Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease

Inclusion Criteria:

• Age 18 years or older.

• A confirmed PMD diagnosis caused by a known pathogenic gene mutation or deletion ofthe mitochondrial genome (category 6 of the International Classification of InbornMetabolic Disorders [ICIMD])12 according to American College of Medical Genetics (ACMG)/Association of Molecular Pathology (AMP) criteria1, with multisystemicdisease expressions, including:

1. m.3243A>G associated MELAS-MIDD spectrum disorders,

2. single large scale mtDNA deletion associated KSS-CPEO spectrum disorders,

3. other multisystemic mtDNA-related disease (including MERRF).

• Presence of chronic mitochondrial fatigue:

• History of mitochondrial fatigue for at least 3 months prior to the ScreeningVisit AND

• Presence of at least moderate level of fatigue, assessed by PROMIS® Fatigue PMDShort form raw score ≥ 27 at Screening and Baseline

• Presence of mitochondrial myopathy defined as:

• Myopathy (proximal muscle weakness), NMDAS Section III Clinical Assessment,item 5 score ≥ 1, which reads: "minimal reduction in hip flexion and/orshoulder abduction only (e.g. MRC 4+/5)". For the inclusion only hip flexion,but not shoulder abduction, should be taken into account. AND / OR

• Exercise Tolerance: NMDAS Section I, item 9 score ≥ 1, which reads: "unlimitedon flat - symptomatic on inclines or stairs".

• Patients must be able to perform at least 2 repetitions and the maximal capacitymust not exceed 17 repetitions in males or 16 repetitions in females in a 30s STStest at screening.

• Clinically stable, apart from symptoms associated with the diagnosis ofmitochondrial disease, at Screening and Baseline, as determined by medical history,physical examination, 12-lead ECG, vital signs measurements, and clinical laboratoryevaluations at Screening, as assessed by the investigator.

• The patient is willing and able to attend study appointments within the specifiedtime windows.

• Willingness and ability to complete electronic PROs.

• Willingness to maintain a stable diet during the Screening and study periods.

• Patients who take any mitochondrial disease-focused vitamins or supplementaltherapies, including coenzyme Q10 (CoQ10), niacin/nicotinamide (vitamin B3), andL-arginine, has been on a stable dose regimen of these for 3 months prior torandomisation and intends to stay on a stable dose for the duration of the studyperiod.

• Willingness to suspend treatment with idebenone during the study.

• Female patient is not pregnant and at least one of the following conditions apply:

1. Not a woman of childbearing potential (WOCBP)

2. WOCBP must agree not to try and become pregnant and use a highly effectivemethod of contraception from the time of informed consent through at least 36days (~5 half-lives of KL1333 plus 30 days) after the last dose ofinvestigational medicinal product (IMP) administration.

• Male patients with female partner(s) of childbearing potential must agree to use amale condom in addition to using highly effective contraception throughout thetreatment period and for 96 days after the last dose of IMP administration. Therequirement to use a male condom also applies to male patients with a pregnant orbreastfeeding partner.

• Female patients must agree not to breastfeed starting at Screening and throughoutthe study period and for 36 days after the last dose of IMP administration.

• Female patients must agree to not donate ova throughout the study period and for 36days after the last dose of IMP administration, and male patients must agree to notdonate sperm throughout the study period and for 96 days after the last dose of IMPadministration.

Exclusion Criteria:

• Primary mitochondrial disease with predominant neurodegenerative phenotypes, suchas, but not limited to, Leigh syndrome, Leber hereditary optic neuropathy (LHON) andNeuropathy ataxia-retinitis pigmentosa syndrome (NARP).

• Primary mitochondrial disease nuclear DNA mutations or mutations causing mtDNAdestabilisation. Genetic mtDNA variants of uncertain significance, likelypathogenic, or pathogenic mutations with degrees of heteroplasmy below what can beconsidered to definitely cause PMD.

• General fatigue or muscle weakness due to causes other than mitochondrial disease,in the opinion of the investigator.

• Significant cardiovascular disease (e.g., sustained or symptomatic arrhythmia;dilated heart chambers or reduced function; Mobitz II atrioventricular block orgreater) OR abnormal ECG that is clinically significant, as determined by theinvestigator. Any QTcF > 450 msec for male patients and > 470 msec for femalepatients is exclusionary. In the case of an exclusionary QTcF, the ECG can berepeated twice and the average of 3 QTcF intervals should be used to determine theQTcF eligibility.

• Recent history of unstable disease, inadequately controlled neurologicalmanifestations or not recovered from stroke-like episodes including but not limitedto:

1. stroke-like episodes within the last 6 months

2. more than 1 seizure/month within the last 6 months

3. hospitalised for Status Epilepticus within the last 6 months

4. more than 4 days of migraine episodes/month within the last 6 months

• History of inflammatory bowel disease, gastric erosions, peptic ulcer disease, orgastrointestinal bleeding episodes. Gastroesophageal reflux disease diagnosed byobjective endoscopic or radiographic means, and clinically symptomatic at any pointover the last 6 months.

• The patient has one or more clinical laboratory test values outside the referencerange, based on the blood and urine samples taken at the Screening Visit, that areof potential risk to the patient's safety, or the patient has, at the ScreeningVisit:

• estimated glomerular filtration rate (eGFR) calculated by the Chronic KidneyDisease Epidemiology Collaboration (CKD-EPI) creatinine equation <30mL/min/1.73 m2

• a serum total bilirubin value > 1.5 times the upper limit of the referencerange unless elevation is related to Gilbert's syndrome and the investigatorcan rule out any underlying liver dysfunction based on other tests, the patienthas a Child-Pugh score ≤6, and after discussing the case with the medicalmonitor

• a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST)value > 2 times the upper limit of the reference range. Values between 2 and 3times the upper limit of the reference range may be allowed if concomitant toelevation in creatine kinase as long as the investigator can rule out anyunderlying liver dysfunction based on other tests, the patient has a Child-Pughscore ≤6, and after discussing the case with the medical monitor

• The patient has, in the investigator's opinion, severe ataxia, neuropathy, balanceproblems or other medical condition that would interfere the evaluation of the 30sSTS test.

• Untreated or undertreated sleep apnoea, in the opinion of the investigator.

• Use of idebenone within 14 days prior to the first dose.

• Patients have a history of unstable or severe pulmonary, immunological, oncological,hepatic disease, renal disease, or another medically significant illness other thanPMD or takes medication that could, in the investigator's opinion, interfere withthe assessments of safety, tolerability, or efficacy, or interfere with the conductor interpretation of the study.

• The patient is, in the investigator's opinion, unlikely to comply with the protocole.g. due to cognitive impairment or is unsuitable for any reason.

• The patient has an immediate family member (defined as family members residing atthe same address) who participates in the study.

• Female patients with a positive pregnancy result at Screening or at Baseline.

• A patient cannot participate if they received an investigational drug 30 days or 5half-lives prior to the Screening Visit (whichever is longer), or plans to use aninvestigational drug (other than the study intervention) during the study

• Hypersensitivity to the active substance or to any of the excipients or placebo.