Open-label extension study of KL1333 for long-term safety, tolerability, and efficacy in adults with primary mitochondrial disease

The primary objective is to evaluate the safety and tolerability of 48 weeks of open-label KL1333 treatment in adults with primary mitochondrial disease who had previously received KL1333 or placebo in the FALCON study. This is clinically relevant because long-term treatment exposure must be assessed for adverse effects and overall tolerability in this chronic disorder. The secondary objectives are to describe the efficacy of 48 weeks of open-label KL1333 treatment on fatigue symptoms and their impact on daily living, functional lower extremity strength and endurance, physical function and activities of daily living, treatment impact and health-related quality of life, progression of mitochondrial disease, and glycemic control in participants with diabetes.

The trial enrolled 62 participants with adult patients with primary mitochondrial disease. The study population included both female and male subjects and was limited to individuals aged 18 years or older who had completed the FALCON study and were considered compliant with study requirements. Selection also required willingness and ability to provide informed consent, attend study appointments within specified windows, and complete electronic patient-reported outcomes. Concomitant medications were expected to remain stable where clinically possible, and idebenone suspension was to be continued. Relevant exclusion or participation-limiting criteria included pregnancy, breastfeeding, and the need for effective contraception and donation restrictions for female and male subjects during the study period and for a defined period after the last dose.

This is an open-label, single-arm, extension Phase 4 study evaluating the long-term safety, tolerability, and efficacy of oral KL1333 in adults with primary mitochondrial disease who previously completed the FALCON study. The planned treatment period is 48 weeks, and overall study duration is from 29 June 2026 to 31 March 2029. Study participation begins with a screening visit to confirm eligibility, informed consent, protocol compliance, stable concomitant medication use where clinically possible, and required reproductive precautions. Eligible participants then enter the treatment period and attend scheduled follow-up visits for ongoing assessment of safety parameters, including adverse events, physical examination, vital signs, ECG, C-SSRS, and laboratory evaluations, as well as efficacy and patient-reported outcomes. The end-of-study visit is performed at completion of treatment to repeat final assessments and document study completion. Participants are expected to remain in the study for approximately 48 weeks, unless early termination occurs because of withdrawal of consent, noncompliance with study requirements, investigator or sponsor decision, pregnancy, or other circumstances requiring discontinuation under the protocol.

The investigational treatment was KL1333 (napazimone), supplied as a tablet for oral administration at a dose of 100 mg. It was administered in an open-label manner for 48 weeks. The study evaluated long-term safety, tolerability, and efficacy in subjects previously treated with KL1333 or placebo in the preceding study.

No additional non-experimental treatment was specified in the source data beyond prior exposure to KL1333 or placebo in the earlier study. Compliance monitoring details and further dosing schedule information were not provided.

Efficacy will be assessed using patient-reported and clinician-assessed measures, functional testing, and disease progression assessments. Patient-reported mitochondrial fatigue will be evaluated with the PROMIS® Fatigue PMD short form. Functional outcome will be assessed with the 30-second Sit-to-Stand Test. Patient-reported lower extremity function will be measured with the Neuro-QOL Lower Extremity Function (Mobility) - short form. Other patient-reported outcomes will include Patient Global Impression of severity and change and EQ-5D-5L. Clinician-assessed global impression of severity and change will be measured with the Clinician Global Impression of PMD. Assessments of mitochondrial disease progression will include NMDAS Subscales I-III. In the subgroup with diabetes, efficacy-related assessment will include HbA1c.