Cyclerion Therapeutics, Inc. (Nasdaq: CYCN), a clinical-stage
biopharmaceutical company on a mission to develop treatments that
restore cognitive function, today announced positive topline data
in its signal-seeking clinical study of CY6463, for the potential
treatment of Mitochondrial Encephalomyopathy, Lactic Acidosis and
Stroke-like episodes (MELAS). Chad Glasser, Pharm.D., Director of
Clinical Research at Cyclerion Therapeutics, will present results
from this clinical study today during the Clinical Trial Updates
Panel at the United Mitochondrial Disease Foundation (UMDF)
Mitochondrial Medicine 2022 Symposium, taking place June 8-11,
2022, in Phoenix, Arizona.
CY6463 is a positive allosteric modulator of soluble guanylate
cyclase (sGC), which amplifies endogenous NO signaling, a pathway
that has been linked to mitochondrial biogenesis and function. In
this open-label, single-arm study of the oral, once-daily sGC
stimulator in eight MELAS patients, improvements were seen across a
range of biomarkers, including mitochondrial disease-associated
biomarkers such as lactate and GDF-15, a broad panel of
inflammatory biomarkers, cerebral blood flow, and functional
connectivity between neural networks. These positive effects after
29 days of dosing were supported by correlations across several
endpoints and were more pronounced in patients with greater
baseline disease burden. A return toward baseline levels after
discontinuation of CY6463 dosing across several biomarkers was also
observed.
CY6463 was well tolerated with no adverse events leading to
treatment discontinuation, and pharmacokinetics (PK) were
consistent with the Phase 1 study in healthy volunteers. The
positive data from this study further support the potential of
CY6463, the first and only CNS-penetrant sGC stimulator in clinical
development, to provide therapeutic benefit to people living with
MELAS.
“MELAS patients currently have no approved treatment options for
a devastating orphan disease that affects multiple organs,
including the CNS, skeletal muscle, and eyes,” said Peter Hecht,
Ph.D., Chief Executive Officer of Cyclerion. “We are excited by the
strength of these data and consistency across disease domains,
which support the further advancement of CY6463 as a potential
treatment option.”
Study Highlights:
- The single-arm, open-label study enrolled eight participants
who spanned a range of disease burden; 6 of the 8 (75%) were also
taking a daily regimen of oral arginine or citrulline, precursors
to nitric oxide that are current standard of care for MELAS
patients.
- CY6463 was well tolerated; there were no reports of serious
adverse events (SAEs) or treatment discontinuation due to adverse
events (AEs).
- The PK profile and concentrations in the cerebrospinal fluid
(CSF) and plasma were consistent with exposures observed in Phase 1
healthy volunteer studies.
- Effects were observed across multiple domains of disease
activity:
- Improvements in biomarkers associated with mitochondrial
function including lactate and GDF-15. These changes correlated
with each other and with CY6463 plasma concentrations
- Improvements across a broad panel of inflammatory
biomarkers
- Increases in cerebral blood flow across all brain regions.
These changes correlated with clinical improvement as assessed by
the patient global impression of change (PGIC) scale
- Increases in functional connectivity between brain regions and
activation of occipital brain regions in response to the visual
stimulus as measured by fMRI BOLD
“In this study we saw positive impacts on important biomarkers
associated with MELAS and other mitochondrial disease following 29
days of once-daily dosing with CY6463,” said Andreas Busch, Ph.D.,
Chief Scientific Officer at Cyclerion Therapeutics. “These findings
are exciting as we think about the potential of our mechanism in
mitochondrial disease and more broadly about the effects of CY6463
on mitochondrial function, which is relevant to numerous CNS
diseases, including schizophrenia and Alzheimer’s Disease.”
A video presentation of the topline data is available on the
Investor page of the Cyclerion website. Additional data from the
MELAS clinical study will be shared in the coming weeks.
About CY6463
CY6463 is the first CNS-penetrant sGC stimulator to be developed
as a symptomatic and potentially disease-modifying therapy for
serious CNS diseases. The nitric oxide (NO)-soluble guanylate
cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling
pathway is a fundamental mechanism that precisely controls key
aspects of physiology throughout the body. In the CNS, the
NO-sGC-cGMP pathway regulates diverse and critical biological
functions including neuronal function, neuroinflammation, cellular
bioenergetics, and vascular dynamics. Although it has been
successfully targeted with several drugs in the periphery, this
mechanism has yet to be fully leveraged therapeutically in the CNS,
where impaired NO-sGC-cGMP signaling is believed to play an
important role in the pathogenesis of many neurodegenerative and
neuropsychiatric diseases and other disorders associated with
cognitive impairment. As an sGC stimulator, CY6463 acts as a
positive allosteric modulator to sensitize the sGC enzyme to NO,
increase the production of cGMP, and thereby amplify endogenous NO
signaling. By compensating for deficient NO-sGC-cGMP signaling,
CY6463 and other sGC stimulators may have broad therapeutic
potential as a treatment to improve cognition and function in
people with serious CNS diseases.
About the Study
The Phase 2a study was an open-label, single-arm study of oral,
once-daily CY6463 in eight adults aged 18 or older with MELAS. The
primary objective of the study was to assess the safety and
tolerability of a 15 milligram, once-daily, oral dose of CY6463
over 29 days. The secondary objectives included pharmacokinetics,
and exploratory pharmacodynamic effects, with the goal of
identifying which biomarkers to carry forward into additional
studies. The study was not powered for hypothesis testing.
About MELAS
Mitochondrial Encephalomyopathy, Lactic Acidosis, and
Stroke-like episodes (MELAS) is a devastating orphan disease
affecting multiple organ systems, including the CNS, with no
approved therapies. It is the most common form of primary
mitochondrial diseases (PMD). MELAS is phenotypically and
genetically defined by a mutation in mitochondrial tRNA. It is
estimated that about 1 in 4,300 individuals has a mitochondrial
disease, and ~80% of individuals with mitochondrial disease have
CNS symptoms. The unmet need in MELAS is immense, symptoms include,
chronic fatigue, muscle weakness, and pain in addition to
neurological manifestations. Life expectancy is estimated at ~17
years from onset of CNS symptoms. The disease impedes the
individual’s ability to live independently, leads to social
isolation, and overall reduced quality of life.
About Cyclerion Therapeutics
Cyclerion Therapeutics is a clinical-stage
biopharmaceutical company on a mission to develop treatments that
restore cognitive function. Cyclerion is advancing novel,
first-in-class, CNS-penetrant, sGC stimulators that modulate a key
node in a fundamental CNS signaling pathway. The multidimensional
pharmacology elicited by the stimulation of sGC has the potential
to impact a broad range of CNS diseases. The most advanced
compound, CY6463, has shown rapid improvement in biomarkers
associated with cognitive function and is currently in clinical
development for Mitochondrial Encephalomyopathy, Lactic Acidosis
and Stroke-like episodes (MELAS), Cognitive Impairment Associated
with Schizophrenia (CIAS) and Alzheimer's Disease with Vascular
pathology (ADv). Cyclerion is also advancing CY3018, a
next-generation sGC stimulator.
Forward Looking Statement
Certain matters discussed in this press release are
“forward-looking statements”. We may, in some cases, use terms such
as “predicts,” “believes,” “potential,” “continue,” “estimates,”
“anticipates,” “expects,” “plans,” “intends,” “may,” “could,”
“might,” “will,” “should”, “positive” or other words that convey
uncertainty of future events or outcomes to identify these
forward-looking statements. In particular, the Company’s statements
regarding trends and potential future results are examples of such
forward-looking statements. The forward-looking statements include
risks and uncertainties, including, but not limited to, the
success, timing and cost of our ongoing or future clinical trials
and anticipated clinical trials for our current product candidates,
including statements regarding the timing of initiation and
completion of the trials, futility analyses and receipt of interim
results, which are not necessarily indicative of or supported by
the final results of our ongoing or subsequent clinical trials; any
results of clinical studies, including in particular single-arm
open-label studies involving a number of patients that is not
statistically significant such as described in this release, not
necessarily being indicative of or supported by the final results
of our ongoing or subsequent clinical trials; our ability to fund
additional clinical trials to continue the advancement of our
product candidates; the timing of and our ability to obtain and
maintain U.S. Food and Drug Administration (“FDA”) or other
regulatory authority approval of, or other action with respect to,
our product candidates; the potential for the CY6463 clinical trial
to provide a basis for approval for treatment of MELAS; the
Company’s ability to successfully defend its intellectual property
or obtain necessary licenses at a cost acceptable to the Company,
if at all; the successful implementation of the Company’s research
and development programs and collaborations; the success of the
Company’s license agreements; the acceptance by the market of the
Company’s product candidates, if approved; and other factors,
including general economic conditions and regulatory developments,
not within the Company’s control. The factors discussed herein
could cause actual results and developments to be materially
different from those expressed in or implied by such statements.
The forward-looking statements are made only as of the date of this
press release and the Company undertakes no obligation to publicly
update such forward-looking statements to reflect subsequent events
or circumstance.
For more information about Cyclerion, please visit cyclerion.com
and follow us on Twitter and LinkedIn.
InvestorsCarlo Tanzi, Ph.D.Kendall Investor
Relationsctanzi@kendallir.com
MediaAmanda SellersVerge Scientific
Communicationsasellers@vergescientific.com
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