Everolimus for Aging

(EVERLAST Trial)

Overseen By Everolimus Aging Study Team

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Wisconsin, Madison

Must not be taking: Immunosuppressants, Corticosteroids, CYP3A4 inhibitors, NSAIDs

Disqualifiers: Heart disease, Cancer, Diabetes, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

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 aims to determine if everolimus, taken daily or weekly, can improve signs of aging in the body. The focus is on individuals who are insulin resistant or prediabetic, as these conditions often accompany aging. Participants will take either everolimus or a placebo (a harmless pill resembling the real medication) for 24 weeks. Those between 55 and 80 who have struggled with managing blood sugar levels may find this trial suitable. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop taking my current medications for the trial?

The trial requires that you stop taking certain medications, such as those that lower the immune system, strong or moderate CYP3A4 and/or P-glycoprotein inhibitors, strong CYP3A4 activators, and daily NSAIDs (except baby aspirin). If you are on any of these, you may need to stop them before participating.

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

Research has shown that everolimus is generally safe for older adults. Studies involving patients with advanced kidney cancer found that everolimus is as safe for those over 65 as it is for younger individuals. Another study with many patients found that side effects were manageable. While some experienced side effects, they were usually mild to moderate. The FDA has also approved everolimus for other uses, indicating its safety. However, side effects can vary from person to person, so consulting a healthcare professional is advisable if there are any concerns. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for aging?

Researchers are excited about Everolimus for aging because it offers a potential new way to slow down the aging process at a cellular level. Unlike most anti-aging treatments that focus on superficial effects, Everolimus is an mTOR inhibitor, which may help improve cellular health and longevity by targeting pathways linked to aging. This could mean not only a longer life but also a healthier one, potentially reducing age-related diseases. With its unique mechanism of action, Everolimus could provide benefits that current treatments do not.

What evidence suggests that everolimus could be an effective treatment for aging?

Research has shown that everolimus can effectively treat certain conditions in older adults. Specifically, it works well and is tolerable for elderly patients with metastatic renal cell carcinoma (mRCC). This suggests that everolimus can benefit older individuals, who often respond differently to treatments than younger people. The treatment targets a protein called mTORC1, which plays a role in cell growth and aging. In this trial, researchers are testing everolimus to determine its effects on aging-related changes. Participants may receive either daily or weekly everolimus, with some receiving placebos for comparison. Early findings suggest that by blocking mTORC1, everolimus might improve signs of aging in humans. Although more research is needed specifically on aging, these initial results are promising. ^{4 6 7 8 9}

Who Is on the Research Team?

Adam Konopka, PhD

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for adults aged 55-80 with insulin resistance or prediabetes, who can take oral medication and are willing to use contraception. Excluded are those with chronic diseases like Alzheimer's, heart disease, kidney disease; tobacco users; on certain drugs affecting everolimus; pregnant/breastfeeding women; and those not proficient in English.

Inclusion Criteria

I can use a phone and be reached by one.

You have high insulin resistance or prediabetes based on specific criteria.

I am using effective birth control and have a negative pregnancy test.

Exclusion Criteria

You don't want to avoid eating grapefruit, grapefruit juice, or other foods that can affect how the study drug works in your body.

I am currently taking medication that strongly activates CYP3A4.

I have been diagnosed with Alzheimer's disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily low dose (0.5 mg/day) or weekly (5 mg/week) everolimus for 24 weeks to improve physiological and molecular hallmarks of aging

24 weeks

Weekly visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

14 weeks

Regular visits for safety assessments and outcome measures

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus

Trial Overview

The study tests if Everolimus (0.5 mg daily or 5 mg weekly) can improve aging signs compared to a placebo over 24 weeks. Participants will be randomly assigned to one of the treatments and monitored up to approximately 38 weeks.

How Is the Trial Designed?

Group I: Daily Placebo and Weekly Everolimus (5mg/week) Experimental Treatment 2 Interventions

Once daily placebo and once weekly (5 mg) everolimus taken orally for 24 weeks

Group II: Daily Everolimus (0.5 mg/day) and Weekly Placebo Experimental Treatment 2 Interventions

Once daily (0.5 mg) everolimus and once weekly placebo taken orally for 24 weeks

Group III: Young Adult Reference Group Active Control 1 Intervention

Baseline testing only

Group IV: Daily Placebo and Weekly Placebo Placebo Group 2 Interventions

Once daily placebo and once weekly placebo taken orally for 24 weeks

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 Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Everolimus, an mTOR inhibitor, significantly reduced the number of lung tumors in transgenic mice with an EGFR mutation, leading to a median survival time of 58 weeks compared to 31.2 weeks in the control group, indicating its potential efficacy in treating lung cancers associated with EGFR mutations.

The mechanism of action for everolimus involved the suppression of angiogenesis rather than directly inducing apoptosis or autophagy, suggesting that it may inhibit tumor growth indirectly by affecting blood vessel formation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. Yasugi, M., Takigawa, N., Ochi, N., et al.[2023]

mTOR inhibitors, such as everolimus and sirolimus, are effective immunosuppressive agents for organ transplant recipients and cancer treatments, but they are associated with a range of adverse events (AEs) including stomatitis, wound-healing complications, and diabetes.

Most AEs related to mTOR inhibitors can be effectively managed or reversed through careful monitoring and appropriate interventions, highlighting the importance of patient selection and management strategies in optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for the management of adverse events associated with mTOR inhibitors. Kaplan, B., Qazi, Y., Wellen, JR.[2022]

Everolimus is an oral medication that inhibits the mTOR pathway, which is important for regulating cell growth and survival, and has been approved for treating several types of cancer, including advanced renal cell carcinoma and pancreatic neuroendocrine tumors.

Current clinical trials are exploring the effectiveness of everolimus in various cancer types, indicating its potential for broader applications in oncology beyond its approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus. Hasskarl, J.[2022]

In a study of 35 pediatric renal transplant patients on everolimus plus low-dose cyclosporine, corticosteroids were successfully withdrawn in 83% of cases, compared to only 39% in the control group, indicating a potential benefit in reducing steroid use.

While patient and graft survival rates were similar between the everolimus group and the control group, everolimus was associated with significantly less BK polyomavirus replication (3% vs. 17%), although it also led to higher rates of arterial hypertension and hyperlipidemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients. Brunkhorst, LC., Fichtner, A., Höcker, B., et al.[2018]

Everolimus, an oral mTOR inhibitor, significantly improves progression-free survival in patients with clear cell renal cancer, increasing it from a median of 1.9 months to 4.9 months in a phase III trial with a hazard ratio of 0.33 (P < 0.001).

The treatment is generally well-tolerated, with mild to moderate side effects that can be managed, and it has been approved as a validated option for patients who have progressed on VEGFR inhibitors, with ongoing trials exploring its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Coppin, C.[2021]

The combination of everolimus and vatalanib (PTK/ZK) showed at least additive and potentially synergistic anti-tumor effects in a mouse model of melanoma, enhancing efficacy without increasing toxicity compared to either drug alone.

Pharmacokinetic studies revealed that vatalanib increased the plasma concentration of everolimus, but this interaction did not fully explain the enhanced anti-tumor activity, suggesting that the two drugs may work together through distinct mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. O'Reilly, T., Lane, HA., Wood, JM., et al.[2021]

In a study of 65 lung transplant recipients, conversion to everolimus was primarily due to bronchiolitis obliterans syndrome (BOS) and renal insufficiency, with 21% of patients able to eliminate calcineurin inhibitors (CNI) from their regimen.

While renal function improved significantly in patients with renal insufficiency, the effects of everolimus on BOS were inconclusive, as forced expiratory volume (FEV1) remained stable among those with BOS after 12 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective 12-month study of conversion to everolimus in lung transplant recipients. Roman, A., Ussetti, P., Zurbano, F., et al.[2015]

Everolimus, used in combination with aromatase inhibitors for treating metastatic ER-positive and HER2-negative breast cancer, can lead to serious side effects like interstitial lung disease and acute kidney injury.

This case highlights a patient who developed Pneumocystis pneumonia without typical respiratory symptoms and acute kidney injury while on everolimus, emphasizing the need for careful monitoring of lung and kidney health during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pneumocystis Pneumonia and Acute Kidney Injury Induced by Everolimus Treatment in a Patient with Metastatic Breast Cancer. Nakamura, M., Matsunuma, R., Yamaguchi, K., et al.[2020]

In a clinical trial with 213 lung transplant patients, everolimus significantly reduced the incidence of efficacy failure (21.8% vs. 33.9% for azathioprine) at 12 months, indicating its effectiveness in slowing the progression of bronchiolitis obliterans syndrome (BOS).

While everolimus showed benefits in reducing acute rejection and decline in lung function at 12 months, it also had a higher rate of treatment discontinuations and serious adverse events, highlighting the need for careful monitoring of patients on this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Snell, GI., Valentine, VG., Vitulo, P., et al.[2023]

Everolimus, an mTOR inhibitor, showed promising antineoplastic activity in four elderly patients with multiple basal cell carcinomas (BCC) who refused surgery and did not respond to other treatments, with one complete response and two partial responses observed over a treatment period of 12 months or longer.

The treatment was well tolerated among the patients, suggesting that everolimus could be a viable option for those unable or unwilling to undergo surgical intervention for BCC, warranting further controlled clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus for compassionate use in multiple Basal cell carcinomas. Eibenschutz, L., Colombo, D., Catricalà, C.[2021]

Citations

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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 ...

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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 ...

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0302283811014424

Efficacy and Safety of Everolimus in Elderly Patients With ...

In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9954606/

Long-Term Results with Everolimus in Advanced Hormone ...

Using statistical methods fit for real-world data, our findings suggest that the use of everolimus may favorably impact overall survival, and ...

5.

ema.europa.eu

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

Votubia | EMA

b No efficacy data available in elderly patients. 0. 10. 20. 30. 40. 50. Exacerbation. ≤-25. No change. >-25 to <25. 25% resp. 25 to <50. 50% resp. 50 to <75.

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2012/022334s016lbl.pdf

AFINITOR (everolimus) tablets - accessdata.fda.gov

The median age of patients was 61 years (range 28-93), and 75% were. Caucasian. Safety results are based on a median follow-up of approximately 13 months. The ...

7.

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 ...

8.

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 ...

9.

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, ...