Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Background
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.


Results
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.


Conclusion
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.


Clinical Trial Registration
ClinicalTrials.gov, identifier NCT03613129.
['Pereira|Gerard|G|', 'Gillies|Hunter|H|', 'Chanda|Sanjay|S|', 'Corbett|Michael|M|', 'Vernon|Suzanne D|SD|', 'Milani|Tina|T|', 'Bateman|Lucinda|L|']
ME/CFS homeostasis agonist-mediated receptor endocytosis CRF2 corticotropin-releasing factor receptor 2 myalgic encephalomyelitis chronic fatigue syndrome serotonin