Sage Therapeutics Announces Clinical Updates and Progress Across Neuroscience Pipeline During “Sage FutureCast”
July 24 2019 - 6:30AM
Business Wire
Data from Phase 2 open-label study of SAGE-217
in bipolar depression demonstrate rapid improvement compared to
baseline; analysis of datasets from previously completed studies
reveal encouraging findings relevant to the development of SAGE-217
in treatment-resistant depression and generalized anxiety
disorder
Data from Phase 1 study with SAGE-324 show
activity in essential tremor; differentiated profile opens
potential pathways for development in additional neurological
indications
Data from Phase 1 program for SAGE-718, Sage’s
lead molecule in its NMDA portfolio, show it was well-tolerated and
improved executive function compared to placebo in healthy
volunteers
Webcast today at 8:00 a.m. EDT
Today, Sage Therapeutics (NASDAQ: SAGE), a biopharmaceutical
company committed to developing novel therapies with the potential
to transform the lives of people with debilitating disorders of the
brain, will host “Sage FutureCast: An R&D Portfolio Review” and
report clinical progress in select depression, neurology, and
neuropsychiatry franchise programs.
“Our goal at Sage has always been to step into the void in CNS
drug development through an innovative approach we believe to be
unique,” said Jeff Jonas, chief executive officer of Sage. “By
thinking differently about brain disorders, we’ve built a pipeline
with the potential to deliver a broad range of new medicines across
multiple indications. The clinical findings presented today are a
result of our differentiated approach to discovery and translation.
While these are still early data, we believe these data not only
meaningfully expand our pipeline opportunities, but more
importantly, represent the potential benefits our medicines may
provide for patients if we’re successful in our development
efforts.”
Clinical Program
Updates:
Sage is advancing a portfolio of novel and differentiated
product candidates designed to improve brain health by targeting
the GABA and NMDA receptor systems. Dysfunction in these systems is
known to be at the core of numerous neurological and
neuropsychiatric disorders.
Depression Franchise:
SAGE-217, a next-generation positive allosteric modulator (PAM)
of GABAA receptors, is being evaluated in Phase 3 clinical
development as a treatment for major depressive disorder (MDD),
postpartum depression (PPD), and comorbid MDD and insomnia, and is
also being evaluated for bipolar depression and additional
affective disorders, including treatment-resistant depression (TRD)
and generalized anxiety disorder (GAD). SAGE-217 received
breakthrough therapy designation from the U.S. Food & Drug
Administration (FDA) for the treatment of MDD.
- SAGE-217 in bipolar depression (ARCHWAY Study):
- Sage’s Phase 2 open-label ARCHWAY Study evaluated the safety
and activity of SAGE-217 in 35 adult men and women with moderate to
severe bipolar I/II disorder with a major depressive episode.
Patients were treated with 30 mg of SAGE-217 once daily for two
weeks. The main efficacy measure was Montgomery–Åsberg Depression
Rating Scale (MADRS). MADRS baseline total score was 34.4.
- Results from the trial demonstrated a rapid and durable
response to treatment as measured by the MADRS score and a
statistically significant improvement compared to baseline at Day
15. The effect was maintained through the end of the follow-up
period at Day 42.
- The average change from baseline in MADRS total score was 15.5
points at Day 15 (n=23; p<0.0001) and 16.4 points at Day
42.
- At Day 15 (n=23), 43.5% of patients receiving SAGE-217 achieved
remission (MADRS ≤12) with an additional 4% achieving response
(≥50% reduction in MADRS Total score).
- Roughly one-third of subjects discontinued the study due to a
variety of social/personal reasons, which is consistent with
discontinuation rates across global studies in bipolar depression.
No discontinuations due to adverse events were reported.
- SAGE-217 was generally well-tolerated with a safety profile
consistent with GABAA positive allosteric modulation. The most
common adverse events (>5%) were somnolence, headache, diarrhea,
and sedation. There were two cases of transient hypomania
off-treatment; no mania or serious adverse events (AEs) was
reported in the trial.
- SAGE-217 in patients who didn’t respond to a single
anti-depressant:
- Sage conducted a post hoc analysis of 51 patients from the
MDD-201B and ROBIN (PPD) studies with ongoing symptoms of
depression despite receiving standard anti-depressant
pharmacotherapy. Of the 51 total patients with major depressive
disorder or postpartum depression, 28 received SAGE-217 and 23
received placebo.
- Results from the analysis demonstrated a rapid and durable
response to treatment and reduction in depressive symptoms in the
SAGE-217-treated group compared to placebo in patients with ongoing
symptoms of depression despite receiving standard anti-depressant
therapy.
- At Day 15, patients receiving SAGE-217 experienced a 7.2-point
greater reduction (p=0.004) in Hamilton Rating Scale for Depression
(HAM-D-17) compared to patients receiving placebo.
- At the last study visit (Day 42 or 45), patients receiving
SAGE-217 experienced a 4.9-point greater reduction (p=0.07) in
HAM-D-17 compared to patients receiving placebo.
- Based on outcomes of the Sequenced Treatment Alternatives to
Relieve Depression (STAR*D) trial, improvements observed in
SAGE-217 studies suggest opportunity to address unmet need for
rapid treatment response in patients with treatment-resistant
depression.
- Findings from this analysis, if replicated in further
development, suggest SAGE-217 may have utility as an oral
medication for people who are struggling with depression,
regardless of their resistance to standard therapies.
- SAGE-217 in patients with anxiety:
- Sage evaluated response on the Hamilton Anxiety Rating Scale
(HAM-A), a secondary endpoint, in all patients randomized in the
MDD-201B and ROBIN (PPD) studies of SAGE-217. This analysis
evaluated 240 patients, 89 patients from the MDD-201B study with
major depressive disorder and 151 patients from the ROBIN Study
with postpartum depression.
- Findings demonstrated rapid onset of activity and durable
effect past initial treatment, with a clinically meaningful
anxiolytic effect within days in the SAGE-217-treated group
compared to placebo.
- At Day 15, patients receiving SAGE-217 experienced a 4.6-point
greater reduction (p=0.0008) in HAM-A score and 3.9-point greater
reduction (p=0.006) in HAM-A score compared to placebo in the
MDD-201B study and ROBIN Study, respectively.
- At Day 42 (last visit), patients receiving SAGE-217 experienced
a 2.3-point greater reduction (p=0.20) in HAM-A score compared to
placebo in the MDD-201B study; at Day 45 (last visit), patients
receiving SAGE-217 experienced on average a 5-point greater
reduction (p=0.0002) in HAM-A score compared to placebo in the
ROBIN Study.
- Sage plans to evaluate SAGE-217 in patients with TRD and will
discuss plans for how to sequence opportunities in bipolar
depression, TRD and GAD during the FutureCast webinar.
Neurology Franchise:
SAGE-324, a next-generation PAM of GABAA receptors, is in
development as a potential therapy for neurological conditions,
such as essential tremor (ET) and epileptiform disorders.
- SAGE-324 pharmacokinetics and tolerability:
- Sage conducted single-ascending dose (SAD) and
multiple-ascending dose (MAD) studies of SAGE-324 in healthy
volunteers. Results demonstrate a pharmacokinetic (PK) profile
suitable for chronic dosing in indications amenable to the GABA PAM
mechanism.
- Little variability was observed in steady state plasma
concentrations over the dose interval, which may provide consistent
trough concentrations while minimizing peak-related tolerability
issues.
- SAGE-324 demonstrated a long half-life of approximately 90 –
120 hours. This attribute supports the low peak to trough ratio and
provides flexibility in dosing paradigms, making SAGE-324
well-suited for development in neurological conditions where stable
plasma levels are a clinical challenge.
- SAGE-324 was generally well tolerated. The most common (>5%)
adverse events were feeling of relaxation, dizziness, and
somnolence.
- Data with respect to tolerability in context with EEG biomarker
data suggest that the therapeutic index with respect to sedation
for SAGE-324 is potentially broader than for SAGE-217, making it an
asset that may have utility in indications where sleep
consolidation is not desirable.
- SAGE-324 in ET:
- Sage conducted a Phase 1b single dose, open-label study
evaluating SAGE-324 in six patients with ET. Patients were
administered a non-optimized single dose of SAGE-324 that was below
the maximum tolerated dose. Data demonstrated a reduction in tremor
from baseline, with a maximum mean reduction in accelerometer upper
limb total score of 48%.
- Sage evaluated plasma concentration of SAGE-324 over 24 hours
and observed a clear pharmacokinetic/pharmacodynamic
relationship.
- Sage plans to initiate a Phase 2 study evaluating SAGE-324 in
essential tremor in 2H 2019. This study will also inform clinical
expansion into adjacent opportunities in neurological conditions
such as epileptiform disorders and Parkinson’s.
Neuropsychiatry
Franchise:
SAGE-718, a first-in-class NMDA receptor PAM, is in development
as a potential therapy for cognitive disorders associated with NMDA
receptor dysfunction.
- Five Phase 1 healthy volunteer studies with SAGE-718 have been
completed, including SAD, MAD, and three target engagement
biomarker studies.
- SAGE-718 demonstrated linear pharmacokinetics, a long half-life
consistent with once-daily dosing, and was generally safe and
well-tolerated.
- A suite of three target engagement studies with SAGE-718 were
recently completed:
- Results of an integrated analysis in healthy volunteers
demonstrate SAGE-718 had effects on electrophysiological,
functional neuroimaging, and cognitive measures consistent with CNS
activity.
- Healthy volunteers dosed with SAGE-718 also received low-dose
ketamine as a selective antagonist of the NMDA receptor (used here
to induce a state of relative NMDA hypofunction). Among the
findings, SAGE-718 was found to modulate the effects of ketamine on
regional and global measures of resting brain activity, indicating
functional interaction with NMDA receptors and potential NMDA PAM
activity.
- 19 healthy volunteers administered SAGE-718 once-daily for 10
days exhibited significantly better performance on tests of working
memory and complex problem solving compared to 20 healthy
volunteers administered placebo, at times reaching statistical
significance (p<0.05).
- If these data are replicated in further development, SAGE-718
may demonstrate a distinct profile from currently available
cognitive-enhancing agents, and the potential to improve
higher-order cognitive processes more closely linked to real-world
functioning.
- In the SAD and MAD studies, SAGE-718 demonstrated a long
half-life consistent with once-daily dosing and was well-tolerated.
The most commonly reported adverse event was mild orthostatic
hypotension, which occurred in 2 subjects.
- Sage plans to move forward to evaluate SAGE-718 in Phase 2
development programs in neurodegenerative disorders and other
conditions where executive function is impaired. Additional timing
for these studies will be provided in 2H 2019.
About Sage Therapeutics
Sage Therapeutics is a biopharmaceutical company committed to
developing novel therapies with the potential to transform the
lives of people with debilitating disorders of the brain. We are
pursuing new pathways with the goal of improving brain health and
our depression, neurology and neuropsychiatry franchise programs
aim to change how brain disorders are thought about and treated.
Our mission is to make medicines that matter so people can get
better, sooner. For more information, please visit www.sagerx.com.
Forward-Looking Statements
Various statements in this release concern Sage's future
expectations, plans and prospects, including without limitation:
our views and expectations regarding our development plans, goals
and strategy and the potential timing and results of our
development efforts; our belief in the potential of our product
candidates in various indications; the potential profile and
benefit of our product candidates; and the goals, opportunity and
potential for our business. These statements constitute
forward-looking statements as that term is defined in the Private
Securities Litigation Reform Act of 1995. These forward-looking
statements are neither promises nor guarantees of future
performance, and are subject to a variety of risks and
uncertainties, many of which are beyond our control, which could
cause actual results to differ materially from those contemplated
in these forward-looking statements, including the risks that: we
may not be successful in our development of any of our current or
future product candidates in any indication we are currently
pursuing or may in the future pursue; success in earlier stage
clinical trials or nonclinical studies may not be repeated or
observed in ongoing or future studies of any of our product
candidates; ongoing and future clinical or nonclinical results may
generate results that are different than we expect or may not
support further development or be sufficient to gain regulatory
approval of our product candidates; we may decide that a
development pathway for one of our product candidates in one or
more indications is no longer feasible or advisable or that the
unmet need no longer exists; the FDA may decide that the
development program for any of our product candidates, even if
positive, is not sufficient for a new drug application filing or
approval; decisions or actions of the FDA or other regulatory
agencies may affect the initiation, timing, design, size, progress
and cost of clinical trials and our ability to proceed with further
development; we may experience slower than expected initiation or
enrollment in ongoing or future clinical trials; we may encounter
unexpected safety or tolerability issues with our product
candidates; the internal and external costs required for our
ongoing and planned research and development efforts, and to build
our organization in connection with such activities, and the
resulting expense increases and use of cash, may be higher than
expected which may cause us to change or curtail some of our plans;
and we may encounter technical and other unexpected hurdles in the
development of our product candidates; as well as those risks more
fully discussed in the section entitled "Risk Factors" in our most
recent quarterly report filed with the Securities and Exchange
Commission (SEC), and discussions of potential risks,
uncertainties, and other important factors in our subsequent
filings with the SEC. In addition, any forward-looking statements
represent our views only as of today, and should not be relied upon
as representing our views as of any subsequent date. We explicitly
disclaim any obligation to update any forward-looking
statements.
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Investor Contact Maren Killackey 617-949-4113
maren.killackey@sagerx.com Media
Contact Alexis Smith 617-588-3740 alexis.smith@sagerx.com
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