Sage Therapeutics Stock

Sage Therapeutics, Inc. operates as a biopharmaceutical company.

Alongside the company’s postpartum depression commercial products, the company is targeting diseases and disorders of the brain across its clinical development and earlier stage pipeline. The company’s focus as a company is on brain health, and the company is targeting two critical central nervous system, or CNS, receptor systems, GABA and NMDA. The GABA receptor family, which is recognized as the major inhibitory neurotransmitter in the CNS, mediates downstream neurologic and bodily function via activation of GABAA receptors. The NMDA-type receptors of the glutamate receptor system are a major excitatory receptor system in the CNS. Dysfunction in these systems is implicated in a broad range of CNS disorders.

The company’s product ZURZUVAE (zuranolone) was approved by the U.S. Food and Drug Administration, or FDA, on August 4, 2023 for the treatment of postpartum depression, or PPD, in adults. ZURZUVAE is a neuroactive steroid that is a positive allosteric modulator of GABAA receptors, targeting both synaptic and extrasynaptic GABAA receptors, and is the first oral, once-daily, 14-day treatment specifically indicated for adults with PPD. ZURZUVAE became commercially available in the U.S. as a treatment option for women with PPD in December 2023. The company and its collaboration partner, Biogen MA Inc., or BIMA, and Biogen International GmbH, or, together with BIMA, Biogen, are jointly commercializing ZURZUVAE in the U.S. under a collaboration and license agreement, or the Biogen Collaboration Agreement, that became effective in December 2020.

ZURZUVAE (zuranolone) received a Schedule IV classification from the U.S. Drug Enforcement Administration, or DEA. ZURZUVAE includes a boxed warning that instructs healthcare providers to advise patients that ZURZUVAE causes driving impairment due to CNS depressant effects, and that people who take ZURZUVAE should not drive a motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness until at least 12 hours after ZURZUVAE administration for the duration of the 14-day treatment course.

The company and Biogen are jointly developing zuranolone and another of the company’s late-stage compounds, SAGE-324, in the U.S. pursuant to the Biogen Collaboration Agreement. The company jointly commercializes ZURZUVAE with Biogen in the U.S. and has the right to jointly commercialize any additional products containing zuranolone, which, along with ZURZUVAE, the company refers to as Licensed 217 Products, and products containing SAGE-324, which the company refers to as Licensed 324 Products, if the company’s ongoing and any future development efforts are successful. The company refers to the Licensed 217 Products and Licensed 324 Products individually as a Product Class and collectively as the Licensed Products. In addition, the company has granted Biogen sole rights to develop and commercialize the Licensed Products outside the U.S., other than in Japan, Taiwan and South Korea, or the Shionogi Territory, with respect to zuranolone, where the company has granted rights to Shionogi & Co., Ltd., or Shionogi. The company refers to the territories outside the U.S. to which Biogen has rights under the Biogen Collaboration Agreement with respect to the applicable Licensed Product as the Biogen Territory.

The company also has a collaboration agreement with Shionogi for the development of zuranolone in the Shionogi Territory. Shionogi is developing zuranolone for the treatment of patients with moderate to severe MDD in Japan.

On August 4, 2023, the FDA issued a complete response letter, or CRL, related to the new drug application, or NDA, for zuranolone for the treatment of major depressive disorder, or MDD. The CRL stated that the NDA did not provide substantial evidence of effectiveness to support the approval of zuranolone for the treatment of MDD and that one or more additional clinical trials will be needed. The company and Biogen are continuing to seek feedback from the FDA and evaluating next steps.

The company’s product ZULRESSO (brexanolone) CIV injection is approved in the U.S. for the treatment of PPD in individuals 15 years old and older. ZULRESSO may only be administered in qualified medically-supervised healthcare settings. Brexanolone is chemically identical to allopregnanolone, a naturally occurring neuroactive steroid that acts as a positive allosteric modulator of GABAA receptors.

The company is also developing a portfolio of other novel compounds that target GABAA receptors, including SAGE-324, which is a novel GABAA receptor positive allosteric modulator intended for chronic oral dosing. The company has completed enrollment of patients with essential tremor in a Phase 2b placebo-controlled dose-ranging clinical trial of SAGE-324, known as the KINETIC 2 Study, and expects to announce topline results from the KINETIC 2 Study in mid-2024. In May 2022, the company also initiated an open-label Phase 2 clinical trial designed to evaluate the long-term safety and tolerability of SAGE-324 in patients with essential tremor, with incidence of treatment-emergent adverse events as the primary endpoint. This is intended to be a multi-year clinical trial, and will initially be open to rollover patients from other SAGE-324 clinical trials in patients with essential tremor, including the KINETIC 2 Study. SAGE-324 also has potential for the treatment of a number of other neurological conditions, including epilepsy and Parkinson’s disease. Additional development plans for SAGE-324 will be determined as part of the company’s strategic collaboration with Biogen.

The company’s second area of focus for development is novel compounds that target the NMDA receptor. The company’s lead product candidate selected in this area is dalzanemdor (SAGE-718), an oxysterol-based positive allosteric modulator of the NMDA receptor, which the company is exploring in certain cognition-related disorders associated with NMDA receptor dysfunction, including cognitive impairment associated with diseases such as Huntington’s disease, Parkinson’s disease and Alzheimer’s disease. The FDA has granted dalzanemdor (SAGE-718) Fast Track designation as a potential treatment for patients with Huntington’s disease. In addition, in October 2023, the FDA granted Orphan Drug Designation to dalzanemdor (SAGE-718) for the potential treatment of Huntington’s disease. The European Medicines Agency previously granted Orphan Drug Designation to dalzanemdor (SAGE-718) for the potential treatment of Huntington’s disease in February 2023. Dalzanemdor (SAGE-718) has also been granted Innovative Licensing and Access Pathway (ILAP) designation from the Medicines & Healthcare products Regulatory Agency (MHRA) in the United Kingdom for the development of dalzanemdor (SAGE-718) for the treatment of cognitive impairment associated with Huntington’s disease. Dalzanemdor (SAGE-718) is being studied in several ongoing clinical trials, including the placebo-controlled Phase 2 DIMENSION Study, the placebo-controlled Phase 2 SURVEYOR Study, and the Phase 3 open-label PURVIEW Study evaluating patients with Huntington’s disease cognitive impairment; the double-blind placebo-controlled Phase 2 PRECEDENT Study evaluating dalzanemdor (SAGE-718) in patients with mild cognitive impairment due to Parkinson’s disease; and the randomized placebo-controlled Phase 2 LIGHTWAVE Study evaluating dalzanemdor (SAGE-718) in patients with mild cognitive impairment and mild dementia due to Alzheimer’s disease.

The company expects to report topline data from the PRECEDENT Study in early 2024; the SURVEYOR Study in mid-2024; and the DIMENSION and LIGHTWAVE studies in late 2024.

The company has other programs at earlier stages of development with a focus on both acute and chronic brain health disorders. The company expects to continue its work on allosteric modulation of the GABAA and NMDA receptor systems in the brain. The company may have the opportunity to develop molecules from its internal portfolio with the goal of addressing a number of these disorders in the future. The company may also have the opportunity to use its scientific approach to explore targets beyond the GABAA and NMDA receptor systems and to develop compounds in areas of unmet need outside of brain health.

Strategy

The key elements of the company’s strategy are to:

Successfully commercialize ZURZUVAE, along with the company’s collaboration partner, Biogen, for the treatment of women with PPD in the U.S.; and potentially advance the development of zuranolone in additional indications as part of the company’s strategic collaboration with Biogen;

Complete ongoing and planned clinical trials of SAGE-324 as part of the company’s strategic collaboration with Biogen;

Complete ongoing and planned clinical trials of dalzanemdor (SAGE-718);

Support the company’s collaboration with Biogen with respect to zuranolone and SAGE-324 in the U.S., and support Biogen’s development of zuranolone and SAGE-324 in the Biogen Territory and Shionogi’s development of zuranolone in the Shionogi Territory;

Provide support for existing, active ZULRESSO treatment sites;

Advance the company’s earlier-stage compounds;

Continue the company’s research and development efforts to evaluate the potential for its existing product candidates for the treatment of additional indications or in new formulations;

Identify new targets, and generate and test new compounds and product candidates, with a focus on indications where the company can make well-informed, rapid go/no-go decisions, with the goal of developing a diversified portfolio of assets with differentiated features;

Prepare and file NDAs with the FDA, and conduct permitted pre-launch activities with respect to any of the company’s product candidates that have been successfully developed;

Commercialize any product candidates for which the company obtains regulatory approval, including the manufacture of commercial supplies;

Evaluate the market potential and regulatory pathways for the company’s product candidates beyond zuranolone and SAGE-324 in the European Union, or EU, and other jurisdictions outside the U.S., and determine how best to move forward where and when it may make business and strategic sense;

Continue to build, maintain, defend, leverage, and expand the company’s intellectual property portfolio, including by utilizing the strengths of the company’s proprietary chemistry platform and scientific know-how to expand its portfolio of new chemical entities with the goals of lessening the company’s long-term reliance on the success of any one program and facilitating long-term growth; and

Continue to explore opportunities to establish licenses, collaborations, or other agreements or alliances with other biotechnology and pharmaceutical companies, at the appropriate time, where a collaboration may add significant value to the company’s efforts, including through capabilities, infrastructure, speed or financial contributions, or to acquire new compounds, product candidates or products if such opportunities will help the company achieve its goals or meet other strategic objectives.

Product Pipeline

ZURZUVAE (zuranolone)

The company’s product ZURZUVAE (zuranolone) was approved by the FDA on August 4, 2023 for the treatment of PPD in adults. ZURZUVAE is a neuroactive steroid that is a positive allosteric modulator of GABAA receptors, targeting both synaptic and extrasynaptic GABAA receptors, and is the first oral, once-daily, 14-day treatment specifically indicated for adults with PPD. ZURZUVAE became commercially available in the U.S. for women with PPD in December 2023. The company and its collaboration partner, Biogen, are jointly commercializing ZURZUVAE in the U.S. under the Biogen Collaboration Agreement. The company and Biogen equally share in all operating profits and losses arising from sales of ZURZUVAE in the U.S., with Biogen recording such product sales.

ZURZUVAE (zuranolone) received a Schedule IV classification from the DEA. The approval of ZURZUVAE to treat PPD in adults was based on two pivotal clinical trials, the SKYLARK Study and the ROBIN Study, in adult women with PPD. ZURZUVAE includes a boxed warning that instructs healthcare providers to advise patients that ZURZUVAE causes driving impairment due to central nervous system depressant effects, and that people who take ZURZUVAE should not drive a motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness until at least 12 hours after ZURZUVAE administration for the duration of the 14-day treatment course. ZURZUVAE can cause CNS depressant effects. The most common side effects of ZURZUVAE include sleepiness or drowsiness, dizziness, common cold, diarrhea, feeling tired, weak, or having no energy, and urinary tract infection.

ZURZUVAE is the first and only oral product approved by the FDA for women with PPD (and the second approved product for PPD after ZULRESSO). The current standard of care for PPD is consisted of psychotherapy and, in women with moderate or severe PPD, the cautious use of pharmacological therapies such as selective serotonin reuptake inhibitors, or SSRIs, and serotonin and norepinephrine reuptake inhibitors, or SNRIs.

Naturally occurring allopregnanolone is found at its highest levels in women during the third trimester of pregnancy, returning to normal levels generally within 24 hours after giving birth. Levels of allopregnanolone have been found to be lower in women with PPD than in healthy women. It may be that women with PPD are particularly sensitive to the rapid decline in allopregnanolone after birth, potentially causing GABAA-system mediated mood disruption. These data led to the company’s interest in evaluating allosteric modulators of the GABAA receptor—such as brexanolone and zuranolone—for the treatment of PPD.

On August 4, 2023, the FDA issued a CRL related to the NDA for zuranolone for the treatment of MDD. The CRL stated that the NDA did not provide substantial evidence of effectiveness to support the approval of zuranolone for the treatment of MDD and that one or more additional clinical trials will be needed. The company and Biogen are continuing to seek feedback from the FDA and evaluating next steps.

The company has granted Biogen sole rights to develop and commercialize the zuranolone outside the U.S., other than in Japan, Taiwan and South Korea where the company has granted rights to Shionogi. Shionogi is developing zuranolone for the treatment of patients with moderate to severe MDD in Japan.

The company may consider additional development opportunities for zuranolone as part of the Biogen collaboration.

ZULRESSO (Brexanolone) CIV Injection

The company’s product ZULRESSO is a proprietary IV formulation of brexanolone approved in the U.S. for the treatment of PPD in individuals 15 years old and older. Brexanolone is chemically identical to allopregnanolone, a naturally occurring neuroactive steroid that acts as a positive allosteric modulator of GABAA receptors. The company launched ZULRESSO commercially in the U.S. in June 2019. The DEA placed ZULRESSO into Schedule IV of the Controlled Substances Act, or CSA. ZULRESSO is administered as a continuous infusion given over two and a half days. Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness during the ZULRESSO infusion, ZULRESSO must be administered in a medically-supervised healthcare setting that has been certified under a Risk Evaluation and Mitigation Strategy, or REMS, program and meets the other requirements of the REMS program, including requirements related to monitoring of the patient during the infusion. Patients who are prescribed ZULRESSO are required to enroll in a registry, which may allow the company to compile additional information to further the company’s understanding of the risk of excessive sedation or sudden loss of consciousness during administration of ZULRESSO and management of the risk. Given the mode and setting of administration of ZULRESSO and the requirements of the REMS program, ZULRESSO has been administered to date primarily to treat women with severe PPD, and the company expects that to continue to be the case.

The approval of ZULRESSO in the U.S. was based on positive results from the company’s HUMMINGBIRD Phase 3 clinical program, which was consisted of two multicenter, randomized, double-blind, parallel-group, placebo-controlled, Phase 3 clinical trials designed to evaluate the safety and effectiveness of brexanolone in women with PPD, with supportive evidence from a Phase 2 clinical trial of brexanolone in PPD.

SAGE-324

In addition to zuranolone, the company has a portfolio of other novel compounds that target GABAA receptors, including SAGE-324, which the company is jointly developing with Biogen under the Biogen Collaboration Agreement. SAGE-324 is a novel GABAA receptor positive allosteric modulator intended for chronic oral dosing. In April 2021, the company and Biogen reported topline results from the company’s placebo-controlled Phase 2 clinical trial evaluating the safety and efficacy of SAGE-324 for the treatment of essential tremor, known as the KINETIC Study.

The Phase 2 KINETIC Study evaluating SAGE-324 for the treatment of adults with essential tremor (n=67 full analysis set) achieved its primary endpoint of a statistically significant reduction from baseline compared to placebo in The Essential Tremor Rating Assessment Scale, or TETRAS, Performance Subscale Item 4 upper limb tremor score on Day 29 (p-value=0.049), which corresponded to a 36% reduction from baseline in upper limb tremor amplitude in patients receiving SAGE-324 compared to a 21% reduction in patients receiving placebo. Patients were randomized 1:1 to receive SAGE-324 (60 mg) or matched placebo once daily in the morning. The trial evaluated treatment of SAGE-324 at the higher end of the dose range and the daily dose could be down-titrated to 45 mg or 30 mg. Activities of daily living, or ADL, scores showed a statistically significant correlation with upper limb tremor score at all timepoints. Although the clinical trial was not powered to fully examine TETRAS ADL, SAGE-324 was numerically superior to placebo at all time points during treatment. Reported treatment emergent adverse events, or TEAEs, were generally consistent with the safety profile of SAGE-324 previously reported. The most common TEAEs that were reported by 10% or more of patients in the SAGE-324 treatment group and at a rate at least twice as high as that of patients in the placebo group were: somnolence 68%; dizziness 38%; balance disorder 15%; diplopia 12%; dysarthria 12%; and gait disturbance 12%. In the KINETIC Study, patients with a more severe tremor at baseline (at or above the median TETRAS Performance Subscale upper limb tremor Item 4 score of 12) (n=47) who received SAGE-324 demonstrated a statistically significant reduction (p-value=0.007) from baseline in TETRAS Performance Subscale Item 4 upper limb tremor score compared to placebo at Day 29, corresponding to a 41% reduction from baseline in upper limb tremor amplitude in patients receiving SAGE-324 compared to an 18% reduction for placebo.

A Phase 2b double-blind, randomized, placebo-controlled, dose-response study of SAGE-324 in patients with moderate to severe essential tremor, known as the KINETIC 2 Study, has completed enrollment and the company expects to announce topline results in mid-2024. The primary intent of the KINETIC 2 Study is to evaluate different doses of SAGE-324 in reducing upper limb tremors. The primary endpoint of the study is change from baseline in TETRAS Performance Subscale Item 4 total score at Day 91. In May 2022, the company initiated an open-label Phase 2 clinical trial designed to evaluate the long-term safety and tolerability of SAGE-324 in patients with essential tremor, with incidence of TEAEs as the primary endpoint. This is intended to be a multi-year clinical trial, and will initially be open to rollover patients from other SAGE-324 clinical trials in patients with essential tremor, including the KINETIC 2 Study. SAGE-324 also has potential for the treatment of a number of other neurological conditions, including epilepsy and Parkinson’s disease.

The company is jointly developing SAGE-324 in the U.S. with Biogen, and will jointly commercialize Licensed 324 Products with Biogen in the U.S. if the company’s development efforts are successful and SAGE-324 is approved in the U.S. The company has granted Biogen sole rights to develop and commercialize SAGE-324 outside the U.S. The company may consider additional development plans and opportunities for SAGE-324 as part of the company’s collaboration with Biogen. If the company obtains regulatory approval of SAGE-324, the company will record sales of Licensed 324 Products.

Dalzanemdor (SAGE-718)

The company’s second area of focus is the development of novel compounds that target the NMDA receptor. Examples of indications involving NMDA receptor dysfunction include certain types, aspects or subpopulations of a number of diseases, such as Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, depression, attention deficit hyperactivity disorder, schizophrenia, and neuropathic pain.

The company’s lead product candidate selected in this area is dalzanemdor (SAGE-718), an oxysterol-based positive allosteric modulator of the NMDA receptor, which the company is exploring in certain cognition-related disorders associated with NMDA receptor dysfunction, including cognitive impairment associated with diseases, such as Huntington’s disease, Parkinson’s disease and Alzheimer’s disease.

Huntington’s Disease

The FDA has granted dalzanemdor (SAGE-718) Fast Track designation as a potential treatment for Huntington’s disease. In addition, in October 2023, the FDA granted orphan drug designation to dalzanemdor (SAGE-718) for the potential treatment of Huntington’s disease. The European Medicines Agency previously granted orphan drug designation to dalzanemdor (SAGE-718) for the potential treatment of Huntington’s disease in February 2023. Dalzanemdor (SAGE-718) has also been granted Innovative Licensing and Access Pathway (ILAP) designation from the Medicines & Healthcare products Regulatory Agency (MHRA) in the United Kingdom for the development of dalzanemdor (SAGE-718) for the treatment of cognitive impairment associated with Huntington’s disease. Dalzanemdor (SAGE-718) is being studied in three ongoing clinical trials in patients with Huntington’s disease cognitive impairment:

DIMENSION Study

In February 2022, dosing commenced in the DIMENSION Study, a double-blind placebo-controlled Phase 2 clinical trial of dalzanemdor (SAGE-718) in patients with Huntington’s disease cognitive impairment. The DIMENSION Study is designed to evaluate the efficacy of once-daily dosed dalzanemdor (SAGE-718) over three months. The company expects to report topline data from the DIMENSION Study in late 2024.

SURVEYOR Study

In March 2022, the company initiated the SURVEYOR Study, a placebo-controlled Phase 2 clinical trial of dalzanemdor (SAGE-718) in patients with Huntington’s disease cognitive impairment, with a healthy volunteer component, with the goal of generating evidence linking changes in cognition to real-world functioning. The SURVEYOR Study is not designed or powered to demonstrate a statistically significant difference between dalzanemdor (SAGE-718) and placebo. The company expects to report topline data from the SURVEYOR Study in mid-2024.

PURVIEW Study

In December 2022, the company initiated the PURVIEW Study, a Phase 3 open-label study to evaluate the long-term safety and tolerability of dalzanemdor (SAGE-718) in patients with Huntington’s disease cognitive impairment.

Parkinson’s Disease

In May 2021, the company announced results from the 14-day dosing cohort, or Cohort A, of a Phase 2a open-label clinical trial of dalzanemdor (SAGE-718) evaluating patients with mild cognitive impairment due to Parkinson’s disease, known as the PARADIGM Study. In Cohort A of the clinical trial, eight patients aged 50 to 75 years with mild cognitive impairment due to Parkinson’s disease received 3 mg of dalzanemdor (SAGE-718) daily for 14 days. Patients showed performance improvements from baseline on multiple tests in the cognitive domain of executive function during the 14 days of treatment. Emerging signals on several measures also suggested improved performance from baseline on cognitive tests in the domains of learning and memory over a similar timeframe.

In October 2022, the company presented additional results from the 28-day cohort, or Cohort B, of the open-label PARADIGM Study. In Cohort B of the clinical trial, seven patients aged 50 to 75 years with mild cognitive impairment due to Parkinson’s disease received 3 mg of dalzanemdor (SAGE-718) daily for 28 days. Patients showed performance improvements from baseline on multiple tests in the cognitive domain of executive function during the 28 days of treatment, as well as during the 14 day follow-up period. Dalzanemdor (SAGE-718) was generally well-tolerated in both cohorts of the clinical trial; there were no serious adverse events reported, and no TEAEs were determined to be related to dalzanemdor (SAGE-718) or resulted in study drug discontinuation or withdrawal from the study. As expected, given its profile, dalzanemdor (SAGE-718) demonstrated neutral results in certain tests of attention and psychomotor speed.

In March 2022, the company initiated a double-blind, placebo-controlled Phase 2 clinical trial of dalzanemdor (SAGE-718) in patients with mild cognitive impairment due to Parkinson’s disease, known as the PRECEDENT Study. The PRECEDENT Study is designed to evaluate the safety and efficacy of dalzanemdor (SAGE-718) in patients with mild cognitive impairment due to Parkinson’s disease over 42 days, followed by a controlled follow-up period. The company expects to report topline data from the PRECEDENT Study in early 2024.

Alzheimer’s Disease

In December 2021, the company reported topline data from the LUMINARY Study, a Phase 2a open-label clinical trial of dalzanemdor (SAGE-718) in patients with mild cognitive impairment and mild dementia due to Alzheimer’s disease (n=26 full analysis set), who received 3 mg of dalzanemdor (SAGE-718) daily for 14 days. The results showed performance improvements from baseline on five out of five unique tests in the cognitive domain of executive function and two out of four unique tests in the cognitive domains of learning and memory during the 14 days of treatment, consistent with positive signals seen in open-label clinical trials evaluating dalzanemdor (SAGE-718) as a treatment for cognitive impairment due to Parkinson’s disease and Huntington’s disease. Patients also showed performance improvement as measured by the Montreal Cognitive Assessment (MoCA) Test, a global measure of cognition, that reached statistical significance at Day 28 when compared to baseline in patients treated with dalzanemdor (SAGE-718). As expected, in certain tests of attention and psychomotor speed, dalzanemdor (SAGE-718) demonstrated neutral results. Dalzanemdor (SAGE-718) was generally well tolerated in the LUMINARY Study. Seven subjects reported a total of 11 TEAEs, seven of which were considered related to the study treatment and all of which were rated as mild or moderate in severity. The most commonly reported TEAEs were headache (n=2) and constipation (n=2). In December 2022, the company initiated the LIGHTWAVE Study, a randomized placebo-controlled Phase 2 clinical trial of dalzanemdor (SAGE-718) in patients with mild cognitive impairment and mild dementia due to Alzheimer’s disease. The company expects to report topline data from the LIGHTWAVE Study in late 2024.

Further Exploration of GABAA and NMDA Receptors and New Areas of Interest

The company expects to continue to focus its research and development efforts on allosteric modulation of the GABAA and NMDA receptor systems in the brain. The company’s portfolio of novel GABAA receptor positive allosteric modulators includes SAGE-689, a product candidate in Phase 1 clinical development intended for intramuscular administration, and SAGE-319, an extrasynaptic GABAA receptor-preferring positive allosteric modulator in Phase 1 clinical development for its potential use as an oral therapy in treating neurodevelopmental and motor disorders. The company also has earlier stage compounds focused on NMDA receptor modulation, including SAGE-421, an NMDA receptor positive allosteric modulator that the company plans to study for its potential use as an oral therapy in treating cognitive impairment and schizophrenia. The GABAA and NMDA receptor systems are broadly accepted as impacting many psychiatric and neurological disorders, spanning disorders of mood, seizure, cognition, anxiety, sleep, pain, and movement among others. The company may have opportunities to develop molecules from its internal portfolio to address a number of these disorders in the future. The company’s ability to identify and develop such novel brain health therapies is enabled by its proprietary chemistry platform that is centered, as a starting point, on knowledge of the chemical scaffolds of certain endogenous neuroactive steroid compounds. The company’s knowledge of the chemistry and activity of allosteric modulators allows the company to efficiently design molecules with different characteristics. This diversity enables the company to regulate important properties, such as half-life, brain penetration and receptor pharmacology to develop product candidates that have the potential for better selectivity, increased tolerability, and fewer off-target side effects than either current therapies or previous therapies which have failed in development. The company may also have the opportunity to use its scientific approach to explore targets beyond the GABAA and NMDA receptor systems and to develop compounds in areas of unmet need outside of brain health disorders.

The company’s ability to design and develop novel molecules with distinct profiles and receptor subtype selectivity may also provide the company with the option, if the company chooses, to potentially partner certain assets with third parties who possess the development and commercialization capabilities to pursue these programs, like the company’s strategic collaboration with Biogen. The company may also evaluate opportunities to acquire new compounds, product candidates or products from other companies or from academic institutions if such opportunities will help the company achieve its goals or meet other strategic objectives.

Sales and Marketing

The company’s product ZURZUVAE became commercially available in the U.S. in December 2023 as the first and only oral product approved by the FDA specifically for the treatment of adults with PPD. The company and Biogen are jointly commercializing ZURZUVAE as a treatment for women with PPD in the U.S. under the Biogen Collaboration Agreement. The company and Biogen equally share in all operating profits and losses arising from sales of ZURZUVAE in the U.S., with Biogen recording such sales.

The company and Biogen are utilizing a specialty pharmacy distribution model by which ZURZUVAE is shipped directly to women with PPD who are prescribed the treatment. The company and Biogen have active field sales forces supported by experienced sales leadership teams and professionals in marketing, access and reimbursement, managed markets, market research, commercial operations, and sales force planning and management. The company and Biogen are engaging in discussions with national, regional and government payors to advocate for broad and equitable access to ZURZUVAE for women with PPD with minimal restrictions. While coverage decisions by insurers across all payor segments can take time, the company and Biogen are focused on helping women with PPD who are prescribed ZURZUVAE gain access to ZURZUVAE as quickly as possible. To support the company’s objectives of optimizing access, driving urgency to treat women with PPD, and breaking stigma associated with PPD, the company is using a broad omnichannel approach, consisted of dynamic digital tools, to provide education about PPD to healthcare providers, patients, and patient advocates. Sage and Biogen field sales teams are engaging in promotional dialogues with healthcare providers who diagnose and treat women with PPD. In December, the company saw balanced prescribing across OBGYNs and psychiatrists with a small number of primary care physicians also prescribing. The company has also launched a patient support program, ZURZUVAE For You, which provides educational resources, help with understanding insurance coverage, and assistance navigating the prescription fulfillment process.

The company and Biogen are also working to help raise awareness of the importance of treating PPD rapidly and removing barriers to treatment. The company’s commercialization infrastructure also includes capabilities in medical affairs, manufacturing, quality control, drug safety and pharmacovigilance, health economics and outcomes research (HEOR), and compliance.

The company’s product, ZULRESSO, is commercially available in the U.S. as a treatment for PPD in individuals 15 years old and older. ZULRESSO is administered as a continuous infusion given over two and a half days. Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness during the ZULRESSO infusion, ZULRESSO is approved for administration only in a medically-supervised healthcare setting that has been certified under a REMS program and meets the other requirements of the REMS program, including requirements related to monitoring of the patient during the infusion. The actions required for a healthcare setting to be ready and willing to treat women with PPD are complex and time-consuming. These actions include becoming REMS-certified; achieving formulary approvals; establishing protocols for administering ZULRESSO; and securing satisfactory reimbursement. Sites must often negotiate reimbursement on a payor-by-payor basis under commercial coverage. The availability, terms and timing of coverage for ZULRESSO vary from payor to payor, both for commercially insured patients and from state Medicaid systems, and the company has encountered some states that impose significant coverage restrictions or lengthy delays on reimbursement of ZULRESSO. As a result, certain healthcare settings will not treat Medicaid patients with ZULRESSO even if they are active sites of care for ZULRESSO. These requirements have created significant barriers to treatment for women with PPD.

The company’s commercial operations for ZULRESSO are limited to account management focused on geographies that have existing, active ZULRESSO treatment sites. The company expects that the commercial availability of ZURZUVAE for women with PPD, the company’s limited commercial efforts for ZULRESSO, and barriers to treatment with ZULRESSO will continue to substantially limit the revenue opportunity for ZULRESSO and the number of healthcare settings that are or become treatment sites for ZULRESSO. The company may also find that certain healthcare settings that have in the past been active treatment sites may not be willing to remain infusion-ready as a result of the complex requirements related to administration of ZULRESSO and compliance with the REMS, related limitations and restrictions, or because of actual or perceived difficulties obtaining satisfactory reimbursement or limitations on reimbursement or for other reasons, including staffing shortages, or as a result of the commercial availability of ZURZUVAE. Healthcare settings that are active sites may also limit capacity used for ZULRESSO infusions. Sage Central, the company’s patient support center located in Raleigh, North Carolina, continues to provide a range of patient support resources to assist women with PPD and their families in the ZULRESSO treatment journey.

In addition to the company’s joint commercialization of ZURZUVAE for the treatment of women with PPD in the U.S., the company and Biogen have agreed as part of its collaboration that the company will jointly commercialize in the U.S. other Licensed 217 Products and Licensed 324 Products if pursued and successfully developed and approved, including sharing equally in sales and marketing activities and profits and losses in the U.S. If the company obtains regulatory approval of SAGE-324, the company will record sales of Licensed 324 Products. The company has granted Biogen sole rights to commercialize the Licensed Products outside the U.S., other than in the Shionogi Territory with respect to zuranolone, where the company has granted such rights to Shionogi.

Licenses

The company has entered into several material license agreements with respect to the company’s product and clinical-stage product candidates, which are described below.

CyDex Pharmaceuticals

In September 2015, the company amended and restated its existing commercial license agreement with CyDex Pharmaceuticals, Inc., a wholly owned subsidiary of Ligand Pharmaceuticals Incorporated, or CyDex. Under the terms of the commercial license agreement, as amended and restated, CyDex has granted the company an exclusive license to CyDex’s Captisol drug formulation technology and related intellectual property for the manufacture of pharmaceutical products incorporating brexanolone and the company’s compound known as SAGE-689, and the development and commercialization of the resulting products for the treatment, prevention or diagnosis of any disease or symptom in humans or animals other than the ocular treatment of any disease or condition with a formulation, including a hormone; topical ocular treatment of inflammatory conditions; treatment and prophylaxis of fungal infections in humans; and any ocular treatment for retinal degeneration.

Pursuant to and during the term of the CyDex license, the company is required to use commercially reasonable efforts to continue active, diligent development of the licensed product, to seek regulatory approval of the licensed product and to commercialize the licensed product following regulatory approval. The company must deliver periodic progress reports to CyDex.

The company is also party to a supply agreement with CyDex. Under the supply agreement, the company is required to purchase all of its requirements for Captisol with respect to brexanolone and SAGE-689 from CyDex, and CyDex is required to supply the company with Captisol for such purposes, subject to certain limitations.

University of California

In October 2013, the company entered into a license agreement with The Regents of the University of California, or the Regents, which was amended in May 2014. Pursuant to this agreement, and subject to certain rights of the U.S. government and rights retained by the Regents, the Regents granted the company a non-exclusive, non-transferable license under all personal property rights of the Regents covering the tangible personal property in an investigational new drug, or IND, application package owned by the Regents, or the Data, and a specified quantity of cGMP grade allopregnanolone, or the Material, to use the Data for reference or incorporation in an IND for the use of the Material as a treatment of status epilepticus, or SE, essential tremor and/or PPD; and use the Material or modifications of the Material to develop a pharmaceutical formulation for clinical trials for SE, essential tremor and/or PPD. The rights licensed to the company is not sublicensable.

In June 2015, the company entered into an exclusive license agreement with the Regents whereby the company was granted an exclusive license to certain patent rights related to the use of allopregnanolone to treat various diseases.

Collaboration and License Agreement with Biogen

In November 2020, the company entered into the Biogen Collaboration Agreement with Biogen for the development, manufacture and commercialization of Licensed 217 Products and Licensed 324 Products, which became effective in December 2020.

The company and Biogen have agreed that the company will jointly develop and commercialize the Licensed Products in the U.S., and that Biogen solely will develop and commercialize the Licensed Products outside the U.S., except, with respect to the Licensed 217 Products, in the Shionogi Territory. Each of the company and Biogen is obligated to use commercially reasonable efforts to develop at least one product in each Product Class in the U.S., and Biogen is also obligated to use commercially reasonable efforts to develop at least one product in each Product Class in the Biogen Territory. The company and Biogen have agreed to share jointly in the performance of the activities under the Biogen Collaboration Agreement in the U.S. and to share all operating profits and losses for activities under the Biogen Collaboration Agreement solely for the U.S. equally. The Biogen Collaboration Agreement provides that Biogen has sole responsibility and decision-making authority with respect to such activities in the Biogen Territory. Biogen is solely responsible for all costs for activities under the Biogen Collaboration Agreement in the Biogen Territory. The company has an Opt-Out Right (as defined below) in the U.S. with respect to a Product Class.

The company has granted to Biogen a non-transferable, sublicensable, except for certain specified exceptions, license to certain of the company’s intellectual property as needed to perform the activities under the Biogen Collaboration Agreement. Such license is co-exclusive with the company in the U.S. and exclusive, even as to the company, in the Biogen Territory, subject to certain retained rights to allow the company to exercise the company’s rights and perform the company’s obligations under the Agreement and with respect to the Shionogi Territory.

The company’s activities for the U.S. are conducted pursuant to joint plans agreed to by the company and Biogen, on a Licensed Product-by-Licensed Product basis, and overseen by a joint steering committee, or the JSC. The JSC is composed of an equal number of representatives from each of the company and Biogen.

Collaboration Agreement with Shionogi & Co., Ltd.

In June 2018, the company entered into a collaboration agreement with Shionogi. Pursuant to this agreement, Shionogi is responsible for all clinical development, regulatory filings and commercialization of products containing zuranolone for the treatment of MDD and potentially other indications in the Shionogi Territory.

Shionogi has also granted the company certain rights to co-promote zuranolone in Japan. As between the company and Shionogi, the company maintains exclusive rights to develop and commercialize zuranolone outside of the Shionogi Territory.

Intellectual Property

Patents

The company holds issued patents and pending patent applications in the U.S., and in certain foreign countries. The company’s intellectual property holdings include, but are not limited to:

One issued U.S. patent, exclusively licensed to the company, covering a method of using the company’s proprietary brexanolone formulation to treat PPD, which will expire in 2033; one U.S. issued patent and one granted patent in Europe covering the company’s proprietary formulation of brexanolone, which will expire in 2033; and one U.S. issued patent covering the dosage regimen of brexanolone to treat PPD, which will expire in 2037.

Pending U.S. and foreign patent applications covering certain aspects of brexanolone, including courses of treatment, dosage regimens, methods for manufacturing, and additional uses of the formulation of brexanolone to treat various brain health diseases and disorders, including PPD.

One issued U.S. patent covering the composition of matter of zuranolone, three issued U.S. patents covering methods of using zuranolone, one granted European patent covering the composition of matter of zuranolone, and one granted European patent covering methods of using zuranolone, each of which expires in April 2034, subject to any potential extensions; one issued U.S. patent covering certain solid forms of zuranolone, which expires in August 2037, and one issued U.S. patent covering methods of using certain solid forms of zuranolone, which expires in December 2037, subject to any potential extensions; and pending U.S. and foreign patent applications covering zuranolone, uses of zuranolone to treat various brain health diseases and disorders, and solid forms of zuranolone.

Issued patents covering the composition of matter for SAGE-324 in Europe and Japan, expiring in May 2035, and the U.S. and foreign patent applications covering SAGE-324, SAGE-319, and many other modulators of the GABAA receptor and uses of these compounds to treat various brain health diseases and disorders.

Two issued U.S. patents covering composition of matter and method of use of SAGE-689 which expire in December 2033, and the U.S. and foreign patent applications covering SAGE-689 and uses of SAGE-689 to treat various brain health diseases and disorders. These patents and patent applications are co-owned with Washington University, and Sage has an exclusive license to Washington University’s rights in these patents and patent applications.

The U.S. and foreign patents and patent applications covering dalzanemdor (SAGE-718) and many other modulators of the NMDA receptor, and uses of these compounds to treat various brain health diseases and disorders.

Government Regulation

The company’s product candidates must be approved by the FDA through the NDA process before they may be legally marketed in the U.S.

The company relies on third parties for the production of clinical and commercial quantities of the company’s products in accordance with cGMP regulations.

The federal Physician Payment Sunshine Act, implemented as the Open Payments Program, which requires manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to the Centers for Medicare & Medicaid Services, or CMS, the agency that administers the Medicare and Medicaid programs, information related to direct or indirect payments and other transfers of value to physicians, physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, and certified nurse-midwives, and teaching hospitals, as well as ownership and investment interests held in the company by physicians and their immediate family members.

Research and Development

The company’s research and development expenses were $356.2 million for the year ended December 31, 2023.

Competition

In the field of neuroactive steroids focused specifically on modulation of GABAA receptors, the company faces competition from a number of companies, including Marinus Pharmaceuticals, Inc., which received FDA approval of ganaxolone, a known GABAA positive allosteric modulator neuroactive steroid, to treat seizures associated with CDKL5 deficiency disorder, a rare, genetic epilepsy. Other GABAA competitors include darigabat, which is being developed by Cerevel Therapeutics, Inc. for the treatment of epilepsy and panic disorder.

History

The company was founded in 2010. It was incorporated under the laws of the state of Delaware in 2010. The company was formerly known as Sterogen Biopharma, Inc. and changed its name to Sage Therapeutics, Inc. in 2011.