According to a recent announcement, Alkermes has initiated its randomized, double-blind, dose-range-finding, placebo-controlled phase 2 Vibrance-1 trial (NCT06358950) assessing the safety and efficacy of ALKS 2680, an investigational oral orexin 2 receptor (OX2R) agonist, as a once-daily treatment for patients with narcolepsy type 1 (NT1).1 The company also announced that it anticipates to start Vibrance-2, a planned phase 2 study in patients with narcolepsy type 2, in the second half of 2024.
In Vibrance-1, participants will be randomized to receive 1 of 3 doses of ALKS 2680 (4 mg, 6 mg or 8 mg) or placebo, once-daily, for 6 weeks. The primary end point assesses decreases in sleepiness using change in mean sleep latency on the maintenance of wakefulness test (MWT). Secondary end points will include change in Epworth Sleepiness Scale (ESS) score, mean weekly cataplexy rate and incidence of adverse events (AEs). The trial is expected to enroll approximately 80 participants across sites in the U.S., Australia, and Europe. Notably, all patients participating in the double-blind portion of the study will be eligible to continue in the open-label safety extension portion of the trial.
Top Clinical Takeaways
- ALKS 2680's once-daily dosing in the Vibrance-1 trial aims to reduce sleepiness in patients with NT1, assessed through various end points including mean sleep latency and cataplexy rate.
- The study's global scope, enrolling patients across the U.S., Australia, and Europe, underscores the potential international impact of narcolepsy research and treatment development.
- Continuation of an open-label safety extension portion will further provide insights into the long-term safety profile and potential durability of ALKS 2680's effects.
"ALKS 2680 offers the potential to harness the orexin system, the master regulator of wakefulness, by addressing the loss of orexin signaling common in people with narcolepsy type 1. Based on data from our phase 1, proof-of-concept study, we are excited to advance this novel oral compound to phase 2," Craig Hopkinson, MD, chief medical officer and executive vice president, research & development at Alkermes, said in a statement.1 "Initiation of the Vibrance-1 study is a significant milestone for the ALKS 2680 development program, and we look forward to further characterizing ALKS 2680's safety and efficacy profile throughout this phase 2 study."
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Data from the proof-of-concept phase 1 study showed that ALKS 2680 was safe among healthy volunteers and patients with narcolepsy, with observed dose-dependent improvements in sleep latency.2 Presented at the 2023 World Sleep Congress, held October 20-25, in Rio de Janeiro, Brazil, the data was from single- and multiple-ascending dose evaluations in healthy participants and the first cohort of 4 patients with NT1.3 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. 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.
After an initial 2-week washout period of all existing medications, patients in the study 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 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.
The study’s main goal was to assess safety and tolerability of the agent. At the conclusion of the treatment period, drug-related AEs were documented only at the 8 mg dose and were mild in severity. Insomnia (n = 3), pollakiuria (n = 2), and salivary hypersecretion (n = 2) were the only treatment-emergent AEs, observed in at least 1 treated participant. Investigators observed no serious AEs or AEs that led to discontinuation, as well as no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram parameters.
"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," lead author Brendon Yee, PhD, respiratory and sleep physician, Woolcock Institute of Medical Research, told NeurologyLive® in a previous interview about the phase 1 findings.
In the healthy volunteer phase of the study, each cohort included 8 participants, 6 of whom were randomized to either ALKS 2680 and 2 of whom received placebo. In the single-dose portion (n = 48), ALKS 2680 was dosed from 1 mg to 50 mg whereas in the multiple-dose portion (n = 32), patients received single daily doses of the agent at 3 mg, 8 mg, 15 mg, and 25 mg strengths for up to 10 days. In healthy individuals, ALKS 2680 was orally absorbed and showed biphasic distribution/elimination, with a terminal half-life suitable for maintaining daytime wakefulness with once-daily administration.
“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,” Yee said previously.
Preliminary analysis of the qualitative electroencephalogram data suggests central activity consistent with the mechanism of action. Similar to patients with narcolepsy, healthy volunteers who received the agent did not show any safety signals in vital signs, safety laboratory tests, ECGs at any dose level. There were no serious or severe AEs; however, 1 participant in the multiple-ascending dose portion discontinued after the first dose because of non-serious, non-severe AE that resolved without treatment. In single-dose escalation, pollakiuria, nausea, and blurred vision were the most reported AEs whereas insomnia, dizziness, pollakiuria, and visual disturbance were mostly observed in the multiple-ascending dose portion.
“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,” Yee said in a prior conversation with NeurologyLive. “We’ve entered very exciting times in narcolepsy research, with lots of promise on the horizon.”
REFERENCES
1. 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 May 9, 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
2. Alkermes presents first clinical data for orexin 2 receptor agonist ALKS 2680 at World Sleep Congress. News release. October 23, 2023. Accessed May 9, 2024. https://www.prnewswire.com/news-releases/alkermes-presents-first-clinical-data-for-orexin-2-receptor-agonist-alks-2680-at-world-sleep-congress-301963945.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
