Study results of an experimental agent that improves symptoms of major depression and boosts quality of life in as little as 3 days suggest it may be an effective short-term treatment option.
Phase 3 results of a randomized, placebo-controlled trial compared zuranolone, an neuroactive steroid that binds to both synaptic and extra-synaptic GABA-A receptors, to placebo in patients with major depressive disorder (MDD). Overall, 30% of participants were already taking antidepressants.
Investigators found the drug was associated with a significant improvement in depression scores versus placebo, with benefit observed as early as day 3. This was accompanied by improved function and well-being.
The drug was also “generally well-tolerated” and had a safety profile that was “consistent” with what has been seen previously with the drug, said study presenter Colville Brown, MD, Sage Therapeutics, Cambridge, Massachusetts.
“These data continue to support the development of zuranolone as a potential 14-day short course treatment for major depressive disorder episodes.”
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
High Placebo Response
However, despite being significant, the drug’s benefit was only slightly higher than placebo, raising questions about the study design and the true performance of the drug.
Brown explained that patients with MDD were randomized to oral zuranolone 50 mg or placebo once daily for 14 days, with dose reductions to 40 mg or matching placebo permitted in case of perceived intolerance.
Patients were assessed at baseline and day 15 using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before entering a 28-day follow-up period off study drug.
Among the 268 participants who received zuranolone, 90.3% completed the study, compared with 87.4% of 269 patients in the placebo group.
The mean age of participants was 40 years. Women made up 69.4% of those who received zuranolone and 61.7% assigned to placebo.
The mean HAMD-17 score at baseline was 26.8 and 26.9 in the zuranolone and placebo groups, respectively. Brown noted that 29.5% of patients in the zuranolone group and 30.1% of those assigned to placebo were taking antidepressants at baseline.
The study’s primary endpoint was met, with patients taking the study drug experiencing a significantly greater reduction in HAMD-17 scores from baseline to day 15 versus those given placebo, at 14.1 versus 12.3 points (P = .0141).
Brown highlighted that the difference in reduction in HAMD-17 scores between the zuranolone and placebo groups was already significant at day 3 (P < .0001), and again at day 8 (P < .0001) and day 12 (P < .001).
At day 3, response rates on the HAMD-17 were significantly higher among zuranolone-treated patients than those given placebo, at 29.3% versus 16.3% (P < .001). However, the differences on day 15 and on day 42 were no longer significant.
A similar effect was seen for HAMD-17 remissions, which were seen in 7.6% of zuranolone-treated patients and 2.3% of those given placebo at day 3 (P < .01), rising to 29.8% versus 27.1% at day 15, and 30.8% versus 29.6% at day 42, and neither difference was significant.
Brown also showed that, at all time points during the treatment and follow-up periods, improvements in response rates in Global Improvement on the Clinical Global Impression scale favored zuranolone.
On the SF-36v2 quality of life questionnaire, improvements again favored zuranolone on all domains, although the difference between active treatment and placebo was significant only for vitality on day 15, at 12.8 versus 9.7 points (P < .05).
Treatment-emergent adverse events were more common with zuranolone, with 60.1% of patients experiencing at least one event of any grade versus 44.6% with placebo. However, severe events were seen in only 3.0% versus 1.1% of patients, and serious adverse events were recorded in only two patients (0.7%) in both groups.
The most common adverse events were somnolence, dizziness, headache, sedation, and diarrhea, with no increase in suicidal ideation or withdrawal. Brown also noted that there was “no change in the safety signal” between patients with or without prior antidepressant therapy.
From the audience, Marie-Josée Filteau, MD, Department of Psychiatry, Laval University, Quebec, Canada, drew attention to the similarly in the improvement in HAMD-17 scores between the zuranolone and placebo groups, asking: “How is that compelling?”
Brown replied that “what they are excited about is that change from baseline with zuranolone,” adding, “You do see it in the placebo group as well, and…this isn’t new to psychiatry.”
“This is a heterogeneous disease, and remember this [study] was conducted during COVID, so patients were being seen with clinic visits during COVID.”
Brown asked: “What impact did that have? The placebo is not really placebo” in this case.
More Effective Than Results Suggest?
Approached for comment, Maurizio Fava, MD, executive vice chair, Department of Psychiatry, and executive director, Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, noted there are several issues with the trial.
He told Medscape Medical News that, because of those, the drug “is likely to be much more efficacious that it looks because it achieved statistical significance despite an extremely high placebo response.”
“Whenever your change on placebo is greater than 10 points on the HAMD, you have an excessive response…and a very, very low chance of detecting a signal,” he said.
Fava also noted another issue was including patients who were either on or off antidepressants, which meant the population was not sufficiently homogenous.
Another “flaw” was to assume that the placebo effect would be “transient” and deteriorate over time, whereas the results showed the opposite.
Nevertheless, “it’s a positive study because of the sample size…that provides further evidence for the antidepressant activity of zuranolone” and the drug was “well-tolerated.”
Fava expects zuranolone “will make it to the market,” as an indication from the US Food and Drug Administration is likely, “but if you’re asking me: Is the drug as effective as shown in their studies? It’s probably much more effective.”
The study was funded by Sage Therapeutics and Biogen. Brown is an employee of Sage Therapeutics. Lead investigator Anita Clayton, MD, University of Virginia School of Medicine, Charlottesville, has reported relationships with Dario Bioscience, Janssen, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Fabre-Kramer, MindCure, Ovoca Bio, PureTech Health, S1 Biopharma, Vella Bioscience, WCG MedAvante-ProPhase, Ballantine Books/Random House, Guilford Publications, Euthymics, and Mediflix.
34th ECNP Congress. Abstract S.09.02. Presented October 3, 2021.
Content Source: https://www.medscape.com/viewarticle/960452?src=rss