Evaluating Positive Phase 1 Trial Data for Narcolepsy Agent ALKS 2680


Brendon Yee, PhD, a respiratory and sleep physician at the Woolcock Institute of Medical Research, discussed findings from a recent phase 1 trial presented at World Sleep Congress 2023 in which ALKS 2680 demonstrated improvements in wakefulness among patients with narcolepsy type 1.

Brendon Yee, PhD, a professor and respiratory and sleep physician at the Woolcock Institute of Medical Research

Brendon Yee, PhD

Research shows that orexin neuropeptides are critical regulators of the sleep/wake cycle with orexin 2 receptor (OX2R) activation, and the loss of these neurons in the brain is associated with excessive daytime sleepiness and cataplexy in narcolepsy.1 ALKS 2680 (Alkermes), an investigational OX2R agonist in development for the treatment of patients living with narcolepsy, is designed to address the underlying pathology of narcolepsy with the aim of improving the duration of wakefulness and control of cataplexy.

New preliminary data from a proof-of-concept phase 1 study presented at the 2023 World Sleep Congress, held October 20-25, in Rio de Janeiro, Brazil, showed that treatment with ALKS 2680 was safe to use among healthy volunteers and patients with narcolepsy, with observed dose-dependent improvements in sleep latency.2 The data was from single- and multiple-ascending dose evaluations in healthy participants and the first cohort of 4 patients with narcolepsy type 1 (NT1). Following treatment with ALKS 2680, investigators observed mean improvements of 18, 30, and 37 minutes, in the 1, 3, and 8 mg dosed groups, respectively.

Recently, Brendon Yee, PhD, a professor and respiratory and sleep physician at the Woolcock Institute of Medical Research, sat down with NeurologyLive® to discuss how ALKS 2680's once-daily, oral dosing has potential to expand the narcolepsy treatment landscape. In addition, Yee talked about the key findings from the phase 1 study regarding ALKS 2680's impact on wakefulness in patients with NT1, as well as shared thoughts on how the results of the early proof-of-concept suggest a novel approach to potentially addressing the root cause of narcolepsy.

Clinical Takeaways

  • ALKS 2680 presents a promising avenue for narcolepsy treatment, showing positive findings in safety and efficacy from early-phase studies.
  • The normalization of wakefulness in patients with narcolepsy treated with ALKS 2680 highlights its potential to expand the current treatment paradigm.
  • Ongoing research and upcoming phase 2 and 3 studies may signify significant progress in discovering novel, effective treatments for narcolepsy.

NeurologyLive: Could you provide an overview of the study including the main findings that you thought were notable?

Brendon Yee, PhD: 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 4 patients with NT1 are compelling. In healthy volunteers, ALKS 2680 was evaluated at single- and multiple-ascending doses and was generally well tolerated. ALKS 2680 was observed to have a pharmacokinetic and pharmacodynamic profile that supports once-daily, oral dosing.

The current study also establishes proof-of-concept in 4 patients with NT1. Patients were randomized to a crossover study in which each of them 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 (MWT). Specifically, following treatment with ALKS 2680, mean sleep latency in patients with NT1 improved by 18 minutes, 30 minutes, and 37 minutes from mean pre-treatment baseline sleep latency of 3 minutes at the 1 mg, 3 mg and 8 mg doses, respectively, whereas treatment with placebo reduced sleep latency by 1 minute. The molecule was generally well tolerated across all doses tested in participants with NT1. Drug-related adverse events were seen only at the 8 mg dose and were mild in severity.

At the 8 mg dose of ALKS 2680, patients maintained wakefulness for the full 40-minute MWT duration, up to 10 hours post-dose. The complete normalization of the MWT is an incredibly impressive and clinically meaningful outcome with potential to transform the treatment paradigm for patients with narcolepsy. In particular, seeing these initial results with a once-daily, oral molecule with a low therapeutic dose is exciting.

Based on these results, what are their potential implications for patients with NT1?

The current findings indicate the need for further clinical studies evaluating this molecule as a treatment for narcolepsy. If phase 2 and 3 trials continue to show the promising results from this initial proof-of-concept, it will mark significant progress in our work towards the discovery of novel treatment options for patients with narcolepsy.

Moving forward, what are the next steps in research to be further investigated?

The ongoing phase 1 study is currently recruiting patients with NT1, narcolepsy type 2 (NT2) and idiopathic hypersomnia. Larger, long-term phase 2 and 3 studies are needed to determine the optimal dose range for this molecule and further characterize the safety and efficacy profile. Alkermes plans to initiate a phase 2 study of ALKS 2680 in the first half of 2024.

What do you think is a critical unmet need that should be addressed in this patient population?

Currently approved treatments for narcolepsy generally go after common symptoms without addressing the underlying cause of the disorder. Additionally, some of today’s treatment options may contribute to or affect commonly seen comorbidities, for example by impacting heart rate and blood pressure relevant to cardiovascular comorbidities.

How has the landscape of care changed for patients with narcolepsy over the past couple of decades?

There are more therapies available for the treatment of narcolepsy, many of which have improved quality of life and daily functioning for people living with this disorder. However, none of the currently approved medicines address the root cause or pathophysiology of narcolepsy.

Is there anything you are excited about seeing in this field in the next coming months?

We’ve entered very exciting times in narcolepsy research, with lots of promise on the horizon. I will be awaiting further results from the ongoing phase 1 study of ALKS 2680 and look forward to commencing phase 2 and 3 studies, as well as potentially other studies coming out for molecules in the same class.

Transcript edited for clarity.

1. Nagahara T, Saitoh T, Kutsumura N, et al. Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. J Med Chem. 2015;58(20):7931-7937. doi:10.1021/acs.jmedchem.5b00988
2. Alkermes presents first clinical data for orexin 2 receptor agonist ALKS 2680 at World Sleep Congress. News release. October 23, 2023. Accessed November 9, 2023. https://www.prnewswire.com/news-releases/alkermes-presents-first-clinical-data-for-orexin-2-receptor-agonist-alks-2680-at-world-sleep-congress-301963945.html
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