Q1 and Q2 Psychiatry Updates, with Steve Levine, MD

With the first quarter of the year coming to an end, HCPLive spoke with Steve Levine, MD, from Compass Pathways, for a brief recap of developments in psychiatry this year and a look ahead at what is coming in quarter 2.

Levine said aside from psychedelics, the pipeline is relatively dry, with several cases of failures and discontinuations. Looking ahead to quarter 2, topline results for several treatments in treatment-resistant depression are expected to be announced.

“Because there are multiple data readouts coming up...clinicians should just be paying attention and reading these studies in detail—or at least to the extent that you know it may be sort of top line results, press release, as opposed to published peer review data,” Levine said.

QUARTER 1 PSYCHIATRY RECAP

J&J’s Monotherapy Indication for SPRAVATO1

The US Food and Drug Administration (FDA) approved esketamine (SPRAVATO) CIII nasal spray as the first monotherapy for adults with treatment-resistant depression (TRD), announced by Johnson & Johnson on January 21, 2025. The approval of this supplemental new drug application (NDA) was based on a phase 4 randomized, double-blind, multicenter, placebo-controlled study which found esketamine brought a rapid and superior improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 weeks compared with placebo; 22.5% on esketamine vs 7.6% on placebo reached remission (MADRS ≤ 12) at week 4.

Otsuka and Lundbeck’s NDA for Brexpiprazole 2,3,4

The FDA accepted the sNDA for brexpiprazole alongside sertraline to treat adult PTSD, Otsuka and Lundbeck announced in June 2024. Since then, a phase 3 trial showed brexpiprazole with sertraline significantly reduced PTSD symptoms in 10 days, and Otsuka announced FDA announced plans to host an advisory committee meeting to discuss this decision. The FDA has yet to set a meeting date, but it is anticipated to occur during the first half of 2025. This has pushed back brexpiprazole with sertraline’s original PDUFA target date of February 8, 2025.

Neumora’s Kappa Opioid Receptor, Navacaprant 5

Neumora’s kappa opioid antagonist, navacaprant, failed to show efficacy in the phase 3 KOASTAL-1 trial for major depressive disorder. Navacaprant demonstrated no significant difference from placebo in reducing depressive symptoms after 6 weeks of treatment and even led the company’s shares to drop by > 80%.

Discontinued VENTURA Program on Anticaprant for MDD6

J&J decided to discontinue their phase 3 VENTURA program after the kappa opioid receptor anticaprant failed to show significant improvements in MDD. However, the company said aticaprant could have potential in other therapeutic areas.

Phase 2 data on Methylone for PTSD7

Transcend Therapeutics announced on March 31, 2025, that methylone (TSND-201) signficantly improved PTSD symptoms in the phase 2 IMPACT-1 trial, thus meeting its primary endpoint of significant change from baseline to day 64 in the Clinician-Administered PTSD Scale for DSM05 (CAPS-5) score. This randomized, double-blind, placebo-controlled trial demonstrated patients on methylone had an average CAPS-5 improvement of – 9.64 points on day 64 compared with placebo (-23.28 points vs -13.64 points; P = .0011), with improvement evident on day 10.

QUARTER 2 PSYCHIATRY LOOKAHEAD

COMP360 for Treatment-Resistant Depression8

Levine said Compass Pathways will be reporting topline primary endpoint data on COMP360 psilocybin treatment for treatment-resistant depression during the second quarter. The company’s phase 2b trial, conducted across 22 sites in 10 countries across Europe and North America, assessed the safety and efficacy of COMP360 in 3 doses: 1 mg, 10 mg, and 25 mg. Previous findings demonstrated that a single 25 mg dose of COMP360, in combination with psychological support, was linked to a significantly greater reduction in depressive symptoms after 3 weeks (P < .001), with a rapid, durable response for 12 weeks.

Beckley Psytech’s Intranasal 5-MeO-DMT for Treatment-Resistant Depression 9

Beckley Psytech, developing a novel formulation of intranasal 5-MeO-DMT for treatment-resistant depression, also anticipates announcing topline results in the second quarter.

Last year, the company announced positive initial data from their open-label phase 2a study of 5-MeO-DMT formulation BPL-003 for treatment-resistant depression, finding that a single dose provides a rapid antidepressant response in 55% of patients the day after dosing. More than half (55%) achieved remission from depression at day 29 and 45% at day 85.

References

1. Derman, C. FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression. HCPLive. January 21, 2025. https://www.hcplive.com/view/fda-approves-esketamine-first-monotherapy-treatment-resistant-depression. Accessed April 1, 2025.

2. Derman, C. Brexpiprazole with Sertraline Significantly Reduces PTSD Symptoms in 10 Days. HCPLive. December 19, 2024. https://www.hcplive.com/view/brexpiprazole-sertraline-significantly-reduces-ptsd-symptoms-10-days. Accessed April 1, 2025.

3. Derman, C. FDA Accepts sNDA for Brexpiprazole in Combination with Sertraline for Adult PTSD. HCPLive. June 25, 2025. https://www.hcplive.com/view/fda-accepts-snda-for-brexpiprazole-in-combination-with-sertraline-for-adult-ptsd. Accessed April 1, 2025.

4. Otsuka Announces FDA Plans to Host an Advisory Committee Meeting to Discuss the sNDA for Brexpiprazole in Combination with Sertraline for the Treatment of Adults with Post-Traumatic Stress Disorder (PTSD). Otsuka. January 10, 2025. https://www.otsuka-us.com/news/otsuka-announces-fda-plans-host-advisory-committee-meeting-discuss-snda-brexpiprazole. Accessed April 1, 2025.

5. Derman, C. Phase 3 KOASTAL-1 Trial Fails to Show Navacaprant Significantly Improves MDD. HCPLive. January 2, 2025. https://www.hcplive.com/view/phase-3-koastal-1-trial-fails-show-navacaprant-significantly-improves-mdd. Accessed April 1, 2025.

6. J&J Axes Late-Stage Depression Trial After Underwhelming Efficacy. BioSpace. March 7, 2025. https://www.biospace.com/drug-development/j-j-axes-late-stage-depression-trial-after-underwhelming-efficacy. Accessed April 1, 2025.

7. Derman, C. Methylone Shows Rapid PTSD Symptom Improvement in Phase 2 IMPACT-1 Trial. HCPLive. March 31, 2025. https://www.hcplive.com/view/methylone-shows-rapid-ptsd-symptom-improvement-in-phase-2-impact-1-trial. Accessed April 1, 2025.

8. COMP360 Psilocybin Treatment in TRD. https://compasspathways.com/our-work/comp360-psilocybin-treatment-in-trd/. Accessed April 1, 2025.

9. Beckley Psytech announces positive initial data from Phase IIa study of novel 5-MeO-DMT formulation BPL-003 for Treatment Resistant Depression. Beckley Psytech. March 26, 2024. https://www.beckleypsytech.com/posts/beckley-psytech-announces-positive-initial-data-from-phase-iia-study-of-bpl-003-for-treatment-resistant-depression. Accessed April 1, 2025.