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.

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.

• Cysteamine Bitartrate (Drug), also known as RP103: Cysteamine Bitartrate Delayed-release capsules

Primary outcomes

• Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV [Baseline through Week 24]: The NPMDS evaluates the progression of mitochondrial disease in pediatric patients in 4 domains: I - Current Function (vision, hearing, communication, feeding, and mobility) with scores ranging from 0 to 21; II -System Specific Involvement (seizures, encephalopathy, bleeding diathesis or coagulation defects, gastrointestinal, endocrine, respiratory, cardiovascular, renal, liver, and blood) with scores ranging from 0 to 30. III - Current Clinical Assessment (growth and development over past 6 months, vision, strabismus and eye movement, myopathy, ataxia, pyramidal, extrapyramidal, and neuropathy) with scores ranging from 0 to 28; and IV - Quality of Life with scores ranging from 0 to 25. For sections I-III, higher scores reflect more severe disease. For Section IV, a higher score reflects a lower quality of life.

Secondary outcomes

• Change From Baseline in Glutathione [Baseline and Weeks 4, 8, 12, 16, 20, 24]
• Change From Baseline in Glutathione Disulfide [Baseline and Weeks 4, 8, 12, 16, 20, 24]
• Change From Baseline in Lactic Acid [Baseline and Weeks 4, 8, 12, 16, 20, 24]
• Change From Baseline in 6 Minute Walk Test [Baseline and Weeks 4, 8, 12, 16, 20, 24]: The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: Myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Myopathy was assessed using the 6 minute walk test, which measures the distance walked in a 6 minute walk test.
• Change From Baseline in Jamar Dynamometer Hand Strength [Baseline and Weeks 4, 8, 12, 16, 20, 24]: The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Myopathy was assessed using standard grip strength evaluation, which measures hand strength in both hands using a Jamar dynamometer.
• Change From Baseline in Barry-Albright Dystonia Scale Total Score [Baseline and Weeks 4, 8, 12, 16, 20, 24]: The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Dystonia symptoms were assessed using the Barry-Albright Dystonia Scale for Dystonia. Participants were assessed for dystonia in each of the following regions: eyes, mouth, neck, trunk, and each upper and lower extremity (8 body regions) on a scale from 0 (absent) to 4 (severe symptoms). The individual scores were summed to calculate the total score which ranges from 0 (dystonia absent) to 32 (severe dystonia).
• Change From Baseline in Friedreich Ataxia Rating Scale [Baseline and Weeks 4, 8, 12, 16, 20, 24]: The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Ataxia was assessed using the Friedreich Ataxia Rating Scale (FARS). FARS comprises a functional ataxia staging score of overall mobility (score 0 to 6), an assessment of the activities of daily living (ADL) (score 0 to 36) and a neurological assessment (score from 0 to 117) which is composed of bulbar (score 0-11), upper limb (score 0- 36) and lower limb (score 0-16), peripheral nerve (score 0-26) and upright stability/gait (score 0-28). The scores were summed to calculate the total score which ranges from 0 to 159. A higher score indicates a greater level of disability.
• Change From Baseline in Gross Motor Function [Baseline and Weeks 4, 8, 12, 16, 20, 24]: The investigator selected the two most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms selected for each participant were then assessed at each subsequent study visit. Retarded motor development was assessed using the Gross Motor Function Measure (GMFM)-88 which consists of 88 items scored on a scale of 0 to 3: 0: Does not initiate the task; 1. Initiates the task (completes < 10%); 2. Partially completes the task (10 to 99%); 3. Completes the task (100%). The 88 items are grouped into five dimensions: 1) lying and rolling, 2) sitting, 3) crawling and kneeling, 4) standing, and 5) walking, running and jumping. Scores are expressed as a percentage of the maximum score for that dimension. The total score is the average of the 5 the percentage scores where higher scores indicate better performance.
• Change From Baseline in Modified Lansky Play Performance Scale [Baseline and Weeks 4, 8, 12, 16, 20, 24]: The investigator selected the 2 most preeminent symptoms for each participant during the screening visit from the following: myopathy, dystonia, ataxia, retarded motor development, reduced activities of daily living, and vision. The 2 symptoms were assessed at each subsequent study visit. Reduced activities of daily living was assessed using the modified Lansky Play Performance Scale, completed by parents based on their child's activity in the past week, where 100=fully active; 90=minor restrictions in strenuous physical activity; 80=active, gets tired more quickly; 70=greater restriction of play, less time spent in play activity; 60=up and around, active play minimal; quieter activities; 50=lying around much of the day; no active playing, all quiet play and activities; 40=mainly in bed; quiet activities; 30=bedbound; needs assistance even for quiet play; 20=sleeps often; play limited to very passive activities; 10=doesn't play or get out of bed; 5=unresponsive 0=dead

Sex: All, ages: 6 Years to 17 Years

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.

Participant flow

Outcome results

• Change From Baseline in Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) Sections I-IV (Primary), Mean, units on a scale: Cysteamine Bitartrate Delayed-release -0.3 +/- 0.7 (p 0.1875)
• Change From Baseline in Glutathione (Secondary), Mean, µmol/L: Cysteamine Bitartrate Delayed-release 16.8 +/- 277.1
• Change From Baseline in Glutathione Disulfide (Secondary), Mean, µmol/L: Cysteamine Bitartrate Delayed-release 29.4 +/- 96.8
• Change From Baseline in Lactic Acid (Secondary), Mean, mmol/L: Cysteamine Bitartrate Delayed-release 0.2 +/- 1.0
• Change From Baseline in 6 Minute Walk Test (Secondary), Mean, meters: Cysteamine Bitartrate Delayed-release -23.5 +/- 86.3
• Change From Baseline in Jamar Dynamometer Hand Strength (Secondary), Mean, kg: Cysteamine Bitartrate Delayed-release 1.3 +/- 2.4
• Change From Baseline in Barry-Albright Dystonia Scale Total Score (Secondary), Mean, units on a scale: Cysteamine Bitartrate Delayed-release 1.3 +/- 1.0
• Change From Baseline in Friedreich Ataxia Rating Scale (Secondary), Mean, units on a scale: Cysteamine Bitartrate Delayed-release 16.9 +/- 27.2
• Change From Baseline in Gross Motor Function (Secondary), Mean, units on a scale: Cysteamine Bitartrate Delayed-release 0.4 +/- 4.3
• Change From Baseline in Modified Lansky Play Performance Scale (Secondary), Mean, units on a scale: Cysteamine Bitartrate Delayed-release -2.0 +/- 4.5

Adverse events

Time frame: 24 weeks

Serious adverse events by term

Other adverse events by term

58 more terms not shown.

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• MD, Study director, Amgen