RTB101
RTB101 (dactolisib, BEZ235), low-dose TORC1 inhibitor
Written by Aaron CuhaReviewed Sep 2026
Also known as: Dactolisib, BEZ235
The most important failed trial in geroscience. Positive in phase 2a and 2b, then nothing in a 1,024-person phase 3, while the biomarker it targeted still moved in both.
Overview
If you read one page on this site about why biomarkers are not results, it should be this one.
RTB101 was the drug that carried the mTOR longevity hypothesis into definitive human testing. The sequence went: a positive randomised trial of mTOR inhibition on influenza vaccine response in 2014, a positive multicentre follow-up on immune function and infections in 2018, a positive phase 2b reducing clinically symptomatic respiratory illness with p equal to 0.02, and then a phase 3 in 1,024 patients that found 26 percent against 25 percent, odds ratio 1.07, p equal to 0.65.
The detail that makes this instructive rather than merely disappointing: in both the phase 2b and the failed phase 3, the interferon-induced antiviral genes the drug was designed to upregulate were significantly upregulated. The drug did exactly what it was built to do at the molecular level, in the trial where it produced no benefit.
That is the whole argument against trusting mechanism.
Mechanism of action
A low-dose inhibitor of TORC1. At the higher doses originally developed for oncology, dactolisib is a dual inhibitor of phosphoinositide 3-kinase and mTOR. The geroscience programme used substantially lower doses intended to inhibit TORC1 selectively, on the reasoning that the immune benefits of mTOR inhibition appear at doses well below those causing immunosuppression. Its intended downstream effect was upregulation of interferon-stimulated genes, increasing antiviral readiness in older adults, and that effect was confirmed in the trials.
Human evidence
An unusually complete human programme: two positive early trials, a positive phase 2b, and a properly powered negative phase 3. Very few geroscience hypotheses have been tested this thoroughly.
- Phase 2b: reduced clinically symptomatic respiratory illness, p = 0.02.
- Phase 3: 1,024 patients, 26 percent against 25 percent, odds ratio 1.07, p = 0.65. No effect.
- Target engagement was confirmed in both trials: interferon-induced antiviral genes were significantly upregulated on drug.
- Safe and well tolerated throughout. Only one patient, in the placebo group, had serious adverse events considered drug-related.
- Three deaths in phase 2b and one in phase 3, none considered treatment-related.
- The authors' own interpretation is that endpoints and patient populations may need refinement to determine whether interferon upregulation consistently reduces viral infection in older adults.
What this does not tell you: The failure is specific: it is about this drug, this dose, this endpoint and this population. It does not prove mTOR inhibition has no ageing benefit, and rapamycin's mouse lifespan record is untouched by it. What it does prove is that a confirmed molecular effect plus two positive earlier trials is not enough to predict a phase 3 result. Note also that six authors were employees with equity in the manufacturer, which is a reason to weight the earlier positive trials more cautiously in hindsight.
Reading the research record
Read the mTOR human programme as one sequence rather than three papers. In 2014 a randomised trial found that everolimus improved influenza vaccine response in older adults, which was the first credible human signal that inhibiting this pathway could improve an age-related function. In 2018 a follow-up reported that TORC1 inhibition enhanced immune function and reduced infections. Then in 2021 the phase 2b and phase 3 trials were published together: phase 2b reduced clinically symptomatic respiratory illness with an odds ratio whose confidence interval ran from 0.391 to 0.922 at p = 0.02, and the 1,024-person phase 3 found 26 percent against 25 percent, odds ratio 1.07, p = 0.65. Nothing. In both trials the interferon-induced antiviral genes the drug was designed to upregulate were significantly upregulated. The mechanism was confirmed and the benefit vanished, which is the single best argument on this site for distrusting biomarker endpoints.
The reason this belongs on a longevity site rather than only in an immunology journal is that almost every compound sold for ageing is sold on a mechanism or a moving marker. This programme had more than that. It had a plausible pathway, mouse lifespan data behind the pathway, confirmed target engagement in humans, and two positive randomised trials. It still failed when properly powered, and the target engagement held in the trial where it failed.
That is the standard anything on this site should be measured against, and nothing sold as a supplement comes close to clearing it.
The evidence, charted
Fig. 1 · evidence composition
3of 3 citations (100%) are in people
Every citation cited here is Human work; no other study type is cited on this page. This count is of our own citation list and understates any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 3 distinct years, 2014 to 2021, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Not approved
CA
Not approved
Approved in 1 of 4, prescription route in 0, not approved in 3. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2021
Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials
Phase 2b reduced clinically symptomatic respiratory illness, odds ratio confidence interval 0.391 to 0.922, p = 0.02. Phase 3 enrolled 1,024 patients, 513 to RTB101 10 mg daily and 510 to placebo, and found 134 of 511 (26%) against 125 of 510 (25%) with clinically symptomatic respiratory illness, odds ratio 1.07 (90% CI 0.80 to 1.42), p = 0.65. Significantly more interferon-induced antiviral genes were upregulated on drug than placebo in both trials. Safe and well tolerated. Funded by resTORbio and the National Institute on Aging. Six authors were employees of, and held equity in, resTORbio, which manufactured the drug.
Lancet Healthy Longevity - Human2018
TORC1 inhibition enhances immune function and reduces infections in the elderly
The positive multicentre phase 2a that justified advancing to phase 2b and 3.
Science Translational Medicine - Human2014
mTOR inhibition improves immune function in the elderly
The original positive result on influenza vaccine response that started the programme.
Science Translational Medicine
Frequently asked questions
What happened to RTB101?
It was positive in a phase 2a, positive in a phase 2b at p equal to 0.02, and then produced nothing in a 1,024-person phase 3, with 26 percent of the drug group and 25 percent of the placebo group developing clinically symptomatic respiratory illness. Development for that indication did not continue.
Does that mean mTOR inhibition does not work for ageing?
Not quite. It means this drug at this dose did not reduce respiratory illness in older adults. Rapamycin's mouse lifespan record stands, and it is the most reliable pharmacological lifespan result there is. What the failure removes is the claim that the human immune benefit is established.
Why does the biomarker detail matter so much?
Because the drug did upregulate the antiviral genes it was designed to upregulate, in the trial where it produced no clinical benefit. Target engagement was confirmed and the outcome was flat. Any claim built on a marker moving should be read against that.
Can I get it?
No. It was never approved and is not available.