Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Result in Sustained Improvement in ME/CFS - Pereira, Bateman et al, 2021

I noticed they used an objective outcome indicator* - interesting to see the raw data --- is it available/has anyone had a look at it?
*"Secondary endpoints included: ---- (ii) FitbitTM metrics (activity, HR, and sleep), continuously monitored throughout the trial;---"

@Jonathan Edwards has highlighted actimetry as a possible research area** - an actimetry study would also help to establish objective outcome criteria for studis like this.
**"When I acted as MRC advisor this recent time around the GWAS project was the one thing that looked worthwhile, apart from maybe some actimetry studies." [https://www.s4me.info/threads/georg...e-bps-and-long-covid.20126/page-4#post-319043]

 

I recall @Snow Leopard post here re Fluge & Mella's recent paper*. Is this theory related to HPA axis and if so is this at odds with Fluge & Mella's recent paper?

*"Another key finding buried in the text:

Corticosteroids* did not seem to be involved, since they depended on age and BMI instead of physical function scores (Supplemental Data 3) and we did not find changes in morning cortisol and ACTH in ME/CFS compared with HC.
Which rules out HPA axis related hypotheses."
https://www.s4me.info/threads/a-map...ome-2021-fluge-mella-et-al.22052/#post-367205

 

Yes, their theory does involve the HPA axis, even though they don't explicitly mention it in the current manuscript.

The Corticotropin-releasing hormone receptors lead to a release of ACTH, which in turn stimulates the production of corticoids.

The Urocortins are part of the corticotropin-releasing factor family of proteins, and this would include CT38, which is a synthetic analog of these peptides.


Here is Cort's take (I don't necessarily agree with the details, but it is more readable than what the Cortene people have written)
https://www.healthrising.org/blog/2018/02/17/cortene-chronic-fatigue-syndrome-hypothesis/

Note, many of the hypothesised outcomes, eg increased norepinephrine or serotonin haven't actually been observed. No consistent differences in catecholamines in circulation have been observed in adults.
Findings involving serotonin also tend to be inconsistent see the 5-HT section in the following paper: https://academic.oup.com/edrv/article/24/2/236/2424377
Studies attempting to infer serotonin release sensitivity due to D-fenfluramine stimulation were inconsistent.
Also note that 100% of the participants in Cleare's 2005 study had a past history of antidepressant use. Keeping in mind that SSRI use is known to cause the observed reduction in 5-HT1A binding, and has been found to persist for a while in otherwise healthy people after they cease taking SSRIs.

 

Wow I'm conscious of how complicated this is and your grasp of the material - thank you very much for this detailed response. I think I read Cort's article when this all kicked off (2018); I'll re-read it.

 

The use of a very basic form of actimetry (activity monitoring), i.e. FitBit, in this study seems to challenge the dependence on questionnaires in UK Government studies. Then again it's not as easy to manipulate the results to show the intervention worked - hence the continued reliance on questionnaires.

 

Nice work. If there is a response it is at that specific threshold, 3cmax. I think that was the dosage that came right after the first 2, who had adverse events. I have to admit the proposed explanation went over my head. It seems there can be a significant increase in HR associate with the infusion if I read that chart correctly, which sort of tracks with the symptoms improving the most being orthostatic intolerance and abnormal temperature.

 

Dr Bateman wrote a statement about Cortene and her role in the study:
https://batemanhornecenter.org/dr-bateman-on-cortene-and-ct38/



When Cortene contacted BHC with an idea, and an early draft protocol designed to test CT38 as a treatment for ME/CFS, Dr. Suzanne Vernon and I agreed to help them refine the protocol and conduct the trial. The Cortene-funded trial was an FDA and IRB-approved protocol, and BHC carried out the protocol with detailed precision. We had a routine contract with Cortene to carry out the trial. It was challenging, because CT38 is a novel substance that has previously been tested only in healthy controls, as there is no animal model for ME/CFS.

Cortene has a vision that CT38 will be curative for people with ME/CFS based on the known mechanisms and their hypotheses. Before CT38 was tested in ME/CFS, I had no clinical data to form an opinion about efficacy, but I was willing to put the drug to the test. The phase 1/2 trial was meticulously carried out at BHC, with courageous volunteers. We learned that even the lowest starting dose, an estimate based on responses previously in healthy controls, resulted in a strong physiologic response in the first two ME/CFS subjects. Revisions were made to the protocol to revise the dosing regimen, with full disclosure to and oversight by the IRB and FDA. Once the study was complete, the contracted role of BHC ended; it then became Cortene’s responsibility to analyze the data. I have stayed on as a medical advisor to the company as the data were analyzed, the paper published, and next steps determined. Cortene is optimistic about the results, and I am pleasantly surprised by the results and hope the next phases of research can move forward.

It is hard for all of us to remain dispassionate and allow the scientific process to take its course when the needs are great and so much is at stake. However, science, and especially clinical trials, must be carried out with an intellectual willingness to accept whatever the data teach us, regardless of our emotional or financial investment. Research protocols are usually carried out under a business contract at a separate institution than the pharmaceutical company, to reduce the risk or perception of bias. Research participants, so understandably eager for a positive response, are subjected to placebo assignment or other study designs to reduce subject bias in larger clinical trials.

We should be careful how we use or react to the word “cure” at this stage of the scientific process. None of us know what CT38 can really do for a larger pool of people with ME/CFS or anyone withLong COVID until larger, controlled trials are complete. Cortene asserts that if the disease mechanism reversed by CT38 is a primary cause of ME/CFS, then the drug has the potential to be curative rather than supportive. That is exciting but remains to be proven. The preliminary results from the first, small, proof-of-concept CT38 trial in ME/CFS provide a strong enough signal to move forward with the next steps. Given the known heterogeneity of ME/CFS, it is unlikely any treatment breakthrough will have the same response in everyone who meets the diagnostic criteria. We must be prepared for that outcome. But for all with ME/CFS, I hope that CT38 proves to be an effective treatment for as many as possible.

Now it is Cortene’s responsibility, like all pharmaceutical companies, to raise money for these larger, placebo-controlled trials of CT38. BHC’s role with the company was to help them understand ME/CFS, develop an illness-specific protocol, oversee implementation of the protocol and interpret the data.

My resolve, and BHC’s mission, is to broadly encourage and develop research, education, and clinical expertise to improve the lives of people with ME/CFS and related conditions, not to support or promote any specific product or ideology. I do not own stock in Cortene, and Cortene has not donated funds to BHC. BHC has purposely maintained a collaborative approach with all working toward solutions for ME/CFS. We remain steadfastly invested in our mission.

 

She tweeted about it so you could ask her questions there, possibly

https://twitter.com/user/status/1436074966319976456

 

I didn't quite catch what the proposed disease mechanism is....

 

If I've understood them, the range of symptoms* comes about due to inappropriate serotonin production in certain serotonergic neurons (brainstem raphé nuclei and limbic system). These neuronal pathways control the response to homeostatic threat. Under certain conditions the threat response can fail to return to normal after the threat has resolved and leaves the system in a self-perpetuating, heightened state of alert.

The elevated response is said to be caused by sustained reversal of the positions of Corticotropin Releasing Factor Receptor types 1 and 2, where normally CRFR1 is on the neuronal cell membrane and CRFR2 is in standby mode in the cytoplasm. Their drug is targeting the (now membrane-bound) CRFR2 receptor, aiming to overactivate it so that it declares game-over and reverses positions with CRFR1, bringing the neurons back to their normal threat posture. I.e. DEFCON1 back to DEFCON5.

I think this proposed mechanism is analagous to the metabolic trap and the glial activation hypotheses, but is a completely different mechanism. Michael VanElzakker is not a fan and has tweeted that the neuronal systems under discussion are those responsible for learned helplessness / conditioned defeat.

*In the paper, serotonin-related functions governed by this homeostatic threat response are said to include emotion, motivation, memory consolidation, motor control, sensory sensitivity, respiration, thermoregulation, and downstream autonomic, endocrine, metabolic and immune actions.

 

"Cortene Inc., an American pharmaceutical company, recently published findings of a preliminary treatment trial in the scientific journal Frontiers in Systems Neuroscience. In the trial, Cortene’s experimental drug ‘CT38’, was administered to 14 patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). An accompanying press release claimed that the drug “achieved sustained symptom improvement” and that the trial “provides preliminary evidence of a cure for ME/CFS”. Both statements are incorrect. This blog post tries to move beyond hyperbole and figure out what the trial showed."

https://mecfsskeptic.com/intime-the-results-of-cortenes-ct38-trial/

 

A New Pathway to Solving Chronic Neurological Diseases - Maybe Long COVID?

https://www.biospace.com/article/a-...c-neurological-diseases-including-long-covid/