Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D. Vernon, Tina Milani and Lucinda Bateman in Front. Syst. Neurosci., 01 Sep 2021 [doi.org/10.3389/fnsys.2021.698240]
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.
Materials and Methods:
This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.
ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.
The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.
Cortene believes the CRFR2 pathway is upregulated and therefore overactive, leading to the wide variety of symptoms in ME/CFS. “The conventional approach would be to block the overactive pathway. Instead, our counterintuitive approach seeks to overstimulate CRFR2, causing it to downregulate, without the need for chronic treatment.”
Health arising: The Cortene drug trial results for ME/CFS are in
Dr. Bateman indicated that many of the participants reported subtle but noticeable improvements of their symptoms over the 1-2 years following the trial.
In an interview, Cortene proposed that partial downregulation of the CRFR2 receptor had indeed occurred, and that further trials would determine if they could fully return it and the stress response system in ME/CFS to a healthy state.
Cortene hopes to embark on a 60-person $4 million trial next.