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

Discussion in 'ME/CFS research' started by Kalliope, Sep 1, 2021.

  1. Kalliope

    Kalliope Senior Member (Voting Rights)

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    frontiers in Systems Neuroscience
    Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Result in Sustained Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Pereira, Bateman et al

    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.
     
  2. dreampop

    dreampop Senior Member (Voting Rights)

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    This is the drug CT-38 that was talked about some time ago.

    There were no controls and it was unblinded, but there was some partial blinding of dosage.

    Not a fan of the TDSS because it conflates it all together and chances are good at least some natural improvement will occur or there will be a natural response to being treated (e.g. depression).

    So, a very modest result given the circumstances. https://www.frontiersin.org/files/A...8240-HTML-r2/image_m/fnsys-15-698240-g008.jpg has sf-36.
     
    Last edited: Sep 2, 2021
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  3. dreampop

    dreampop Senior Member (Voting Rights)

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  4. Hutan

    Hutan Moderator Staff Member

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    So, objective outcomes were planned, but, sadly, somehow they weren't possible. As @dreampop reminds us, this is a trial of Cortene. There is a substantial commercial interest in showing this drug is a successful treatment. Without picking through the biological justification (which may be based on faulty ideas including about cortisol levels), I think we are still in the 'very modest benefits from subjective open label trials run by people with a vested interest in the treatment being successful' territory here.


    Reaching in acronyms seems to be correlated with biased trials. Just saying.
     
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  5. Hutan

    Hutan Moderator Staff Member

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    I found it quite difficult to know how much of the drug each participant was given.

    Regarding the number of steps recorded by a Fitbit:
    Of the 14 people in the trial, 13 people had data on the change in the number of steps (as a mean of the number of steps per day for the 28 day period prior to treatment, and then the same in the 28 day period after treatment).

    Only 3 people showed an increase in the mean number of steps per day. Most didn't vary by much, and there's nothing there to suggest that the treatment made any sort of positive difference in people's daily steps.

    One of the people (Person 24) reporting an increase in the mean number of steps per day also reported a worsened total symptom score. The person reporting the second biggest improvement in the total symptom score (Person 29) reported the biggest decrease in mean change in daily steps. That is, the person had a mean decrease in the number of daily steps of 2699 steps per day (which is a major reduction in steps) while reporting a moderate level of symptom improvement.
     
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  6. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    So what? Post the ITT data anyway, since this is a pilot trial. It just sounds like excuses for not doing things properly.

    I don't find any of this compelling given it was a open label trial with no objective outcomes.
     
    Michelle, alktipping, MeSci and 6 others like this.
  7. strategist

    strategist Senior Member (Voting Rights)

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    A mean TDSS improvement of −7.5, with the TDSS asking about 13 symptoms, is a 0.57 point improvement per symptom (0= no symptom, 5 = very severe). This is underwhelming and could be purely due to nonspecific factors.
     
    Last edited: Sep 2, 2021
    Michelle, alktipping, Simon M and 2 others like this.
  8. Kalliope

    Kalliope Senior Member (Voting Rights)

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    oh my..

    press release from Cortene inc: Clinical trial provides preliminary evidence of a cure for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid

    quote:
    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.
     
  9. Braganca

    Braganca Senior Member (Voting Rights)

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    I don’t think this looks very promising unfortunately..

    The effect of CT38s on activity was variable (Table 2). For Cmax < 0.25 ng/ml, patients completed their ADL more (pre: 1.8 ± 0.6, post: 2.0 ± 0.6, p = 0.078, change: +0.2 ± 0.3 or +10.0%) and avoided PEM-inducing activities less (pre: 2.2 ± 0.7, post: 2.0 ± 0.6, p = 0.115, change: −0.2 ± 0.3 or −10.1%), but were less active by patient-reported level of physical/mental exertion (pre: 2.4 ± 0.8, post: 2.2 ± 0.7, p = 0.099, change: −0.3 ± 0.3 or −10.3%) and FitbitTM-recorded steps (pre: 5,065 ± 2,675, post: 4,670 ± 2,246, p= 0.351, change: −395 ± 1,053 or −7.8%). There was no correlation between patient-reported level of physical/mental exertion and FitbitTM recorded steps (Pearson’s correlation coefficient = 0.09 for all patients).
     
  10. Braganca

    Braganca Senior Member (Voting Rights)

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    Agree, but I’m still very very glad a biotech took the risk in investigating a drug for ME. It’s a very high risk business, and investors will lose money on this since it looks unlikely to be successful. (They’ll lose even more if they fund a second larger more expensive trial). But they took the risk, not one of our charities funded by patient dollars, so it’s good for us. At least it rules something out.
     
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  11. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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  12. Hutan

    Hutan Moderator Staff Member

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  13. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Also note, the claims that patients were more sensitive to the hemodynamic effects of the drug is not generalisable, given they are not matched cohorts - the "healthy controls" from the "Phase 1 clinical trial" were 100% male, with mean age 34.1±7.6 years, whereas this study was 57% female with mean age 43.7±9.7.
     
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  14. Braganca

    Braganca Senior Member (Voting Rights)

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    I mean — ruled out if they do a second larger trial and it fails.

    What does it matter? It’s the investors risk. It’s hard to prove efficacy, so if not effective through a series of trials, it will not be approved. This is the process for pharmaceutical development.
     
  15. Trish

    Trish Moderator Staff Member

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    I wish they wouldn't claim the outcome measures are a mix of subjective and objective, but only cherry pick one subjective outcome that showed some improvement to report in the abstract. It all looks very underwhelming to me.

    I appreciate the effort to get a clearer overall picture of symptom changes by recording daily changes in a range of symptoms, but the simple additive model gives a spurious numerical weight to some symptoms that are not generally recognised as core ME symptoms.

    For example, there is the same weight given to 5 what are normally regarded as core symptoms:
    fatigue, muscle/joint pain, sleep issues, cognitive impairment, OI,

    as to another 5 which are not normally included as core ME symptoms:
    shortness of breath, gastrointestinal function, urogenital function, anxiety and depression.

    That makes no sense to me in a clinical trial for treating ME/CFS.
     
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  16. strategist

    strategist Senior Member (Voting Rights)

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    Do the authors really believe this is promising or is it just hype meant to attract more investors? At the very least they got some experience and safety data out of this. If they keep testing this drug in other illnesses they might find one where it has more substantial effects.
     
  17. Creekside

    Creekside Senior Member (Voting Rights)

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    While the trial doesn't seem to show strong evidence to support the claims for the drug, I haven't seen any dismissal of the hypothesis for the root cause of ME. The drug might fail to work as theorized for any number of reasons. I hope that someone follows up on the hypothesis itself. Maybe some other treatment might be theoretically possible.

    I wonder about the interaction of this CRFR2 mechanism and glial cells. Glial cells support and modulate other brain cells, and may in turn be affected by CRFR2. Perhaps they form a feedback loop that can lock up. It's not a simply hypothesis to examine, since the brain has small subsets of the main types of glial cells, some of which may be localized to fairly tiny portions of the brain, and thus aren't well-studied.

    While it's unproven, I find it the most exciting hypothesis for ME so far.
     
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  18. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Really? I posted in prior threads why I disagree with their proposed hypothesis and why it doesn't match what is already known about the endocrinology of ME/CFS.

    I didn't find the mechanism proposed in the manuscript to be terribly plausible.

    They are claiming that one or two or three infusions of agonist (increases signalling) is going to magically fix a problem of increased sensitivity/upregulation of cell-surface receptor that has a short half-life. That is not how biology works.
    In principle what they should really be proposing is that they are breaking some sort of feedback loop, but they haven't provided strong evidence of pathological CRF2 upregulation in the first place, let alone proposed a plausible feedback loop that would maintain the upregulation of the receptor. They also have to explain why there is a constrained range of expression of the receptor. This is unlikely to be explained purely on a cellular level. Normally if there is impaired function due to impaired signalling of a particular pathway, there will be increased perturbation at a cellular level (and most cells have a substantial range of perturbation at their disposal) to get out of the dysfunctional steady state, else apoptosis. Now biological systems as a while might be more susceptible to dysfunctional steady state with less scope of large perturbations, so they need a proper neuroendocrine model to explain their hypothesis - which currently lacks underlying evidence.
     
    Last edited: Sep 4, 2021
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  19. dreampop

    dreampop Senior Member (Voting Rights)

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    https://www.healthrising.org/blog/2021/09/03/cortene-drug-trial-chronic-fatigue-syndrome/

     
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  20. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Given that generally, mature neurons are required to be very resistant to apoptosis, could that range of correctable perturbation be exceeded without inducing apoptosis for these specific neurons? That might differentiate ME/CFS from neurodegenerative diseases such as Parkinson's, as well as explain the limited structural changes observable on neuro-imaging.

    Would be good if this theory were true, as complete correction of the pathological state would presumably result in a cure back to baseline (downstream organ systems notwithstanding).
     

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