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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the drug Sirolimus for safety and effectiveness in people with Leigh syndrome, a rare genetic disorder affecting the nervous system and causing developmental delays and movement problems. Participants will take Sirolimus for at least 24 weeks, with the option to continue for up to two years. Individuals with Leigh syndrome experiencing symptoms such as developmental delays or muscle weakness may be suitable for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 there any evidence suggesting that Sirolimus is likely to be safe for humans?

Research has shown that sirolimus is already FDA-approved for other conditions, indicating its safety is well-known. In earlier studies on Leigh syndrome, researchers tested sirolimus for potential benefits. Although these studies provide limited safety information specifically for Leigh syndrome, sirolimus is generally considered safe based on its use in other conditions.

In studies with mice with Leigh syndrome, blocking the mTOR pathway with sirolimus improved some symptoms. However, another study found that different doses of sirolimus did not improve certain important aspects of the disease in animals.

Overall, sirolimus has been used in people for other conditions, and its safety is fairly well understood in those cases. However, its specific effects and safety for Leigh syndrome remain under investigation. Participants should discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Sirolimus is unique because it targets the mTOR pathway, which is crucial for cell growth and metabolism, potentially offering a new approach for treating Leigh Syndrome. Most current treatments for Leigh Syndrome focus on managing symptoms rather than addressing the underlying disease mechanisms. Researchers are excited about Sirolimus because it may modify the disease process itself, offering hope for improved outcomes over standard care options like vitamin and cofactor supplements. This novel mechanism of action could lead to better management of this challenging condition.

What evidence suggests that Sirolimus might be an effective treatment for Leigh syndrome?

Research has shown that Sirolimus, a drug affecting a specific cell pathway, may help treat Leigh syndrome. In mice with the disease, this treatment extended their lifespan and slowed disease progression. A study involving a child with Leigh syndrome also reported lasting benefits from Sirolimus. However, not all studies agree, as some have shown no improvement in symptoms or cell function. Despite these mixed results, the potential benefits of this treatment warrant further exploration. Participants in this trial will receive Sirolimus for at least 24 weeks, with an option for a long-term extension of up to two years. ^{1 2 3 5 6}

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6764630/

Exploring mTOR inhibition as treatment for mitochondrial ... The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06843811?cond=Leigh%20syndrome&viewType=Table&rank=1

Study Details | NCT06843811 | Sirolimus for 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 ...

3. thelancet.com thelancet.com/article/S2352-3964(19)30165-3/fulltext

Rapamycin administration is not a valid therapeutic ... However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4055856/

mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse ... Taken together, our results demonstrate that inhibition of mTOR improves survival and health in the Ndufs4−/− model of Leigh syndrome. These ...

5. withpower.com withpower.com/trial/sirolimus-for-leigh-syndrome-e846f

Sirolimus for Leigh Syndrome · Info for Participants Research shows that inhibiting the mTOR pathway, which Sirolimus targets, has extended lifespan and slowed disease progression in mouse models of Leigh ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03747328

Study Details | NCT03747328 | ABI-009 (Nab-sirolimus) in ... A phase 2a, open-label study to evaluate the safety, tolerability, and clinical activity of ABI-009 (nab-sirolimus) in patients with genetically-confirmed ...