In March 2019, the US Food and Drug Administration (FDA) approved the world’s first drug specifically for post-partum depression (PPD), Sage Therapeutics’ Zulresso (brexanolone). The drug is now available to patients in the US.
PPD is the most common medical complication resulting from childbirth, affecting at least 15% of new mothers. The condition is associated with a range of symptoms, including depressed mood, lack of energy, loss of interest in and difficulty bonding with their newborn, and suicidal thoughts.
Importantly it differs from the ‘baby blues’, which are simply a normal hormonal adjustment period following birth, whereas PPD lasts longer than the two weeks immediately following birth and can start any time during the first year after giving birth.
Despite PPD’s frequent occurrence and the devastating consequences it can have on women and their families, standard of care has been cognitive behavioural and interpersonal therapy, sometimes accompanied by antidepressants developed for many types of depression, meaning the condition has, until now, represented an urgent unmet need.
Zulresso as a ‘game-changing approach’
Discussing Zulresso’s approval, primary investigator of the drug’s clinical development and director of perinatal psychiatry at UNC Centre for Women’s Mood Disorders Samantha Meltzer Brody commented: “Today’s approval of Zulresso represents a game-changing approach to treating PPD.
“The potential to rapidly reduce symptoms in this critical disorder is an exciting milestone in women’s mental health. PPD is recognised to have a significant and long-term impact on women and their families, but with Zulresso we may finally have the opportunity to change that.”
Zulresso is an allosteric modulator of both synaptic and extrasynaptic GABAA receptors, the chief inhibitor of the central nervous system. Throughout the drug’s clinical development programme, its mechanism of action has substantially reduced post-partum depression symptoms.
In an exploratory Phase II trial, Zulresso caused four patients with severe post-partum depression to achieve depression remission within 60 hours after administration of the drug; their Hamilton Rating Scale for Depression (HAM-D) score declined from 26.5 at baseline to 1.8. A patient with a score below 7.0 is considered symptom-free.
These impressive results were supported by consistent improvement in recordings on the Clinical Global Impression-Improvement scale and led to the drug being given breakthrough status by the FDA in 2016.
Zulresso’s Phase II results were confirmed in three subsequent placebo-controlled, randomised studies, which formed the basis of the FDA’s approval. Women with moderate and severe post-partum depression were recruited into these trials and all doses of the two patient groups had a significant mean reduction from baseline in HAM-D at 60 hours with a meaningful reduction in depressive symptoms observed as early as 24 hours into treatment.
The speed of Zulresso’s onset is a crucial element of the drug – it can take a few weeks or months for anti-depressants to kick in – however, the FDA noted the importance of the drug continuing to improve depression over a 30-day follow-up period.
Administration-related risks flagged by FDA
Although Zulresso’s GABAA mechanism of action was efficacious and the drug was generally well tolerated by patients, the FDA was concerned by “serious risks, including excessive sedation or sudden loss of consciousness during administration”, as noted by the regulator’s Center for Drug Evaluation and Research’s Division of Psychiatry Products acting director Tiffany Farchione; in early trials two patients experienced sedation as a side effect.
These types of adverse events are of particular concern because the drug is administered through a continuous IV infusion for 60 hours, thus a sudden loss of consciousness could cause a patient serious harm. There is also the clear disadvantage that this administration method is highly inconvenient for a patient and a caregiver.
As a result, the FDA only approved Zulresso for use by patients “through a restricted distribution program at certified health care facilities where the health care provider can carefully monitor the patient” under the regulator’s Risk Evaluation and Mitigation Strategy (REMS).
Zulresso as a catalyst for PPD treatment
Despite concerns over the administration of Zulresso, the drug’s proven successful GABAA mechanism of action caused Sage’s stock to jump 5% following the approval announcement, building on a 60% rise in anticipation of approval, according to CNBC.
Zulresso’s approval was centre stage at Sage’s first quarter 2019 results, with CEO Jeff Jonas commenting: “It was gratifying that our first drug approval generated extensive media coverage of a disorder that for too long has been shrouded by stigma and shame.”
Being the first to market in post-partum depression with Zulresso gives Sage early access to a growing market. According to Credence Research, the PPD market’s growth is primarily due to rising awareness among women about the condition; it has been common for social stigma and lack of understanding to hinder diagnosis of this type of depression.
Sage is thus seeking to expand its portfolio of post-partum depression drugs targeting GABAA receptors; the company sees Zulresso as “a catalyst in starting a new dialogue emphasizing the importance of women’s mental health, and the importance of diagnosing and treating PPD”, as Jonas noted in a statement.
SAGE-217: a new, oral PPD candidate
The company has been developing its drug candidate SAGE-217 for post-partum depression, as well as other mood disorders; the FDA granted Sage breakthrough therapy designation for this drug too.
In January this year, Sage announced SAGE-217 met both its primary and secondary endpoints in the Phase III ROBIN study. Following two weeks of outpatient treatment, patients in the drug group had a 17.8 point improvement in HAM-D score, compared to 13.6 for the placebo group. There were also statistically significant reductions in HAM-D score at the end of a four-week follow-up period. Presentation of this data at the JP Morgan Healthcare Conference caused Sage’s share price to rise 40%, according to Pharmaphorum.
Jonas commented: “Data from the ROBIN Study, along with earlier data from our studies with Zulresso in post-partum depression and SAGE-217 in major depressive disorder [MDD], all point to the promise that our approach may hold – not only in changing the way PPD and MDD are treated, but also in potentially improving the lives of patients suffering from these mood disorders. The team at Sage has shown what rethinking CNS really means.”
Although SAGE-217 does not have as quick an onset as Zulresso, it still works more rapidly than most antidepressants. Also, as it is an oral drug, it will not be as inconvenient or require an FDA REMS, making it suitable for more patients. If SAGE-217 is approved, Sage and its post-partum depression portfolio would be well placed to take a leading role in a therapeutic field that is likely to grow in step with the public’s awareness of PPD and its potentially lethal effects.