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]
 
That was a masterstroke for publicity, Cortene getting Cort Johnson on the board.


Cort said:
The results were dose-dependent, which, with caveats for the small trial, suggests biology over chance.
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I am not sure that results were dose-dependent. As I mentioned, I found it hard to work out exactly what dose each participant received. I came up with some numbers, There's the Cmax and AUC, but when I graphed them, both against change in TDSS and change in daily steps, the dose dependent relationship was very weak. I may have got something wrong.
 
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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
 
There's the Cmax, the maximum concentration of the drug, averaged over the two treatments. And there's the AUC, the total amount under the curve.

Here's the chart of the change in the total symptom score (TDSS) against Cmax. Negative changes in the TDSS are good, as that means less symptom load. It's true that the two people with relatively high Cmax's did worse than those who had lower maximum concentrations, but it's a stretch to say that there's a dose dependent relationship. (x axis is the Cmax; y axis is the change in TDSS)

upload_2021-9-4_22-40-0.png

Here's the chart for the AUC measure
(x axis is the AUC; y axis is teh change in TDSS)
upload_2021-9-4_22-44-52.png
You could argue that there is a dose dependent relationship there from AUC 0 to 3, with higher doses having a negative effect. But there are so few data points, so it's a big stretch.
 
FWIW, here's the change in mean daily steps from 4 weeks before and the 4 weeks after the treatment. x axis is the AUC (i.e. a measure of the dose); y axis is the change in steps. A positive change is good - that's an increase in the mean number of steps. (There isn't step data for one participant.)

Not much of a dose dependent relationship there. And most participants had lower mean step counts after treatment.

upload_2021-9-4_22-52-9.png
 
FMMM1 said:
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?
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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.
 
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Snow Leopard said:
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 health people after they cease taking SSRIs.
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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.
 
It's frustrating getting only partial information on patient outcomes. I had a go at combining the symptom change scores with the step change scores, taking a change in steps of 100 steps per day as equivalent of a 1 point change in symptoms. For me, an increase of 100 steps average would be about as significant as a decrease of 1 point in one of the listed symptoms, as someone whose fitbit currently records me averaging around 600 'steps' per day (actually far fewer, since it records some arm movements as steps). But for someone who normally averages around 5000 steps per day, a change in average of 100 would be just a minor fluctuation. But then questionnaire improvement averaging 1 point could be just due to a simple dietary change that led to improvement in gut problems, or taking part in a study could make them feel more positive so depression score improving.

When I used my assumed 100 step change as equivalent to 1 point change on the symptom scale, I ended up with only 1 patient improving by more than 5 points, which seems to me about the level at which clinical significance could be a realistic interpretation.

To be fair it's only a tiny pilot study, basically testing safety and acceptability in this patient population, but I hope in any larger study they will write a proper protocol with any primary outcome measures including objective measures of physical and cognitive function, and a predefined cut off point for what they and patients regard as clinically significant improvement.
 
Hutan said:
There's the Cmax, the maximum concentration of the drug, averaged over the two treatments. And there's the AUC, the total amount under the curve.

Here's the chart of the change in the total symptom score (TDSS) against Cmax. Negative changes in the TDSS are good, as that means less symptom load. It's true that the two people with relatively high Cmax's did worse than those who had lower maximum concentrations, but it's a stretch to say that there's a dose dependent relationship. (x axis is the Cmax; y axis is the change in TDSS)

View attachment 14989

Here's the chart for the AUC measure
(x axis is the AUC; y axis is teh change in TDSS)
View attachment 14990
You could argue that there is a dose dependent relationship there from AUC 0 to 3, with higher doses having a negative effect. But there are so few data points, so it's a big stretch.
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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.
 
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dreampop said:
If there is a response it is at that specific threshold, 3cmax.
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Yes - although 3AUC, not 3cmax.

And, if you were going to look at the impact of dosage on the semi-objective measure of steps you might come to a different conclusion.
Edit: i.e. that a lower dose is not better than a higher dose.

Have a look at the chart below. The quadrant where we would all want to be is the top left - less symptoms while walking more steps. Only two participants were in that quadrant - one of whom received a dose of more than 3AUC.

If you were basing your conclusion about dosage rates on the step results only (ie looking at all the data points above the x axis vs those below it), it looks as though a dosage rate over 3AUC (shown by the orange triangles) is not a problem. Conversely, a dosage rate of less than 3AUC does seem to be associated with a decrease in steps walked.


upload_2021-9-6_13-24-40.png

The idea of a dose dependent result really is a manipulation of the data. And, given we are talking about people with ME/CFS, the result of most of the participants being in the bottom left and top right quadrants shouldn't be surprising - those who walked less tended to have less symptoms; those who walked more tended to have more symptoms. There's really nothing here that makes me think that the drug had any significant effect.
 
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Dr Bateman wrote a statement about Cortene and her role in the study:
https://batemanhornecenter.org/dr-bateman-on-cortene-and-ct38/

samuel-ramos-RXVfrhCswCQ-unsplash-200x300.jpg


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.
 
It's nice to see Dr Bateman dialling back the expectations about CT-38 and making it clear that she and her clinic are not promoting the drug. It's still a bit surprising though that she is as positive about the prospects for the drug as she is. I'm not sure what she is seeing.
Dr Bateman said:
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.
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Wonko said:
I didn't quite catch what the proposed disease mechanism is....
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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?
In a proof-of-concept trial dubbed InTiME, Cortene infused 14 ME/CFS patients with CT38, at one of four infusion rates for a maximum of 10.5 hours, in 14 ME/CFS patients. The drug was associated with a significant reduction in mean 28-day total daily symptom score (TDSS), which aggregated 13 patient-reported, daily symptom scores. The 0.03 μg/kg/h infusion rate seemed to be the sweet spot, as patients achieved a 26% improvement in TDSS –effects Pereira said are still evident after two years. Cortene recently published a peer-reviewed paper with full results of this study in Frontiers in Systems Neuroscience.

Dr. James Baraniuk, M.D., professor of medicine in the Neuroscience program at Georgetown University, was one of these peer reviewers. He offered further insight into the CRFR2 pathway (also referred to as the CRHR2 receptor)

“Once the CRHR2 receptor gets switched on, it's as if it is permanently switched on. When that happens, it has downstream effects on the limbic system and serotonin system.” Then, any stressor the person is exposed to – including exercise, heat or bright lights – is interpreted as being a major stressor. Other potential stressors are mental trauma, physical trauma, viruses and toxins.

While expressing cautious optimism about the potential of the approach, Baraniuk stated that this particular study had a number of limitations, including a small patient sample.

“Some of the subjects had adverse events like fast heartbeat, low blood pressure,” he said, adding that these effects were easy to treat at the time of the infusion, but that “fatigue and cognitive problems” also occurred. “The problem is with the variation in any CFS, you have good days and bad days, so some of the adverse events they had could be just the normal variation of this disease.”

Baraniuk noted that the 26% symptomatic improvement, measured at 28 days as opposed to immediately following the infusion, was significant.

“Let’s put it into perspective,” he said. “There’s no treatment for ME/CFS, and they gave one infusion of the drug, and then 28 days later, people had a continuing beneficial effect. So that is very encouraging to suggest that they should definitely do more studies to understand and prove that the symptoms are getting better.”

Baraniuk indicated that the right dose could be the most difficult for Cortene to determine, as it is typical to have a U-shaped dose response curve in the brain.
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https://www.biospace.com/article/a-...c-neurological-diseases-including-long-covid/
 
Baraniuk noted that the 26% symptomatic improvement, measured at 28 days as opposed to immediately following the infusion, was significant.

“Let’s put it into perspective,” he said. “There’s no treatment for ME/CFS, and they gave one infusion of the drug, and then 28 days later, people had a continuing beneficial effect. So that is very encouraging to suggest that they should definitely do more studies to understand and prove that the symptoms are getting better.”
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Hutan said:
And most participants had lower mean step counts after treatment.
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I find it disappointing that a researcher that we are hoping will contribute to improving the understanding of ME/CFS thinks that this trial is 'very encouraging'. It's not that hard to look at the evidence properly.
 
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