Cyclerion Therapeutics, Inc. (Nasdaq: CYCN), a clinical-stage
biopharmaceutical company on a mission to develop treatments that
restore cognitive function, today participated in a webinar hosted
by the United Mitochondrial Disease Foundation (UMDF). The Company
shared additional positive clinical data from its signal-seeking
study of CY6463, a first-in-class, CNS-penetrant sGC stimulator, in
patients with Mitochondrial Encephalomyopathy, Lactic Acidosis and
Stroke-like episodes (MELAS). Data from the 8-participant,
open-label study demonstrate CY6463 was well tolerated, with no
reports of serious adverse events (SAEs) or treatment
discontinuation due to adverse events (AEs), and showed
improvements across multiple mitochondrial disease-associated
biomarkers, inflammatory biomarkers, cerebral blood flow, and
functional connectivity between neural networks.
The webinar included MELAS and mitochondrial
disease community insights from Philip Yeske, Ph.D., Science &
Alliance Officer of UMDF, and the perspective of MELAS
clinician-researcher, Amel Karaa, M.D., Assistant Professor and
Director of the Mitochondrial Disease Program and Lysosomal
Disorders Program at Harvard Medical School and Massachusetts
General Hospital, and recent president of the Mitochondrial
Medicine Society, on the implications and potential impact of these
data for patients with MELAS.
“With no approved therapies for this devastating progressive
orphan disease that affects multiple organ systems, including the
CNS, MELAS patients living with debilitating symptoms are in
desperate need of therapeutic options,” said Dr. Karaa. “I am
excited and encouraged by these data and am convinced that further
study and development should be undertaken to pursue CY6463 as a
potential treatment for MELAS.”
“UMDF was pleased to partner with Dr. Karaa and Cyclerion to
provide MELAS patients, their loved ones, researchers and medical
experts, who know the most about this debilitating mitochondrial
disease, with an opportunity to understand the study data,” said
Brian Harman, President and Chief Executive Officer of UMDF. “We
will continue to lift up the voices of the mitochondrial disease
community and do everything in our power to chart a course toward
future treatments through awareness, education, and
support.”Key Webinar Highlights Dr. Yeske and Dr.
Karaa provided key insights into the MELAS patient burden of
disease and treatment options, and Cyclerion’s Christopher Winrow,
Ph.D., Vice President, Translational Medicine & Development
Program Lead, and Chad Glasser, Pharm.D., Director of Clinical
Research, discussed the results from the Phase 2a study,
including:
- The single-arm, open-label study enrolled eight participants
who spanned a range of disease severity; 6 of the 8 (75%) were also
taking a daily regimen of oral arginine or citrulline, precursors
to nitric oxide that are often prescribed as 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 pharmacokinetic 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 objective domains of
disease activity in 6 of the 8 participants enrolled following 29
days of CY6463 dosing:
- Improvements in at least 1 plasma biomarker associated with
mitochondrial dysfunction were observed in 7 of the 8 participants.
- Reductions in lactate were observed in 6 of the 8 participants
with a mean percentage change of 24% and a range of 7% to 46%
- Reductions in GDF-15 concentrations were observed in 4 of the 8
participants with the greatest reductions (up to 39%) observed in
participants with higher concentrations of GDF-15 at baseline
- Changes across these biomarkers, including FGF-21, an
additional biomarker of mitochondrial dysfunction, were also
strongly correlated with each other and with CY6463 plasma
concentrations at the end of treatment
- Approximately two thirds of a panel of 40 plasma biomarkers of
inflammation were decreased from baseline following dosing with
CY6463. The largest effect sizes were observed in serum amyloid P,
Beta2-microglobulin. Effects were also observed in tumor necrosis
factor receptor 2 and vascular cell adhesion protein 1, which are
known to be implicated in mitochondrial disease. Overall, the
greatest reductions in these biomarkers were observed in
participants with the highest concentrations at baseline.
- Increases from baseline in cerebral blood flow were observed
for 5 of the 8 participants, ranging from 19% to 60% (mean change
of 42%). Changes in cerebral blood flow were strongly correlated
with clinical improvement as assessed by the Patient Global
Impression of Change (PGIC) scale (r value of -0.84).
- Increases from baseline in functional connectivity between
brain regions associated with sensorimotor processing and executive
function were observed via resting state functional MRI (fMRI).
fMRI BOLD response to visual stimulation, which is known to be
markedly reduced in symptomatic MELAS patients compared to healthy
controls, also improved following CY6463 dosing for 29 days as
shown by increased activation of occipital brain regions in
response to the visual stimulus compared to screening. Minimal
change was observed between screening and pre-dose on day 1.
“In a disease category with no approved therapies, we are
pleased to gather additional evidence that targeting a fundamental
CNS signaling pathway with CY6463 could potentially help people
with MELAS,” said Peter Hecht, Ph.D., Chief Executive Officer of
Cyclerion. “We are eager to work with mitochondrial disease experts
and the Food and Drug Administration (FDA) to design a development
program to further advance CY6463 as a potential treatment for
MELAS as quickly as possible.”
Webinar Replay Information A
replay of the event can be accessed on both the UMDF and Cyclerion
websites at https://www.umdf.org/mito-university or
https://ir.cyclerion.com/news-events/event-calendar.
About
MELAS Mitochondrial Encephalomyopathy, Lactic
Acidosis, and Stroke-like episodes (MELAS) is one of the most
complex orphan diseases affecting multiple organ systems, including
the CNS, with different degrees of severity, and no approved
therapies. MELAS is caused by some of the most common mitochondrial
DNA mutations affecting the mitochondrial tRNA, and results in
large clusters of familial cases of primary mitochondrial diseases
(PMD). 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 can affect virtually any organ and cause intense 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 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 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 Cyclerion
Therapeutics Cyclerion Therapeutics is a
clinical-stage biopharmaceutical company on a mission to develop
treatments that restore cognitive function. Cyclerion’s lead
molecule is CY6463, a novel, first-in-class, CNS-penetrant, sGC
stimulator that modulates a key node in a fundamental CNS signaling
network. The multidimensional pharmacology elicited by the
stimulation of sGC has the potential to impact a broad range of CNS
diseases. CY6463 has shown rapid improvement in biomarkers
associated with cognitive function and is currently in clinical
development for Alzheimer's Disease with Vascular pathology (ADv)
and Mitochondrial Encephalomyopathy, Lactic Acidosis and
Stroke-like episodes (MELAS) and Cognitive Impairment Associated
with Schizophrenia (CIAS). Cyclerion is also advancing CY3018, a
next generation sGC stimulator.
For more information about Cyclerion, please
visit https://www.cyclerion.com/ and follow us on Twitter
(@Cyclerion) and LinkedIn (www.linkedin.com/company/cyclerion).
Forward Looking StatementCertain 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.
InvestorsCarlo Tanzi, Ph.D.Kendall Investor
Relationsctanzi@kendallir.com
MediaAmanda SellersVerge Scientific
Communicationsasellers@vergescientific.com
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