Full Press Release Details
Cyclerion Announces Positive
Data from IW-6463 CNS Translational Pharmacology Study in Healthy Elderly Subjects
Showed significant improvements in neurophysiological
and objective performance measures associated with age-related cognitive decline and neurodegenerative diseases
Confirmed blood-brain-barrier penetration,
desired CNS exposure levels, target engagement and a favorable safety and tolerability profile
Proceeding with its upcoming Phase 2
clinical trials in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) and Alzheimer's disease
with vascular pathology (ADv)
Company to focus on developing treatments
for serious diseases of the central nervous system
Webcast at 8:30 a.m. ET today
CAMBRIDGE, Mass., October 14, 2020 - Cyclerion
Therapeutics, Inc. (Nasdaq: CYCN), a clinical-stage biopharmaceutical company developing innovative medicines for people with
serious diseases of the central nervous system (CNS), today announced results from its Phase 1 translational pharmacology study
of IW-6463, the first soluble guanylate cyclase (sGC) stimulator in clinical development for CNS disorders.
Treatment with IW-6463 in this 15-day 24-subject crossover study
confirmed and extended results seen in earlier Phase 1 studies: once daily oral treatment demonstrated blood-brain-barrier penetration,
desired CNS exposure levels and target engagement. In this study, IW-6463 was shown to be safe and generally well-tolerated.
Subjects receiving IW-6463 showed meaningful improvements in certain neurophysiological and objective performance measures that
are associated with age-related cognitive decline and neurodegenerative diseases. Effects on cerebral blood flow and markers of
bioenergetics were not observed in this study.
These results support the ongoing development of IW-6463 in
serious CNS diseases. Cyclerion will soon begin enrolling its Phase 2 clinical trial in Mitochondrial Encephalomyopathy, Lactic
Acidosis, and Stroke-like episodes (MELAS). Over the coming months the company will use the findings of the translational pharmacology
study, in addition to observations from the previous Phase 1 study of 110 healthy subjects, to inform further clinical development
activities, including the initiation of a planned Phase 2 clinical trial in Alzheimer's disease with vascular pathology (ADv)
in 2021, as well as to explore other potential indications.
"These data show that IW-6463 has a positive effect on
brain neurophysiology that has been associated with age-related cognitive decline and neurodegenerative diseases. Furthermore,
these data support the role of nitric oxide as an important neurotransmitter whose potential therapeutic benefits remain underexplored,"
said Chris Wright, M.D., Ph.D., Cyclerion's Chief Medical Officer. "We expect to initiate enrollment of the MELAS study
later this year and are excited to incorporate the learnings from our translational pharmacology study into the design of our planned
Phase 2 ADv study. Looking beyond these studies, we will evaluate the potential of IW-6463 to provide clinical benefit for people
suffering from a range of serious CNS diseases. Seeing such robust, consistent and rapidly occurring changes in this study gives
us confidence that IW-6463 targets a relevant mechanism in cognition and neurodegeneration."
IW-6463 Phase 1 Translational
Pharmacology Study Design
The exploratory Phase 1 study conducted in 24 healthy elderly
volunteers age 65 and older evaluated safety and tolerability, pharmacokinetics, measures of CNS pharmacodynamic activity, including
cerebral blood flow, and a range of measures associated with age-related cognitive decline and neurodegenerative diseases. Participants
received study drug once daily across two 15-day dosing periods (Period 1 and Period 2). The dosing periods were separated by a
27-day washout. Participants were randomized to a sequence of receiving IW-6463 for Period 1 and then placebo for Period 2, or
vice versa. All 24 subjects completed the first period, and 12 completed the entire crossover due to operational challenges associated
IW-6463 Phase 1 Translational
Pharmacology Study Results
IW-6463 demonstrated blood-brain-barrier penetration, desired
CNS exposure levels and engagement of the targeted nitric oxide (NO)-signaling pathway. Mean concentrations of IW-6463 in cerebrospinal
fluid (CSF) achieved levels projected to be pharmacologically active based on preclinical studies. Consistent with this, pathway
target engagement was confirmed through monitoring blood pressure and CSF cyclic guanosine monophosphate (cGMP) levels. This study
reproduced the brain exposure and safety and tolerability data set of the prior Phase 1 study in young healthy volunteers (n=110).
Key results in this healthy elderly population demonstrate an
impact on certain neurophysiological and objective performance measures known to be affected by aging and neurodegenerative disease
with cognitive impairment. Specifically, Cyclerion observed:
| improvements in the N200 auditory event-related potential, a measure associated with stimulus identification and distinction. Latency was significantly shorter with IW-6463 at day 14 compared to untreated subjects (p=0.02). | ||
| positive effects of IW-6463 on an objective saccadic eye movement task that is related to attention and cognitive processing. Saccadic reaction times were significantly shorter (p=0.02) and there was a trend increase in saccadic velocity (p=0.07). |
Cyclerion will continue to analyze the data to more fully understand
the relationship between IW-6463 and the biomarker effects observed. All p-values are unadjusted for multiplicity. The company
intends to present further results of this exploratory study, which represents a novel area of CNS science, in peer-reviewed journals
and medical conferences.
"These results bring into focus the exciting opportunity
to deliver innovative medicines, with the possibility to improve brain function, for an area in desperate need of new treatment
options," said Andy Busch, Ph.D., Chief Innovation Officer. "We are working at the forefront of CNS drug development
and we are learning a great deal about this novel mechanism of action. IW-6463 is a promising molecule with potential in a variety
of serious CNS diseases, and we look forward to building on the insights from this study to drive the path forward for the company,
the compound, and patients in need beyond our planned clinical trials and current target indications."
"These exciting and unique results demonstrate that stimulating
sGC can positively modulate alpha rhythm and N200 in the elderly, potentially improving age-related deficits in these neurophysiologic
measures," said Brandon Westover, M.D., Ph.D., McCance Center for Brain Health, Associate Professor, Neurology, Massachusetts
General Hospital and Harvard Medical School, and Co-Founder of Beacon Biosignals. "Given the relationships between alpha
rhythm, N200, brain aging, and cognitive impairment, further study is warranted in patients with debilitating age-associated neurodegenerative
The company's planned Phase 2 trial of IW-6463 in ADv
will be supported partially by a grant from the Alzheimer's Association's Part the Cloud-Gates Partnership Grant Program,
which is expected to provide Cyclerion with $2 million of funding over the next two years.
IW-6463, a CNS-penetrant sGC stimulator, is being developed
as a symptomatic and potentially disease modifying therapy for serious CNS diseases. Nitric oxide (NO) is one of several fundamental
neurotransmitters, but it has yet to be leveraged for its full CNS therapeutic potential. IW-6463 stimulates sGC, a signaling enzyme
that responds to the presence of NO, to enhance the body's natural ability to produce cyclic guanosine monophosphate (cGMP),
an important signaling molecule, naturally. An impaired NO-sGC-cGMP signaling pathway is believed to play an important role in
the pathogenesis of neurodegenerative diseases and is critical to basic neuronal functions. Agents that stimulate sGC to produce
cGMP may compensate for deficient NO signaling.
About Cyclerion Therapeutics
Cyclerion Therapeutics is a clinical-stage biopharmaceutical
company focused on discovering, developing and commercializing innovative medicines for people with serious diseases of the central
nervous system (CNS). Cyclerion's lead program is IW-6463, a pioneering CNS-penetrant sGC stimulator in clinical development
for Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) and Alzheimer's disease with vascular pathology
For more information about Cyclerion, please visit https://www.cyclerion.com/
Webcast and Conference Call Details
Cyclerion will host a webcast, with accompanying slide presentation,
on Wednesday, October 14, 2020 at 8:30 a.m. EDT to discuss the study results and plans for further development of IW-6463.
To access the webcast, please visit https://edge.media-server.com/mmc/p/2zzfo75c. To access the call, please dial (800)
360-8162 (toll-free) or (409) 937-8760 (international) and provide the conference ID 2554703. The archived webcast will remain
available online for 30 days. For more information, please visit the investor section of Cyclerion's website at www.cyclerion.com
Forward Looking Statement
This press release contains forward-looking statements within
the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act
of 1934, as amended. Our forward-looking statements are based on current beliefs and expectations of our management team that involve
risks, potential changes in circumstances, assumptions, and uncertainties, including statements about the results and conduct of
our Phase 1 translational pharmacology clinical trial of IW-6463; our interpretation of the data from the clinical trial; the potential
of further evaluation of IW-6463; the clinical potential of IW-6463; our future business focus; the anticipated timing of our planned
clinical trials; and the receipt of cash from the Alzheimer's Association's Part the Cloud-Gates Partnership Grant Program,