Sirolimus for Aging

Overseen By Irina Timofte

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Irina Timofte

Disqualifiers: Chronic liver disease, Cardiovascular diseases, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 12 months

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Aging is associated with progressive impairment of tissue and organ function, resulting in increased susceptibility to chronic disease, frailty and disability. Currently there are limited treatment options to alter this inevitable process. The proposed work has the potential to identify a new therapeutic intervention to decrease aging-related degenerative processes. Rapamycin or sirolimus is a macrocyclic immunosuppressive drug that inhibits the mammalian target of rapamycin (mTOR). The mammalian target of rapamycin (mTOR) pathway is part of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway which is a fundamentally linked to cell metabolism, proliferation, differentiation, and survival. This pathway is altered in a variety of diseases, including cancers, immunosuppressed states, and fibroproliferative diseases. The mTOR kinase is considered one of the leading regulators of this pathway. Changes in mTOR signaling are closely associated with inflammation, cell growth and survival, leading to the development of chronic diseases. Recent evidence also suggests that mTOR inhibitors are promising modulators of the aging process by slowing the mechanisms of aging at the cellular level. There is a growing appreciation of the potential impact of sirolimus in slowing aging processes and in prolonging healthy lifespan. The proposed study addresses critical gaps in our understanding of the safety and efficacy of sirolimus in delaying aging processes and is based on findings in animal studies and incidental clinical observations. The investigators will overcome potential biases with a randomized control trial. The proposed intervention study is intended to improve our insight into clinical outcomes leading to prevention of chronic diseases such as skin cancer and mortality. Our overarching hypothesis is that sirolimus is one of the first pharmacological agents that will impact the aging process and chronic disease development. Specifically, the investigators aim to investigate whether sirolimus can reduce the occurrence or increase in biomarkers of aging processes.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss your specific situation with the trial coordinators or your doctor.

Is Sirolimus (Rapamune) generally safe for human use?

Sirolimus (Rapamune) has been shown to be a safe immunosuppressive drug in adult kidney transplant patients and has a lower risk of certain complications compared to other similar drugs. It has also been used safely in pediatric patients with chronic kidney issues and in adults for off-label use to promote healthspan. ^{1 2 3 4 5}

How is the drug Sirolimus unique for aging?

Sirolimus is unique for aging because it inhibits the mTOR pathway, which is known to slow aging and extend lifespan in various species. Unlike other treatments, it has the potential to rejuvenate stem cells and improve immunity and metabolism, making it a promising option for preventing age-related diseases. ^{1 3 5 6 7}

Research Team

Irina Timofte, M.D.

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for individuals who are 55 years or older. It's designed to explore if Sirolimus, a drug that affects cell growth and survival, can slow down the aging process and prevent age-related diseases.

Inclusion Criteria

I am 55 years old or older.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 0.5 mg sirolimus orally every day, with weekly monitoring in the first month and monthly follow-ups thereafter

12 months

Weekly visits (first month), monthly visits (thereafter), in-person every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

1 month

1 follow-up phone call

Treatment Details

Interventions

• Sirolimus

Trial Overview The study tests whether Sirolimus can delay signs of aging by affecting cellular pathways linked to inflammation and chronic disease development. Participants will be randomly assigned to receive either Sirolimus or no treatment in a controlled environment.

Participant Groups

Group I: Intervention Experimental Treatment 1 Intervention

Patients will be randomized using age-based randomization to initial treatment with 0.5 mg sirolimus p.o. (orally) everyday vs standard of care. The medications would be dispensed from UT Southwestern Medical Center. To ensure patent's safety, all patients will be closely monitored. We will start with a 0.5 mg tablet- the smallest sirolimus dose available. Sirolimus level will be checked weekly in the first month to ensure we maintain a low goal (5-7) that will decrease the risk of developing side effects. In order to monitor study drug compliance, we will ask the patient to keep a pill diary. After the first month, the patient will have monthly blood work and monthly phone call to enquire about potential side effects. The patients will be followed in clinic in person every 3 months. Functional assessment will be obtained at baseline, 3 months 6 months 9 months and 1 year follow up. Completion of the 1-year treatment period will be followed by a follow-up phone call 1 month later.

Group II: Control Active Control 1 Intervention

Interventions: standard of care Patients are not going to receive any additional intervention.

Sirolimus is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in European Union as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Canada as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Japan as Rapamune for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

Irina Timofte

Lead Sponsor

Trials

1

Recruited

10+

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Findings from Research

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

In a study involving 209 kidney transplant recipients in Korea, Rapamune (Sirolimus) demonstrated an acceptable safety profile, with 54.07% of subjects reporting adverse events, most of which were mild and resolved by the end of the study.

The efficacy of Rapamune was notable, with a low incidence of biopsy-proven acute rejection at 2.87% and a high graft survival rate of 99.51%, indicating its effectiveness in preventing kidney allograft rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Rapamune® (Sirolimus) in kidney transplant recipients: results of a prospective post-marketing surveillance study in Korea. Jeon, HJ., Lee, HE., Yang, J.[2019]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

A survey of 333 adults using rapamycin off-label for healthspan maintenance suggests that the drug can be used safely in individuals with normal health status.

This study provides initial evidence regarding the characteristics of those using rapamycin, addressing the limited data on its side effects and efficacy in a preventative context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of off-label rapamycin use to promote healthspan in 333 adults. Kaeberlein, TL., Green, AS., Haddad, G., et al.[2023]

Inhibitors of mTOR, like rapamycin and Everolimus, are effective in suppressing cellular aging and can extend lifespan across various species, while also preventing age-related diseases such as cancer and neurodegeneration.

Combining rapamycin with other medications like metformin and statins, along with lifestyle changes such as exercise and a healthy diet, can enhance its anti-aging effects and reduce potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From rapalogs to anti-aging formula. Blagosklonny, MV.[2021]

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

Rapamycin can effectively extend the lifespan of bone marrow mesenchymal stromal cells (BM-MSCs) derived from healthy donors, although the degree of effectiveness varies among different samples.

The mechanism behind rapamycin's ability to delay senescence is linked to the repression of the p16INK4A protein, rather than changes in other senescence or pluripotency markers like IL6 and NANOG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Individual response to mTOR inhibition in delaying replicative senescence of mesenchymal stromal cells. Antonioli, E., Torres, N., Ferretti, M., et al.[2021]

References

1. Denmark pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Rapamune® (Sirolimus) in kidney transplant recipients: results of a prospective post-marketing surveillance study in Korea. [2019]

3. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Evaluation of off-label rapamycin use to promote healthspan in 333 adults. [2023]

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

From rapalogs to anti-aging formula. [2021]

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

Sirolimus: a comprehensive review. [2019]

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

Individual response to mTOR inhibition in delaying replicative senescence of mesenchymal stromal cells. [2021]