The phase 1b study of ALKS 2680, presented at SLEEP 2024, demonstrates improvements in wakefulness and alertness in patients with narcolepsy type 1.


Summary: Alkermes plc has announced new data from a phase 1b, proof-of-concept study evaluating ALKS 2680, an investigational oral orexin 2 receptor (OX2R) agonist for treating narcolepsy type 1. The data, presented at SLEEP 2024, highlight improvements in wakefulness and self-reported alertness in patients. The study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALKS 2680 in a cohort of 10 patients with narcolepsy type 1. The results support further clinical development of ALKS 2680.

Key Takeaways:

  • ALKS 2680 demonstrated a clear dose-response, significantly improving mean sleep latency on the Maintenance of Wakefulness Test (MWT) compared to placebo across all doses tested.
  • Patients reported dose-dependent improvements in alertness on the Karolinska Sleepiness Scale (KSS), with meaningful enhancements observed between 1 and 8 hours post-dose.
  • ALKS 2680 was generally well tolerated, with most treatment-emergent adverse events being mild and transient. There were no severe adverse events or clinically meaningful changes in laboratory values or cardiovascular safety signals.

Alkermes plc announced new data from the full narcolepsy type 1 cohort 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. 

The data are being presented at SLEEP 2024, the 38th annual meeting of the Associated Professional Sleep Societies (APSS), taking place June 1-5 in Houston.

The phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of ALKS 2680 via once-daily, single, oral administration. Ten patients with narcolepsy type 1 were randomized to one of four crossover sequences in which each participant received 1 mg, 3 mg, and 8 mg of ALKS 2680, and placebo, with washout periods between each treatment. 

Initial results from the first four patients in this narcolepsy type 1 cohort were previously presented at the 2023 World Sleep Congress.

“Data from this phase 1b study provide evidence of a significant treatment effect of single doses of ALKS 2680 in patients with narcolepsy type 1. In addition, patients’ self-reported measures of alertness further support continued clinical development of this investigational treatment, which has the potential to help address significant unmet needs for people living with excessive daytime sleepiness associated with narcolepsy,” says Ron Grunstein, MD, PhD, head of sleep and circadian research at the Woolcock Institute of Medical Research, in a release.

Data Highlights 

Data highlights from the SLEEP poster presentation include:

Mean Sleep Latency Over Eight Hours:

  • In patients with narcolepsy type 1, treatment with ALKS 2680 demonstrated improved wakefulness compared to placebo at all doses tested, with a clear dose-response.
  • Treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in mean sleep latency on the Maintenance of Wakefulness Test (MWT), with a mean change from baseline versus placebo of 18.4 minutes at the 1 mg dose (p=0.0002), 22.6 minutes at the 3 mg dose (p=0.0001), and 34 minutes at the 8 mg dose (p≤0.0001) (least squares mean difference). Placebo treatment resulted in an approximately 1.4 minute reduction in mean sleep latency from baseline. Prior to treatment with ALKS 2680, these patients had a mean sleep latency on the MWT of approximately six minutes at baseline.
  • At the 3 mg and 8 mg doses, the observed mean MWT scores over an eight-hour period post-dose were within the reported normal range for healthy individuals.

Patient-Reported Alertness on the Karolinska Sleepiness Scale (KSS):

  • The KSS is a subjective measure of self-reported alertness over the past five minutes, using a nine-point scale (with 1 being “extremely alert,” 9 being “extremely sleepy,” and 5 being “neither alert nor sleepy”). Change from baseline on KSS was an exploratory endpoint.
  • ALKS 2680 demonstrated clinically meaningful, dose-dependent improvements in self-reported alertness in patients with narcolepsy type 1. The average self-reported score at baseline was approximately 7. ALKS 2680 showed improvements of 2 to 3 points in self-reported alertness between 1 and 8 hours, indicating clinically meaningful improvements (p<0.001 at all dose levels vs. placebo).

Safety:

  • ALKS 2680 was generally well tolerated across all doses tested in patients with narcolepsy type 1. Most treatment-emergent adverse events (TEAEs) were mild in severity, transient, and self-resolving (with one moderate case of nausea that resolved with food intake). There were no severe adverse events (AEs). AEs observed in >1 patient and deemed to be related to study drug were insomnia, pollakiuria, salivary hypersecretion, decreased appetite, dizziness, and nausea.
  • There were no serious AEs reported or TEAEs leading to study drug discontinuation in patients with narcolepsy type 1. There were no drug-related, treatment-emergent, clinically meaningful changes from baseline in laboratory values at any dose. Additionally, no cardiovascular safety signals were identified in vital signs or electrocardiogram parameters.

“We’re encouraged by the results of this proof-of-concept study of ALKS 2680 in patients with narcolepsy type 1. The clear dose-response reinforced our design principles for this program, and we are looking forward to further characterizing the efficacy and safety of ALKS 2680 in patients with narcolepsy type 1 in the ongoing Vibrance-1 phase 2 study,” says Craig Hopkinson, MD, chief medical officer and executive vice president of research and development at Alkermes, in a release.

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