Phase 2a Study of IW-6463 in Adults Diagnosed With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS)

IW-6463 tablets will be orally administered once-daily (QD) for up to 29 days

• IW-6463 Tablets (Drug), also known as CY6463, zagociguat: IW-6463 tablets administered orally (daily)

Primary outcomes

• Number of Participants With Study Drug Dose Reductions or Discontinuations Due to ≥ 1 Treatment Emergent Adverse Event (TEAE) [From first dose date to Day 43 (±4)]: A TEAE is defined as an adverse event (AE) with an onset that occurs between the first dose of study drug and the end of study period. AEs are defined as an untoward medical occurrence that does not necessarily have a causal relationship with study drug treatment.
• Number of Participants Who Experienced ≥1 AE, TEAE, Serious AE (SAE), or TEAE of Special Interest (AESI) [From first dose date to Day 43 (±4)]: AEs are defined as an untoward medical occurrence that does not necessarily have a causal relationship with study drug treatment. A TEAE is defined as an AE with an onset that occurs from the first dose of study drug up until the end of study period. An SAE is an AE that fulfills 1 or more of the following: results in death; is immediately life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event that may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes listed above. Events were categorized as mild, moderate, or severe and as related or unrelated to study drug. AESIs include bleeding events, symptomatic hypotensive events and/or tachycardia, dizziness, syncope, and TEAEs related to change of neurobehaviors (ie, suicidality or euphoria).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Prior genetic confirmation of a known mitochondrial disease mutation
2. Neurological features of MELAS (can be based on medical history)
3. Elevated plasma lactate levels at Screening Visit (≥1.0 mmol/L)
4. Women of childbearing potential must have a negative pregnancy test prior to randomization and must agree to use protocol-specified contraception from the Screening Visit through 90 days after the final dose of study drug.
5. Male participants must be surgically sterile by vasectomy (conducted ≥60 days before the Screening Visit or confirmed via sperm analysis) or must agree to use protocol-specified contraception and agree to refrain from sperm donation from the Screening Visit through 90 days after the final dose of study drug.
6. Other inclusion criteria per protocol

Exclusion Criteria:

1. Positive pregnancy test at Screening or on Day 1
2. Hypotension defined as systolic blood pressure (BP) ≤90 mmHg or diastolic BP ≤60 mmHg at Screening or predose at Day 1
3. Hypertension defined as systolic BP >160 mmHg or diastolic BP >100 mmHg, at Screening or predose at Day 1
4. Uncontrolled diabetes
5. Severe gastrointestinal dysmotility as determined by the investigator that may impact compliance and/or oral drug administration, absorption and exposure.
6. Unable to fast for 3-4 hours after a meal
7. Unable or unwilling to adhere to the study schedule, lifestyle restrictions, assessment requirements or, in the clinical judgment of the investigator, is otherwise not suitable for study participation.
8. Current or past history of clinically significant cardiomyopathy and/or cardiac conduction abnormality
9. Used any nicotine-containing products (eg, cigarettes, e-cigarettes, vape pens, cigars) within 1 month of enrollment
10. Other exclusion criteria per protocol

Participant flow

Outcome results

• Number of Participants With Study Drug Dose Reductions or Discontinuations Due to ≥ 1 Treatment Emergent Adverse Event (TEAE) (Primary), Count of participants, Participants: IW-6463 1
• Number of Participants Who Experienced ≥1 AE, TEAE, Serious AE (SAE), or TEAE of Special Interest (AESI) (Primary), Count of participants, Participants: IW-6463 8

Adverse events

Time frame: From signing of informed consent (all-cause mortality) or first dose date (adverse events) to Day 43 (±4).

Other adverse events by term

• Study Protocol (PDF, 2021-07-23)
• Statistical Analysis Plan (PDF, 2022-03-21)

• Chad Glasser, PharmD, Study director, Cyclerion Therapeutics, Inc.