Trial of CT38 for ME/CFS by Cortene Inc.: big claims being made...

feeb said:
Well. At least they've had the honesty to pre-register the outcome most likely to be subject to bias as the primary outcome, instead of switching it later, I guess?
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From Cort Johnson, July 2018
"The study consists of a 4-week PRE-treatment period, a 2-week treatment period, and a 4-week POST-treatment period. Both the PRE- and POST-treatment periods will commence with a cardiopulmonary exercise test (CPET), where the investigators will record patient performance on a stationary bicycle."

https://www.healthrising.org/blog/2...ic-fatigue-syndrome-me-cfs-drug-trial-begins/

What happened to the CPET? That was the outcome measure that lent the most credibility to this study for me!
 
Rain said:
Almost seems like they have realized that their theories can’t affect PEM? ;)
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It could still hold potential if PEM is a downstream problem. For example I'm not sure how Robert Phair's metabolic trap hypothesis explains PEM any better, since it assumes certain cells flip to a trapped state and remain stuck there, whether in PEM or not.

Their theory sounds to me a bit unconvincing, but it may not necessarily mean the drug doesn't work. Lots of drugs were originally developed for a different purpose or were developed assuming a model that later turned out wrong.

strategist said:
This is beginning to look like a disaster that can be recognized from far away.
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Why is it a disaster that somebody finally got as far as performing actual trials on a drug for ME/CFS (and seems like a drug with much less side effects than rituximab and currently trialed cyclophosphamide)?
 
JES said:
Why is it a disaster that somebody finally got as far as performing actual trials on a drug for ME/CFS (and seems like a drug with much less side effects than rituximab and currently trialed cyclophosphamide)?
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No research is better than bad research, and I think it is fairly clear by now that this is bad research.

They appear to have decided that ME is accurately described by a learned helplessness / uncontrollable stress model. In particular they claim that ME involves excessive levels of a receptor called CRF2 on certain neurons in the brain that create a constant stress response. There is no evidence this true.

Van Elzakker suggests this theory could be tested by measuring receptor expression on immune cells, but instead the company proceeded straight to testing this new drug on patients.

He further says that this wouldn't be able to explain many other abnormalities in patients.

They claim that they received only positive responses from consulted experts asked to review their theory. Van Elzakker has just said that he was consulted and "shredded" it.

As another poster mentioned, the safety study included CPET but now that it has been completed, there is no mention of what the results were. There may be innocent reasons for this but outcome data that is mysteriously missing is also what you often see when the data don't support the theory of the researchers.

In my opinion the proposed illness model is inconsistent with what happens in the real world. It may seem consistent only if you know little about ME. But I'm not an expert, just an amateur with too many opinions.
 
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JES said:
I'm not sure how Robert Phair's metabolic trap hypothesis explains PEM any better, since it assumes certain cells flip to a trapped state and remain stuck there, whether in PEM or not.

Their theory sounds to me a bit unconvincing, but it may not necessarily mean the drug doesn't work. Lots of drugs were originally developed for a different purpose or were developed assuming a model that later turned out wrong.
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Yes, the metabolic trap model has issues but, pending publication, it looks like the genetic basis is so common in us that the chance of it occurring randomly in their study is one in about ten to the twelve or so. My math might be way off, could someone check it? I still don't have my math brain.

(PS Doh, example, its more like seven by ten to the eighteenth from memory, but my brain glitched. I have taught and tutored math at the university level but now it does not compute.)

However most of the issues in the tryp-trap would have to be downstream I think, and for all we know the Cortene drug might well fix that. It might not also do it via the stated mechanism.

SSRIs work on many people with depression, though often not on PWME, but it was known in the late 80s it was not due to fixing serotonin levels. We still to this day do not know for sure why it helps anyone at all. Serotonin deficiency has a marketing basis, not a scientific one.

There is no substitute for a clinical trial, but I would love to get some of these patients involved in repeat CPET testing if they claim improvement. Other tests such as Seahorse analysis and electrical impedence under cellular and molecular stress would also be nice.

Even the tryp-trap might well be mediated by this as yet unidentified blood factor. No model is yet complete.
 
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From Cortene's website, under their 'Science' tab:
Our research suggests that the upregulation of a single, stress-related receptor, CRF2, (in the raphe nuclei and limbic system of the brain) can explain the symptoms and anomalies of ME/CFS. Overstimulating this receptor induces many of the symptoms of ME/CFS in healthy animals, and we have developed a therapeutic candidate (CT38) that downregulates the receptor.

Having successfully completed a Phase 1 clinical trial (in healthy human subjects) under FDA oversight, we are planning to test CT38 in ME/CFS patients. We believe that a short course of treatment with CT38 may be curative.
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Clearly not any reliable evidence as yet then.

There are all sort of conditions sharing "many of the symptoms" of ME, which is why diagnostic criteria is so important. I wonder what diagnostic criteria they plan to use in any of their research.

People used to believe the moon was made of cheese, but as yet hard evidence has been lacking.

On their ME/CFS tab they have:
ME/CFS is one of a group of etiologically unexplained diseases, including:
  • fibromyalgia syndrome;
  • chronic lyme disease;
  • Gulf War Illness;
  • post-traumatic stress disorder;
  • atypical depression;
  • irritable bowel syndrome; and
  • others
Collectively, these have been argued to represent one underlying common basic syndrome, sometimes referred to as functional somatic syndrome or bodily distress syndrome.
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This really does not inspire confidence.
 
Being a very skeptical person I have not followed much about Cortene so I apologize if I am repeating things others have already commented on.
I see that there was to be a pre and post trial period and @Barry notes the Cortene website says they think a short course of Cortene may be curative. But their post trial period is 4 weeks. How does that give any info to claim cure - especially with the vagaries/ups-and-downs/wax-wane of ME?

Many patients note a difference when they initially start a new treatment but many ME patients I know also note that after a short period of time (perhaps a couple of months), they no longer derive any benefit from the treatment.
So with Cortene, what's to say that their trial and short follow-up is during that period of temporary improvement patients often experience, and that it's not really a cure at all?

(For quite some time I have thought that follow-up for any trials for ME should be at least 6 months because of the vagaries of this disease. Ideally I think follow-up should be longer but $$...)
 
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alex3619 said:
SSRIs work on many people with depression, though often not on PWME, but it was known in the late 80s it was not due to fixing serotonin levels. We still to this day do not know for sure why it helps anyone at all. Serotonin deficiency has a marketing basis, not a scientific one..
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Exactly, the entire model around depression was built around the monoamine hypothesis and later serotonin more specifically. To this day, there seems to be no consensus on serotonin levels and depression, I recently even read about a study that suggested anxiety is caused by too much serotonin in the brain, which goes against the entire idea of prescribing SSRIs. But to this day we don't understand why one depressed patient responds to one SSRI, a second to another SSRI and a third to none. I'm skeptical for there being one nice unifying model for ME/CFS, so while I can understand the problem with this hypothesized stress response model, it wouldn't bother me much if the drug actually turned out to be efficient for even a subgroup.
 
Barry said:
There are all sort of conditions sharing "many of the symptoms" of ME, which is why diagnostic criteria is so important. I wonder what diagnostic criteria they plan to use in any of their research.
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The following are the case definitions used for this Cortene trial:
"Diagnosed with ME/CFS and meet the following 3 case definitions: Fukuda Research Case Definition for CFS (1994), Revised Canadian Consensus Criteria for ME/CFS (2010) and the Institute of Medicine (IOM) Clinical Diagnostic Criteria for ME/CFS (2015)"

https://clinicaltrials.gov/ct2/show/NCT03613129
 
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2 things on the learned helplessness / motivation thing:

1. My motivation has never changed since as long as I can remember, I've always had very high self-motivation, no difficulty starting things, been plenty able to finish things. Zero change before and since I was ill. This is simply not a factor in this disease.

2. Association of some receptor with some psychiatric behavior is always dodgy and possibly completely wrong. As we painfully know, cherry-picking loose correlation is the bread-and-butter of psychiatry and so it's entirely possible that absolutely no part of this receptor model has anything to do with helplessness or motivation. Mouse models that have to do with motivation are shady at best and nothing of value can be concluded from them yet.

As for stress/anxiety, it's impossible to distinguish from purely physiological processes, whether from a subjective experience or, especially, for clinicians. It's all guesswork, more often than not uninformed. Peptic ulcers would still be 100% blamed on stress/anxiety/helplessness/whatever today if it wasn't for the stubborn researchers who showed otherwise.

It's almost entirely meaningless to speak of stress-related receptors other than as a possible loose association that may be any of cause, effect or cascading downstream effects from unknown related causes. As claims go, it's as much validated as bears causing Bigfoots (Bigfeet?) since Bigfoot was always "sighted" in forests, where obviously bears poop and so must be present near any Bigfoot sighting.

Still, this is not particularly encouraging unless the trial is extremely rigorous, double-blinded, placebo-controlled, as should always be the case anyway. But I would not make much of a purely speculative model based on possible loose association of things that can't be validated in any meaningful way.
 
rvallee said:
Peptic ulcers would still be 100% blamed on stress/anxiety/helplessness/whatever today if it wasn't for the stubborn researchers who showed otherwise.
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It took about 108 years after discovery of bacteria causing ulcers before Barry Marshall did his experiments. I was informed it was being discussed to suspend his medical licence because, presumably as I don't have details, he was considered a quack. In 2005 he shared the Nobel prize for the discovery. Some quack.

Hypotheses without hard evidence, without testing, are just hypotheses. Many psychiatrists have not woken up to that yet.
 
The owner of the molecule may be pumping its value for resale. One way to do this is a performative and non-substantive open-label study, make a press release and get some buzz to increase its right's of manufacture price and sell it to another entity. This guy is Garry Marshall not Barry Marshall, putting on a good wholesome show. The company is just a house.

You know why CFS researchers gave good feedback? Because they are not neuroscientists. None of them. Younger is but I do not think he has a pharmacology background, I could be wrong.

Cortene's not the problem. But not listening to Van Elzakker - no one really is. This metabolic stuff is "secret messages in the bible predicting 9/11" and I think he is getting frustrated. Turns out he can read Greek and actually so can other people.
 
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Milo said:
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I see this sometimes in creative writing. Young writers who don't read very much, or at all, think they've stumbled across some great innovation, only to discover it's really not. It's all about arrogance and not doing one's research.

Example:

Writer: I want to write about a day in the life of my protagonist, describing all the normal things they do that are left out of stories, in a stream-of-consciousness fashion.

Me: You mean exactly like the 1920s classic Ulysses by James Joyce?

Writer: I don't know. I've never read it. But mine ends with a marriage proposal and the character going through the decision-making process in their head.

Me: Yes. Exactly like the 1920s classic Ulysses by James Joyce.

Writer: But it's a magnificent, original idea! I can write about my character going to the loo.

Me: It's really not, and Ulysses* is a terrible read anyway.


*It really is awful, but I know that because I read it and studied the whole thing for a term. In other words, I did my research.
 
If the research is rigorously conducted then it largely doesn't matter what the underlying model is. I think it's worth focussing on the methods and not worrying too much about the model. High quality research should eventually lead to more accurate models.

Having said that, some of the premature hype around this has left me feeling wary. Any embrace of premature hype is likely to be unhelpful. I guess that the medical community tend to be a sceptical of claims coming from pharmaceutical companies which should limit the harm?
 
Esther12 said:
If the research is rigorously conducted then it largely doesn't matter what the underlying model is. I think it's worth focussing on the methods and not worrying too much about the model. High quality research should eventually lead to more accurate models.

Having said that, some of the premature hype around this has left me feeling wary. Any embrace of premature hype is likely to be unhelpful. I guess that the medical community tend to be a sceptical of claims coming from pharmaceutical companies which should limit the harm?
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I wish I could be as sanguine as you. The model of "learned helplessness" that van Elzakker believes they are using coupled to an ostensibly effective treatment, will strand us in an inappropriate category and kick open the door to the truly moronic "bodily distress syndrome", giving this hell spawn of a framing legitimacy. The BPS gang will just claim that they were right all along and shouldn't be excluded from sharing in the spoils of this validation.

There will be consequences if a drug that affirms a stress hypothesis is approved for M.E. Perhaps this will happen only in the short term. But I'm not optimistic about that either.

Milo said:
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