Frontiers in Pharmacology · Oct 30, 2026
Metabolic effects of Rapamycin in Amyotrophic Lateral Sclerosis patients: secondary analysis of an RCT
By Elisabetta Zucchi, Federico Banchelli, Ilaria Martinelli et al.
Introduction: Rapamycin is an immunosuppressive agent that has been shown to promote the in vitro expansion of Tregs, a subset of CD4+T cells with immunomodulatory functions whose frequency inversely correlates with the rate of disease progression in ALS. Rapamycin has been previously tested in a phase II trial on ALS patients to investigate whether it could enhance Treg expansion in vivo. The first aim of this study was to test whether rapamycin induced modifications in the metabolic parameters of ALS patients. Secondly, we interrogated whether these rapamycin-induced changes could affect Tregs and other clinical outcomes. Methods: During the RAP-ALS trial, 63 patients with ALS were allocated to rapamycin (n=42, with two treatment arms receiving 1 or 2 mg/m2/day) or placebo (n=21) (ClinicalTrials.gov registration: NCT03359538), standard laboratory parameters were measured at several time points, together with the ALS Functional Rating Scale-revised (ALSFRS-r) and forced vital capacity (FVC). Non-linear longitudinal trends were evaluated for laboratory data. Moreover, the association between the biological and clinical outcomes, namely Tregs, ALSFRS-r and FVC, with candidate explanatory variables, including previously reported explanatory lab values and rapamycin-affected variables, was explored. Results: In the rapamycin-treated patients, total and LDL cholesterol, and triglycerides rose compared to placebo, with average values at week 18 of 236.0 mg/dl, 151.7 mg/dl and 159.4 mg/dl, respectively (versus 219.6 mg/dl, 136.8 mg/dl, and 133.2 mg/dl in the placebo arm). Creatinine declined more slowly in the rapamycin arm. C-reactive protein (CRP) increased during rapamycin treatment, while hemoglobin-related parameters tended to decrease, both with reversion to baseline ranges during follow-up. ALSFRS-r and FVC declined without significant differences between the two treatment arms, with creatinine showing closer temporal associations with these clinical measures variations compared to plasma NfL values (for each 0.1 mg/dl increase in creatinine, the ALSFRS-r varied on average of +1.22 points/month, 95%CI 0.64-1.80, p<0.001). Conclusions: In this brief course of rapamycin treatment, ALS patients had lowered values of haemoglobin-related parameters and raised CRP and cholesterol values. These laboratory modifications did not affect the biological and clinical outcomes of the trial, though they shed light on the multiple mechanisms of action of rapamycin.