Sirolimus for Leigh Syndrome

The purpose of this study is to evaluate the safety and efficacy of the drug Sirolimus in participants with Leigh syndrome.

This is a pilot phase 2 study with long-term extension to evaluate the safety and efficacy of enteral sirolimus in patients with genetically-confirmed Leigh syndrome.

Sirolimus will be given daily at a starting dose of 0.8 to 1.3 mg/m2 depending on subject age, weight, and BSA (body surface area). Dosage will be adjusted as needed based on sirolimus trough level to maintain patients within a range of 5 to10 ng/mL, a level lower than what is targeted in renal transplant recipients. Patients will be followed through this study for up to 24 weeks in the active phase. Participants who are eligible for the long-term extension may choose to stay on drug for up to 2 years thereafter

Eligibility Criteria:
Inclusion Criteria:

1. Genetically-confirmed diagnosis of Leigh syndrome with neurodevelopmental manifestations, which include documented developmental delay, developmental regression, or abnormal neurologic exam findings including but not limited to hypotonia, hypertonia, dystonia, chorea, nystagmus, ataxia, dysmetria, tremor or muscle weakness.
2. Age 6 months to 55 years at the time of enrollment.
3. Weight ≥ 5 kg at the time of enrollment.
4. Adequate liver function as evidenced by total bilirubin \< 1.5x upper limit of normal (ULN) and liver function tests, alanine transaminase (ALT) and aspartate aminotransferase (AST), \< 3x ULN.
5. Adequate renal function as evidenced by glomerular filtration rate (GFR) \> 60 mL/min/1.73m2 (cystatin C for pediatric population).
6. Normal hematologic parameters as defined as:

   1. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
   2. Platelet count ≥ 100,000/mm3 (100 x 109/L)
   3. Hemoglobin ≥ 9 g/dL
7. Non-fasting serum triglycerides and cholesterol \< 300 mg/dL.
8. Serum amylase and lipase \< 2x ULN.
9. Adequate immunoglobulin levels as outlined below that, in the opinion of the investigator, will not place the patient at increased risk of infection.

   1. Immunoglobulin G (IgG) ≥ 200 mg/dL
   2. Immunoglobulin M (IgM) ≥ 30 mg/dL
   3. Immunoglobulin A (IgA) ≥ 10 mg/dL
10. All sexually active participants must agree to use effective contraception:

    1. Females of child-bearing potential must agree to use effective contraception without interruption from 28 days prior to starting Investigational Product (IP) throughout 3 months after last dose of IP and have a negative urine pregnancy test result at screening and agree to ongoing pregnancy testing during the course of the study.
    2. Male patients must practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study and throughout 3 months after the last dose of investigational drug.
11. The patient or parent(s)/legal guardian(s) is/are willing and able to comply with the study visit schedule and other protocol requirements, in the opinion of the investigator.
12. The patient or the patient's parent(s)/legal guardian(s) understand(s) and voluntarily sign(s) the informed consent documents(s) prior to any study-related assessments/procedures being conducted.

Exclusion Criteria:

1. Cardiac ejection fraction ≤ 50 %, shortening fraction ≤ 25% on cardiac echocardiogram within one year of screening and/or severe end-organ hypo-perfusion syndrome (secondary to cardiac failure) resulting in lactic acidosis.
2. Patients with implanted cardiac assist/medical devices (including pacemakers), unless device was implanted prophylactically, and the patient is clinically asymptomatic.
3. In the opinion of the investigator, clinically significant ECG and/or echocardiogram alterations at the time of screening.
4. Myocardial infarction within 6 months prior to enrollment.
5. Symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or unstable coronary artery disease.
6. Prior history of hypersensitivity to sirolimus or other mTOR (Mechanistic Target of Rapamycin inhibitors).
7. Prior history of angioedema requiring treatment or cessation of a presumed causative agent.
8. Planned surgical procedure during the study period.
9. Confirmed or highly suspected immunodeficiency disorder(s), including but not limited to, common variable immune deficiency (CVID), complement deficiency, etc.
10. Clinically significant proteinuria that requires ongoing medical therapy.
11. Any uncontrolled psychiatric or medical condition which, in the opinion of the investigator, would interfere with the patient's participation in the study.
12. Patients who are breastfeeding or are pregnant.
13. History of solid organ transplant (kidney, liver, heart, lung) or bone marrow transplant.
14. Treatment with any investigational drug (i.e., a drug for which there is no approved indication), including an investigational drug for mitochondrial disease within 1 month prior to receiving the first dose of study drug (or within 3 months for a trial with an investigational biologic).
15. Patients with confirmed or suspected increased intracranial pressure, pseudotumor cerebri (PTC)/idiopathic intracranial hypertension, and or papilledema.
16. Currently active malignancy (other than adequately treated non-melanoma skin cancers \[i.e., squamous cell and/or basal cell carcinoma\], carcinoma in situ of the cervix, or other adequately treated carcinoma in situ) and/or ongoing treatment for malignancy are ineligible. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for ≥ 1 year.
17. Recent infection requiring systemic anti-infective treatment that was completed ≤ 14 days prior to enrollment.
18. Uncontrolled diabetes mellitus, as defined by HbA1c \> 8%, despite adequate therapy.
19. History of interstitial lung disease and/or pneumonitis.
20. Use of strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4 (CYP3A4) and/or p-glycoprotein (p-GP) within the 14 days prior to receiving the first dose of study drug. Additionally, use of any known CYP3A4 substrates with a narrow therapeutic window (e.g., fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfenadine) within the 14 days prior to receiving the first dose of study drug.
21. Use of medications with a high risk of angioedema
22. Known human immunodeficiency virus (HIV), active hepatitis B or hepatitis C infection(s).