Recently, Sage Therapeutics issued a statement saying that the FDA has extended the PDUFA date for priority review of new drug applications for its new drug Zulress (brexanolone) for the treatment of postpartum depression. This means that the previously disclosed PDUFA on December 19, 2018 will be extended by three months to March 19, 2019.
Two weeks before the FDA announced a delay (November 2), the FDA Psychiatric Pharmacology Advisory Committee and the Drug Safety and Risk Management Advisory Committee supported the benefit of brexanolone with overwhelming voting data (17:1).
Based on safety and efficacy data from three placebo-controlled clinical studies, the Advisory Committee requested Sage to submit a proposed Risk Assessment and Mitigation Strategy (REMS) program to the FDA containing elements to ensure safe use (ETASU).
According to the PDUFA VI, the FDA may choose to extend the PDUFA target date by three months in order to submit the REMS of the ETASU that was not submitted in the original NDA. As part of the extension, FDA has not required Sage to provide any other clinical data or any other information.
Brexanolone was developed by Sage, which previously had a 14% clinical failure in super-refractory epilepsy, with stocks falling 14%. Fortunately, Sage’s R&D team is unyielding and extends clinical trials to postpartum depression.
In the United States, the FDA has granted brexanolone a breakthrough drug qualification for postpartum depression. In the European Union, EMA has also been granted priority drug qualification (PRIME).
Only patients who were given a 60-hour intravenous infusion of the drug required patients and providers to commit to long-term clinical infusion. The results of a phase III clinical study, recently published in The Lancet, showed that all doses of the brexanolone treatment group achieved the expected efficacy. At the 60th hour of treatment, the brexanolone treatment group had a depression scale score compared with the placebo group. Significantly lower.
Dr. Jeff Jonas, CEO of Sage, said, “Our main goal remains to provide treatment for women with PPD as soon as possible. Given this unexpected delay, we will work with the FDA to ensure that PPD is quickly resolved. Unmet medical needs of women,”.
Brexanolone is an allosteric modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A receptors (GABAA receptors). GABAA receptors and NMDA (N-methyl-D-aspartate) receptors act to inhibit and stimulate brain neurons to produce nerve impulses, respectively. The imbalance between the two receptor activities is responsible for a variety of mental illnesses including depression.
About postpartum depression (PPD)
PPD is a clear and easily recognizable major depression that usually begins in the third trimester of pregnancy or within 4 weeks of delivery. It is the leading cause of maternal postpartum suicide and the most common medical complication of childbirth.
The main clinical manifestations include obvious dysfunction, depression, loss of interest in newborns, and associated symptoms of depression such as loss of appetite, sleep disturbance, inattention, listlessness, lack of self-esteem, and suicidal tendencies. More than half of the first episodes of PPD will recur in the next 5 years, and one third of patients will relapse even in the first year.
The data shows that there are 300 million postpartum depression patients in the world, about 400,000 cases per year in the United States. The prevalence of PPD reported in China is 1.1% to 52.1%, with an average of 14.7%, and 50% to 80% of postpartum depression occurs. mood. However, there is currently no FDA-approved postpartum depression therapy, and there are significant medical needs in this area that are not being met.
About stage III clinical trial of brexanolone
The phase III clinical study was conducted at 30 medical centers in the United States, 18-45 years old, less than 6 months postpartum, 17 Hamilton Depression Rating Scale (HAMD) scores ≥ 26 (Study 1), or HAMD scores 20-25 (Study 2) Maternal involvement was randomized to 90 μg/kg/h brexanolone (BRX90), 60 μg/kg/h brexanolone (BRX60) or placebo for 60 hours. The primary efficacy endpoint was a 60-hour HAMD score change.
138 maternal women participated in the study1, divided into BRX90 group (n=45), BRX60 group (n=47) primary placebo group (n=46), 108 patients participated in study 2, divided into BRX90 group (n=54) ) and placebo group (n=54). In Study 1, after 60 hours, the HAMD score in the BRX60 group decreased by 19.5 compared with baseline, the BRX90 group decreased by 17.7, and the placebo group decreased by 14.0. In Study 2, the 60-hour HAMD score for the BRX90 group decreased by 14.6 compared with baseline, and the placebo group decreased by 12.1. The most common brexanolone treatment-related adverse events were headache, dizziness, and lethargy. Four treatment-related serious adverse events occurred, including suicidal ideation, intentional drug overdose, altered state of consciousness, and syncope during follow-up.