SAGE Therapeutics, Inc.

iStock, NUniverse On its third-quarter earnings call Tuesday, Sage highlighted the launch of its Biogen-partnered postpartum depression drug Zurzuvae but said it will stop pursuing approval for major depressive disorder, which the FDA previously denied. Amid a season of setbacks, Sage Therapeutics reported strong third-quarter growth for its recently approved postpartum depression drug Zurzuvae, while announcing that it will no longer develop the therapy in major depressive disorder. In its Q3 earnings report released Tuesday afternoon, the company also noted a highly anticipated mid-stage readout in Huntington’s disease. Specifically, Sage reported $11 million in third-quarter revenue for Zurzuvae—50% of the net revenue reported by partner Biogen—representing 49% growth from the second quarter of 2024. The biotech’s cash position was slightly less favorable on September 30, 2024, than it was four months prior, with $569 million in cash, cash equivalents and marketable securities compared to $647 million on June 30. Sage was down 6.6% in premarket trading Wednesday, following the Q3 reveal. Sage and Biogen won approval for Zurzuvae in August 2023 as the first pill for postpartum depression (PPD), but the milestone was somewhat overshadowed by the FDA’s rejection of the drug in major depressive disorder (MDD) —a much larger market. On an investor call Tuesday, Sage CEO Barry Greene said Biogen and Sage would not pursue development of Zurzuvae in MDD in the U.S. “based on the significant new investment and time we expect would be needed to conduct the additional studies.” Greene added that Sage is “prioritizing our resources and supporting the PPD patient community.” Sage also announced it would discontinue Zulresso, an older PPD drug, as part of a strategic shift to more fully focus on the commercialization of Zurzuvae. Zulresso will be commercially available until Dec. 31, 2024. Sage executives on the call also highlighted an upcoming Phase II readout for dalzanemdor in Huntington’s disease patients with cognitive impairment. The readout follows a string of recent failures, as Sage reported earlier this month that dalzanemdor missed the primary endpoint in the Phase II LIGHTWAVE study in Alzheimer’s disease on the heels of another Phase II failure in Parkinson’s disease in April 2024. A Sage representative previously told BioSpace that Alzheimer’s and Huntington’s have differences in their underlying pathophysiology and symptomatology that can influence study outcomes. Sage Chief Medical Officer Laura Gault added that the Huntington’s disease patient population is “genetically defined” and younger than those seen in some of dalzanemdor’s previous studies. “That means this population is more homogeneous, has fewer medical comorbidities, and as a consequence, it’s easier to detect a signal in this population.” Sage executives also addressed the recently announced strategic reorganization , in which it will part with over 165 employees. Greene said Tuesday that the decision was intended to strengthen the company’s balance sheet, focus on the Zurzuvae launch and Huntington’s readout, and explore opportunities across its early-stage pipeline. “We believe that this restructuring will right-size Sage for future success,” Greene said.

Biogen and Sage Therapeutics are discontinuing further development of their drug Zurzuvae as a potential treatment for major depressive disorder, a move that follows last year’s FDA rejection of the therapy in that indication. The regulator had asked the companies to provide more evidence of efficacy from additional clinical testing. In its report of third quarter 2024 financial results posted Wednesday, Biogen said the discontinuation decision is based on the “significant new investment and time we expect would be needed to conduct additional studies.” Going forward, the two Cambridge, Massachusetts-based companies plan to focus their efforts on commercializing this drug in postpartum depression, for which it was approved last year. But postpartum depression is a much smaller market than major depressive disorder, which means Zurzuvae is unlikely to achieve the lofty sales once expected for the pill. With the renewed focus on Zurzuvae for postpartum depression, Sage will discontinue Zulresso, a product that in 2019 became the first FDA-approved postpartum depression drug. Zulresso is administered as a 60-hour infusion, a challenging dosing regimen that has limited market uptake of this Sage drug. By contrast, Zurzuvae is a pill taken once daily for 14 days. For the nine months ended Sept. 30, Sage reported Zulresso accounted for $3.1 million in revenue, down 63% compared to the same period in 2023. Sage said Zulresso will be commercially available until Dec. 31. Sponsored Post The Future of Hospitals and Pharma Companies Will Depend on Strength of Healthcare Analytics Insights PurpleLab® stands out from others in this sector by providing its data analytics services to several different groups of users across healthcare and pharma companies. By Stephanie Baum The collaboration between Biogen and Sage dates to 2020. Biogen committed $1.5 billion up front to begin the R&D alliance focused on depression and movement disorders. Results have been disappointing. Besides Zurzuvae’s rejection in major depressive disorder, collaboration on the movement disorders program SAGE-324 is ending. In July, the companies reported this oral drug failed a Phase 2 test in essential tremor. Biogen gave Sage a termination notice for SAGE-324 last month. When the termination becomes effective in February, Sage will become fully responsible for the program. In its quarterly report, Sage said it plans to evaluate other potential indications for this drug. In a note sent to investors, Leerink Partners analyst Marc Goodman said the discontinuation of further development of Zurzuvae in major depressive disorder was expected. While Leerink projects the drug could achieve $200 million to $300 million in peak sales in postpartum depression, physicians have told the firm they’re skeptical of a paradigm shift in treatment and the black box warning on the product’s label could further limit use. Sage does have other programs in the pipeline, but the company will have fewer workers to support them. In its quarterly report, the company said it will commence a business restructuring to strengthen its balance sheet and focus on the ongoing launch of Zurzuvae for postpartum depression. Sage said it will shed about 33% of its workforce. With the restructuring, the company said it expects to have enough capital to support operations into 2026.

: SP-624 may treat depression in women by modulating the distinct female genetic profile. Credit: Prathankarnpap/Shutterstock Arrivo BioVentures’ SIRT6 activator SP-624 has been found to significantly reduce symptoms of major depressive disorder (MDD), but only in women. Steve Butts, Arrivo CEO, stated that data from a Phase IIa trial (NCT04479852) showed SP-624 elicited a significant reduction in MDD symptoms, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) score. However, reduction was only evident among female patients; for males, no statistically significant difference could be found. Following this trial, the Morrisville, North Carolina-based biotech announced it enrolled its first subject in a Phase I trial (NCT06570369) of the drug for this indication in a 10 October 2024 release. In parallel, Arrivo is running a Phase IIb trial (NCT06254612) specifically focussed on evaluating the drug’s efficacy in female patients as the primary endpoint, which dosed the first patient in April 2024. To explain the disparity, Butts pointed to  research indicating gene expression profiles associated with MDD differ between the sexes. A 2018 meta-analysis published in Biological Psychiatry found that of 706 and 882 genes differentially expressed in men and women with MDD, respectively, only 21 genes in common changed in the same direction—were either up- or downregulated for both sexes. “Our drug is the first epigenetic mechanism being tested in depression that can really test that theory”, claims Butts, adding, “this is the first time that a SIRT6 activator has ever been used in a patient with depression.” See Also: Novartis’ Scemblix gains FDA approval for leukaemia GSK to acquire Chimagen’s CMG1A46 for autoimmune disease SP-624 is a small molecule developed by Sirtsei Pharmaceuticals, a subsidiary of Arrivo, which targets Sirtuin 6 (SIRT6). An NAD-dependent enzyme, SIRT6 modulates gene expression, metabolism, and repair associated with MDD, the activation of which is thought to alleviate depression. Beyond mechanistic differences, MDD also presents at different incidence rates between sexes. As per GlobalData analysis , the prevalence of MDD among females was double that of men in  across the eight major markets (the US, France, Germany, Italy, Spain, the UK, Japan and Canada) 2023. The MDD market is expected to become $9.6bn in size in 2029 in those same eight markets, as per a GlobalData report. GlobalData is the parent company of Pharmaceutical Technology There are so far no marketed therapies indicated exclusively to treat MDD in women, despite its prevalence and distinct genetic profile, and development in the female-oriented clinical space has met resistance. However, in recent years, drugs like Johnson and & Johnson Innovation Medicines’ (J&J) Spravato (esketamine) and Axsome Therapeutics’ Auvelity (dextromethorphan-bupropion) have been approved to treat MDD. J&J also saw some success in the MDD arena earlier this year when its Phase III study with seltorexant improved depressive symptoms in patients as per the MADRS scale. However, not all have been successful. Sage Therapeutics axed 40% of its staff in September 2023 following the rejection of their drug Zurzuvae (zuranolone) for MDD by the US Food and Drug Administration (FDA). The drug is approved to treat postpartum depression (PPD). Earlier this month (17 October 2024), the company fired 55% of the remaining R&D staff to support the drug’s ongoing launch for PPD.