Sponsor decision to end development of RP103 for mitochondrial disease due to lack of efficacy demonstrated in base study RP103-MITO-001.

A long-term extension study to assess the safety, tolerability and efficacy of cysteamine bitartrate delayed-release capsules (RP103) in children with inherited mitochondrial diseases who previously enrolled into study RP103-MITO-001 (NCT02023866).

Patients with inherited mitochondrial diseases associated with nuclear or mitochondrial deoxyribonucleic acid (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 stroke-like syndrome (MELAS); Kearn-Sayre syndrome; subacute necrotizing encephalopathy (Leigh Syndrome); polymerase gamma (POLG)-related disorders (Alpers-Huttenlocher Syndrome, Autosomal Dominant Progressive External Ophthalmoplegia, Autosomal Recessive Progressive External Ophthalmoplegia, Childhood Myocerebrohepatopathy Spectrum Disorders, Myoclonic Epilepsy Myopathy Sensory Ataxia, POLG-Related Ataxia Neuropathy Spectrum Disorders); Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), also called myoneurogastrointestinal encephalopathy syndrome or polyneuropathy-ophthalmoplegia-leukoencephalopathy- Intestinal pseudoobstruction (POLIP) syndrome; others, e.g., mitochondrial cardiomyopathies and other syndromes due to multiple mitochondrial DNA deletions.

Patients completing study RP103-MITO-001 (NCT02023866) are eligible for enrollment into the extension study RP103-MITO-002 if all inclusion and exclusion criteria are fulfilled. Subjects continue on the last total daily dose of cysteamine bitartrate delayed-release capsules taken during RP103-MITO-001. Dose-adjustments are permitted.

Study with completed results acquired from Horizon in 2024.

Inclusion Criteria:

1. Completed all visits in Study RP103-MITO-001 (NCT02023866).

2. Body weight ≥ 5 kg.

3. The subject must be willing to abstain from initiating dietary supplements and non-prescribed medications except as allowed by the Investigator, throughout the study (from Day 1 to Study Exit).

4. 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.

5. 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 Day 1 to Study Exit):

   • Hormonal contraception: birth control pills, injection, patch, vaginal ring or implant;
   • Condom or diaphragm, with spermicide;
   • Intrauterine device (IUD);
   • Sterile male partner (vasectomy performed at least 6 months prior to the study).

6. Patient's legally authorized representative must provide written informed consent; Patient must provide assent, if required by local/institutional requirements.

Exclusion Criteria:

1. Documented diagnosis of concurrent inborn errors of metabolism.
2. Platelet count, lymphocyte count or hemoglobin below the lower limit of normal (LLN) at the Baseline visit.
3. 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 Baseline Visit.
4. Bilirubin > 1.2 g/dL at the Baseline Visit.
5. Inability to complete the elements of the study, e.g., coma, hemodynamic instability or requiring continuous ventilator support.
6. Malabsorption requiring total parenteral nutrition (TPN), chronic diarrhea, bouts of pseudo obstruction.
7. Severe end-organ hypo-perfusion syndrome secondary to cardiac failure resulting in lactic acidosis.
8. Patients with suspected elevated intracranial pressure, pseudotumor cerebri (PTC) and/or papilledema.
9. Severe gastrointestinal disease including gastroparesis.
10. History of drug or alcohol abuse.
11. History of pancreatitis.
12. Participated in an investigational drug trial (except the RP103-MITO-001 study) within 30 days or, within 90 days for a biologic, device, or surgical treatment, for inherited mitochondrial diseases prior to the Baseline Visit.
13. Known or suspected hypersensitivity to cysteamine and penicillamine.
14. Female subjects who are nursing, planning a pregnancy, known or suspected to be pregnant, or with a positive serum pregnancy test at the Baseline visit.
15. Patients who, in the opinion of the Investigator, are not able or willing to comply with the protocol.

Horizon requests that any Investigator/institution that plans on presenting or publishing results provide written notification of their request a minimum of 60 days prior to presentation or publication. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsors' Intellectual Property rights .