Garth T. Whiteside, PhD, head of preclinical development at Imbrium Therapeutics, discussed a phase 2 clinical study that explored the use of sunobinop in patients with insomnia during recovery from alcohol use disorder.
Sunobinop (Imbrium Therapeutics) is oral compound in development as a potential treatment for multiple disorders, including insomnia for patients in recovery from alcohol use disorder (AUD). The compound aims to bind to and activate the nociceptin/orphanin-FQ peptide receptor and is also in a range of biological functions such as stress response, anxiety modulation, and substance misuse.1,2 In December 2022, Imbrium Therapeutics announced the safety and efficacy results from a phase 2 study (NCT04035200) exploring sunobinop (V117957) for patients with insomnia in recovery from AUD.3
At the 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana, Garth T. Whiteside, PhD, head of preclinical development at Imbrium Therapeutics, presented in a panel discussion on sunobinop. In his presentation, he discussed the discovery and development of sunobinop as the first selective NOP agonist in development for sleep disorders, notably, insomnia during recovery from alcohol use disorder.
Following the meeting, Garth sat down in an interview with NeurologyLive® to talk about the main findings of the clinical study, including how the agent compared with the placebo in terms of reducing wakefulness after sleep onset among the patients. In addition, he spoke about the implications of these findings for individuals in recovery from AUD who experience insomnia.
Garth T. Whiteside, PhD: First, let me say that we are talking about investigational uses of a drug product in development, and I do not intend to convey conclusions about efficacy or safety. There is no guarantee that sunobinop will successfully complete development or gain FDA approval.
During the symposium on NOP receptors at SLEEP 2023, we presented an updated overview of sunobinop’s development including preclinical data, pharmacokinetics, safety, and tolerability in healthy patients, as well as efficacy in both patients with DSM5 insomnia disorder and patients in recovery from AUD who are also suffering from insomnia. We assessed the safety and tolerability of sunobinop in this patient population as well as determined the effects on sleep parameters as measured by polysomnography and patient-recorded diaries.
The phase 2 randomized, double-blind, multi-center, placebo-controlled, parallel-group clinical study enrolled 114 people experiencing insomnia during recovery from AUD. Enrolled individuals were 18-64 years old with history of moderate or severe AUD based on DSM-5 criteria, self-reported to have consumed no alcoholic beverages for at least 3 weeks and up to 6 months prior to screening, and had persistent insomnia symptoms that emerged or worsened during AUD or during the period of abstinence. Patients were randomly assigned in a 1:1:1 ratio to receive sunobinop 1 mg or 2 mg or placebo every night at bedtime for 21 days, and 89% of patients completed the study. The primary end point was change from baseline on wakefulness after sleep onset (WASO) or the time spent awake after falling asleep, as measured by two consecutive nights of overnight polysomnography (PSG) on nights 1 and 2 and at on nights 20 and 21 of dosing.
Both doses of sunobinop met the primary end point, with significant and clinically meaningful reductions in WASO, compared with placebo, that were maintained across the 3 weeks of dosing in the study. On nights 1 and2, the least squares mean (LS) difference between sunobinop 1 mg and placebo was −12.03 minutes (95% CI, −22.1 to −1.9; P = .050), and the LS difference between sunobinop 2 mg and placebo was −18.35 minutes (95% CI, −28.5, −8.2; P = .003). On nights 20 and 21, the LS difference between sunobinop 1 mg and placebo was −12.35 minutes (CI, −24.7 to 0.0; P = .099), and the LS difference between sunobinop 2 mg and placebo was −15.80 minutes (CI, −28.6, −3.0; P = .043). Impact on sleep was further suggested by a statistically significant effect on multiple secondary end points as measured by polysomnography; however, some effects were significant only at the higher dose or only on nights 1 and 2. Effects on subjective sleep measures collected did not reach statistical significance.
Sunobinop was well tolerated across both doses. No serious adverse events were reported. One patient receiving sunobinop 2 mg discontinued due to sedation. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAE was somnolence (or drowsiness), which was reported in 5% of the sunobinop 1 mg group and 26% of the sunobinop 2 mg group. Baseline alcohol craving scores as assessed via the Penn Alcohol Craving Scale (PACS) were low, with no increase in craving observed in any treatment group.
We hope to understand how sleep is impacted and how healthy sleep can be restored to help individuals maintain their recovery from alcohol. While results from clinical studies vary, the prevalence of sleep disturbances in people recovering from AUD range from 69% to as high as 91% during the early phase of withdrawal4,5. These individuals often experience changes in sleep latency, maintenance, and architecture, characterized by more time spent in the initial stages of sleep, more awakenings, and reduced total sleep time.6 These symptoms can often persist for years following alcohol cessation and studies of patients with AUD have found untreated insomnia may interfere with recovery from alcohol addiction and contribute to relapse.7
Secondary efficacy end points for subject-reported (subjective) end points including wake after sleep onset (sWASO), sleep efficiency (sSE), and sleep onset latency (sSOL) were highly variable and failed to demonstrate statistical differences between sunobinop and placebo. While this is commonly observed in sleep studies, this was inconsistent with results from earlier studies of sunobinop in patients with insomnia, which demonstrated a correlation between objective and subjective sleep measures. Potential confounders in the study of patients with AUD may include e-diary complexity/monitoring and subject non-compliance.
Despite the lack of statistical significance in subjective end points, we noted a reversion to pre-drug baseline levels across both objective and subjective end points when all patients were switched in a blinded fashion to placebo.
Sunobinop is currently in clinical development for multiple indications including, insomnia during recovery from AUD, overactive bladder, and interstitial cystitis/bladder pain syndrome. In studies of patients with AUD, we will employ alternative approaches to further investigate subjective effects and to confirm compliance.
Transcript edited for clarity. Click here for more coverage of SLEEP 2023.