ALKS 2680 Significantly Improves Wakefulness for Narcolepsy Type 2 and Idiopathic Hypersomnia in Phase 1b Trial

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ALKS 2680, an investigational orexin 2 receptor agonist, showed promise for improving sleep latency in patients with narcolepsy type 2 and idiopathic hypersomnia in a phase 1b study.

 Ron Grunstein, MD, PhD, head of Sleep and Circadian Research at the Woolcock Institute of Medical Research

Ron Grunstein, MD, PhD

Credit: Woolcock Institute of Medical Research

New topline results of a phase 1b proof-of-concept study showed that treatment with ALKS 2680 (Alkermes), an investigational orexin 2 receptor (OX2R) agonist, resulted in significant improvement in mean sleep latency compared with placebo at all doses tested in narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) cohorts. The company noted that it plans to move forward and initiate a phase 2 study in patients with NT2 in the second half of 2024, according to a recent announcement.1

In the phase 1b study, the NT2 (n = 9) and IH (n = 8) cohorts were used to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily, single, oral administration of ALKS 2680. Investigators randomized participants to a 4-way crossover study in which each patient either with NT2 or IH received 5 mg, 12 mg and 25 mg of ALKS 2680, and placebo, with washout periods between each treatment given.

"These data support further clinical evaluation of ALKS 2680 and demonstrate that OX2R agonists such as ALKS 2680 may have utility in treating sleep disorders in patients without known orexin deficiency," Ron Grunstein, MD, PhD, head of Sleep and Circadian Research at the Woolcock Institute of Medical Research, told NeurologyLive®. "Alkermes has recently initiated the Vibrance-1 study, a phase 2 clinical trial evaluating ALKS 2680 versus placebo in patients with narcolepsy type 1 (NT1). The phase 1b data from the NT2 cohort will inform dose selection for a phase 2 study in patients with NT2, which is planned to initiate in the second half of 2024."

Top Clinical Takeaways

  • ALKS 2680 significantly improved sleep latency in patients with narcolepsy type 2 and idiopathic hypersomnia at various doses in a phase 1b study.
  • The study found that ALKS 2680 was generally well-tolerated across different doses, with most treatment-emergent adverse events being mild and self-resolving.
  • Alkermes plans to initiate a phase 2 study of ALKS 2680 in patients with narcolepsy type 2 in the second half of 2024.

Prior to initiating ALKS 2680 treatment, patients with NT2 had baseline sleep latencies ranging from 3 to 33 minutes and a mean sleep latency of 14 minutes at baseline. After treatment with ALKS 2680, findings showed a mean change in sleep latency of 12 minutes at the 5 mg dose (P <.05), 19 minutes at the 12 mg dose (P <.001), and 21 minutes at the 25 mg dose (P <.001) compared with placebo. Notably, the placebo in this cohort had no change in mean sleep latency. The reported mean MWT scores over an 8-hour period post-dose at the 12 mg and 25 mg doses were in the normal range for healthy individuals in this cohort.2

READ MORE: Meta-Analysis Reveals Safety Concerns With FDA-Approved Dual Orexin Receptor Antagonists for Insomnia

Before ALKS 2680 treatment in the IH cohort, patients had baseline sleep latencies ranging from 6 to 34 minutes and a mean sleep latency of 23 minutes at baseline. In these patients, treatment with ALKS 2680 resulted in a mean change in sleep latency from baseline of 8 minutes at the 5 mg dose (P <.05), 11 minutes at the 12 mg dose (P <.01), and 18 minutes at the 25 mg dose (P <.001) compared with placebo. Notably, treatment with placebo treatment in this cohort had a 2-minute reduction in mean sleep latency. In this cohort, the reported mean MWT scores over an 8-hour period post-dose were in the normal range for healthy individuals at the 12 mg and 25 mg doses.2

"Despite currently available therapies, significant unmet need remains for patients with narcolepsy, as many patients may still experience excessive daytime sleepiness (EDS), and in patients with NT1, cataplexy. No currently available treatments address the underlying biology of the disease: orexin deficiency or dysfunction," Grunstein added.

Investigators reported that ALKS 2680 was generally well tolerated in the both cohorts across all doses, as all treatment-emergent adverse events (TEAEs) were transient and self-resolving. The TEAEs reported were as mild except for 1 moderate case of pollakiuria at the 25 mg dose in both cohorts. The AEs related to the drug were observed in at least 1 patient with NT2 and were reported as pollakiuria, insomnia and dizziness. At the 25 mg dose, there was 1 patient reported case of a mild, transient occurrence of photophobia or visual disturbance, which self-resolved in 2 hours of onset or less. No serious AEs or AEs reported led to discontinuation for patients in both cohorts. Additionally, there were no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters observed among all participants.

"Orexin is considered the master regulator of wakefulness by virtue of its unique role as the principal activator of multiple wake-promoting neurotransmitter pathways that project widely throughout the brain," Grunstein said. "Reduced orexin tone or signaling has been identified as the root cause of excessive daytime sleepiness and cataplexy in NT1, and is thought to play a role in EDS in NT2 and IH. ALKS 2680 has shown initial proof of concept in a phase 1, single dose study in patients with NT1, NT2, and IH."

REFERENCES
1. Alkermes Announces Positive Topline Results From Phase 1b Study of ALKS 2680 Demonstrating Improved Wakefulness in Patients With Narcolepsy Type 2 and Idiopathic Hypersomnia. News Release. Alkermes. April 9, 2024. Accessed April 11, 2024. https://www.prnewswire.com/news-releases/alkermes-announces-positive-topline-results-from-phase-1b-study-of-alks-2680-demonstrating-improved-wakefulness-in-patients-with-narcolepsy-type-2-and-idiopathic-hypersomnia-302111041.html
2. Krahn LE, Arand DL, Avidan AY, et al. Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine [published correction appears in J Clin Sleep Med. 2022 Aug 1;18(8):2089]. J Clin Sleep Med. 2021;17(12):2489-2498. doi:10.5664/jcsm.9620
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