Sirolimus for Leigh Syndrome

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Matthew Demczko

Must not be taking: CYP3A4 drugs, Angioedema drugs

Disqualifiers: Cardiac failure, Immunodeficiency, Transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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

Will I have to stop taking my current medications?

The trial requires that you stop using strong inhibitors or inducers of certain liver enzymes (CYP3A4) and p-glycoprotein, as well as medications with a high risk of causing angioedema, at least 14 days before starting the study drug. If you're taking any of these, you may need to stop or switch medications.

Is Sirolimus generally safe for human use?

Sirolimus is widely used as an immunosuppressant in organ transplantation and has been studied for other conditions. Common side effects include anemia (low red blood cell count), high cholesterol, joint pain, swelling, and delayed wound healing. There are also reports of more severe side effects affecting the lungs and kidneys. ^{1 2 3 4 5}

How does the drug Sirolimus differ from other treatments for Leigh Syndrome?

Sirolimus is unique because it targets the mTOR pathway, which is overactive in Leigh Syndrome, and has shown promise in extending lifespan and reducing disease progression in animal models. Unlike other treatments, it shifts metabolism away from glycolysis (sugar breakdown) towards amino acid use, potentially alleviating symptoms. ^{2 4 5 6 7}

What data supports the effectiveness of the drug Sirolimus for treating Leigh Syndrome?

Research shows that inhibiting the mTOR pathway, which Sirolimus targets, has extended lifespan and slowed disease progression in mouse models of Leigh syndrome. Additionally, a similar drug, everolimus, showed sustained benefits in a child with Leigh syndrome, suggesting potential effectiveness. ^{4 5 7 8 9}

Who Is on the Research Team?

Matthew Demczko, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for individuals aged 6 months to 55 years with genetically-confirmed Leigh syndrome, showing developmental issues. Participants must have normal blood counts, adequate organ function, and agree to use contraception if sexually active. Those with uncontrolled medical conditions, recent heart problems, certain infections or treatments, or a history of severe allergies to mTOR inhibitors like Sirolimus cannot join.

Inclusion Criteria

I am between 6 months and 55 years old.

I weigh at least 5 kg.

Normal hematologic parameters (ANC ≥ 1.0 x 109/L, Platelet count ≥ 100,000/mm3, Hemoglobin ≥ 9 g/dL)

Exclusion Criteria

Implanted cardiac assist/medical devices (unless clinically asymptomatic)

Uncontrolled psychiatric or medical conditions interfering with study participation

Breastfeeding or pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Sirolimus daily for at least 24 weeks with dosage adjustments based on sirolimus trough levels

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-Term Extension

Eligible participants may continue Sirolimus treatment for up to two years

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Sirolimus

Trial Overview The study tests the safety and effectiveness of Sirolimus in patients with Leigh syndrome. It aims to see how well they tolerate the drug and whether it improves their condition.

How Is the Trial Designed?

Group I: Phase 2A Experimental Treatment 1 Intervention

Participants will receive Sirolimus for at least 24 weeks at a starting dose of 0.8 to 1.3 mg/m2 two (2) times daily.

Group II: Long-Term Extension Experimental Treatment 1 Intervention

Eligible participants may continue Sirolimus treatment for up to two (2) years.

Who Is Running the Clinical Trial?

Matthew Demczko

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

In a study of 39 patients with lymphangioleiomyomatosis, low-dose sirolimus showed a trend towards stabilizing lung function decline, but was less effective than conventional-dose sirolimus in improving lung function metrics like FEV1 and DLco.

Both low-dose and conventional-dose sirolimus had similar rates of adverse events, with 89.7% of patients experiencing side effects, the most common being hypercholesterolemia and stomatitis, indicating that safety profiles were comparable between the two dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of low-dose Sirolimus in Lymphangioleiomyomatosis. Yoon, HY., Hwang, JJ., Kim, DS., et al.[2019]

In a study of 522 liver transplant patients, 6.7% of those switched to sirolimus developed interstitial pneumonitis, highlighting this as a notable side effect of the drug.

Pneumonitis symptoms, such as cough and dyspnea, were reversible upon discontinuation of sirolimus, emphasizing the importance of early recognition to avoid unnecessary complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interstitial pneumonitis is a frequent complication in liver transplant recipients treated with sirolimus. Morcos, A., Nair, S., Keane, MP., et al.[2021]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Exploring mTOR inhibition as treatment for mitochondrial disease. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

mTORC1 is required for expression of LRPPRC and cytochrome-c oxidase but not HIF-1&#945; in Leigh syndrome French Canadian type patient fibroblasts. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Case report: malignant hypertension associated with catecholamine excess in a patient with Leigh syndrome. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of low-dose Sirolimus in Lymphangioleiomyomatosis. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Anaemia, microcytosis and sirolimus--is iron the missing link? [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Sirolimus--challenging current perspectives. [2013]

9. Ireland pubmed.ncbi.nlm.nih.gov

Interstitial pneumonitis is a frequent complication in liver transplant recipients treated with sirolimus. [2021]