Alkermes’ phase 1b study of ALKS 2680 demonstrates significant enhancements in sleep latency and good tolerability across all doses.


Summary: Alkermes plc announced positive results from a phase 1b study evaluating ALKS 2680, an oral orexin 2 receptor agonist, for treating narcolepsy type 2 and idiopathic hypersomnia. The study showed statistically significant improvements in wakefulness and sleep latency compared to placebo across various doses. ALKS 2680 was well tolerated, with most adverse events being mild and transient. These results support further clinical trials, highlighting its potential as a new treatment for sleep disorders. Plans for a phase 2 study are underway.

Key Takeaways:

  • Orexin 2 receptor agonist ALKS 2680 demonstrated clinically meaningful and statistically significant improvements from baseline in mean sleep latency compared to placebo at all doses. It was tested in both narcolepsy type 2 and idiopathic hypersomnia.
  • ALKS 2680 was generally well-tolerated at all doses tested. 
  • The dose-dependent effects and pharmacodynamic profile support advancement into a planned phase 2 study.

Alkermes plc announced positive topline results from the narcolepsy type 2 and idiopathic hypersomnia (IH) cohorts of a phase 1b, proof-of-concept study evaluating ALKS 2680, the company’s novel, investigational oral orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. 

ALKS 2680 data demonstrated clinically meaningful and statistically significant improvements from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT) compared to placebo at all doses tested. ALKS 2680 was generally well tolerated in both patient populations at all doses tested.

The phase 1b narcolepsy type 2 (n=9) and IH (n=8) study cohorts evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of ALKS 2680 via once-daily, single oral administration. Participants were randomized to a four-way crossover study in which each participant received 5 mg, 12 mg, and 25 mg of ALKS 2680, and placebo, with washout periods between each treatment. 

Topline Study Results

Topline results from each cohort are as follows:

Narcolepsy type 2:

  • In the nine patients with narcolepsy type 2, treatment with ALKS 2680 demonstrated improved wakefulness compared to placebo at all doses tested, with a clear dose response. Prior to treatment with ALKS 2680, these patients had baseline sleep latencies ranging from 3 to 33 minutes, with a mean sleep latency of 14 minutes at baseline. 
  • Treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in sleep latency in these patients with narcolepsy type 2, with a mean change from baseline versus placebo of 12 minutes at the 5 mg dose (p<0.05), 19 minutes at the 12 mg dose (p<0.001), and 21 minutes at the 25 mg dose (p<0.001) (least squares mean difference). Placebo treatment in this cohort resulted in no change in mean sleep latency. 
  • At the 12 mg and 25 mg doses, the observed mean Maintenance of Wakefulness Test scores over an eight-hour period post-dose were within the reported normal range for healthy individuals.1
  • ALKS 2680 was generally well tolerated across all doses tested in participants with narcolepsy type 2. All treatment-emergent adverse events (TEAEs) were transient and self-resolving. TEAEs were mild in severity, with the exception of one moderate case of pollakiuria at the highest dose (25 mg). Adverse events observed in >1 participant with narcolepsy type 2 and deemed to be related to study drug were pollakiuria, insomnia, and dizziness. One mild, transient occurrence of photophobia was reported in a single patient at the 25 mg dose, which self-resolved within two hours of onset.
  • There were no serious adverse events or adverse events leading to discontinuation in patients with narcolepsy type 2. Additionally, there were no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.
  • The company plans to initiate a phase 2 study in patients with narcolepsy type 2 in the second half of 2024.

Idiopathic hypersomnia:

  • In the eight patients with IH, treatment with ALKS 2680 demonstrated improved wakefulness compared to placebo at all doses tested, with a clear dose response. Prior to treatment with ALKS 2680, these patients had baseline sleep latencies ranging from six to 34 minutes, with a mean sleep latency of 23 minutes at baseline. 
  • Treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in sleep latency in these patients with IH, with a mean change from baseline versus placebo of eight minutes at the 5 mg dose (p<0.05), 11 minutes at the 12 mg dose (p<0.01), and 18 minutes at the 25 mg dose (p<0.001) (least squares mean difference). 
  • Placebo treatment in this cohort resulted in a two-minute reduction in mean sleep latency. At the 12 mg and 25 mg doses, the observed mean Maintenance of Wakefulness Test scores over an eight-hour period post-dose were within the reported normal range for healthy individuals.
  • ALKS 2680 was generally well tolerated across all doses tested in participants with IH. All TEAEs were transient and self-resolving. TEAEs were mild in severity, with the exception of one moderate case of pollakiuria at the highest dose (25 mg). Adverse events observed in >1 participant and deemed to be related to study drug were pollakiuria, insomnia, and dizziness. One mild, transient occurrence of visual disturbance was reported in a single patient at the 25 mg dose, which self-resolved approximately one hour after onset.
  • 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 ECG parameters.

“The magnitude and durability of effect of ALKS 2680 seen in this proof-of-concept study in patients with narcolepsy type 2 and idiopathic hypersomnia is exciting. These data support further clinical evaluation of ALKS 2680 and demonstrate that orexin 2 receptor agonists such as ALKS 2680 may have utility in treating sleep disorders in patients without known orexin deficiency,” states Ron Grunstein, MD, PhD, head of sleep and circadian research at the Woolcock Institute of Medical Research, in a release. “New treatment options are needed, and orexin agonists have the potential to transform the current treatment landscape for people living with narcolepsy.”

Alkermes expects to submit results from this phase 1b, proof-of-concept study to a peer-reviewed journal for publication and to present additional ALKS 2680 study results at upcoming scientific meetings.

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