Rapamycin for Alzheimer's Disease

(REACH Trial)

Overseen By Sudha Seshadri, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: The University of Texas Health Science Center at San Antonio

Must be taking: AD medications

Must not be taking: Antidiabetics, Anticoagulants, CYP3A4 drugs

Disqualifiers: Diabetes, Liver disease, Heart failure, others

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

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

Compensation: Varies

Number of Visits: 3

Duration: 52 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if rapamycin is safe and effective for individuals with early-stage Alzheimer's disease or amnestic mild cognitive impairment (aMCI), a condition where memory problems exceed the norm for one's age but are not as severe as Alzheimer's. Participants will receive either rapamycin or a placebo to compare outcomes. The trial suits those aged 55 to 89 diagnosed with mild cognitive issues related to memory, excluding those with severe health issues like diabetes or heart problems. As a Phase 2 trial, this research measures rapamycin's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that participants have a stable dose of Alzheimer's medications like Donepezil, rivastigmine, Memantine, or galantamine for at least three months. However, you cannot participate if you are taking medications that affect cytochrome 450 3A4 (CYP3A4) or certain other medications. It's best to discuss your current medications with the trial team to see if any changes are needed.

Is there any evidence suggesting that rapamycin is likely to be safe for humans?

Research has shown that rapamycin is under investigation for Alzheimer's due to its potential benefits demonstrated in animal studies. In these studies, rapamycin improved memory and brain function in mice with conditions similar to Alzheimer's.

Regarding safety, a small initial study tested rapamycin in humans with Alzheimer's to assess its safety and tolerability. Although details are not provided here, testing in humans suggests some confidence in its safety. Additionally, the FDA has already approved rapamycin for other uses, further supporting its potential safety. However, like any treatment, side effects may occur. Those interested in clinical trials should discuss these details with their doctors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Most treatments for Alzheimer's disease focus on managing symptoms by targeting neurotransmitter imbalances, like donepezil or memantine. But rapamycin works differently, targeting the underlying mechanisms of aging and cellular damage. This unique mechanism of action makes rapamycin an exciting candidate because it could potentially slow the progression of the disease itself, rather than just alleviating symptoms. Researchers are particularly interested in rapamycin's ability to modulate the immune response and enhance cellular repair processes, offering a novel approach to tackling Alzheimer's.

What evidence suggests that rapamycin might be an effective treatment for Alzheimer's?

Research has shown that rapamycin, which participants in this trial may receive, might help treat Alzheimer's disease, particularly based on animal studies. In studies with mice, rapamycin prevented or even reversed memory problems related to Alzheimer's. It also improved brain function and structure. Although most evidence comes from animal studies, these findings suggest rapamycin could potentially alleviate symptoms in humans as well. Overall, these early results offer hope for those seeking new treatments for Alzheimer's disease. ^{1 2 4 5 6}

Who Is on the Research Team?

Sudha J Seshadri, MD

Principal Investigator

UT Health San Antonio

Are You a Good Fit for This Trial?

Adults aged 55-89 with mild cognitive impairment or early Alzheimer's, who have a representative to assist them and are on stable Alzheimer's medication. They must show amyloid presence in PET imaging, have normal organ function and blood counts, and controlled glucose levels. Excluded are those with recent severe illnesses, immunosuppressant use, untreated high triglycerides, heart issues, certain neurological conditions other than AD/MCI.

Inclusion Criteria

My gender or ethnicity does not limit my participation.

I am between 55 and 89 years old.

Labs: Normal blood cell counts without clinically significant excursions; normal liver and renal function; and glucose control (HbA1c < 6.5%). Fasting lipid panel and prothrombin time/prothrombin time test/international normalized ration (PT/PTT/INR) within normal limits

Exclusion Criteria

Current tobacco or illicit drug use or alcohol abuse

I have diabetes with HBA1c levels of 6.5% or higher, or I am on medication for it.

Untreated hypertriglyceridemia (fasting triglycerides < 250 mg/dl)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

12 weeks

1 visit (in-person)

Treatment

Participants receive oral rapamycin or placebo for 12 months

52 weeks

Monthly visits (in-person)

Post-treatment assessment

Assessment completed within 14 days of the final study drug dose

2 weeks

1 visit (in-person)

Follow-up

Final assessment conducted 6 months after the final study drug dose

26 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Rapamycin

Trial Overview

The trial is testing the safety of rapamycin over a year in older adults with memory loss due to mild cognitive impairment or early Alzheimer's disease. Participants will either receive rapamycin or a placebo (a substance with no therapeutic effect) to compare outcomes.

How Is the Trial Designed?

Group I: RAPA (rapamycin) treatment group Active Control 1 Intervention

Subjects will receive active drug

Group II: Placebo group Placebo Group 1 Intervention

Subjects will receive placebo

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

Approved in European Union as Rapamune for:

• Prevention of organ transplant rejection
• Lymphangioleiomyomatosis
• Perivascular epithelioid cell tumors

Approved in United States as Rapamune for:

• Prevention of organ transplant rejection
• Lymphangioleiomyomatosis
• Perivascular epithelioid cell tumors

Approved in Canada as Rapamune for:

• Prevention of organ transplant rejection
• Lymphangioleiomyomatosis

Approved in Japan as Rapamune for:

• Prevention of organ transplant rejection

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

Alzheimer's Association

Collaborator

Trials

103

Recruited

44,300+

Published Research Related to This Trial

Everolimus, an mTOR inhibitor, was found to effectively reduce Alzheimer's disease pathology and improve cognitive function in a mouse model (3×Tg-AD mice) when administered directly into the brain, showing promise as a potential treatment for early stages of Alzheimer's.

The study demonstrated that everolimus has higher stability and effectiveness in the central nervous system when delivered directly into the brain compared to peripheral administration, with minimal impact on peripheral organs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease. Cassano, T., Magini, A., Giovagnoli, S., et al.[2019]

Rapamycin, an mTOR inhibitor, significantly improved cognitive dysfunction in mice with Alzheimer's disease induced by amyloid β(1-42), as evidenced by better performance in maze tests over a 14-day treatment period.

The treatment with rapamycin reduced levels of amyloid β(1-42) and increased Homer3 expression in the hippocampus, suggesting that its mechanism of action involves modulating mTOR phosphorylation and enhancing synaptic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of mammalian target of rapamycin on cognitive dysfunction of Alzheimer's Disease via regulating Homer3]. Huang, YQ., Liu, XG., Zhang, L., et al.[2021]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

Rapamycin, an mTOR inhibitor, shows promise as a potential treatment for Alzheimer's disease by enhancing autophagy, which helps clear toxic protein aggregates like amyloid β (Aβ) and reduces tau hyper-phosphorylation.

The neuroprotective effects of rapamycin may lead to improvements in cognitive function by addressing key pathological processes associated with Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin, Autophagy, and Alzheimer's Disease. Cai, Z., Yan, LJ.[2022]

The study reveals that the accumulation of amyloid-beta (Abeta) in Alzheimer's disease increases mTOR signaling, which is linked to cognitive decline, suggesting a critical relationship between these two factors.

Using an animal model, the research demonstrates that the FDA-approved drug rapamycin can restore mTOR signaling, improve cognitive function, and reduce both Abeta and Tau pathology by enhancing autophagy, providing a potential therapeutic approach for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. Caccamo, A., Majumder, S., Richardson, A., et al.[2022]

Rapamycin treatment in OXYS rats, which exhibit early signs of aging, significantly improved behavior and prevented brain abnormalities, such as increased hippocampal area and hydrocephalus, compared to untreated rats.

The treatment also reduced neurodegeneration markers, including Tau and phospho-Tau levels, suggesting that low doses of rapamycin can effectively suppress brain aging without causing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats. Kolosova, NG., Vitovtov, AO., Muraleva, NA., et al.[2021]

Rapamycin, a macrolide antibiotic and mTOR inhibitor, has shown promise in various Alzheimer's disease models by potentially delaying disease progression through mechanisms like reducing β-amyloid deposition and inhibiting tau protein hyperphosphorylation.

Despite its therapeutic potential, the effectiveness of rapamycin in Alzheimer's treatment is still debated due to variability in experimental conditions, including model types, administration methods, and dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin Responds to Alzheimer's Disease: A Potential Translational Therapy. Hou, SJ., Zhang, SX., Li, Y., et al.[2023]

The mTOR pathway is crucial for various brain functions, and its dysregulation is linked to Alzheimer's disease (AD), contributing to issues like the buildup of harmful proteins and disrupted neuronal metabolism.

mTOR inhibitors, such as rapamycin, show promise as potential treatments for AD by reducing key disease markers and improving cognitive function, but more research is needed to fully understand their effects and develop effective human therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies. Tramutola, A., Lanzillotta, C., Di Domenico, F.[2022]

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]

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]

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]

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