Open-Label, Dose-Escalating Study Assessing Safety, Tolerability, Efficacy, of RP103 in Mitochondrial Disease

To evaluate safety, tolerability and efficacy of cysteamine bitartrate delayed-release capsules (RP103) administered at a target maintenance dose of 1.3 g/m²/day in two divided doses, every 12 hours, for up to 6 months in patients with inherited mitochondrial disease.

This is an open-label, dose-escalation study to assess the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of cysteamine bitartrate delayed-release capsules (RP103) for treatment of children with inherited mitochondrial disease.

Prior to treatment, patients will undergo a Screening Visit. If eligible, each participant will return for the Day 1 study visit and begin dosing. Every 2 weeks over the subsequent 8 weeks, participants will alternate between returning to the clinic for detailed assessments (Weeks 4 and 8) and receiving a telephone call from the Investigator team to assess safety and RP103 dose (Weeks 2 and 6) and the potential need for an immediate unscheduled study visit. Thereafter, participants will continue to return to the clinic every 4 weeks for detailed assessments at Weeks 12, 16, 20, and 24 (the Study Exit visit).

The Study Exit visit will occur at Week 24, and participants will be offered the opportunity to continue on to an extension study (RP103-MITO-002 \[NCT02473445\]) until results of the present study are known.

Study with completed results acquired from Horizon in 2024.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 6 years and \< 18 years
2. Body weight ≥ 5 kg
3. Documented (genetically confirmed known mutation, i.e. no variants of uncertain significance) diagnosis of inherited mitochondrial disease other than Friedreich's ataxia (FRDA)
4. Moderate disease severity based on Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) score, with a score between 15 to 45 inclusive \[Leber's Hereditary Optic Neuropathy (LHON) subjects are exempt of this inclusion criteria\], if approved by the sponsor.
5. For patients regularly taking dietary supplements such as creatinine, alpha-lipoic acid, coenzyme Q10 (CoQ10), vitamin B, carnitine, etc. they have to have been taking them for at least 3 months pre-study and will agree to keep these the same throughout the study (from the Screening Visit to Study Exit)
6. With respect to concomitant medications, the subject must:

   1. Be willing to abstain from initiating dietary supplements and non-prescribed medications, except as allowed by the Investigator, throughout the study (from the Screening Visit to Study Exit);
   2. Be on a stable dose of medications prescribed for seizure management and prevention. Stable dose in this context means unchanged for at least 30 days prior to the Screening Visit.
7. Willing and able to comply with study drug dosing requirements, i.e. ingest the RP103 capsules intact, or sprinkled in liquid or soft food, or using a g-tube
8. Sexually active female subjects of childbearing potential (i.e., not surgically sterile \[tubal ligation, hysterectomy, or bilateral oophorectomy\]) must agree to utilize two of the following acceptable forms of contraception throughout the study (from the Screening Visit to Study Exit):

   1. Hormonal contraception: birth control pills, injection, patch, vaginal ring or implant;
   2. Condom or diaphragm, with spermicide;
   3. Intrauterine device (IUD)
   4. Sterile male partner (vasectomy performed at least 6 months prior to the study).
9. Subjects's legally authorized representative must provide written informed consent; Subject must provide assent, if required by local/institutional requirements
10. Have mitochondrial myopathy as evidenced by one or more of the following criteria:

    1. Weakness consistent with myopathy (e.g. accompanied by muscle wasting and/or absence of neuropathy) on physical exam
    2. OR documented myopathy on the basis of muscle biopsy consistent with mitochondrial myopathy disease
    3. OR weakness and/or progressive exercise intolerance (in which modest exercise typically provokes heaviness, weakness, aching of active muscles, or tachycardia). Weakness should be due to myopathy and not neuropathy or other causes as deemed by investigator

Exclusion Criteria:

1. Documented diagnosis of concurrent inborn errors of metabolism
2. Non-elective hospitalization related to mitochondrial disease or direct complication of disease within 60 days prior to the Screening Visit.
3. Platelet count, lymphocyte count or hemoglobin below the lower limit of normal (LLN) at the Screening Visit
4. Hepatic insufficiency with liver enzyme tests (alkaline phosphatase, aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\]) greater than 2.5 times the upper limit of normal (ULN) at the Screening Visit
5. Bilirubin \> 1.2 g/dL at the Screening Visit
6. Inability to complete the elements of the study, e.g., coma, hemodynamic instability or requiring continuous ventilator support.
7. Malabsorption requiring total parenteral nutrition (TPN), chronic diarrhea, bouts of pseudo obstruction
8. Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis
9. Patients with suspected elevated intracranial pressure, pseudotumor cerebri (PTC) and/or papilledema
10. Severe gastrointestinal disease including gastroparesis
11. History of angina, myocardial infarction, or cardiac surgery within 2 years prior to the Screening Visit
12. Any clinically significant electrocardiogram (ECG), including dysrhythmia, or clinically significant abnormal laboratory finding not already listed above at the Screening Visit
13. History of drug or alcohol abuse
14. History of pancreatitis
15. Participated in an investigational drug trial within 30 days or, within 90 days for a biologic, device, or surgical treatment, for inherited mitochondrial diseases prior to the Screening Visit
16. Known or suspected hypersensitivity to cysteamine and penicillamine
17. Female subjects who are nursing, planning a pregnancy, known or suspected to be pregnant, or with a positive serum pregnancy test at the Screening Visit
18. Subject's who, in the opinion of the Investigator, are not able or willing to comply with the protocol.