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

Patients with inherited mitochondrial diseases associated with nuclear or mitochondrial DNA
mutations that impair the respiratory chain. These include, but are not limited to the
following clinical syndromes: Leber's hereditary optic neuropathy; myoclonic epilepsy and
ragged-red fibers (MERFF); mitochondrial encephalomyopathy, lactic acidosis, and strokelike
syndrome (MELAS); KearnSayre syndrome; subacute necrotizing encephalopathy (Leigh Syndrome);
POLGrelated disorders (Alpers-Huttenlocher Syndrome, Autosomal Dominant Progressive External
Ophthalmoplegia, Autosomal Recessive Progressive External Ophthalmoplegia, Childhood
Myocerebrohepatopathy Spectrum Disorders, Myoclonic Epilepsy Myopathy Sensory Ataxia,
POLGRelated Ataxia Neuropathy Spectrum Disorders); Mitochondrial neurogastrointestinal
encephalopathy syndrome (MNGIE), also called myoneurogastrointestinal encephalopathy syndrome
or POLIP syndrome; others, e.g., mitochondrial cardiomyopathies and other syndromes due to
multiple mitochondrial DNA deletions.

Prior to treatment, patients will undergo a Screening Visit. If eligible, each subject will
return for the Day 1 study visit and begin RP103 dosing on that day. Every 2 weeks over the
subsequent 8 weeks, subjects 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, subjects 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 Week 24
visit will be the same as the Study Exit visit (i.e. a single visit rather two separate ones)
if a subject elects to continue on to the RP103-MITO-002 (NCT02473445) extension study, and
that study has been IRB approved at the site or if the subject does not continue on to the
extension study. If the extension study has not yet been IRB approved by the time a subject
reaches Week 24, and that subject elects to continue on RP103, then Study Exit visit will
take place later and separately from the Week 24 visit.

The extension study will continue until results of the present RP103-MITO-001 study are
known.

Inclusion Criteria:

1. Age ≥ 6 years and < 18 years

2. Body weight ≥ 5 kgs

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
(NPMD) score, with a score between 15 to 45 inclusive [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, 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 relative 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, AST or 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 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 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.