Rapalogs for Aging

Overseen by Adam Konopka, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of Wisconsin, Madison

Must not be taking: Immunosuppressants, CYP3A4 inhibitors, others

Disqualifiers: Heart disease, Cancer, Diabetes, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The objective of RAP PAC is to identify safe and effective weekly dose(s) for the mTOR inhibitors sirolimus and everolimus that intervene on the underlying fundamental biology of aging. Participants who are 55-89 years old that are free of overt chronic diseases will be assigned to either 6 weeks of sirolimus or everolimus (5 mg, 10 mg, or 15 mg once per week). The investigators will complete the everolimus arm first and then subsequently complete the sirolimus arm of the study. Total time on study would be up to 17 weeks to complete baseline and follow up visits.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, especially those that affect the immune system or interact with the study drugs, like azathioprine, cyclosporine, and others. If you're on any of these, you would need to stop them before participating.

What data supports the effectiveness of the drug Everolimus for aging?

Research shows that Everolimus, a type of drug called a rapalog, can slow aging and extend lifespan in various species. It also helps prevent age-related diseases and improves cellular health in conditions like laminopathies, suggesting potential benefits for aging. ^{1 2 3 4 5}

What safety data exists for rapalogs like everolimus and sirolimus?

Everolimus and sirolimus, used in transplant patients, have shown a tolerable safety profile with low rates of acute rejection. However, everolimus can cause blood-related side effects like low white blood cells, platelets, and red blood cells. Sirolimus has a lower risk of kidney and nerve issues compared to other drugs. ^{2 4 6 7 8}

How is the drug Everolimus/Sirolimus unique for aging?

Everolimus and Sirolimus are unique because they inhibit the mTOR pathway, which is linked to aging and longevity. This mechanism, originally used for organ transplant patients, is being explored for its potential to slow aging-related issues in older adults. ^{2 9 10 11 12}

Research Team

Adam Konopka, PhD

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

The RAP PAC study is for adults aged 55-80 without chronic diseases, willing to follow the study's procedures for up to 17 weeks. Participants must have good organ function, not be on certain medications or have specific health conditions, and males must use contraception during the study.

Inclusion Criteria

I will use birth control to prevent pregnancy during and for 4 weeks after the study.

I am a middle-aged adult with no chronic diseases.

I am willing and able to follow the study rules and attend all appointments.

Exclusion Criteria

I have chronic kidney disease or my blood tests show poor kidney function.

I have diabetes or my blood sugar levels are high.

I have bleeding issues or take medication that affects my bleeding time.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sirolimus or everolimus for 6 weeks to evaluate PK/PD, safety, and mTOR signaling

6 weeks

Weekly visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-7 weeks

Follow-up visits to assess outcomes and adverse events

Treatment Details

Interventions

• Everolimus (mTOR Inhibitor)
• Sirolimus (mTOR Inhibitor)

Trial Overview This trial tests weekly doses of mTOR inhibitors sirolimus and everolimus (5 mg, 10 mg, or 15 mg) over a period of six weeks to see if they can positively affect aging biology. The trial will first complete testing with everolimus followed by sirolimus.

Participant Groups

Group I: Sirolimus Experimental Treatment 1 Intervention

1mg tablets of sirolimus that total the assigned dose

Group II: Everolimus Experimental Treatment 1 Intervention

1mg tablets of everolimus that total the assigned dose

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

In kidney transplant recipients, using target of rapamycin inhibitors (TOR-I) instead of calcineurin inhibitors (CNI) did not change the rate of acute rejection but resulted in lower serum creatinine levels, indicating better kidney function.

When TOR-I replaced antimetabolites, there was a reduction in acute rejection and cytomegalovirus infections, although it increased the risk of hypercholesterolemia, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Webster, AC., Lee, VW., Chapman, JR., et al.[2021]

Pan-mTOR inhibitors, such as Torin1 and PP242, have been shown to effectively suppress cellular aging processes, outperforming rapamycin in reducing senescence-associated changes and preserving the ability of cells to re-proliferate.

These inhibitors work by targeting both mTORC1 and mTORC2 pathways, leading to significant reductions in cellular hypertrophy and promoting a longer 'chronological life span' at concentrations that are lower than those typically used for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gerosuppression by pan-mTOR inhibitors. Leontieva, OV., Blagosklonny, MV.[2021]

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]

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]

A systematic review of phase II and III trials involving patients with solid tumors taking 10mg of everolimus daily revealed significant hematologic toxicities, with anemia occurring in 61.2% of patients and thrombocytopenia in 36.0%.

Everolimus significantly increases the risk of various hematologic toxicities, including high-grade thrombocytopenia (RR=7.46) and high-grade anemia (RR=3.92), indicating a need for careful monitoring of blood cell counts in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of hematologic toxicities in patients with solid tumors treated with everolimus: a systematic review and meta-analysis. Funakoshi, T., Latif, A., Galsky, MD.[2018]

Long-term use of calcineurin inhibitors (CNIs) in kidney transplant recipients can lead to chronic kidney injury and increased risks of serious health issues, highlighting the need for alternative immunosuppression strategies.

Sirolimus, an alternative immunosuppressant, has shown benefits in preserving kidney function and improving long-term graft and patient survival, making it a suitable option for various patient populations, especially those at higher immunologic risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation. Tedesco-Silva, H., Del Carmen Rial, M., Cruz Santiago, J., et al.[2020]

In a 24-month study involving 394 kidney transplant patients, switching from calcineurin inhibitors (CNI) to everolimus did not show significant improvements in renal function compared to continuing CNI treatment, indicating no overall renal benefit from this conversion.

However, patients with a baseline creatinine clearance greater than 50 mL/min experienced a notable increase in renal function after CNI elimination, suggesting that this group may benefit from a change in therapy, despite higher rates of adverse events leading to treatment discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. Holdaas, H., Rostaing, L., Serón, D., et al.[2021]

A pilot study involving 25 healthy older adults (ages 70-95) showed that short-term treatment with rapamycin (RAPA) is generally safe, with only mild side effects reported, such as facial rash and gastrointestinal issues.

While some changes in blood parameters were observed in the RAPA group, no clinically significant effects on metabolism, cognitive function, or physical performance were noted, suggesting that RAPA may be a tolerable option for further investigation in aging populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Kraig, E., Linehan, LA., Liang, H., et al.[2021]

Sirolimus effectively prolongs graft survival in various transplantation models and reduces acute allograft rejection in human renal transplantation when used with ciclosporin, but prolonged use can lead to renal damage, making early elimination of ciclosporin ideal for optimal outcomes.

While sirolimus has beneficial effects such as low nephrotoxicity and improved management of hypertension and diabetes, it can cause significant adverse effects like hypercholesterolemia and infections, which must be considered when tailoring immunosuppressive therapy for individual patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit-risk assessment of sirolimus in renal transplantation. Kuypers, DR.[2018]

References

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

From rapalogs to anti-aging formula. [2021]

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

Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. [2021]

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

Gerosuppression by pan-mTOR inhibitors. [2021]

4. Canada pubmed.ncbi.nlm.nih.gov

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

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

Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts. [2023]

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

Experience with everolimus. [2015]

7. 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]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Risk of hematologic toxicities in patients with solid tumors treated with everolimus: a systematic review and meta-analysis. [2018]

9. Denmark pubmed.ncbi.nlm.nih.gov

Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation. [2020]

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

Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study. [2021]

11. England pubmed.ncbi.nlm.nih.gov

A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. [2021]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Benefit-risk assessment of sirolimus in renal transplantation. [2018]