MedCheck: Psilocybin for Depression, LSD for Anxiety, Donanemab, LSD, and More

Vanda Pharmaceuticals Inc. announced in April that the Food and Drug Administration (FDA) approved the antipsychotic Fanapt (iloperidone) for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Iloperidone has been approved for the acute treatment of schizophrenia since 2009.

The approval was based on a phase 3 clinical trial of 414 adults with a history of bipolar I disorder. After four weeks of treatment, patients treated with iloperidone exhibited a 14-point drop on the Young Mania Rating Scale, compared with a 10-point drop among patients taking placebo. A statistically significant difference in mania improvement between iloperidone and placebo was evident after two weeks.

The success of iloperidone offsets the decision that Vanda received in March, when the FDA rejected its melatonin receptor-blocking drug Hetlioz (tasimelteon) as a treatment for insomnia. The agency stated that it “identified deficiencies that precluded discussion of labeling and postmarketing requirements/commitments.”

In March, the FDA granted Breakthrough Therapy designation to the psilocybin analog CYB003 for the adjunctive treatment of major depressive disorder (MDD), Cybin announced. The FDA’s Breakthrough Therapy designation expedites the development and review of drugs for serious conditions. The criteria for Breakthrough Therapy designation require preliminary clinical evidence that indicates that the drug may demonstrate substantial improvement over available therapy on at least one clinically significant endpoint.

The Breakthrough Designation was based on data from a phase 2 trial that compared CYB003 and placebo in 34 patients with moderate to severe MDD. Patients in the trial who received two doses of either 12 mg or 16 mg of CYB003 experienced an average 22-point reduction from baseline on the Montgomery–Åsberg Depression Rating Scale (MADRS) after four months. Sixty percent of patients who received 12 mg and 75% of those who received 16 mg were in remission (MADRS score of less than or equal to 10) after four months.

There were no drug-related serious adverse events, incidents of suicidal ideation or behavior, or discontinuations due to adverse events.

The FDA also gave Breakthrough Therapy designation to another psychedelic therapy in March, Mind Medicine Inc’s MM120 (lysergide d-tartrate) for the treatment of generalized anxiety disorder. MM120 is a tartrate salt form of lysergide, more commonly known as LSD. The FDA granted the designation based on data from the phase 2 MMED008 study.

The study included 194 patients who had severe symptoms of generalized anxiety disorder with an average baseline score of roughly 30 on the Hamilton Anxiety Rating Scale (HAM-A). Patients were then randomized to receive treatment with 25, 50, 100, or 200 μg of MM120 or placebo. Those who received 100 µg had an average 21.3-point reduction in HAM-A score at week 4, compared with an average reduction of 13.7-point reduction in those who took placebo. Results were similar at week 12, suggesting this medication provides a durable response.

Patients with schizophrenia who took Nuplazid (pimavanserin) in the phase 3 ADVANCE-2 trial did not experience a statistically significant improvement in their negative symptoms compared with patients who took placebo, Acadia Pharmaceuticals announced in March.

In the 26-week trial, 454 adults with predominant negative symptoms of schizophrenia were randomized to receive either two 17 mg tablets of pimavanserin or placebo daily. At study’s end, those who took pimavanserin experienced a mean reduction of 11.8 points from baseline on the Negative Symptom Assessment-16, compared with a mean reduction of 11.1 points among those in the placebo group.

“We are disappointed the trial did not meet its primary endpoint given the significant unmet need in patients with negative symptoms of schizophrenia,” said Steve Davis, J.D., Acadia’s chief executive officer in the announcement. “We will continue to analyze these data with our scientific advisors, but we do not intend to conduct any further clinical trials with pimavanserin.”

In March Eli Lilly & Co. announced that the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee will hold a meeting to discuss the Phase 3 TRAILBLAZER-ALZ 2 trial on the efficacy and safety of donanemab in early symptomatic Alzheimer’s disease. As Psychiatric News went to press, the FDA had not yet set a date for the meeting. Lilly had expected the FDA to approve donanemab in the first quarter of 2024, and this meeting will delay that decision.

According to the statement by Lilly, the FDA wanted to further understand the safety results in donanemab-treated patients and how the unique trial design of the TRAILBLAZER-ALZ 2 study might affect efficacy findings. The study required participants to have evidence of both amyloid and tau pathology and featured a limited-duration dosing regimen that allowed patients to complete treatment based on an assessment of amyloid plaque.

The FDA had previously granted Breakthrough Therapy designation to donanemab based on the Phase 2 clinical trial TRAILBLAZER-ALZ. In that trial, patients who received donanemab experienced less cognitive and functional decline over the course of the trial, as measured by the change from baseline on the Integrated Alzheimer’s Disease Rating Scale.

The FDA later declined to accept donanemab into the accelerated approval pathway. ■