Cortene’s appearance in the chronic fatigue syndrome (ME/CFS) world a couple of years ago was like a breath of fresh air. The small drug company wanted to do something unusual in the annals of this neglected disease – run a clinical trial – and not with a drug anyone was familiar with. They weren’t trying to repurpose a drug used for other diseases: instead, they proposed testing a novel drug not being offered in any other disease.
We last heard from Cortene almost two years ago when they announced the results of the 14-person InTime trial which took place at the Bateman Horne Center between July 2018 and April 2019.
Since then, one change has affected me personally. In 2019, I was a blogger reporting on Cortene’s efforts – now I’m a member of Cortene’s advisory board. That means that should Cortene make it through the long and treacherous drug approval road and become an FDA-approved drug for ME/CFS, I could financially benefit. My commitment is to be as objective as possible and support Cortene’s efforts, as I have supported other efforts that have the potential to help people with ME/CFS.
In 2019, Health Rising reported that Cortene had concluded that its drug, CT38, was safe, that its hypothesis – that the CRFR2 receptor was involved in ME/CFS – was validated, and that the limited CT38 doses given in the trial could bring about a lasting improvement in symptoms.
Now we have the full deal – a peer-reviewed paper detailing exactly what happened. Strap yourself in – you’re in for a kind of wild ride.
The title, “Acute corticotropin easing factor receptor type 2 agonism results in sustained symptom improvement in myalgic encephalomyelitis / chronic fatigue syndrome”, doesn’t indicate how novel Cortene’s approach is, but it does present something rather unusual: it states that the treatment delivered “sustained symptom improvement” in ME/CFS, and you don’t see that every day.
The CT38 trial is specifically about myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) but it’s also potentially about other chronic disease states. It’s all about “homeostasis” – the ability of the body to respond to a threat and then return to a normal resting state. Cortene believes the pathway they’ve targeted – the CRFR1/CRFR2 pathway – plays a special, even fundamental role in homeostasis.
Cortene became particularly interested in ME/CFS because it presented the most extreme case of “dyshomeostasis” they could find. Where else, after all, do you find dramatic declines in functionality, such difficulties responding to stressors such as exertion, mental activity, even such seemingly innocuous things like lights or sounds?
Cortene believes a neuronal “switch” exists in the limbic system which turns the threat response on and off. The switch is found in the corticotropin-releasing factor (or hormone) system which regulates serotonin. Two receptors – the CRFR1 and CRFR2 – are involved.
Under minor stress or at baseline, CRFR1 dominates; sitting on the surface of GABA-producing neurons, the CRFR1 receptors trigger the release of GABA – a neurotransmitter that inhibits serotonin. During these low-stress periods, CRFR2 is inactive and remains embedded inside serotonin neurons.
Under high (or prolonged) stress levels, the two receptors switch places. CRFR1 drops inside the GABA neurons and goes dormant. CRFR2, on the other hand, pops up onto the surface of serotonin-producing neurons and triggers the release of serotonin.
Once the stress/threat is resolved, the CRFR2 receptors should drop back into the neurons and the CRFR1 receptors should return to the surface – thus restoring the calm state one usually associates with health.
Cortene doesn’t believe that happens in ME/CFS. They believe the CRFR2 receptor remains upregulated, leaving the stress response system in a hypersensitive, easily-provoked state – which can have major consequences. From the metabolic to the autonomic, to the immune, to the endocrine systems, the authors cite papers demonstrating the wide reach of the CRFR1/CRFR2 system. They believe everything from movement problems, to energy issues, to stimuli sensitivities, to the cognitive and emotional ramifications of ME/CFS, could potentially be caused by an upregulation of this system. Because the upregulation exists on the neurons, the type of symptoms any one person with ME/CFS experiences would depend on which neurons are affected.
The fact that we can’t actually measure what’s happening with the CRFR1/CRFR2 switch Cortene is attempting to turn off means problems with it will not show up in the blood tests – which, potentially fits ME/CFS – the disease that perpetually seems to fall between the cracks – quite well. The only way to assess if CRFR2 has been turned on or off is to hit it with a drug. Fortunately, CT38 is a good drug to do that as, so far as we know, it only interacts with CRFR2. If an effect with this drug is seen then, we can assume that it was because CT38 impacted CRFR2.
Cortene chose an interesting way to damp down what they believe is an overactive CRFR2 pathway. Instead of using an antagonist to block the pathway – as is usually done – their objective was to use an agonist to overstimulate the pathway.
It might seem strange to attempt to overstimulate an already hyped-up pathway, but that approach simply takes advantage of how neurons function. If they get overstimulated, they basically fold; i.e. they turn themselves off. Faced with the CT38 agonist, the neurons should move the CRFR2 receptors back inside the cell – returning it to its normal resting state – and turning off a multitude of problems.
Cortene’s approach is different, but it potentially has some real advantages. Pathway blockers (antagonists) may stop the final expression of the pathway, but because they don’t turn it off, they often need to be taken for life. An agonist which overstimulates the pathway, on the other hand, might allow it to reset itself and return to a healthy state.
The 14-person open-label trial took place at the Bateman Horne Center under the direction of Dr. Lucinda Bateman and Suzanne Vernon Ph.D. With some animal trials and just one human trial done, Cortene didn’t have a lot to go on regarding dosing, and several dosing regimens were tried. The total exposure to the drug each person would receive was estimated from animal studies. Four dose levels were used in the trial. In general, treatments consisted of three, 3.5-hour infusions.
The primary endpoint compared the mean 28-day total daily symptom score (TDSS) before and after treatment. The TDSS consisted of 13 individual, patient-reported symptoms, each assessed daily throughout the trial. The 36-Item Short Form Survey was also done. Metrics taken from a Fitbit (activity, heart rate, sleep) were taken (but the trial ended up being too small to use them).
Of the 14 people in the trial, one discontinued the drug after the first treatment produced headaches, dizziness, flushing feelings, shortness of breath, and some other symptoms, but remained in the trial until the planned exit. Another had a problem giving blood samples, and received only 2 treatments (instead of 3), but remained in the trial until the planned exit.
This was an exploratory study in several ways. The first goal was to determine that the drug was safe. Next, the investigators wanted to learn if it had the potential to be effective. They also wanted to get some idea about dosing. Determining optimal dosing was out of the question – the trial was too small for that – but observing how people with ME/CFS reacted to the various doses given turned out to be illuminating.
The twist came learning how to properly administer the dose – a key objective of the trial. Providing more of the drug achieved better results – so long as it was done in the right way.
Providing higher doses of the drug (concentrations>0.25 ng/ml) over shorter periods of time didn’t work. Providing lower doses of the drug (<0.25 ng/ml) over longer periods of time did. When giving the drug in smaller amounts, Cortene was able to provide the drug for longer and get better results (26% improvement -mean TDSS). The same was true with regard to the SF-36 functional status assessments. (It should be noted that only ten people in the study received what turned out to be the correct dose; i.e. Cortene attempted to get statistically significant results – and did get them – from a quite small sample size – not an easy thing to do. )
Imagine a beaker (the neuron), filled with a liquid, whose level represents the degree of CRFR2 activation present. Overstimulation is achieved by filling the beaker. The almost full beaker in ME/CFS overall, and in the more severely ill ME/CFS patients, in particular, should only require a small amount of liquid to fill the beaker; i.e. the worse off you are – the less of the drug you need.
When the drug was given in this manner, the more severely ill patients saw – as expected – more symptom improvement with less of the drug. This also explains why people with ME/CFS reacted more strongly to lower levels of the drug than did the healthy controls in a prior study. The ME/CFS patients’ CRFR2 receptors were already primed, so to speak, to respond to the drug.
This unusual pattern suggests that something is indeed up with the CRFR2 pathway in people with ME/CFS. Hunter Gillies, MD, InTiME’s medical monitor, asserted that, “These data support there being a pathological hypersensitivity in the CRFR2 pathway.”
Note that this runs opposite to what happens with most drugs. More severely ill patients usually need more of a drug – not less. This is a counterintuitive result that obviously messes with some of our medical norms. Given that ME/CFS seems to mess with just about all our medical norms, perhaps it’s fitting that a drug that does the same had a positive effect in this trial.
The authors believed that the side-effects initially seen – almost all of which reflected ME/CFS symptoms – resulted from the CRFR2 problems that were already present in ME/CFS. Once the investigators were able to determine the proper dosing over time that worked for patients, the side effects virtually disappeared.
CT38’s half-life in the body is only 1.5 hours, and is essentially gone from the body after six or so hours. Dr. Bateman’s follow-up data (from 1 to 2-years) from 9/14 study participants suggested that some long-term shifts in the CRF2 pathway may have occurred. They reported subtle but recognizable long-term improvements in a wide range of symptoms (sleep, brain fog, appetite, activity, and PEM (crashed less often, recovered more rapidly).
While the participants are clearly not over ME/CFS, that’s not a bad result for a couple of first-time treatments done over a year ago in a small exploratory study of a novel drug that’s never been tested in ME/CFS before. Dr. Bateman MD, one of the co-authors of the paper, and the principal investigator in the clinical trial, reported:
“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. In fact, a few patients expressed a desire for ‘just a little bit more drug’.”
- Several years ago, Cortene presented the ME/CFS community with a surprising commitment – to produce a clinical trial using a novel drug.
- They proposed that a key stress response pathway called CRFR1/CRFR2 had become dysregulated in ME/CFS and was producing a hypersensitive, easily provoked stress response.
- They believe that the surfaces of serotonin-producing neurons in ME/CFS had become overloaded with CRFR2 receptors – causing them to fire at the slightest stimuli. These twitchy neurons could be affecting systems across the body. Cortene proposed that the kind of ME/CFS one has might depend on which neurons are affected.
- Cortene’s unusual approach was to take advantage of an interesting neuronal property: they would attempt to overstimulate the neurons with CT38 – which should cause them to stand down and allow a healthy state to resume.
- This is strikingly different from how many drugs work, which try to block the pathway in question. That course, however, leads to a chronic drug regimen that essentially never stops. Cortene, on the other hand, hoped to reset the pathway in hopes that it would remain in a healthy state.
- Since Cortene presumed that the neurons of the most severely ill patients were the most activated of all, it stood to reason that the more severely ill patients would need less of the drug, while the less severely ill needed more.
- The 14-person, open-label trial done at the Bateman-Horne Center was done to determine if the drug was safe, if it might have efficacy, and to learn about dosing regimens. Several different dosing regimens were tried. In general, the trial consisted of three several hour-long infusions.
- The study found that more of the drug was better – but only if the drug was administered in a certain way. Providing higher amounts of the drug over shorter periods of time produced side effects. Providing lower amounts of the drug over longer periods of time did not produce side effects and resulted in symptomatic improvement.
- When the drug was given properly (a smaller concentration of the drug over longer periods of time), patients reported about a 25% improvement of symptoms. Dr. Bateman indicated that many of the participants reported subtle but noticeable improvements of their symptoms over the 1-2 years following the trial. Dr. Bateman called the study results “encouraging”
- As Cortene suspected, more severely ill patients needed less of the drug to receive improvement than did less severely ill patients.
- The trial provided validation for Cortene’s hypothesis that the CRFR1/CRFR2 pathway was, as Dr. Hunter Gilles put it, “pathologically dysregulated” in ME/CFS.
- In an interview, Cortene proposed that partial downregulation of the CRFR2 receptor had indeed occurred, and that further trials would determine if they could fully return it and the stress response system in ME/CFS to a healthy state.
- Cortene hopes to embark on a 60-person $4 million trial next.
- Please note that my situation with Cortene has changed. Two years ago, I was a blogger reporting on their efforts. Now I am a member of the Cortene Board. That means if Cortene were to get FDA approval for their drug, I could benefit financially. My goal is to be as objective as possible.
“Cortene worked long and hard to raise the money to fund InTiME. I hope this paper piques the interest of many and makes it easier to raise money for a larger trial. I also hope the results of this trial get the attention of pharmaceutical companies to show them that treatment trials for ME/CFS are possible, feasible, and urgently needed.”
There’s also the broader issue of whether Cortene’s approach could ultimately be applied to a broad swath of chronic diseases that feature “disturbed homeostasis” including fibromyalgia, long COVID, and many others. The potential reach of the serotonergic system is so broad that a dysregulation could impact many systems. This is the first time, I believe, that anyone has directly attempted to affect this system in this way.
The trial demonstrated that CT38 is safe, suggested that the CRFR2 pathway is indeed impacted in ME/CFS and that the drug has promise. Larger studies with more extended dosing regimens are needed to determine how effective this unique approach to ME/CFS may be.
How did you latch onto CT38 in the first place? Were you thinking in the broad terms that you are now – of a drug that might have the potential of restoring homeostasis in stress-response disorders?
Not at all. CT38 had been shown to prevent muscle wasting, but by an unknown mechanism. The search for the mechanism, led to fundamental biology involving control of calcium, and a vast body of literature on the CRF system, and its control of serotonin (misunderstood to be the ‘happy hormone’) in the limbic system (historically relegated to an emotional role). Further studies showing that various body systems input into, and receive output from, the limbic system led to the ideas expressed in our paper, and partially ratified by the trial (and supporting animal and Phase 1 data).
Can you explain how CT38 is different from other drugs you’ve worked on and what challenges it presents?
The last 40Ys of drug development have focused primarily on the development of drugs for chronic conditions. The paradigm involves identifying an abnormality in a bodily fluid (e.g., cytokines in the joint of a patient with rheumatoid arthritis), and then masking this with a drug (an antibody in the case of the wayward cytokines).
Three caveats: (i) the reason for the joint cytokines remains unresolved, so the drug has to be taken chronically; (iii) the chronic use of the drug results in drug concentrations in the body that optimize between efficacy and side-effects, so greater efficacy is not possible (e.g., 35-39% of patients achieve at least 50% improvement in the number of tender/swollen joints, versus 8-10% with placebo), and (iii) the patients exhibit other symptoms unrelated to joint cytokines that are not resolved by the cytokine-masking drug, and may require other partially effective and side-effect-limited drugs.
This is critically different with CT38. It attempts to remove the cause of symptom and is not side-effect limited. The treatment was limited by the planned number and duration of the infusions, which had been estimated without an animal model.
The small trial resulted in improvements – some potentially long-term – but didn’t produce earthshaking results. Are you satisfied with it?
The results were dose-dependent, which, with caveats for the small trial, suggests biology over chance. Of course, we would have preferred larger improvements, but it must be remembered that a therapeutic based on removing a receptor from a neuron (or cell) has never been done, and so we were delighted to see an effect, more so because the results shed light on the dosing paradigm. The next step is a larger trial (60 patients), with a now known dosing paradigm.
The goal was to reset the CRF system, turning off the CRFR2 receptors and allowing the CRFRI receptors to return. The hope was that a permanent system reset could result. If that’s possible how would that occur?
With caveats for small numbers, the trial showed that a peptide which only binds to CRFR2 and only lasts hours in the body, was still having effect 2 years from treatment, suggesting partial, but not full, CRFR2 downregulation. We project that at the right dose, the treatment will achieve full CRFR2 downregulation.
What’s the status of CT38 now? Do you have funding for the next study and what would it look like?
We are seeking $4 million to conduct a 60-patient trial in possibly 2 indications.
More on Cortene
The Cortene Series on Health Rising
- Cortene I: The Cortene Way – New Drug to Be Trialed in Chronic Fatigue Syndrome (ME/CFS) Soon
- Cortene II: A New Drug & A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)
- Cortene III: A New Drug for Chronic Fatigue Syndrome (ME/CFS): The Clinical Trial
- The Cortene Chronic Fatigue Syndrome (ME/CFS) Drug Trial Begins
- Cortene to Move Forward on New Drug for Chronic Fatigue Syndrome (ME/CFS)
- The Cortene Drug Trial Results for ME/CFS Are In
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