Research funding for chronic fatigue syndrome (ME/CFS) has been poor at best but clinical trials have elicited a wholly different degree of disappointment altogether. Few clinical trials are ever done and those often involve alternative approaches. The six active clinical trials listed in clinicaltrials.gov, for instance, include treatments like acupuncture, moxibustion, oral rehydration and CoQ10.

That makes it shocking to see a “new” drug – a drug not being used in other diseases – get a clinical trial in ME/CFS. It wasn’t supposed to happen this way. First, it’s been assumed that repurposed drugs – drugs already in use in other disease – would be tested in ME/CFS to improve symptoms – and only later, as we understood the disease better, would we get to a drug that gets at the core problems in ME/CFS. This group believes they have a drug that gets at the core of ME/CFS now, and in the first quarter of this year they expect to test that drug.

Over the next month, Health Rising will be publishing a 3 or 4-part blog series telling the story of the small group of researchers that are bringing a drug to ME/CFS they believe could get at the core of this disease.

The drug itself is highly experimental and the researchers behind it come from the biotechnology and drug development fields. They stumbled on ME/CFS by chance, but when they did, the light bulbs went on. For the past year or two, they’ve devoted their time to understanding ME/CFS and getting to the place where a clinical trial can take place.

It’s important to realize that these researchers/investors – like all good researchers/investors – are essentially agnostic regarding which disease to test their drug in. They’re fully aware of the history of neglect in ME/CFS and my sense in talking to them is that that neglect, and the opportunity to provide help to such an underserved community excites them.

Their decision to spend the time, money and effort to test this drug in chronic fatigue syndrome is not because of the great need ME/CFS patients are in, but because this is the disease they believe this drug will work in. In order to come to that conclusion, they’ve explored ME/CFS very carefully.

The upshot of this very different approach (for us anyway) is that, while this drug is new, it probably enjoys a more robust theoretical foundation than any other drug that’s been tested in ME/CFS. That provides, at least for me, some reason for hope.

The group has flown under the patients’ radar but have not hid their light under a bush. Over the past year they’ve conducted an impressive outreach program – a kind of learning and enrolling tour – communicating with several major ME/CFS doctors and researchers across the country. None, they report, have been able to find any flaws in their hypothesis and all agree that their drug should be tested. The trial is expected to take place in the first quarter of this year at a well-known ME/CFS expert’s clinic. (The details of the trial will be released in the last blog.)

The upshot is that to virtually everyone’s surprise, a new and experimental drug will soon be tested in chronic fatigue syndrome (ME/CFS). It’s a fascinating story. Enjoy…

Part I – Beginnings and the Hypothesis

Part II – The Hypothesis Pt. II

Part III – Treating ME/CFS and the Clinical Trial

A New Hypothesis on the Cause of ME/CFS – Part 1/3

Gerard Pereira didn’t know much about chronic fatigue syndrome (ME/CFS) but what he was hearing was setting off all sorts of bells and whistles in his head. Sometime before, he’d come across an intriguing drug (CT38) being developed by the pharmaceutical division of Proctor & Gamble. CT38 prevented muscle wasting in animals, and it had been through a Phase 1 clinical trial and tested safe in healthy humans.

Despite the promising test results, after Proctor & Gamble decided to exit the drug industry entirely, CT38 was left available for licensing.

Pereira had been tasked with finding promising new drugs and he liked this one. Despite strong animal data, though, Pereira’s employer wasn’t interested. The commercial potential, they felt, just wasn’t there. One population CT38 might help (people on mechanical ventilators) was hard to study and short in supply. A chronic disease like muscular dystrophy might fit the bill, but would require big money for long-term animal safety studies.

Pereira, though, was intrigued. CT38 targeted the stress response – a system getting a lot of attention, and it appeared to impact inflammation – a bigger and bigger concern all the time. Plus, the animal data was really good. Eventually Pereira decided to license the drug and start his own company, Cortene Inc. He and his partners (Sanjay Chanda, Hunter Gillies, Michael Corbett) would try to develop the drug themselves.

Pereira was at a cocktail party discussing his drug with a well-known Stanford doctor, who was talking about some immune findings in a strange disease called ME/CFS. Pereira had not heard of the disease before, but the immune findings, and ME/CFS in general, seemed eerily reminiscent of the data he’d seen produced for CT38.

Pereira took a deep dive into the ME/CFS literature. The more he saw, the more he liked the fit. He was particularly taken by four facets that seemed to separate ME/CFS from other diseases: the diversity of the apparent triggers, the unusual suddenness with which the disease often appeared, the gender imbalance, and the wide range and variability of symptoms – both across patients and over time. Explaining those four facets, he thought, might lead to the cause of the disease. Most of the current hypotheses couldn’t. Could he?

Take the idea that a pathogen or an immune system issue was the key culprit. Could either explain how a healthy person – often a female – could be turned into an invalid, sometimes overnight? He didn’t think so. Too many different pathogens had been connected to ME/CFS for one pathogen to do it, and pathogens usually affected both genders equally. Plus, no one had been able to definitively show a pathogen was still present and/or still responsible for the symptoms seen in the chronic phase of ME/CFS.

The immune system was certainly involved, but the patient stories he’d heard suggested that the disease happened too fast for the big guns of the immune system – which took time to get worked up – to take down a patient so suddenly. Too many people with ME/CFS caught a cold, and then were suddenly floored by the illness, for that to make sense. He didn’t think the metabolic ideas sweeping the field fit the bill either. Metabolic changes were certainly present, but a rapid metabolic breakdown that happened predominately in females was hard to explain.

Instead, he thought the initial insult (infection, stress, etc) must have caused changes in some integral system; a system able to touch the immune and autonomic nervous systems and ultimately even glucose metabolism .

An adaptation (or perhaps maladaptation) of the limbic system that determines our responses to stressors like infection, trauma, emotional distress, etc., could fit the bill. The limbic system had been considered in ME/CFS for decades, but no one had ever proposed a drug for it.

A change to the stress receptors governing those responses could happen very quickly. When it did, Pereira thought it would push the immune system in exactly the way it’s showing up in ME/CFS – and impair patients’ ability to fight off infection. That made sense given the Dubbo study reports that more severe, difficult to fight off infections, tend to trigger ME/CFS. It could also affect the autonomic nervous system, and eventually impact the glucose metabolism. The more he looked, the more he liked the idea that alterations to the stress receptors in the limbic system could explain ME/CFS. These were the same stress receptors that CT38 was designed to work on.

The HPA axis received a good deal of study in ME/CFS early on, but the results weren’t always consistent, and interest had waned somewhat over time. Still, the axis had a way of popping up. Gordon Broderick’s models suggested issues with the HPA axis could explain the gender imbalance in ME.CFS, and Dr. Bateman had proposed that ME/CFS might be an inflammatory disorder centered on the hypothalamus. Just a month ago, a study suggested an immune-neuro-endocrine interaction might be causing the fatigue in ME/CFS.

The main endocrine finding in ME/CFS was low cortisol (hypocortisolism). Hypocortisolism also occurs in chronic stress, where the initial excess of cortisol becomes low cortisol over time – and the development of something like cortisol sensitivity.

Pereira thought the HPA axis might be able to explain the gender imbalance issues as well. Women have more stress receptors than men, and another part of the hypothesis (covered in the next blog) fits women particularly well. Because the stress response is intended to take control and divert resources to/from critical/non-critical functions, it impacts most of the systems in the body. All in all, Peireira thought HPA axis issues could explain the wide range of symptoms in ME/CFS.

Long-Term Illness – Short-Term Treatment?

There was still the long-term animal safety data problem, though. CT38 had been developed initially for short-term use and gathering long-term animal safety data would be prohibitively expensive. How could a drug with short-term animal safety data be applied to a chronic, often life-long, illness like ME/CFS?

Now comes the most intriguing and exciting part of Pereira’s hypothesis. Pereira doesn’t need long-term animal safety data because he doesn’t plan on doing long-term treatments. If his hypothesis is correct, he believes CT38 will be able to reset the limbic system almost as quickly as it fell off the tracks in the first place; i.e., a couple of treatments might be enough to return the system to normal and begin the healing process.

If the idea of a more or less instantaneous reversal after decades of illness seems like some sort of fairy tale, consider that Suzanne Vernon and Gordon Broderick proposed something similar about ten years ago. Their model suggested that an HPA axis reset – by dramatically lowering cortisol levels for a short period of time – could cause the system to spontaneously reset.

This is not to say that over time other medical issues haven’t shown up in some ME/CFS patients that could complicate their situation. That’s to be expected in any decades long disease. If Pereira and Cortene are right, though, the core of this disease might be amenable to a dramatic change.

Part 2 will examine Cortene’s hypothesis in greater detail and show how it attempts to explain the many symptoms and anomalies of ME/CFS. Part 3 will explain the treatment approach and provide details on the upcoming clinical trial. (Health Rising is not affiliated with Cortene in any manner.)

To sum up – With the help of a physician, well-known within the ME/CFS community, Cortene will be conducting a small proof-of-concept trial, at a single site in the US. The details will follow, but the trial design is intended to obtain a rapid, objective assessment of their drug, and they will release the data as soon as possible. They reiterate that this is early-stage research and that caution is appropriate.

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