Rapamycin Improves PROMs in Patients With ME/CFS in Early Trial

Weekly rapamycin improved patient-reported outcome measures (PROMs) in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) after 3 months of use.1

These findings, from a phase 1 trial, were presented by Stephanie L. Grach, MD, MS, assistant professor of medicine at Mayo Clinic, at the American College of Physicians (ACP) Internal Medicine (IM) Meeting 2025, held April 3-5, in New Orleans, Louisiana.

“ME/CFS is a devastating infection-associated multisystem illness characterized by debilitating fatigue, autonomic dysfunction, and post exertional malaise (PEM), among other symptoms,” Grach and colleagues wrote in their poster.1

The data reported were from the study’s first 40 participants that had completed the 3-month follow-up period. Participants received 0.5 or 1 mg rapamycin weekly up-titrated weekly to 6mg weekly or as tolerated. Participants completed functional outcome questionnaires at baseline (pre-rapamycin), 1 month (T=1), 2 months (T=2), and 3 months (T=3) after beginning therapy. The questionnaires completed were Bell Activity Scale (BAS); Multidimensional Fatigue Inventory (MFl); RAND 36-Item Short-Form Health Survey (SF-36); and Fatigue, sleep, PEM, and orthostatic intolerance symptoms of the Symptom Severity Scale version 2.2 (SSS). Investigators also performed safety labs at each timepoint for monitoring.

“Rapamycin has been of increasing interest as a geroprotective drug, having potential longevity and systematic inflammation modulation effects via promoting autophagy through inhibition of mTOR. Accordingly, patients managed by a leading ME/CFS clinician reported clinical improvements with use of rapamycin prompting further investigation utilizing PROMs and ATG13 biomarker,” Grach and colleagues wrote.1

Participants had a mean age of 47.43 years (range, 24.80-76.38), weight of 171.35 lbs (range, 115.00-310.00), BMI of 26.64 (range,18.85-47.13), and a disease duration of 16.45 years (rang<e 0.56-49.48). The cohort consisted of 32% males and 68% females, with 92% identifying as non-Hispanic White.1

The investigators found that PROMs statistically significantly improved from baseline to the 3-month time point, with BAS, MFI, SF-36 subscores, SSS fatigue, disrupted sleep. PEM, and orthostatic intolerance all demonstrating improvements (P <.05).

Specifically, BAS scores improved from 34.84 (standard deviation [SD], 3.13) to 42.26 (SD, 3.87; P <.001); SSS sleep scores improved from 7.35 (SD, 0.38) to 5.03 (SD, 0.58; P <.001); SSS PEM scores improved from 7.05 (SD, 0.39) to 3.77 (SD, 0.56; P <.001); SSS OI scores improved from 5.33 (SD, 0.46) to 3.50 (SD, 0.50; P <.001)); and MFI aggregated scores improved from 79.63 (SD, 1.43) to 72.26 (SD, 2.28; P <.001). More detailed data, including subgroup analyses, will be published at a later time.

“In line with suspected abnormalities of mTOR inhibition, the results of our study support the potential use of rapamycin in ME/CFS,” Grach and colleagues concluded.1

Other investigators on the study previously completed preclinical investigations of rapamycin in models of CE/MFS that suggested that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.2

REFERENCES

1. Grach SL, Roy A, Kaufman DL, et al. Effect of Rapamycin on Functional Outcomes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

2. Gottschalk G, Peterson D, Knox K, et al. Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE). Mol. Cell. Neurosci. 2022; 120 (103731). doi: 10.1016/j.mcn.2022.103731