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

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The Cortene peptide CT38 in a Bateman study:

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.
https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full
 

MonkeyMan

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https://corteneinc.com/press-release-2021-09-01/

Clinical trial provides preliminary evidence of a cure for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Long Covid.

BURLINGAME, CA, September 1, 2021 – Cortene Inc. announces publication of its InTiME clinical trial in which a short subcutaneous infusion of its experimental drug, CT38, achieved sustained symptom improvement in ME/CFS. The company intends to test CT38 in Long Covid, the post-acute stage of COVID-19 infection, which is considered by many to be the latest trigger for ME/CFS.

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,” said Sanjay Chanda, PhD, Cortene’s Chief Development Officer. “Instead, our counterintuitive approach seeks to overstimulate CRFR2, causing it to downregulate, without the need for chronic treatment.”

CT38 was subcutaneously infused at one of four infusion rates for a maximum of 10.5 hours, in 14 ME/CFS patients. CT38 treatment was safe and generally well-tolerated. It was associated with significant reduction in mean 28-day, total daily symptom score (TDSS), which aggregated 13 patient-reported, daily symptom scores. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by 26% (p < 0.01, n = 7).

“Infusing CT38 is known to cause temporary cardiovascular changes and InTiME revealed that patients were significantly more sensitive to these changes than healthy subjects from a previous safety study”, said Hunter Gillies, MD, InTiME’s medical monitor. “These data support there being a pathological hypersensitivity in the CRFR2 pathway. Given that InTiME showed i) dose-dependent improvements in TDSS; and ii) additional infusions provide additional benefit, the next trial should test CT38 using longer or additional infusions. While infusion rates are somewhat limited by tolerability, it is total exposure at low rates that appears to drive symptom improvement.”

“The persistent improvement in symptoms over weeks using a limited exposure is encouraging. Many patients are still showing signs of improvement almost 2 years after treatment,” said Lucinda Bateman, MD, founder and Medical Director of the Bateman Horne Center, scientific advisor to Cortene, and the Principal Investigator of the InTiME study. “In fact, a few patients expressed a desire for ‘just a little bit more drug’.”

Full details of the trial have been peer reviewed and published in Frontiers in Systems Neuroscience, Acute corticotropin-releasing factor receptor type 2 agonism results in sustained symptom improvement in myalgic encephalomyelitis / chronic fatigue syndrome. The publication explains how the CRFR2 pathway controls homeostasis (maintaining biological system stability), how this pathway can become disrupted at the neuronal level leading to the individual symptoms of ME/CFS and how these same symptoms manifest in many other chronic diseases. Cortene plans to conduct additional trials in patients with ME/CFS and other diseases with similar symptoms using well-tolerated infusion rates and greater total exposure.

Article Reference: https://www.frontiersin.org/articles/10.3389/fnsys.2021.698240/full


About ME/CFS
ME/CFS is an unexplained, life-long disease, usually triggered by infection, physical/mental trauma, or chemical exposure. Symptoms include diminished physical capacity, pain, sleep issues, cognitive impairment, orthostatic intolerance, among many others, which worsen with innocuous stimulation (referred to as post-exertional malaise) and are not improved by sleep. ME/CFS afflicts 3 million Americans. There are no approved therapeutics and quality of life is worse than in most chronic diseases.

About InTiME
InTiME was a proof-of-concept, single-site, open-label interventional trial, with patients blind as to dose, to investigate the safety and efficacy of CT38 in ME/CFS patients. Efficacy was assessed by a variety of endpoints, including patient-reported daily symptoms scores for each of 13 symptoms, general health (via SF-36), and continuous FitbitTM monitoring. The primary endpoint was the change in the mean total daily symptom score over the 28-day periods immediately prior to the first treatment (pre-treatment) and immediately prior to exit from the trial (post-treatment).

About CT38
A proprietary peptide agonist, selective/specific for Corticotropin-Releasing Factor Receptor Type 2 (CRFR2).

About Cortene
Cortene Inc. (http://corteneinc.com, @corteneinc) is a biopharmaceutical startup headquartered in Burlingame, CA, developing therapeutics for treating disorders related to disrupted homeostasis.
 
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something from 2012
Chronic Activation of Corticotropin-Releasing Factor Type 2 Receptors Reveals a Key Role for 5-HT1A Receptor Responsiveness in Mediating Behavioral and Serotonergic Responses to Stressful Challenge

" Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders. "

People have suggested HPA axis might be relevant to cfs for a long time, I never really looked into it much though as not much research talked about it and I didn't understand it very well. I had general anxiety disorder after having a panic attack for the first time in my life in the 6 months preceding coming down with me/cfs, I also had episodes during that time where I felt way too hot, but my onset was viral and seemed like a result of exercise overtraining.
 

ljimbo423

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People have suggested HPA axis might be relevant to cfs for a long time,
It makes sense to me that the HPA axis could be very involved in ME/CFS given it's functions. This is what Wikipedia says about the function of the HPA axis-

Hypothalamic–pituitary–adrenal axis
(HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland (a pea-shaped structure located below the thalamus), and the adrenal (also called "suprarenal") glands (small, conical organs on top of the kidneys).

These organs and their interactions constitute the HPA axis, a major neuroendocrine system[1] that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure.
https://en.wikipedia.org/wiki/Hypothalamic–pituitary–adrenal_axis
 

Irat

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I don t know,but what they are trying to target is the limbic system, which controls the response to homeostatic threat.

thats excactly what the neuroplasticity programmes doing based on the amygdala and insular hypothesis.overactive limbic system, etc

Gupta( brain retraining programe) says :
medical research seems to indicate that these conditions are neurological in nature, and may be caused by abnormalities in a brain structure called the ‘amygdala,’ and the ‘insula’.involved in protection mechanisms and conditioned immune responses related to chemical and immunological threats as well.
 
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Wishful

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Very interesting. I suppose I'm biased, because I believed that ME's root cause was neurological and probably limited to a small portion of the brain, so this fits. The hypothesis explains why researchers haven't found any clear markers for ME in serum or tissues, and why antivirals haven't been a reliable cure for ME (for some people, eliminating the immune response to the virus might be enough to allow this CRFR2 dysfunction to stop). This is the first hypothesis that really fits most of the weirdness of ME.

I expect that many of us are now going to google CRFR2 and whatever effective treatments or sensitivities we've experienced and see if there's a link. :)
 

Wishful

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I skimmed but say 26% improvement and that the patients wanted 'a bit more of the drug' two years later. That sounds promising, but very far from a cure.
If this proves true, it's a major breakthrough in understanding ME. The result will be much more funding focused on what is known to be involved in ME, rather than wasted on hunting for a lead. Maybe in 2 years there will be more discoveries due to the new focus, leading to better, longer-lasting treatments.

This paper certainly makes me a lot more optimistic about a treatment or cure in the relatively near future. :thumbsup:
 
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Oliver3

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something from 2012
Chronic Activation of Corticotropin-Releasing Factor Type 2 Receptors Reveals a Key Role for 5-HT1A Receptor Responsiveness in Mediating Behavioral and Serotonergic Responses to Stressful Challenge

" Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders. "

People have suggested HPA axis might be relevant to cfs for a long time, I never really looked into it much though as not much research talked about it and I didn't understand it very well. I had general anxiety disorder after having a panic attack for the first time in my life in the 6 months preceding coming down with me/cfs, I also had episodes during that time where I felt way too hot, but my onset was viral and seemed like a result of exercise overtraining.
Both my brother and me have terrible anxiety. I don't dispute what you're saying but there must be another factor involved as he runs 10 km most days after a long day at work.
I'm mostly housebound. It feels like I never heal properly. Anything that stops the adrenal drive is very welcome tho
 

Irat

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Both my brother and me have terrible anxiety. I don't dispute what you're saying but there must be another factor involved as he runs 10 km most days after a long day at work.
I'm mostly housebound. It feels like I never heal properly. Anything that stops the adrenal drive is very welcome tho
Mabey his bucket is not full yet.just a few more triggers and the ship could sink.depends on how big ones bucket is (resilience) and how many triggers thrown at