CNS

CNS is a high reward space where the large unmet needs are growing, given aging patient populations and the dearth of approved and effective treatments.

CNS Opportunities

CNS is a high reward space with large and growing unmet need due to an aging population and a dearth of approved and effective treatments.  Rapidly evolving science, including both genetic insights and technologies, is accelerating the discovery and development of new CNS drugs.

The sGC mechanism has the potential to create a meaningful medical breakthrough by stimulating a previously undrugged neurotransmitter system in the CNS. Other successfully drugged neurotransmitter systems opened entirely new therapeutic categories and created significant market opportunities. This type of therapeutic potential creates broad opportunity to help a wide range of patients suffering from CNS diseases, and thus makes our CNS program an exciting strategic focus today and a core part of Cyclerion going forward.

NO-sGC-cGMP and Brain Health

In the CNS, NO-sGC-cGMP signaling underlies multiple physiological processes that contribute to overall brain health, including neurotransmission, neurovascular function, cellular bioenergetics, and inflammation. Nitric oxide is a gas with a short half-life (0.5-5s) that acts locally (100-200 uM range). These properties enable the precise and dynamic spatial and temporal regulation seen with NO and other neurotransmitters.

NO-sGC-cGMP signaling underlies multiple physiological
processes that contribute to overall brain health

Our systems biology approach combines genetic and proteomic data to identify CNS diseases in which the NO-sGC-cGMP pathway plays a central role. This approach identified a broad range of both neurodegenerative diseases (e.g., Alzheimer’s Disease) and neuropsychiatric diseases (e.g., schizophrenia) – with dysfunctional NO-sGC-cGMP signaling as the common pathophysiologic thread.

IW-6463 is an sGC stimulator, a positive allosteric modulator of sGC that amplifies endogenous NO signaling. In diseases associated with deficits in the NO-sGC-cGMP pathway, IW-6463 has the potential to address the underlying pathophysiology by restoring appropriate endogenous signaling and maintaining the precise spatial and temporal control that is the hallmark of this signaling pathway.

IW-6463 is the first CNS-penetrant sGC stimulator designed and in development for neurodegenerative diseases. In preclinical studies, IW-6463 showed benefits in multiple animal models and across four domains of human neurodegenerative diseases.

Pre-clinical evidence across domains

Improves

Cerebral
Blood Flow

Increased blood flow in areas associated with memory and arousal by fMRI BOLD imaging

Enhances

Cellular
Bioenergetics

Increased ATP and restored gene expression in cells from patients with mitochondrial diseases

Reduces

Neuro-
inflammation

Decreased markers of LPS-induced neuroinflammation (ICAM1, VCAM1, IL6) in vitro

Improves

Neuronal
Function

Enhanced memory performance & spine density in aged animals; increased LTP in neurodegenerative disease models

MELAS

Biomarker-Driven Development

The fundamental objective of our biomarker approach is to connect drug mechanism to disease pathophysiology and in turn to individual patients and their clinical outcomes. By employing this approach, we aim to increase precision and efficiency in the development of our drugs for the treatment of patient populations that are often genetically and phenotypically heterogeneous.

We employ a multimodal array of biomarkers to generate an integrated and detailed profile of our drug. Modalities include:

  • Magnetic resonance imaging (MRI) techniques
    • Arterial spin labeling (ASL)
    • Functional blood oxygen level dependent (fMRI BOLD)
    • Magnetic resonance spectroscopy (MRS) of brain metabolites
  • Quantitative electroencephalography (qEEG)
  • Biofluid-based chemical and genetic markers
  • Sensitive neuropsychological assessments

We select modalities that can be used in both preclinical and clinical settings so we can demonstrate mechanistic translation in our earliest clinical studies. The biomarker profiles generated in these early studies, combined with disease-specific biomarkers, inform subsequent clinical development and can be used to define patient selection and trial endpoints.

MELAS

Early Clinical Results for IW-6463

Our comprehensive, first-in-human Phase 1 study demonstrated favorable safety, CNS pharmacokinetics, and evidence of target engagement that support our ongoing clinical development.

 To learn more about the study, see the study listing on ClinicalTrials.gov.

Translational pharmacology study

Designed to evaluate safety, pharmacokinetics, and target engagement
in the CNS, as well as assess an array of biomarkers across
four domains of neurodegenerative disease.

Cerebral
Blood Flow

Cellular
Bioenergetics

Neuro-
inflammation

Neuronal
Function

Translational pharmacology study; topline data expected late summer 2020

Designed to evaluate safety, pharmacokinestics, and target engagement
in the CNS, as well as assess an array of biomarkers across
four domains of neurodegenerative disease.

24 subjects completed the first parallel phase of the study and 12 subjects completed the full crossover study due to regulations imposed as a result of COVID

To learn more about the study, see the study listing on ClinicalTrials.gov.

MELAS

Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is one of the most common and severe mitochondrial diseases.

Mitochondrial diseases are a group of rare genetic disorders that affect the function of mitochondria, the powerhouses of the cell. Mitochondrial disease can affect almost any part of the body. The tissues and organs that are most often affected are those with the highest energy demands, such as the brain, heart, eyes, and skeletal muscles. It is estimated that about 1 in 4,300 individuals has a mitochondrial disease, and ~80% of individuals with mitochondrial disease have CNS symptoms.

MELAS is a genetically defined orphan disease for which there is no approved treatment. The defining features of MELAS are stroke-like episodes and lactic acidosis, a buildup of lactic acid in the bloodstream. Other common CNS symptoms include seizures, headaches, migraines, and cognitive impairment.

MELAS

sGC stimulation may have beneficial effects on several key pathological mechanisms of mitochondrial disease. The NO-sGC-cGMP signaling pathway is critical for the regulation of mitochondrial function and biogenesis.

Scientific Rationale for MELAS

Clinical precedence for NO-sGC-cGMP pathway

  • Though not FDA-approved, L-Arginine (NO precursor) recommended for acute treatment of stroke based on limited supportive evidence

Pathophysiology

  • CNS metabolic dysfunction, elevated lactate, decreased NO
  • CNS vascular pathology – impaired blood flow, inflammation, endothelial dysfunction, small vessel disease

IW-6463 Pharmacology

  • Preclinical data suggest IW-6463 has the potential to improve mitochondrial function and cerebral blood flow

sGC stimulation may have beneficial effects on several key pathological mechanisms of mitochondrial disease. The NO-sGC-cGMP signaling pathway is critical for the regulation of mitochondrial function and biogenesis.

Scientific Rationale for MELAS

We plan to initiate a Phase 2a multi-center, open-label study in MELAS at centers of excellence for mitochondrial diseases.

In addition to safety, the study will assess the impact of short-term IW-6463 treatment on biomarkers of mitochondrial dysfunction, brain perfusion, neurodegeneration, and cognition.

This study is being conducted at medical centers of excellence for mitochondrial disease. All of our clinical sites are part of the Mitochondrial Care Network  and the North American Mitochondrial Disease Consortium.

To learn more about the study, see the study listing on ClinicalTrials.gov.

For additional information, visit International mito-patients, MitoAction, and United Mitochondrial Disease Foundation

Phase 1

Enrichment Strategy

  • Genetically defined MELAS with neurological features and elevated plasma lactate (disease biomarker)

Treatment

  • Once-daily IW-6463
  • 29 Days
  • Up to 20 adults (targeting 12 completers)

Objectives

  • Evaluate safety, tolerability, and pharmacodynamics
  • Assess near-term impact on disease-soecific biomarkers
  • De-risk and accelerate future developement.

Alzheimer’s Disease with Vascular Pathology (ADv)

ADv – Alzheimer’s Disease with vascular pathology – is a focused dementia population. ADv reflects the complex interplay of multiple pathological mechanisms underlying dementia, including neurovascular dysfunction, impaired cellular bioenergetics, and inflammation.

In standard classifications, Alzheimer’s Disease (AD) and Vascular Dementia (VD) are the two most common forms of dementia. However, it is well accepted that many dementia patients have more than one form of underlying pathology. Over 50% of individuals with AD also have signs of VD, and these patients often have more rapidly progressing disease and higher symptom severity. There are no approved therapies for VD, and only symptomatic treatments with limited benefit are approved for AD.

The ADv patient is defined by a combination of AD pathology, sub-cortical vascular disease, and cardiovascular (CV) risk factors. We selected this population of dementia patients because IW‑6463 has the potential to address the pathophysiological processes driving their disease.

In ADv patients, NO dysregulation, endothelial cell loss, impaired blood flow, vascular leakage, inflammation, neuronal dysfunction, and neurodegeneration are major contributing factors to rapid disease progression.  Our preclinical data suggest IW‐6463 has potential to provide meaningful symptomatic benefit by improving cerebral blood flow, endothelial health, neuroinflammation, and cellular energetics. IW-6463 also has the potential to be disease modifying by preventing neurodegeneration.

Scientific Rationale for ADv
ADv – An identifiable subset of dementia patients
  • AD pathology AND
  • Sub-cortical vascular disease AND
  • CV Risk Factors

In ADv patients, NO dysregulation, endothelial cell loss, impaired blood flow, vascular leakage, inflammation, neuronal dysfunction, and neurodegeneration are major contributing factors to rapid disease progression. Our preclinical data suggest IW‐6463 has potential to provide meaningful symptomatic benefit by improving cerebral blood flow, endothelial health, neuroinflammation, and cellular energetics. IW-6463 also has the potential to be disease modifying by preventing neurodegeneration.

Scientific Rationale for ADv
Pathophysiology

Major contributing factors to rapid disease progression:

  • NO dysregulation
  • Endothelial cell loss
  • Neuronal loss
  • Vascular leakage
  • Inflammation
  • Impaired blood flow
IW-6463 pharmacology

Preclinical data suggest IW-6463 has potential to:

Improve

  • Cerebral blood flow
  • Neuroinflammation
  • Endothelial health
  • Cellular energetics

Prevent

  • Neurodegeneration

Phase 2a study of IW-6463 in ADv: emerging design

Emerging Design

Treatment

  • Once-daily IW-6463

Enrichment Strategy

  • Confirmed AD pathology (PET, CSF)
  • 3+ cardiovascular risk factors
  • Mild-moderate subcortical small-vessel disease on MRI
  • Mini Mental State Exam score (16-26)

Objectives

  • Establish safety and pharmacodynamic effects of IW-6463 in a short-term study
  • De-risk progression to larger, longer symptomatic and disease modification trials
Disease Domain
  • Vascular dysfunction
  • Neurodegeneration
  • Neuroinflammation
  • Mitochondrial dysfunction
  • Cognitive impairment
Assessment
  • ASL (CBF)
  • Neurofilament light chain
  • Vascular cell adhesion molecule
  • N-acetyl aspartate (MRS)
  • Cognitive and behavior tests

Improved CBF, particularly in the context of memory improvements, would indicate an impact on the underlying disease mechanism and enable a targeted design for the next development stage.

For more information, visit Alzheimer’s Association

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