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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

The crucial reality check. After the promising phase 2a, the large phase 3 trial (n=1024) FAILED its primary endpoint - RTB101 did not reduce clinically symptomatic respiratory illness (26% vs 25%, p=0.65). It still reliably switched on antiviral genes, so the biomarker moved but the clinical outcome did not. A textbook lesson that a promising biomarker is not a proven benefit.

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.

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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 updated2026-08-22
SourceDOI 10.1016/S2666-7568(21)00062-3 · PMID 33977284 · Free full text (PMC8102040)

Extracted findings

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); antiviral-gene subset 180 placebo + 180 RTB101.
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

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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}
}