Sonlicromanol for symptoms of primary mitochondrial disease due to the m.3243A>G mutation

A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel-group, Pivotal Trial to Assess the Efficacy and Safety of Sonlicromanol in Adult Subjects With a Genetically Confirmed Mitochondrial DNA tRNALeu(UUR) m.3243A>G Variant

This will test whether taking sonlicromanol twice daily for one year can reduce fatigue and improve balance and leg strength in adults with the m.3243A>G mitochondrial mutation.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 220 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Khondrion BV (Industry-sponsored)
• Locations: 10 sites (Boston, Massachusetts and 9 other locations)
• Trial ID: NCT06451757 on ClinicalTrials.gov

What this trial studies

KHENERFIN is a randomized, double-blind, placebo-controlled Phase 3 trial comparing sonlicromanol to a matched placebo in adults with primary mitochondrial disease caused by the m.3243A>G mutation. Participants are randomly assigned to take sonlicromanol or placebo tablets twice daily for 52 weeks, with a final follow-up visit two weeks after the last dose. Primary outcomes measure changes in fatigue severity and the impact of fatigue on daily life, along with balance control and lower-limb muscle strength; a range of secondary and exploratory outcomes plus safety and tolerability are also collected. Eligibility is confirmed during a screening period (up to 4 weeks) and requires specified heteroplasmy thresholds, chronic fatigue, and the ability to complete the 5x sit-to-stand test.

Who should consider this trial

Good fit: Adults (≥18 years) with multi-system primary mitochondrial disease caused by the m.3243A>G mutation who meet the age-adjusted heteroplasmy threshold (≥20% by approved sample types), report chronic fatigue for ≥3 months with a Neuro-QoL fatigue score >22, and can complete the 5x sit-to-stand test are ideal candidates.

Not a fit: People without the m.3243A>G mutation or with heteroplasmy below the required threshold, those whose fatigue is due to other causes, or those unable to complete the required physical tests are unlikely to meet eligibility or benefit from this trial.

Why it matters

Potential benefit: If successful, sonlicromanol could reduce fatigue and improve mobility and leg strength, which may help people with the m.3243A>G mutation perform daily activities more easily.

How similar studies have performed: Prior early-phase studies of sonlicromanol and similar mitochondrial-targeted approaches have shown some promising signals on symptoms or biomarkers, but large randomized Phase 3 evidence is limited.

Eligibility criteria

Inclusion criteria

1. Signed Informed Consent
2. Males and females aged ≥18 years with a multi-system primary mitochondrial disease.
3. A confirmed mitochondrial DNA tRNALeu(UUR) m.3243A\>G mutation (m.3243A\>G PMD) plus an age adjusted heteroplasmy percentage ≥ 20% in white blood cells \[=blood heteroplasmy/0.977(age+12)\]. Or in urine (urinary epithelial cells), or buccal smear or skeletal muscle (results (obtained per local guidance) ≥ 20% must be available prior to the subject being randomized).
4. Presence of chronic fatigue (not attributable to other etiologies than PMD):

   1. Patient self-reported chronic fatigue for at least 3 months prior to the Screening Visit and recorded in the clinical patient files; AND
   2. Presence of fatigue (raw total score \>22), assessed by Neuro-QoL SFv1-F at Screening.
5. Presence of mitochondrial myopathy defined as:

5xSST at Screening and Baseline should be ≥ 11 seconds and participant must demonstrate the ability to complete the test at baseline (i.e., complete the test within 30 seconds).

6\. Other Inclusion criteria per protocol.

Exclusion criteria

1. Treatment with any IMP within 3 months (or 5 times the half-life of the IMP, whichever is longer) prior to screening or plans to use an IMP (other than the study intervention) during the study.
2. Bone deformities, motor abnormalities or chronic ulcers that in the opinion of the PI may interfere with and/or confound the interpretation of the subject's performance during the 5 times sit to stand test (5XSST).
3. Surgery of gastrointestinal tract that might interfere with drug absorption. Or severe GI dysmotility, chronic vomiting, diarrhea, bouts of pseudo-obstruction which will impair appropriate IMP absorption in the opinion of the investigator.
4. Clinically significant respiratory disease and/or cardiac disease (medical history or current clinical findings) in the opinion of the investigator.
5. Prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening.
6. QTcF \> 450 msec (men) or QTcF \> 470 msec (women).
7. Structural heart disease based on cardiac MRI or Echocardiography (e.g., clinically significant valve disease; i.e., aortic or mitral valve stenosis or regurgitation) and/or abnormal conduction (QRS \>120 msec, PR \> 120 msec), and/or repolarization (QTcF \> 450 msec (men) or QTcF \> 470 msec (women)). Myocardial function (LVEF \<52% in men and \< 54% in women), symptomatic ischemic heart disease (inducible ischemia or coronary obstruction), and/or pathologic hypertrophy (e.g. \> 15mm septal or posterior wall thickness), that is not well controlled under current specialized care. Subjects with congestive heart failure class II and above should also be excluded.
8. Family history of unexplained/uninvestigated syncope or congenital long and short QT syndrome or sudden death (under the age of 60). ECG evidence of acute or recent ischemia, acute or Recent Myocardial Infraction, atrial fibrillation, high grade AV Blocks (Second Degree AV Block Type II or Third-degree AV Block), complete Heart Block or active conduction system abnormalities with the exception of any of the following:

   1. First degree atrioventricular (AV)-block
   2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
   3. Right bundle branch block.
9. History of acute heart failure (within the last 3 months).
10. Higher degree of AV-blocks (AVB II° or III°).
11. Other exclusion criteria per protocol

Where this trial is running

Boston, Massachusetts and 9 other locations

• Massachusetts General Hospital — Boston, Massachusetts, United States (Not_yet_recruiting)
• Cleveland Clinic Neurological Institute Mellen Center — Cleveland, Ohio, United States (Not_yet_recruiting)
• The University of Texas Health Science Center at Houston — Houston, Texas, United States (Not_yet_recruiting)
• Rigshospitalet, University of Copenhagen — Kopenhagen, Region Sjælland, Denmark (Not_yet_recruiting)
• CHU de Bordeaux - Hôpital Pellegrin Service Gynecologie Obstetrique — Bordeaux, Gironde, France (Not_yet_recruiting)
• Groupe Hospitalier Pitie-Salpetriere - Charles-Foix Clinical Investigation Center Paris-Est — Paris, Paris, France (Not_yet_recruiting)
• Klinikum der Universität München Friedrich-Baur-Institut — München, Germany (Not_yet_recruiting)
• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan, Milano, Italy (Not_yet_recruiting)
• Radboud University Medical Center — Nijmegen, Gelderland, Netherlands (Recruiting)
• University College London Hospitals NHS Foundation Trust National Hospital for Neurology and Neurosurgery — London, Greater London, United Kingdom (Recruiting)

Study contacts

• Study coordinator: Jasper Levink, MSc.

Conditions Mitochondrial Diseases; Maternally Inherited Diabetes and Deafness; Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes; Mitochondrial DNA tRNALeu m.3243A<G Mutation; Oxidative Phosphorylation; Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes; Sonlicromanol