A Phase IIb open-label, multi-centre, extension study to explore the long-term safety and efficacy of KH176 in subjects with a genetically confirmed mitochondrial DNA tRNALeu(UUR) m.3243A>G mutation who have completed the KHENERGYZE study KH176-202.

1. Males and females aged 18 years or older at screening.
2. Ability and willingness to provide written Informed Consent prior to
screening evaluations.
3. Having fulfilled all inclusion and exclusion criteria and completed the full
treatment period of study KH176-202.
4. Disease appropriate physical and mental health as established at Screening
by medical history, physical examination, ECG and vital signs recording, and
results of clinical chemistry and haematology testing as judged by the
investigator.
5. Objectified Left Ventricular Ejection Fraction (LVEF) >=45%
(echocardiography, or otherwise).
6. Left Ventricular (LV) wall thickness <=15 mm.
7. Left atrium dilatation <= 40 mL/m2. Note: No need to test LV parameters
(criteria #5, #6, #7) if favourable echocardiography (or otherwise) results
dated less than 13 months prior to Screening are available.
8.Women of childbearing potential must be willing to use highly effective
contraceptive methods during the entire study, i.e. combined (estrogen and
progestogen containing) oral, intravaginal or transdermal hormonal
contraception associated with inhibition of ovulation; oral, injectable or
implantable progestogen-only hormonal contraception associated with inhibition
of ovulation; use of an intrauterine device; an intrauterine hormone releasing
system, bilateral tubal occlusion and vasectomy of the partner. Any hormonal
contraception method must be supplemented with a barrier method (preferably
male condom). Vasectomised partner is considered a highly effective birth
control method provided that partner is the sole sexual partner of the subject
and that the vasectomised partner has received medical assessment of the
surgical success.
Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk
associated with the study treatments. Reliability of sexual abstinence needs to
be evaluated in relation to the duration of the clinical trial and the
preferred and usual lifestyle of the subject. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are
not acceptable methods of contraception.
Note 1: Natural family planning methods, female condom, cervical cap or
diaphragm are not considered adequate contraceptive methods in the context of
this study.
Note 2: To be considered not of childbearing potential, potential female
subjects must be post-menopausal for at least two years, or have been
surgically sterilised (bilateral tubal ligation, hysterectomy or bilateral
oophorectomy) for at least 6 months prior to Screening.
Note 3: Sonlicromanol has been shown non-genotoxic judged from the Ames test,
Chromosomal Aberration test and in vivo Micronucleus test. Moreover,
appreciable systemic exposure from the exposure to (~2.5 mL) semen is extremely
unlikely. However, until reproductive toxicology studies have confirmed that
sonlicromanol does not adversely affect normal reproduction in adult males and
females, as well as causing developmental toxicity in the offspring, the
following contraceptive precautions must be adhered to:
• male subjects with female partners of childbearing potential must be willing
to use condoms during the entire study.
• female partners of childbearing potential of male subjects must be willing to
use adequate contraceptive methods during the entire study, i.e., a hormonal
contraceptive method (pill, vaginal ring, patch, implant, injectable,
hormone-medicated intrauterine device) or an intrauterine device.
9. Able to comply with the study requirements, including swallowing study
medication.

1. Surgery of gastro-intestinal tract that might interfere with absorption.
2. Treatment with an investigational product (except sonlicromanol) within 3
months or 5 times the half-life of the investigational product (whichever is
longer) prior to the first dose of the study medication.
3. Documented history of ventricular tachycardia (HR>110 beats/min), PVC burden
>=5% or daytime Mobitz II AV block on any of the Holter assessments in the
KH176-202 study or in the medical history.
4. History of acute heart failure, (family) history of unexplained syncope or
congenital long and short QT syndrome or sudden death.
5. Clinically relevant abnormal laboratory, vital signs or physical or mental
health;
a) Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x
upper limit of normal (ULN), or bilirubin > 3 x ULN at screening. If a patient
has ASAT or ALAT > 3 x ULN but < 3.5 x ULN, re-assessment is allowed at the
investigator*s discretion.
b) Estimated glomerular filtration rate <= 60 mL/min according to the CKD-EPI
formula at screening.
c) Systolic blood pressure > 150 mmHg at screening or baseline.
d) All other clinically relevant parameters at screening or baseline as judged
by the Investigator.
6. Clinically relevant abnormal ECG or cardiac functioning, defined as
ST-segment elevation > 1 mm in I, II, III, aVL, aVF, V3, V4, V5, V6; > 2 mm in
V1, V2; Mean QTc of triplicate ECG recording > 450 ms for male subjects; mean
QTc of triplicate ECG recording > 470 ms for female subjects (Diagram-read),
T-top inversion in >1 consecutive lead.
7. Serum hyperkalemia (> 5.0 mEq/L).
8. Serum hypokalemia (< 3.5 mEq/L).
9. History of ischemic heart disease.
10. Symptomatic heart failure.
11. Clinically relevant aorta and/or mitralis valvular defect as judged by the
investigator.
12. Pregnancy or breast feeding (females).
13. History of hypersensitivity or idiosyncrasy to any of the components of the
investigational drug.
14. Medical history of drug abuse (illegal drugs such as cannabinoids,
amphetamines, cocaine, opiates or problematic use of prescription drugs such as
benzodiazepines, opiates).
15. The use of any of the following medication and/or supplements within 4
weeks or 5 times the half-life (whichever is longer) prior to the first dosing
of the study medication:
a. (multi)vitamins, co-enzyme Q10, Vitamin E, riboflavin, and antioxidant
supplements (including, but not limited to idebenone/EPI-743, mitoQ or
alternative names for similar products); unless stable for at least one month
before first dosing and remaining stable throughout the study.
b. any medication negatively influencing mitochondrial functioning (including
but not limited to valproic acid, glitazones, statins, anti-virals, amiodarone,
and non-steroidal anti-inflammatory drugs (NSAIDs)), unless stable for at least
one month before first dosing and remaining stable throughout the study.
Note: thus, mitoQ and any medication negatively influencing mitochondrial
functioning are allowed as long as the dose has been stable for at least one
month prior to first dosing and remains stable throughout the study.
c. any strong Cytochrome P450 (CYP)3A4 inhibitors (all *conazoles-
anti-fungals*, HIV antivirals, grapefruit).
d. strong CYP3A4 inducers (including HIV antivirals, carbamazepine,
phenobarbital, phenytoin, rifampicin, St. John*s wort, pioglitazone,
troglitazone).
e. any medication known to affect cardiac repolarisation unless QTc interval at
screening is normal during stable treatment for a period of two weeks, or 5
half-lives of the medication and its major metabolite(s), whichever period is
the shortest (all anti-psychotics, several anti-depressants, e.g.
nor-/amitriptyline, fluoxetine, anti-emetics: domperidone, granisetron,
ondansetron). For a complete list see https://crediblemeds.org.
f. any medication metabolised by CYP3A4 with a narrow therapeutic width. For
reference : KNMP Kennisbank
(https://www.knmp.nl/producten/knmp-kennisbank/inloggen-knmp-kennisbank).