CNS Drug Trailblazer, Sage Therapeutics layout

Postpartum depression is a unique major depressive disorder associated with childbirth that usually occurs
in a subset of women in the third trimester or within four weeks of childbirth.
Postpartum depression can have disastrous consequences for a woman and her family, including severe dysfunction, emotional depression and/or loss of interest in
the newborn.
Other symptoms associated with depression include loss of appetite, inability to sleep, inability to concentrate, and low
self-esteem.

On March 19, 2019, Zulresso®, the world's first postpartum depression drug, was launched in the United States, and it has been more than three years now, but its economic benefits have not reached the expected results, resulting in the drug developer Sage therapeutics' revenue in recent years also far less than expected
.
The company announced a restructuring on April 8, 2020, which included layoffs of 340 people, or 53 percent
of the company's total workforce at the time.

Sage Therapeutics, Inc.
(stock code: SAGE) from the United States is a biopharmaceutical company dedicated to developing and commercializing new drugs to treat life-threatening, rare central nervous system disorders, and it currently has three focus areas for brain diseases and disorders: depression, neurology, and neuropsychiatry
。 Founded by Steven Mark Paul and Douglas Covey, the company is headquartered in Cambridge, Massachusetts, and officially changed its name from the original Sterogen Biopharma to Sage Therapeutics, Inc.

on September 13, 2011.
Sage went public on the NASDAQ on July 18, 2014 ($38.
5 million per share as of September 23, 2022, with a total market capitalization of $2.
274 billion
).

$38.
5 per share with a total market capitalization of $2.
274 billion

Barry E.
Greene, the current CEO of Sage, joined Sage's Board of Directors in October 2020 and became CEO in December of the same year, and has more than 30 years of experience
in the biopharmaceutical industry.
Prior to 2001, Barry served as Executive Vice President and Chief Commercial Officer at Healthcare Consulting Mediconsult.
com, where he also held various leadership positions at AstraZeneca, and was a partner at Hans Christian Andersen Consulting on pharmaceutical/biotechnology marketing and sales
。 In 2001, he served as General Manager of Oncology at Millennium Pharmaceuticals, where he led the global strategy and execution of the firm's oncology business, including strategic business direction and execution, and in 2003 successfully contributed to an FDA-approved launch of VELCADE® (Bortezomib
).
Barry served as Alnylam's Chief Operating Officer in 2003 and the company's president in 2007, where he spent 17 years
at Alnylam Pharmaceuticals.
He is a board member of the American Association of Pharmaceutical Research and Manufacturers (PhRMA), holds a bachelor's degree in industrial engineering from the University of Pittsburgh, and is a senior scholar at Duke University's Fokku School of Business
.

Partnerships

Partnerships

In June 2018, Sage and Shionogi entered into a strategic partnership to develop and commercialize zuranolone (SAGE-217)
for the treatment of major depressive disorder (MDD) and other indications in Japan, Taiwan and South Korea.
The goal of the collaboration is to accelerate the development of a potential drug
for patients in key Asian markets.
Shionogi completed Phase 2 clinical trials
of Zuranolone (SAGE-217) for MDD in Japan.
Under the terms of the partnership, Shionogi is responsible for all clinical development, regulatory filing, and commercialization
of Zuranolone (SAGE-217) in Japan, Taiwan, and South Korea.

On November 27, 2020, Biogen officially announced a $3.
125 billion deal with Sage, including a down payment of $875 million, a $650 million equity investment, and a potential mileage payment of $1.
6 billion in the future, leading to Zuranolone's exclusive global co-development rights (excluding Japan, South Korea and Taiwan
).
。 The agreement was as follows: Bioge and Sage are jointly responsible for the development of Zuranolone in the U.
S.
, sharing profits at a 1:1 cost-sharing ratio; Biogen, on the other hand, is solely responsible for market development and commercialization outside the
United States.

$875 million down payment

Sage business area

Sage business area

Sage has three main areas of expertise: depression, neuroscience, and neuropsychiatry
.

01 Depression franchise

01 Depression franchise

Sage's research and development efforts in this area focus on the modulation of GABA and NMDA receptors, two key neurotransmitter systems responsible for the flow
of information in the complex circuits of the brain and central nervous system.
Both the GABA and NMDA systems play an important role in the regulation of central nervous system function, and dysfunction of both systems is considered to be at the heart of
many psychiatric disorders.
Sage is using its unique development methodology to evaluate research candidates for the treatment of postpartum depression (PPD) and major depressive disorder (MDD
).
Its representative product, zuranolone, is a studied oral neuroactive steroid (NAS) GABA-A receptor-positive allosteroid modulator (PAM
).

▲ZURANOLONE's clinical development plan

02 Neuroscience franchise

02 Neuroscience franchise

Sage is exploring new disease pathways for certain neuroscience disorders, focusing on diseases that are highly in-demand and where there are currently not enough treatment options, such as dementia/cognitive dysfunction, epilepsy, idiopathic tremor, Parkinson's disease
.

Dementia, including Alzheimer's disease and a wide range of other forms, affects more than 36 million people
worldwide.
This neurodegenerative disease is characterized by decreased
cognitive function.
There is evidence that enhancing the excitatory NMDA pathway in the brain can treat several types of dementia
.
The researchers found that many people with dementia had elevated
levels of anti-NMDA antibodies.

Epilepsy is a group of neurological disorders
characterized by recurrent seizures (sudden surges in electrical activity).
Although more than 25 treatments for epilepsy have been approved, about 30% of patients still have refractory (refractory) seizures
.
An imbalance in the inhibition and excitatory pathways in the brain leads to the frequency and duration
of seizures.
Sage is exploring how enhanced GABA or NMDA signaling could potentially help these patients
.

Idiopathic tremor is the most common movement disorder and is 8 times
more prevalent than Parkinson's.
This is a progressive disorder, usually hereditary, that causes rhythmic tremors
in the hands, head, voice, or legs.
The researchers believe this may be caused
by electrical fluctuations in the brain that send abnormal signals to the muscles.
Tremor usually exacerbates with stress, fatigue, and stimulant use, and idiopathic tremor is associated
with decreased GABA receptor activity.

Parkinson's is a chronic progressive movement disorder that affects
about 700,000 people in the United States.
In this disease, nerve cells in the brain slowly stop producing dopamine, the neurotransmitter
responsible for coordinating movement.
As Parkinson's progresses, dopamine production in the brain decreases, making patients even less able to direct their movements
.
Parkinson's disease can cause tremors, stiffness, slow movement and balance disorders, as well as mood changes and sleep difficulties
.
Current treatments for Parkinson's are focused on dopamine replacement therapy, which was initially effective in relieving symptoms but lost its effectiveness
over time.
GABA receptors may be a possible therapeutic target for treating Parkinson's disease, and GABA signaling helps regulate dopamine-producing nerve cells
.
The researchers also found that levels of alloxyprogesterone in Parkinson's patients, a naturally occurring GABA regulator
, are in their bodies.

03 Neuropsychiatry franchise

03 Neuropsychiatry franchise

SAGE is investigating potential causes of brain and central nervous system (CNS) disorders, and its neuropsychiatric research compound SAGE-718 regulates certain receptors in the brain in a unique way that play a key role
in the way the brain processes information.
Sage is exploring the role of SAGE-718 in neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, and Parkinson's disease, with the aim of evaluating whether SAGE-718 has the potential to improve cognitive/behavioral symptoms
in these difficult-to-treat diseases.
Disease categories include Huntington's disease, Parkinson's disease, Alzheimer's disease, and Huntington's disease
.

Huntington's disease is a rare inherited neurodegenerative disease
.
In the United States, as many as 30,000 adults are diagnosed with Huntington's disease each year, usually between the ages of 30-45, which worsens within 15-20 years of diagnosis, eventually leading to death
.

Parkinson's is considered a disease that affects multiple systems in the body, with about 60,000 adults in the United States diagnosed with Parkinson's disease each year, and about 19-38% of Parkinson's patients also have mild cognitive impairment (MCI
).
The data suggest that changes in a specific receptor in the brain called NMDA receptors may be one of the causes of
Parkinson's cognitive impairment.

Alzheimer's disease is the most common cause of dementia, with about 5.
8 million Americans (ages 65 and older) suffering from Alzheimer's disease in 2020
.
Cognitive decline in patients with Alzheimer's disease, including memory impairment, changes in language ability, and executive dysfunction
.
Preclinical evidence suggests that positive modulation of NMDA receptors in the brain may treat several types of dementia, including dementia caused by Alzheimer's disease
.

▲Clinical development plan of SAGE-718

The first approved drug to treat PPD, Zulresso®

The first approved drug to treat PPD, Zulresso®

On March 19, 2019 local time, the US FDA approved the intravenous injection of Zulresso® (brexanolone) developed by Sage Therapeutics, which® is the first approved drug for the treatment of postpartum depression for the treatment of moderate and severe postpartum depression
in adult women.

depression

depression

Medications to treat depression began in the 1950s, when the anti-tuberculosis drug isoniazid was found to improve
patients' mood.
This discovery led to the discovery and development
of the monoamine oxidase inhibitor isonicotinyl isopropionide.
In 1959, imipramine (approved for the treatment of depression, tricyclic antidepressants came into being
.
Both monoamine oxidase inhibitors and tricyclic antidepressants are effective drugs
for the treatment of depression.
But they are not selective and interact
with many central nervous system targets in the brain.
Therefore, they are "dirty drugs"
with significant toxicity.
These toxic side effects cause most depressed patients to be unable to complete the entire course of treatment, so the use of these old antidepressants is limited
.

In 1988, the emergence of Eli Lilly's fluoxetine (Prozac) as an SSRI, revolutionized the treatment
of depression.
Prozac is a highly selective drug, so it is a "clean drug" with far
fewer side effects than older antidepressants.
Most patients can complete the entire course
.
Many "me-too" SSRIs followed, mainly GSK's Paroxetine (1992) and Pfizer's Sertraline (1997
).

As mentioned earlier, the causes of depression are very complex
.
Therefore, many drugs have more than one mechanism of
action.
For example, Wyeth's venlafaxine (1993) is a combination
of norepinephrine-5-serotonin reuptake inhibitors.
GSK's bupropion (1985) is a combined inhibitor of norepinephrine and dopamine
.
Finally, Vothioxetine (2013) of Denmark Lingbei Pharmaceuticals is a combination inhibitor of 5-HT3A and 5-HT1A receptors with serotonin transporters
.

Ketamine is an abuse drug and a notorious "drug of infatuation"
.
However, ketamine's (S)-enantiomer has been shown to be rapid and effective
in treating depression.
In 2019, the FDA approved Janssen's esketamine (Spillato ) as a fast-acting nasal spray for the treatment of refractory depression
.
Esketamine is a regulator of glutamic acid and the gamma-aminobutyric acid (GABA) neurotransmitter system
.
Unlike most existing antidepressants, esketamine is a brain stimulant
based on a non-monoamine strategy.
Like esketamine, buxanolone is a non-monoamine antidepressant
.

All of the above medications can be used to treat postpartum depression
.
However, they all take two to six weeks to see mood improvement
.
This onset of action is too slow, as postpartum depression is most severe in the first month of the postpartum period
.

Postpartum depression

Postpartum depression

For postpartum depression, the timing of the onset of symptoms coincides
with a timeline of a sharp drop in steroid hormone levels.
These steroid hormones are estrogen, progesterone, and tetrahydroprogesterone
.
Tetrahydroprogesterone is an endogenous inhibitory progesterone neuroactive steroid whose levels rise during pregnancy, peak in the third trimester, and then drop
sharply after childbirth.
A sharp drop in tetrahydroprogesterone levels after childbirth is associated
with postpartum mood disorders.
Tetrahydroprogesterone itself has anxiolytic and antidepressant effects
.
Major depressive mood disorders have decreased levels of tetrahydroprogesterone, and antidepressant therapy has been shown to increase tetrahydroprogesterone levels
.

About Zulresso®

About Zulresso®

Sage Therapeutics' Briñolone is a neuroactive steroid that is a positive allosteric modulator (PAM)
of GABAA receptors.
It is defined as an allosteric regulator because its binding site is not on the highly conserved endogenous ligand binding (orthoconformation) site of the
GABAA receptor.

GABA is the main inhibitory neurotransmitter
in the central nervous system.
The rapid inhibitory effect of GABA is mainly mediated by the GABAA receptor, which is widely recognized as an effective clinical drug target
.
In fact, ethanol, benzodiazepines, barbiturates, and general anesthetics are all GABAA receptor modulators
.
Neuroactive steroids, like barbiturates, are high-affinity modulators
of GABAA receptors β-subunits.

Brinandrolone is a synthetic tetrahydroprogesterone analogue that enhances GABA-mediated electrical currents
in mammalian cells expressing recombinant GABAA receptors.
In clinical trials for the treatment of postpartum depression in women aged 10–45 years, 60-hour continuous intravenous infusion of brinandrone was more effective
than placebo.
Mood can improve
immediately after infusion.
Briñolone provides a fast-acting antidepressant to treat postpartum depression, an unmet medical need
.

But Brinosolone is far from perfect, and its mode of administration is continuous intravenous infusion for more than
60 hours.
During the two-and-a-half-day period of briñolone infusion, a medical staff must be present at the site to continuously monitor the patient
.
In addition, each course of treatment, the cost of drugs alone amounts to $34,000
.
If the patient does not have health insurance, the cost of
this drug is difficult for many families to afford.

Sage Therapeutics started with Briandrolone and developed another oral tetrahydroprogesterone analogue, SAGE-217 (zuranolone
).
The process of converting from brinobolone with very low oral bioavailability to oral sularone provides valuable experience
in drug design.
In clinical trials, Shuranandrolone is effective
in both men and women with depression.
Bojian purchased the rights
to Shulacanolone in November 2020 for a whopping $1.
525 billion.

Oral tetrahydroprogesterone analogue SAGE-217 (zuranolone)

Zulresso's® successful approval is based primarily on two double-blind, randomized, placebo-controlled Phase III clinical trials in study 1 in patients with severe postpartum depression (PPD) (NCT02942004) and in study 2 in patients with moderate PPD (NCT02942017
).
In both studies, patients received a 60-hour Zulresso® or placebo with a continuous intravenous injection of the latter, followed by a follow-up of
4 weeks.
A 90mcg/kg dose group and a placebo group were established in both studies, respectively, and a 60mcg/kg dose group
was added in Study 1.
Using a relative baseline change in the 60-hour Hamilton Depression Scale (HAMD) score as the primary treatment endpoint, the results showed that the 90mcg/kg dose group was superior to the placebo group in both studies and the 60mcg/kg dose group was also better than the placebo group
in study 1.
Compared with placebo, Zulresso® has a rapid onset of action and is effective in relieving symptoms
in patients with moderate and severe PPD.

Zulresso comes with a black box warning: excessive sedation and loss of consciousness, patients can only participate in Zulresso®® treatment under close monitoring by medical staff
.
The most common adverse effects are dry mouth, drowsiness, and flushing
.

According to Sage's official website, the retail price of each bottle of Zulresto® is $7,450, and each course of treatment (2.
5 days) is equivalent to $34,000, equivalent to more than
230,000 yuan.
Its mechanism of action: γ-aminobutyric acid A receptor positive allosteric regulator
.

However, the market reaction was not as expected, with Zulresto® sales of only $6.
7 million in 2020 and slipping to $6.
3 million in 2021
.
This figure is only 24%
of the analysts' expectations.

Financial performance

Financial performance

01 2021 Financial Report

01 2021 Financial Report

On February 24, 2022, Sage released its 2021 financial report, which showed that the company's fiscal 2021 operating income was $6.
308 million, down 99.
43%
year-on-year.
Net profit attributable to common shareholders of the parent company was -$458 million, down 175.
55% year-on-year;

The 2021 financial report operating income was 6.
308 million US dollars, down 99.
43%
year-on-year.
-$458 million, down 175.
55% year-on-year;

02 Quarterly & Interim Report for Fiscal Year 2022

02 Quarterly & Interim Report for Fiscal Year 2022

On May 3, 2022, Sage announced its first quarter 2022 report, which shows operating income of $1.
501 million for the first quarter and net profit attributable to common shareholders of the parent company of -$126 million
.

Reported revenue for the first quarter of 2022 was $1.
501 million; -$126 million

On August 2, 2022, Sage announced its fiscal 2022 interim report, which showed that the company's operating income was $3.
082 million, down 4.
46% year-on-year; Net profit attributable to common shareholders of the parent company was -$248 million, down 22.
32% year-on-year;

Reported operating income of $3.
082 million in fiscal 2022, down 4.
46% year-on-year; -$248 million, down 22.
32% year-on-year;

03 Financial projections

03 Financial projections

Sage expects the company's cash, cash equivalents and securities to total approximately $1.
3 billion by the end of 2022; The Company will not receive any milestone payments from the collaboration in 2022; R&D and SG&A spending will increase
as plans and ongoing research on SAGE-718 and SAGE-324 advance and preparations for a possible launch of zuranolone.

By the end of 2022, the company will have $1.
3 billion in cash, cash equivalents and securities

Product lines

Product lines

Sage Therapeutics' pipeline under development (as of June 30, 2022)

Reference source:

Reference source:

NMPA/CDE；

NMPA/CDE；

Pharmaceutical Rong Cloud Data, www.
pharnexcloud.
com;

Pharmaceutical Rong Cloud Data, www.
pharnexcloud.
com;

FDA/EMA/PMDA；

FDA/EMA/PMDA；

Public disclosure by relevant companies;

Public disclosure by relevant companies;

Walton, N.
; Maguire, J.
Allopregnanolone-based treatments forpostpartum depression: Why/how do they work? Neurobiology of Stress2019, 11, 100198.

Walton, N.
; Maguire, J.
Allopregnanolone-based treatments forpostpartum depression: Why/how do they work? Neurobiology of Stress2019, 11, 100198.

SamanthaMeltzer-Brody, etc.
Brexanolone injection in post-partum depression:two multicentre, double-blind, randomised, placebo-controlled, phase3 trials [J].
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SamanthaMeltzer-Brody, etc.
Brexanolone injection in post-partum depression:two multicentre, double-blind, randomised, placebo-controlled, phase3 trials [J].
Lancet, 2018,http://dx.
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1016/S0140-6736(18)31551-4.