An Exploratory Drug Trial For ME/CFS

In the next month or so, Cortene, a small drug development company, will do a very unusual thing – trial a new drug in chronic fatigue syndrome (ME/CFS). The first two parts of the series on this new drug covered how ME/CFS came to the attention of Cortene, why Cortene believes ME/CFS is a possible match for its drug, and introduced Cortene’s novel hypothesis regarding ME/CFS.

Treatment Approach

The novel hypothesis proposes that a receptor called CRF2, which triggers neurons to release serotonin, has become unusually prevalent in parts of ME/CFS patients’ brains. Cortene believes that the elevated release of serotonin – in response to even small levels of stress – in turn causes ME/CFS.

In part three, we look at why Cortene thinks its CT38 drug may be able to reduce CRF2 levels, the possible side-effects of the drug, what past studies have told us about the drug, where Cortene is in the process of getting FDA approval for the trial, and the basic makeup of the trial.

A little recap…

Stress releases CRF in the raphe nuclei, which modulates serotonin in the limbic system.

Normally, low stress (low levels of CRF) acts on CRF1 receptors to inhibit serotonin; high stress (high CRF) acts on CRF2 receptors to increase serotonin.

In ME/CFS, Cortene postulates that CRF2 receptors have become stuck on the surfaces of the serotonin-releasing neurons. Now low stress increases serotonin instead of inhibiting it.

So… serotonin, released in this manner and in the limbic system is the bad actor, but only because CRF2 is stuck.

Two Approaches to De-activating CRF2

The Shotgun Approach: Blocking CRF2

If the disease is in fact driven by the presence of CRF2 on neuronal surfaces, the typical approach would be to block it with a CRF2 blocker or antagonist, similar to Humira® blocking the cytokine TNFα (which decreases inflammation, but lowers immune system defense). This might work, but the drug would have to be taken chronically, and it would block CRF2 receptors all over the body – and likely cause major side-effects – not unlike a shotgun approach to a targeted problem.

The Fine-Tuned Approach – Internalizing CRF2

Instead, and this is the really fascinating aspect of their approach, Cortene is attempting to mimic what the body does naturally to end the stress response; i.e, get the CRF2 receptors off the neuronal surfaces and buried back inside the neurons where they belong.

This kind of receptor internalization – a natural process called endocytosis – is normally triggered when the stress ends, by UCN1, an agonist selective for CRF1 and CRF2. However, Cortene believes that this process failed during the event (or events) that triggered ME/CFS (and some similar diseases). The resulting presence of CRF2 on the surfaces of the neurons means that subsequent stress, even at low levels, activates CRF2, causing rampant serotonin release in the brains of ME/CFS patients.

If Cortene’s approach works, it could theoretically restore the system to a pre-disease configuration by preventing the stress response from becoming easily activated. I asked Cortene two questions: (i) Is there any proof of this idea that CRF2 might be stuck; and (ii) if so, how might it be internalized? For that, we must now turn to Cortene’s animal data.

The Drug – CT38

Cortene’s drug, CT38, is a CRF2 agonist, i.e., it stimulates CRF2. It is comprised only of amino acids that occur naturally in the human body. It has been characterized in animal studies and in a Phase 1 clinical trial in healthy human subjects.

Is there any proof that CRF2 is stuck?

There is no animal model for ME/CFS. However, if in fact the disease results from CRF2 being overactive, over-stimulating the CRF2 pathway in healthy animals should cause the symptoms of the disease. Cortene’s animal data shows just that. High doses of CT38, delivered quickly (or by bolus, to give it its technical term), cause symptoms similar to those found in ME/CFS. The animals’ heart rate increases, their blood pressure, body temperature and gut motility are reduced, their urine production is affected, their movement is dramatically reduced, and their stress hormones are released (norepinephrine and cortisone, the rat equivalent of cortisol). These changes are temporary and revert to normal once CT38 wears off.

These findings support the idea that ME/CFS could result from CRF2 being stuck. They also suggest that once the CRF2 pathway becomes overactive, it can produce a raft of involuntary effects that ME/CFS patients experience, including some that have been confused with behavioral or psychological issues such as difficulty with movement.

How might CRF2 be internalized?

Most receptors internalize when subjected to intense stimulation. Cortene’s animal data demonstrates this: while high bolus doses of CT38 cause ME/CFS-like symptoms in healthy animals, very high bolus doses do not — likely because CRF2 has internalized. However, Cortene’s data also shows that instead of using very high bolus doses, which might be unsafe, lower doses maintained over a period of hours (by infusion) appear to internalize CRF2 without causing symptoms. If Cortene’s hypothesis is correct, this could theoretically bring the stress response system back to normal.

Cortene reports that the animal data for CT38 has been submitted to the FDA and complies with the general requirements for testing this acute (short) treatment in humans.

The Prior Human Trial

CT38 has been tested in a Phase 1 clinical trial in humans. This trial exposed healthy subjects to a single bolus dose, which was successively raised in subsequent groups of subjects. The purpose of the trial was to determine the point beyond which side-effects become unacceptable (known as the maximum tolerated dose) and whether these side-effects were similar to those seen in animals. (As often happens with these trials, the results contain proprietary, unpublished data, but Cortene reports that the full 4-volume study report has been submitted to the FDA.)

Encouragingly, at the bolus doses tested, the side-effects in rats and humans were the same and consisted of two easily monitored effects: temporary increases in heart rate and decreases in blood pressure.

Similar Approaches

Cortene is not the first drug company to attempt to internalize receptors on a cell. An FDA approved drug, Leuprolide™, prevents prostate cancer progression by causing a receptor in the reproductive system to internalize. With the receptor gone, the cell can’t be triggered to release the hormones that spur further tumor growth.

Without continuous Leuprolide™ treatment, however, the receptor re-emerges. Cortene doesn’t believe this will happen with CT38 because, unlike the reproductive system, the limbic system (that CT38 affects) is dynamic in nature; i.e. it’s designed to have CRF2 internalize, come up to the surface, internalize, and so on, in response to intermittent stress.

The Upcoming Clinical Trial

In 2017, Cortene pulled together a small but experienced drug development team (Hunter Gillies, Sanjay Chanda, Michael Corbett) that has been involved in prior drug approvals.

Hunter Gillies, who is an MD and an exercise physiologist, was instrumental in helping a team obtain drug approval in a disease that faced some of the same roadblocks in the drug development world that ME/CFS faces. Not much was known about that disease (it was rare), its cause was unclear, and it lacked widely accepted clinical endpoints to test. The team used cardio-pulmonary exercise testing (CPET) to get regulatory approval for that drug.

Sanjay Chanda ran drug development for a company – later acquired by big pharma – which pioneered a new boron-based, as opposed to carbon-based, approach to drugs. Chanda is a toxicologist by training and is highly knowledgeable in the preclinical side of the drug development process (animal studies, chemistry and formulation, etc.). Michael Corbett is experienced at outreach in online communities, which could be helpful in mobilizing the ME/CFS community if the drug works.

Cortene is currently working with different vendors to make CT38 and to produce the sterile formulation for patients. They are also working with several labs to ensure appropriate medicinal chemistry (e.g., confirm CT38 selectivity and potency for CRF2, test material biocompatibility, enable measurements of the levels of CT38 in patients’ blood during treatment, etc.).

Most importantly, they have convinced one of the most respected physicians in the ME/CFS community to conduct the trial. If all goes well, the trial will start in the second quarter of 2018.

The FDA

Cortene is gearing up to seek FDA and institutional review board (IRB) approval for a Phase 1/2 trial. The trial is Phase 1 because Cortene is testing tolerability and dosing; and it is Phase 2 because efficacy and tolerability can only be tested in patients.

This proof-of-concept trial will be filed under what is known as a physician-sponsored investigational new drug (IND) application. FDA/IRB approvals ensure that all the boxes are checked; i.e. that the drug has been through appropriate animal testing and meets drug manufacturing standards, and that the trial design is safe for patients (or as safe as can be in early-stage research).

Such approval typically takes one month – only after FDA/IRB approval can the study commence. Cortene is beginning the approval process and hopes that the trial can start in late April.

The Trial Basics

The trial will take place under the supervision of Dr. Lucinda Bateman and Suzanne Vernon PhD at the Bateman Horne Center (BHC) in Salt Lake City, Utah. (The trial is not open for enrollment yet). Dr. Bateman came to the ME/CFS field after her sister got sick with the illness. She has focused her practice on ME/CFS and FM since 2000 and has supervised many clinical trials.

Suzanne Vernon, the research director for the Bateman Horne Center, is the former research director for the Solve ME/CFS Initiative and a CDC researcher. At the SMCI she conceived the first ME/CFS Biobank and “built” the Research Institute Without Walls (RIWW) program which emphasized collaboration and data sharing and brought many new researchers into the field.

It has been fun to get to know the Cortene team and work with them. They all bring different expertise to the table, they are all crazy smart and (most important) they push the envelope. I am super excited that Dr. Lucinda Bateman is the Principal Investigator and the Bateman Horne Center is sponsoring this trial. The team at the Bateman Horne Center has extensive experience running clinical trials and we are super excited to apply our clinical research expertise to CT38 for ME/CFS. I am personally excited about this trial because as you noted in the first blog of this series the CT38 mechanism of action is in line with my HPA axis research. – Suzanne Vernon

(In 2009, Vernon and Broderick published a modeling paper which suggested the HPA axis could be quickly reset in ME/CFS.)

The trial will test 3 dose-levels, each in a different group of patients. The initial group will receive the maximum tolerated dose determined in the prior human trial (i.e., the dose at which only acceptable side-effects were reported). However, instead of using a bolus dose of the drug, the drug will be slowly infused over time. The dose-level will be increased in subsequent patient groups, but only if there are no clinically meaningful side-effects at the previous dose-level.

Drug Testing

Cortene will use the most rigorous test of their drug imaginable in this disease – a cardio-pulmonary exercise test (CPET) using a stationary bicycle. (Most trials in ME/CFS have employed self-report measures to assess treatment effectiveness.) The exercise test will be done before and after treatment and will measure oxygen consumption, ventilatory efficiency, work done, time to reach anaerobic threshold, and other metrics.

If I understood it correctly, because exercise capacity is affected by altitude, some altitude requirements may be necessary. The trial will include 18 patients from the Salt Lake City/Utah or similar areas. If this proof-of-concept trial is successful, it will probably warrant larger studies in other locations (and altitudes).

Cortene will also use self-report measures (i.e., daily visual analog scores for fatigue, pain, sleep, cognition, flu-like symptoms, headaches/sensitivities, shortness of breath, gastrointestinal symptoms, anxiety and measures of post-exertional malaise or PEM), as well as continuous monitoring via Fitbit™ and a daily online cognitive test, but their inclusion of an exercise stressor raises the bar on the trial significantly.

If Cortene can move the needle on ME/CFS patients’ ability to exercise, and/or reduce the burden of PEM, it will have proved it can crack probably the toughest nut in this disease. I asked Cortene why they chose such a difficult test as an endpoint?

It all comes down to serotonin. As explained in Part 2 of this series, serotonin increases motor neuron excitability, but too much serotonin (emanating from the raphe nuclei at the top of the brain stem) inhibits motor neuron signals (via 5HT1A receptors on the motor neuron, where it emerges from the cord). During CPETs, ME/CFS patients’ muscles show reduced oxygen uptake relative to healthy subjects (Vermeulen 2014, Vermeulen 2010). Most researchers have taken that to be evidence of a hypometabolism but Cortene believes it may result from inhibited motor neuron signals.

In other words, it’s not that the muscles cannot function because they aren’t getting enough oxygen, glucose, etc.; it’s that the muscles aren’t being triggered to function, so they don’t take up oxygen, glucose, etc., which in the longer term may lead to hypometabolism and muscle atrophy. Removing the excess of serotonin in the cord by causing CRF2 to internalize should, theoretically, resolve the cause of this problem.

Questions

Permanent System Reset?

I asked Cortene why they believe the receptors are getting stuck on the surface of the stress response neurons in the first place, and why they wouldn’t return to their maladapted position once the drug has been stopped?

Cortene stated that they believe that at least one of two conditions are necessary for the CRF2 receptors to become stuck. Either the patients have been exposed to a great deal of prior stress, which has eventually caused the receptors to remain at the neuronal surfaces, and/or they have a genetic predisposition to a more intense than usual stress response.

Several ME/CFS studies (see Pt 2 of this series) suggest a genetic predisposition to an unusually strong stress response may be present, which could manifest in two different ways. Higher than normal levels of stress mediators (e.g. CRF2, CRF1, serotonin, the cortisol receptor, ACTH) may be produced in response to stress, and/or the ability to break down stress mediators (such as serotonin, norepinephrine, dopamine) to return to baseline may be inhibited.

If CT38 successfully internalizes the CRF2 receptors, Cortene believes it should eliminate the maladaptive dynamic that has caused the system to become “stuck”. Because the drug will not change the patients’ genetic predispositions, ME/CFS patients could be at risk from another stressor that causes these receptors to become stuck again.

Since most ME/CFS patients were normal prior to the stress episode that caused the maladaptation, however, Cortene believes it was the intensity of that stress that brought about the dysfunction. That would suggest that avoiding similar stresses might allow one’s stress response system to avoid “getting stuck” again. Plus, if the drug works and an intense stress caused another maladaptation, the patient could, of course, be treated again — although additional research with CT38 would be required.

Targeting Neurotransmitters?

Thinking about their hypothesis and its prediction of increased norepinephrine in the limbic system, I asked Cortene about the failure of the ME/CFS Clonidine trial. Clonidine, after all, reduced norepinephrine levels in adolescent ME/CFS patients, but it not only failed to improve symptoms, it actually made the adolescents worse.

Cortene acknowledged that clear evidence of norepinephrine dysfunction in ME/CFS (e.g. antibodies for adrenergic and muscarinic cholinergic receptors, dysautonomia, elevated plasma norepinephrine) exists, but laid the failure of the Clonidine trial on a lack of specificity.

Clonidine, they reported, is a dirty drug that binds to multiple receptors. It was developed to reduce blood pressure, which it is thought to do by acting on the I1 receptor. It was used in the trial because it is known to reduce norepinephrine in the blood, but because Clonidine also activates the alpha2 receptor, it should theoretically increase norepinephrine in the limbic system. This could explain the trial results.

It is important to understand that, unlike the blood, the brain is not a transport system, and the neurotransmitters (like norepinephrine or serotonin) vary from one neuron to the next. This is why an SSRI, which indiscriminately blocks the serotonin transporter on all neurons, cannot possibly modulate the serotonin system and its 15 sub-receptors without inducing numerous side-effects.

So why is CT38 different? First, Cortene reports that it was tested against a large panel of receptors, transporters and ion channels, and was found only to bind to CRF2; i.e. it is highly selective for CRF2. Second, while CRF2 receptors are found all over the body, Cortene’s hypothesis predicts that these receptors are in excess only in the limbic system, which CT38 will target and hopefully internalize. CT38 will also reach CRF2 receptors elsewhere, but any receptor internalization, in non-adaptive systems, is likely to reverse (like the receptors Leuprolide™ targets). This is supported by the animal data, which showed no obvious loss of effect even over months of continuous dosing. Finally, if receptor internalization occurs and persists, CT38 would not have to be taken chronically.

An Experimental Drug

Cortene cautions that CT38 and their approach are highly experimental with all that that implies. Animal and human data suggests that the drug is safe, but because no animal model for ME/CFS exists, it’s impossible to predict how it will fare in ME/CFS patients – who can be notoriously hypersensitive to drugs.

This Phase 1/2 study should help us understand whether the drug can improve function or symptoms in ME/CFS patients. Cortene’s hypothesis, that the CRF2 receptor activity is causing or contributing to ME/CFS is, however, just that – a hypothesis – as it’s impossible to measure CRF2 levels without doing a biopsy. Cortene’s hope that a slow infusion of the drug will more or less permanently reset the stress response system in ME/CFS is untested as well, and Cortene is unaware of a drug that has produced the kind of system reset that they hope will occur.

FDA and IRB approval will hopefully come in the next month or so.

Please note that the trial will not be open for enrollment until after FDA and IRB approval.

The 4th Cortene blog will announce the opening of the trial and provide the next steps if the trial is a success. The 5th blog will provide the results of the trial.

Stay tuned for a focus on the Bateman-Horne Center over the next couple of weeks.

The Cortene Chronic Fatigue Syndrome (ME/CFS) Drug Trial Begins

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