Sirolimus
Sirolimus (rapamycin), an mTOR inhibitor with immunomodulatory and autophagy-promoting effects, has been studied in idiopathic inflammatory myopathy primarily in inclusion body myositis (IBM) rather than classic DM/PM/IMNM.
In the randomized, double-blind, placebo-controlled phase 2b proof-of-concept trial (single center, Paris), 44 IBM patients (22 sirolimus 2 mg daily; 22 placebo) were treated for 52 weeks; the primary endpoint—relative % change in maximal voluntary isometric knee extension* strength at 12 months—showed no difference (median difference 3.78, 95% CI −10.61 to 17.31; p=0.85). Several secondary outcomes favored sirolimus (including 6-minute walk distance, forced vital capacity, and HAQ-DI), but treatment burden was nontrivial: *serious adverse events occurred in 10/22 (45%) on sirolimus vs 6/22 (27%) on placebo, and 4/22 (18%) discontinued sirolimus due to adverse events (e.g., severe mouth ulcers, aseptic pneumonia, renal insufficiency, edema). [1]
A key “established” quantitative signal from this program comes from the MRI/MRS biomarker analysis of the same placebo-controlled cohort (44 patients) that captured progression more sensitively than strength testing. Over 1 year, the median quadriceps fat-fraction (FF) increase was 3.2% in placebo (P<0.001) versus 0.7% with sirolimus (P=0.033), and the between-group differences in FF and contractile cross-sectional area changes were significant (P<0.001); median quadriceps contractile area decreased 12.6% (placebo) vs 5.5% (sirolimus). These imaging metrics also correlated with functional and strength outcomes, supporting quantitative MRI as a plausible endpoint for future IBM/IIM trials. [2]
On the basis of the phase 2b pattern (negative primary strength endpoint but favorable secondary/biomarker trends), a larger international phase IIb/III *program has been designed to test whether sirolimus can slow IBM progression using a more disability-anchored primary endpoint: *~140 IBM participants randomized 1:1 to sirolimus 2 mg daily vs placebo, with change in IBM Functional Rating Scale (IBM-FRS) from baseline to *Week 84 *as the primary outcome and multiple functional/PRO secondary measures (e.g., 6MWT, timed tests, dynamometry, PROs). [3,4]
Taken together, current evidence supports sirolimus as a still-unproven, IBM-focused strategy where the most reproducible signal so far is on quantitative imaging and selected functional measures, while robust, trial-grade benefit for classic DM/PM/IMNM remains uncertain due to lack of comparable randomized datasets. [1–4]
References (numbered as cited; links included)
1) Benveniste O, Hogrel JY, Belin L, et al. Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial. Lancet Rheumatol. 2021;3(1):e40–e48. doi:10.1016/S2665-9913(20)30280-0.
https://pubmed.ncbi.nlm.nih.gov/38273639/
https://doi.org/10.1016/S2665-9913(20)30280-0
2) Reyngoudt H, Baudin P-Y, Caldas de Almeida Araújo E, et al. Effect of sirolimus on muscle in inclusion body myositis observed with magnetic resonance imaging and spectroscopy. J Cachexia Sarcopenia Muscle. 2024. doi:10.1002/jcsm.13451.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11154752/
https://doi.org/10.1002/jcsm.13451
3) Badrising UA, et al. Optimism in inclusion body myositis: a double-blind randomised controlled trial investigating sirolimus (trial design paper). Clin Exp Rheumatol. 2025.
https://pubmed.ncbi.nlm.nih.gov/40018746/
https://www.clinexprheumatol.org/article.asp?a=21865
4) ClinicalTrials.gov. Phase III Trial of Sirolimus in IBM (NCT04789070).
https://clinicaltrials.gov/study/NCT04789070