SPN-820 Decreases Depressive Symptoms Within Hours of First Dose in Phase 2a Trial

Jonathan Rubin, MD

Credit: Supernus Pharmaceuticals

At Psych Congress 2024, Supernus Pharmaceuticals presented data on their open-label, phase 2a study which revealed participants on SPN-820 experienced meaningful reductions in depressive symptoms as early as 2 hours.^1,2 Not only that, but suicidal ideation decreased by 80%.

“The data shared at the Psych Congress suggest the promise of SPN-820 as a potential first-in-class, novel treatment option for patients with depression, in which it demonstrated rapid-acting antidepressant properties, a favorable tolerability profile, and convenient, oral at-home administration,” said Jonathan Rubin, MD, Chief Medical Officer and Senior Vice President, Research & Development, Supernus Pharmaceuticals, in a statement.

SPN-820, a novel, first-in-class intracellular moderator of the mechanistic target of rapamycin complex 1 (mTORC1), is an oral product candidate for treating depression. This drug enhances synaptic activity and cellular metabolism in the brain and demonstrated a rapid onset of action, with signs at 2 hours, in early clinical studies. An earlier, proof-of-concept phase 1b study showed SPN-820 significantly improved depressive symptoms 4 hours after a single dose.

The new exploratory, open-label phase 2a evaluated SPN-820 in 40 adults with major depressive disorder (MDD) in terms of safety, tolerability, and the rapid onset of improvement in depressive symptoms. The primary efficacy endpoint was the change in baseline in the Hamilton Depression Rating Scale-6 items (HAM-D6), and the secondary endpoint was the change in baseline in the Montgomery Åsberg Depression Rating Scale (MADRS). The safety endpoints were adverse events, suicidal ideation, and behaviors measured by scores on the Columbia Suicide Severity Rating Scale, the Clinician-Administered Dissociative State Scale, and the Brief Psychiatric Rating Scale Positive Total Score.

Participants, aged 18 – 65 (mean: 44.7) years, were mostly White (80%), followed by Asian (10%), Black (7.5%), and unknown (2.5%). More than half were female (67.5%). At baseline, participants had mean scores of 13.6, 33.1, and 4.6 for the HAM-D6, MADRS, and CGI-S, respectively.

Participants received 2400 mg of SPN-820 every 3 days as an adjunctive therapy to the current baseline antidepressant therapy. SPN-820 demonstrated a clinically meaningful improvement of -6.1 at 2 hours and -9.6 at day 10 on the HAM-D6. Additionally, SPN-820 showed clinically meaningful improvement of -16.6 at 4 hours and -22.9 at day 10 on the MADRS.

The results demonstrated a rapid MADRS response rate (≥ 50% reduction) for 50% of participants and a remission (MADRS ≤ 10) for 35% of participants at 4 hours. By day 10, 84.2% and 63.2% of participants, respectively, had improved symptoms.

SPN-820 substantially reduced depressive symptoms as early as 2 hours after the first dose, reflected in changes in the HAM-D6 and MADRS. The study showed a single dose lasted 72 hours. Moreover, Suicidal ideation was reduced by 80%, dropping from 12.5% participants at baseline to 2.6% at day 10.

The analysis showed SPN-820 was well-tolerated with few adverse events (62.5%) and no serious or severe adverse events. Most were mild to moderate and the discontinuation rate due to adverse events was low (2.5%).

The most common adverse events included headache, nausea, somnolence, and dizziness. Other adverse events included cognitive disorder, dry mouth, fatigue, nasal decongestion, and paresthesia oral.

“By decreasing symptoms safely and effectively without certain burdensome side effects, with a majority of patients reaching a remission threshold in just 10 days, SPN-820 exhibited meaningful improvements on the main depression rating scales, and we remain very excited about its potential to make a difference in the lives of those suffering from depression,” Rubin said.

Investigators are now conducting a double-blind, placebo-controlled phase 2b study evaluating SPN-820 for depressive symptoms in approximately 227 adult patients with treatment-resistant depression. The team expects to complete enrollment by November 2024 and release topline data in the first half of 2025.

References

1. ^{Supernus Presents Promising Data from Open-Label Phase 2a Study of SPN-820 Data in Major Depressive Disorder at Psych Congress 2024. GlobeNewswire. October 31, 2024. https://www.globenewswire.com/en/news-release/2024/10/31/2973042/19871/en/Supernus-Presents-Promising-Data-from-Open-Label-Phase-2a-Study-of-SPN-820-Data-in-Major-Depressive-Disorder-at-Psych-Congress-2024.html. Accessed November 1, 2024.}
2. ^{SPN-820 Phase 2a Study: Exploratory Open-Label Study in Adults with Major Depressive Disorder. Supernus Pharmaceuticals. Presented at Psych Congress in Boston on October 17, 2024. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://ir.supernus.com/static-files/ab65cf23-b874-4b16-819b-13eb197962e7.}