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

Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D Vernon, Tina Milani, Lucinda Bateman, Gerard Pereira, Hunter Gillies, Sanjay Chanda, Michael Corbett, Suzanne D Vernon, Tina Milani, Lucinda Bateman

Abstract

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.

Keywords: CRF2; ME/CFS; agonist-mediated receptor endocytosis; corticotropin-releasing factor receptor 2; homeostasis; myalgic encephalomyelitis chronic fatigue syndrome; serotonin.

Conflict of interest statement

GP, HG, SC, MC, and LB are shareholders of Cortene Inc., which owns the commercial rights to the drug being tested. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Cortene, Inc. The funder conceived of the idea to test CT38 in ME/CFS and was involved in the overall study design, protocol preparation, data analysis and writing the manuscript. The funder was not involved in recruiting patients, data collection or the conduct of the clinical trial.

Copyright © 2021 Pereira, Gillies, Chanda, Corbett, Vernon, Milani and Bateman.

Figures

FIGURE 1
FIGURE 1
Etiological hypothesis.
FIGURE 2
FIGURE 2
InTiME schema.
FIGURE 3
FIGURE 3
Patient disposition.
FIGURE 4
FIGURE 4
Effect of CT38 in healthy subjects (triangles, green line) and ME/CFS patients (circles, purple line), on the change from baseline in: mean maximum HR (HRmax) versus (A) mean Cmax or (B) mean AUC; and mean minimum dBP (dBPmin) versus (C) mean Cmax or (D) mean AUC; with relevant p-values (italics) from statistical comparisons by Kolmogorov-Smirnov test.
FIGURE 5
FIGURE 5
Effect of CT38 on the pre-/post-treatment change in the 28-day mean TDSS (bars), with standard deviations (error bars), by patient. All changes are statistically significant (p < 0.05), except ns (not significant).
FIGURE 6
FIGURE 6
Effect of CT38 on the pre-/post-treatment change in the 28-day means (bars), with standard deviations (error bars), of TDSS and individual symptoms scores, for CT38: (A) Cmax < 0.25 ng/ml; or (B) Cmax > 0.25 ng/ml, either improving (green) or worsening (purple) with relevant p-values (in italics). Note that scales for TDSS and individual symptoms are different.
FIGURE 7
FIGURE 7
Effect of CT38 total AUC on the patient-specific change in 28-day mean TDSS, with ρ = Pearson’s correlation coefficient, for CT38: (A) Cmax < 0.25 ng/ml (green), stratified by TDSSpre (moderate: large circles, dark line; mild: small circles, light line); or (B) Cmax > 0.25 ng/ml (purple).
FIGURE 8
FIGURE 8
Effect of CT38 on the means of pre-treatment (purple bars) and post-treatment (green bars), with standard deviations (error bars), of SF-36 physical component score (PCS) and SF-36 mental component score (MCS) for CT38: (A) Cmax < 0.25 ng/ml; and (B) Cmax > 0.25 ng/ml.
FIGURE 9
FIGURE 9
Effect of CT38 individual treatment AUC on mean TDSS pre-treatment (purple bar) and post successive treatments (green bars), with standard deviations (error bars) and the level of AUC delivered in each successive treatment, by patient.

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