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Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials

Mannick JB, Teo G, Bernardo P, Quinn D, Russell K, Klickstein L, Marshall W, Shergill S · 2021 · Lancet Healthy Longevity · Atlas ID MAN2021

What this study shows

This paper reports two trials of RTB101, a drug that blocks mTOR, taken once a day for 16 weeks by adults over 65. In the phase 2b trial (652 people), fewer people on 10 mg had a lab-confirmed respiratory infection than on placebo (19% against 28%), but that result comes from a pooled analysis the authors did not correct for multiple testing, and the corrected analysis did not reach significance. The phase 3 trial (1,024 people) used a different main endpoint, set with the FDA: symptoms with or without a lab test. It found no difference (26% against 25%, p = 0.65), although blood tests still showed more antiviral genes switched on in both trials. In phase 2b, twice-daily dosing and a combination with everolimus did not reach significance, which the authors read as a hint that on-off inhibition may beat constant inhibition. Those numbers are "data not shown" in the paper. Boundary: RTB101 is not rapamycin or everolimus, the phase 3 group was healthier (no COPD, no smokers), and that trial was too small to test the lab-confirmed endpoint. The only everolimus arm (RTB101 plus everolimus 0.1 mg daily) was a combination and did not reach significance, which is why this paper is listed against the everolimus and immune function link on the pathway map. It cannot show what everolimus alone does.

Cited on mTOR drugs in development: RTB101

Abstract

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The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults.

Read the full abstract on PubMed →

At a glance

Evidence type H Human study Marked H because it is direct evidence from a human clinical trial or human cohort; the code names the kind of study, not its quality -- a small, well-run trial is still H.
Study type2 - Human Clinical Trial
Model systemHumans, phase 2b + phase 3 RCT (n=1024 phase 3)
JournalLancet Healthy Longevity
Year2021
Peer reviewedYes
Record last updated2026-10-01
SourceDOI 10.1016/S2666-7568(21)00062-3 · PMID 33977284 · Free full text (PMC8102040)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

InterventionRTB101 (BEZ235), oral mTOR inhibitor; ± everolimus
TargetmTOR (TORC1/2)
ModelHuman – phase 2b + phase 3 RCT (n=1024)
EffectPhase 3 FAILED its primary endpoint (no reduction in symptomatic respiratory infections, 26 vs 25%); antiviral genes still upregulated
DoseRTB101 5 or 10 mg once daily (+/- everolimus in phase 2b); phase 3 used RTB101 10 mg once daily; oral, placebo-controlled.
Sample sizePhase 2b + phase 3 across >1500 adults aged >=65 (phase 3 n=1024).
Effect sizePhase 3 primary endpoint (proportion with >=1 clinically symptomatic respiratory illness) NOT met; RTB101 still upregulated IFN-induced antiviral gene expression. Biomarker moved, clinical outcome did not.
LimitationsFDA changed the primary endpoint between phase 2b and phase 3 (symptom-based vs lab-confirmed), complicating comparison; positive biomarker did not translate to clinical benefit.

In the Atlas

Related topics

mTORImmune functionmTORC1RTB101

Links in the pathway map

Open questions that cite this study

Answers that reference this study

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Cite this paper

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Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., Marshall, W., & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. Lancet Healthy Longevity. https://doi.org/10.1016/S2666-7568(21)00062-3

@article{MAN2021,
  author       = {Mannick, J. B. and Teo, G. and Bernardo, P. and Quinn, D. and Russell, K. and Klickstein, L. and Marshall, W. and Shergill, S.},
  title        = {{Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials}},
  journal      = {Lancet Healthy Longevity},
  year         = {2021},
  doi          = {10.1016/S2666-7568(21)00062-3},
  note         = {PMID: 33977284},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper. 

Barton, O. (2026). Oliver's mTOR Atlas (record MAN2021) [Data set]. https://mtor-atlas.org/study/MAN2021/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_MAN2021,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record MAN2021},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/MAN2021/},
  doi          = {10.5281/zenodo.22059963}
}
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