 2, significant unmet need remains, and we look forward to further characterizing the efficacy and safety profile of ALKS 2680 in the Vibrance studies in both of these important patient populations."

READ MORE: Enrollment Begins for Phase 1 Study of Eisai’s Orexin-2 Receptor Agonist E2086 in Narcolepsy

Patients who have residual excessive daytime sleepiness and are willing and able to discontinue any medications prescribed for the management of narcolepsy symptoms for at least 14 days will also be considered for the study. Those with significant comorbid medical conditions, including other sleep, cardiovascular, psychiatric, hepatic, or other disorders may be exclusionary; eligibility will be determined on an individual basis by the study investigator.

Vibrance-2 follows Vibrance-1, a similarly constructed study that was announced earlier this year. Vibrance-1, a double-blind, dose-range-finding, placebo-controlled trial of patients with NT1, includes 3 doses of ALKS 2680 (4 mg, 6 mg, or 8 mg) that will be assessed against placebo for a 6-week period. Similar to Vibrance-1, this study will include 80 participants who will primarily be assessed on changes in mean sleep latency on the MWT.²

ALKS 2680, an oral, selective, OX2R agonist, previously showed proof-of-concept in a phase 1 study of healthy volunteers and patients with narcolepsy. Presented at the 2023 World Sleep Congress, the data was from single- and multiple-ascending dose evaluations in healthy participants and the first cohort of 4 patients with NT1. Following treatment with the agent, 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.³

REFERENCES
1. Alkermes announces initiation of Vibrance-2 phase 2 study evaluating ALKS 2680 for the treatment of narcolepsy type 2. News release. August 22, 2024. Accessed August 26, 2024. https://www.prnewswire.com/news-releases/alkermes-announces-initiation-of-vibrance-2-phase-2-study-evaluating-alks-2680-for-the-treatment-of-narcolepsy-type-2-302227858.html
2. Alkermes Announces Initiation of Vibrance-1 Phase 2 Study Evaluating ALKS 2680 for the Treatment of Narcolepsy Type 1. News Release. Alkermes Published April 24, 2024. Accessed August 26, 2024. https://www.prnewswire.com/news-releases/alkermes-announces-initiation-of-vibrance-1-phase-2-study-evaluating-alks-2680-for-the-treatment-of-narcolepsy-type-1-302125993.html
3. 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