Rapalogs for Aging

Overseen By Brittany Grasso

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Wisconsin, Madison

Must not be taking: Immunosuppressants, CYP3A4 inhibitors, others

Disqualifiers: Heart disease, Cancer, Diabetes, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, sirolimus (Rapamune) and everolimus (Afinitor, Votubia, or Zortress), to determine safe weekly doses that might slow aging. It examines how these drugs impact the body's aging process. Participants will take one of the drugs for six weeks, followed by some follow-up visits. Suitable candidates are adults aged 55 to 89 without major chronic diseases and who do not plan to start new exercise programs or change their diet during the study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that older adults generally tolerate everolimus well. Clinical studies have found it effective and safe, though some side effects, such as mouth sores and a higher risk of infections, may occur. Older adults should be aware of these potential side effects.

For sirolimus, studies have shown no serious side effects in healthy individuals using this treatment. However, a higher chance of infections is a common side effect. This indicates that sirolimus is generally safe but requires careful monitoring.

Both everolimus and sirolimus have been used for other conditions, with their safety well-documented. Prospective participants should discuss any concerns with a healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments, Everolimus and Sirolimus, because they represent a novel approach to addressing aging. Unlike typical treatments targeting specific age-related diseases, these drugs are rapalogs, which work by inhibiting the mTOR pathway—a key regulator of cell growth and aging. This mechanism is different from the standard care options that often focus on symptoms rather than underlying cellular processes. By potentially slowing the aging process itself, these treatments could have a broader impact on overall healthspan, not just lifespan. This innovative approach gives hope for fundamentally altering how we understand and manage aging.

What evidence suggests that this trial's treatments could be effective for aging?

Research has shown that both sirolimus and everolimus, studied in this trial, may aid in aging. Participants may receive sirolimus, which several early studies found to extend lifespan and delay age-related issues, enhancing immune and heart health. Alternatively, participants may receive everolimus, which reduced inflammation in older adults by improving immune cell function and managing age-related conditions like rheumatoid arthritis. Both treatments block mTOR, a protein that influences cell growth and aging. ^{3 5 6 7 8}

Who Is on the Research Team?

Adam Konopka, PhD

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus
• Sirolimus

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.

How Is the Trial Designed?

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

Everolimus is already approved in United States, European Union for the following indications:

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

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+

Published Research Related to This Trial

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]

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]

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]

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]

Everolimus is an effective immunosuppressant that inhibits T-lymphocyte proliferation, showing low rates of acute rejection in kidney transplant patients when used with cyclosporine-based immunosuppression.

Recent studies indicate that everolimus may also help prevent allograft vasculopathy in heart transplant patients, highlighting its potential benefits beyond kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with everolimus. Augustine, JJ., Hricik, DE.[2015]

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]

Everolimus, an mTOR inhibitor, has been shown to improve cell proliferation and delay aging in fibroblast cell lines from six patients with different laminopathies, suggesting its potential as a treatment for these disorders.

The treatment also significantly reduced nuclear blebbing, a common cellular defect in laminopathies, indicating that everolimus may help correct some of the cellular abnormalities associated with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts. DuBose, AJ., Lichtenstein, ST., Petrash, NM., et al.[2023]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05835999

Study Details | NCT05835999 | Everolimus Aging Study The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/22297244/

Efficacy and safety of everolimus in elderly patients with ... Conclusions: Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05835999?term=mTOR&aggFilters=status:rec&rank=4

Everolimus Aging Study (EVERLAST) The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve ...

4. thelancet.com thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00258-1/fulltext

Targeting ageing with rapamycin and its derivatives in ... Everolimus (6 mg/day orally, for 12 weeks) plus methotrexate was associated with significant improvement in rheumatoid arthritis activity, compared with the ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11493941/

Everolimus alleviates CD4+ T cell inflammation by ... Results · Everolimus alleviates the production of Th17 cytokines in CD4+ T cells from older adults · Everolimus inhibits mTORC1 and improves autophagic flux and ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2010/022334s6lbl.pdf

Afinitor (everolimus) Label - accessdata.fda.gov In the randomized advanced RCC study, 41% of AFINITOR-treated patients were ≥ 65 years in age, while 7% were 75 and over. No overall differences in safety or ...

7. novartis.com novartis.com/us-en/sites/novartis_us/files/zortress.pdf

Zortress® (everolimus) tablets, for oral use The safety and efficacy of Zortress has not been established in the following populations: • Kidney transplant patients at high immunologic risk. • Recipients ...

8. ema.europa.eu ema.europa.eu/en/documents/product-information/afinitor-epar-product-information_en.pdf

Afinitor, INN-everolimus - EMA The safety profile is based on pooled data from 2,879 patients treated with Afinitor in eleven clinical studies, consisting of five randomised, double-blind, ...