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

88 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether the drug everolimus can safely improve health and slow aging in adults aged 55-80 who are insulin resistant or prediabetic. Everolimus works by blocking a protein involved in cell growth and aging. The study aims to see if this can help improve various aspects of health without serious side effects. Everolimus has been studied for various conditions, including cancer and organ transplantation.

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.

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

Everolimus has shown effectiveness in slowing disease progression in conditions like lung transplant rejection and certain cancers, suggesting it may have potential benefits in managing aging-related conditions by affecting cell growth and survival pathways. ^{1 2 3 4 5}

Is Everolimus safe for human use?

Everolimus, used in various treatments, can cause side effects like mouth sores, skin issues, wound-healing problems, high blood sugar, high cholesterol, kidney issues, lung problems, anemia, high blood pressure, and reproductive issues. Most side effects can be managed with careful monitoring and treatment. ^{2 4 6 7 8}

How is the drug Everolimus unique for aging?

Everolimus is unique because it is an mTOR inhibitor, which means it targets a specific pathway in cells that is involved in growth and aging. This mechanism is different from other treatments that might not specifically target the mTOR pathway. ^{3 4 5 9 10}

Research Team

Adam Konopka, PhD

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

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

I am currently taking medication that strongly activates CYP3A4.

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 have been diagnosed with Alzheimer's disease.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

A retrospective 12-month study of conversion to everolimus in lung transplant recipients. [2015]

2. Germany pubmed.ncbi.nlm.nih.gov

Everolimus. [2022]

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

Everolimus for compassionate use in multiple Basal cell carcinomas. [2021]

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

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

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

Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. [2023]

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

Strategies for the management of adverse events associated with mTOR inhibitors. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pneumocystis Pneumonia and Acute Kidney Injury Induced by Everolimus Treatment in a Patient with Metastatic Breast Cancer. [2020]

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

Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. [2023]

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

Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients. [2018]