All posts by Cort Johnson

Through the “Valley of Death”: Dr. Pridgen, Fibromyalgia and the Looming Trials

First there were the anecdotal reports – FM patients were not just getting better but some, and not just a few, were getting well using something entirely new – an antiviral protocol, of all things, created not by a pain specialist or rheumatologist but by a surgeon.

Aside from a few doctors in the U.S., no one was treating FM with antivirals and virtually no research had examined the role of pathogens in the disease. A PubMed search of fibromyalgia and herpesviruses pulled up just two herpesvirus studies – both done over thirty years ago.

Skip Pridgen fibromyalgia

Dr. Pridgen’s hypothesis that FM is a herpesvirus disease may be put to the test by the end of this year.

But here was Skip Pridgen, a Tuscaloosa surgeon, not just asserting that herpesviruses were the cause of FM, but that an unusual antiviral protocol consisting of a herpesvirus antiviral and anti-inflammatory with antiviral properties (celecoxib) was doing the trick.  Plus, he asserted that herpes simplex virus – a virus that has gotten no attention in FM’s sister disease, chronic fatigue syndrome (ME/CFS) – was the culprit.

Pridgen, who’s treated thousands of patients with gastrointestinal issues, came up with the protocol after he noticed that his FM patients with IBS seemed to get better and then relapse. Figuring that a herpesvirus might be responsible, he gave them a herpesvirus drug and was surprised that not only their GI but also their FM symptoms improved. When celecoxib had the same effect in FM patients with arthritis, the idea of a drug combo – IMC-1 – was born.

Pridgen and Carol Duffy – his research partner at the University of Alabama – believe the drug combo is effective because each drug inhibits the virus at different points in its replication cycle and they stop viral reactivation as well.  (Hitting a virus at multiple points is a strategy employed to stop HIV.)

Pridgen created a startup Innovative Med Concepts – and put together a pretty hot team (including a past Vice President of Pfizer) and some respected researchers for its Scientific Advisory Board (including Daniel Clauw and surprise, surprise former ME/CFS researcher Dr. Dedra Buchwald) and got a Phase II clinical trial funded and going. (Dr. Buchwald was a surprise because she was so darn conservative in her approach to ME/CFS…)

The clinical trials are where it gets really serious, though. For all the reports of Pridgen helping FM patients, they mean nothing to Pridgen’s hopes of producing an FDA approved drug. The trials are where the action is, and with the recent publication of Pridgen’s Phase II clinical trial in the Journal of Pain Research, we finally have something we can really get our hands around.

The Trial

A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia. William L Pridgen, Carol Duffy, Judy F Gendreau, R Michael Gendreau. Journal of Pain Research 2017:10 451–460

Pridgen has been almost relentlessly upbeat in his assertions about the effectiveness of his new protocol and he and his co-authors don’t pull any punches in the title of their journal article which boldly states that “A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia”.

Because the trial was distributed across twelve sites, it sampled a broad array of FM patients (and doctors). With 143 patients participating, it was a good size and was double-blinded (neither the patients nor doctors/researchers knew who got the drug or placebo), placebo-controlled 16-week study.

Six questionnaires were used to assess the drug combo’s effectiveness. The primary endpoint – the test the study really had to meet involved two questionnaires – a numerical pain rating scale (NRS) and a past week functional and symptom assessment questionnaire called the Fibromyalgia Impact Quotient (FIQ-R) score.

The first part of the FIQ-R asks how difficult it was over the past week to do things like walk continuously for 20 minutes, vacuum the floor, climb one flight of stairs, go shopping etc. The second part asks each patient to rate their pain, energy, sleep, depression, etc.

The study participants had to be off a variety of drugs (duloxetine, milnacipran, pregabalin, gabapentin, sodium oxybate, and opioids). Over ninety percent of the participants were women and their average age was 49.

Results

Functionality and Symptoms – The FM patients on the IMC-1 protocol showed a statistically significant improvement in their functionality and overall symptom scores on the FIQ-R test relative to the patients not on the protocol.  (The average patient showed a 2.2 point improvement on the eleven point scale.)  Functionality, symptoms and overall impact of FM all showed significant improvement on the drug.

Pain Assessment – Past 24 Hours – With regard to the other primary endpoint – the NSR measurement of pain, only when the data was subjected to “imputation” did the patients report statistically significant improvement in their past 24-hour pain. (Imputation analyses were used to account for missing data.)

IMC-1 was statistically significantly superior to placebo in most of the tests

IMC-1 was statistically significantly superior to placebo in most of the tests

Overall Improvement – Another test called the PGIC which asked patients about how much they had improved. Patients had to report that they were much or very improved to pass the PGIC test. About 35% of patients on the IMC-1 protocol reported they were much or very much improved at weeks 12 or 16 vs about 18% of those on placebo – a statistically significant result.

Another Pain Analysis – Responder analyses used to assess what percentage of patients received a 30-50% reduction in pain found that about 30% of FM patients reported a greater than 50% reduction in pain over the past 24 hours on the IMC-1 drug combo.

Fatigue – Two fatigue assessments (MFI, PROMIS fatigue short form) had differing results; the older MFI test showed no significant improvements in fatigue while the more recently developed PROMIS test showed that those on the drug combo received statistically significant reductions in fatigue.

Depression – The depression findings were intriguing given that one does not ordinarily link depression with herpesvirus infections. When the imputation analyses to account for missing data were performed, however, IMC-1 produced a highly statistically significant (P=0.003) reduction in depression. (This data was not in the published paper.) Since the HSV-1 virus hangs out in three different nerve ganglia in the body, knocking it down could conceivably affect many symptoms – including depression and anxiety.

Safety and Tolerability

With more patients off the drug than on the drug reporting side effects, the IMC-1 drug combo passed the safety test with flying colors. That finding was bolstered by the much higher dropout rates in the placebo arm compared to the drug arm.

The Phase II clinical trials reported on here is a proof of concept trial done to demonstrate that the drug probably works and is safe. Because these trials are also used to help manufacturers determine the best dose to use in a Phase III trial, Phase II trials are also more experimental.

The results were good but not spectacular. I asked Dr. Pridgen if he was satisfied with them. Considering that he felt that Innovative Med Concepts had a hand tied behind its back by the FDA he was:

Given that the FDA restricted our dose to that which we ultimately used, we were thrilled that we met statistical significance with our primary, secondary and even our exploratory endpoints. Being able to show statistically significant improvement in Pain, fatigue, depression, and a dramatic impact on IBS is truly unique. Honestly, I have never seen a proof of concept trial with this broad of an impact. Knowing that the recent toxicology results support our planned ideal dose, as you might imagine, we are incredibly confident in our Phase 3 trial. Dr. Pridgen

Pinpointing the Culprit

One of Pridgen’s and Duffy’s tasks includes demonstrating that herpes simplex one (HSV-1) – the virus they believe is responsible for FM – is, in fact, present. Pridgen reported that Duffy’s analysis of FM patients gut tissue is complete and that the data that emerged “far surpassed” their expectations. They are writing up the manuscript now.

Through the Valley of Death

Pridgen reported a couple of factors that may increase IMC-1’s effectiveness in the next trial. A higher dose will be used in the next trial and the screening process for the participants will be tighter to avoid the impact of confounding factors.

The huge Phase III clinical trials required for FDA approval are called the “Valley of Death” by some for good reason. Pridgen said that testing the drug combination – featuring two drugs that are already FDA approved – will require two 500-1000 person drug trials, each costing from $25-50 million. That’s on top of almost complete animal toxicology testing that’s been done and the large proof of concept Phase II trial.

Trials like that take some heavy lifting and Pridgen’s enrolled some top talent to get IMC-1 through the “Valley”. Rick Burch, the President of Innovative Med Concepts and the former Senior Vice President for Pfizer, oversaw divisions employing more than 6,500 employees and had a hand in launching Lyrica. As chief medical and safety officers, Drs. Michael and Judy Gendreau helped usher Savella to FDA approval.

Pridgen-IMC-1-valley-death

Pridgen hopes to get IMC-1 through the “valley of death” and into its final clinical trials by the end of this year

Pridgen reported that Innovative Med Concepts met with 14 companies (half pharmaceutical, half companies that could provide financing) at JP Morgan in January of this year. He expects the trials to begin in late 2017.

He’s confident enough of the drug’s success to expect to employ in the next trial what he stated was the toughest primary endpoint ever used in an FM drug trial – a 50% or more reduction in pain.

Will Pridgen’s approach revolutionize our understanding and treatment of fibromyalgia? Could FM really come to be viewed as a herpesvirus induced disease – and if it is – what would that mean for chronic fatigue syndrome?

Intriguing questions all. The rubber will really meet the road for surgeon turned drug developer and the many FM patients looking for better treatment options probably at the end of this year.

 More on Dr. Pridgen and His Approach to Fibromyalgia

Simmaron

Inflammation Test Could be Tailor-Made for Chronic Fatigue Syndrome: Are the Mitochondria To Blame?

February 12, 2017

“More than 90 percent of all noncommunicable diseases of aging are associated with chronic inflammation”  David Furman  – Stanford Institute for Immunity, Transplantation and Infection

Inflammation is a big deal in the medical world.  Even mild inflammation, if it’s consistently present, is known to increase one’s risk of getting cardiovascular diseases, diabetes, Alzheimer’s and many others. Standard tests for inflammation such as C-reactive protein or cholesterol, however, are often unrevealing. For instance, inflammation is a key driver of heart disease, but the first sign for many of heart problems is still a heart attack.

inflammation

Chronic, low levels of inflammation are found in many serious diseases.

Likewise it’s been said that chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are inflammatory diseases, but standard tests for inflammation often indicate that none is present. Dr. Montoya believes that current inflammation tests are missing a lot and that future tests will be able to detect the kind of inflammation occurring in ME/CFS.

Given that tests for inflammation are relatively crude, it makes sense that significant efforts would be directed to developing a better test.  It’s no surprise that Mark Davis at Stanford is involved.

Davis’s Institute for Immunity, Transplantation and Infection is spitting out interesting findings like there’s no tomorrow.  Coffee drinkers and dark chocolate lovers were recently pleased to learn that metabolites associated with caffeine and dark chocolate were associated with increased longevity and reduced inflammation. In fact, incubating cells with these metabolites  shut off their inflammatory response.

A 2015 study overturned decades of perceived wisdom that self-attacking or auto-reactive lymphocytes are mostly weeded out early in childhood. (They’re actually very common in adults.)  Davis upended another pillar of orthodoxy when he determined that environment – the microbes, toxins, foods, etc. that we encounter – have far more of an impact on our immune system than our genes. Davis found, for instance, that a single cytomegalovirus infection causes stunningly large and permanent changes to our immune systems.

Davis is bold enough to want to replace all mouse research forever (“Free the mice!”) with a human based approach using immune modeling. In 2015 the Bill Gates foundation gave him $50 million to figure out how to build more effective vaccines. Lastly and most importantly for us, Davis is one of the luminaries sitting on the Open Medicine Foundation’s Scientific Board.  A friend of Ron Davis, I met him at the Davis’ Palo Alto fundraiser a year or so ago. (He said when Ron Davis asks you to do something, you do it).

Davis may have come up with the best test yet for inflammation – an apt subject for ME/CFS and FM patients.  In fact this test sounds like it was made for people with chronic fatigue syndrome and fibromyalgia.

 Old Before Their Time?

The study originated in an attempt to quantify the link between inflammation and something perhaps pertinent to chronic fatigue syndrome and fibromyalgia – aging.  While the evidence is sketchy, it does suggest that people with ME/CFS and/or FM might be aging faster.  Decreased brain gray matter, shortened telomere lengths,  gait alterations, and the cognitive and sleep issues, could all reflect a group of patients who are aging a bit before their time.

The Study

Scientists develop inflammation test that may predict cardiovascular disease Cell Syst. 2016 Oct 26;3(4):374-384.e4. doi: 10.1016/j.cels.2016.09.009. Epub 2016 Oct 13. Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans. Shen-Orr SS1, Furman D2, Kidd BA2, Hadad F3, Lovelace P4, Huang YW4, et. al. 

In this study researchers studied two groups of 40 individuals, one between 40 and 60 years old and one over the age of 60, for nine years. Every year they threw a battery of specialized immune tests at them, and at the end of the study assessed their cardiovascular health by measuring levels of atherosclerotic plaque, arterial stiffness and ventricular function.

Their goal  – to develop a better immune test that can predict cardiovascular risk due to inflammation much earlier than is currently possible.

“Wired and Tired” Immune Systems Spark Inflammation

They hit the jackpot when they measured immune cells responsiveness to cytokines.  Younger study participants demonstrated a quick and dramatic response to the cytokines- their T-cells went into a tizzy, but the older participants produced a more muted response.

Exhausted immune systems

Tired immune systems may be sparking inflammation

We usually think of immune activation as potentially bad – as a driver of inflammation, and  so it is at times. This study suggests, though, that the kind of immune activation present is the key.

The older persons’ immune systems were, in fact, overly activated – but not in response to the cytokines. They were hyped up before the cytokine test; i.e. they were mildly activated (“wired and tired”?) all the time.  When presented with a stressor, though, the immune cells pooped out.

If that pattern sounds familiar, it should.  ME/CFS/FM patients appear to have activated sympathetic nervous systems at rest which also poop out when they’re put under strain. ME/CFS/FM patients low heart rate variability (HRV) scores also demonstrate a less responsive system is present.

A cytokine responsiveness score (composed of 15 different cytokine responsiveness tests) indicated that the always-on-but-muted immune response to danger was not good news. It was associated with signs of atherosclerosis and the inability of the heart to relax between beats.

This study suggests that it’s not the big burst of immune activity that is perilous for most of us. A nice, sharp increase in immune responsiveness is actually a sign of health. It’s the always on, lower levels of immune activation that cause the inflammation that results in so much trouble for so many people – and perhaps in ME/CFS.

It suggests the system doesn’t have to be fully activated to create inflammation; it simply has to be exhausted. The reduced blood and spinal fluid cytokine levels Lipkin and Hornig found in ME/CFS smacked of immune exhaustion. The Columbia-Simmaron Research spinal fluid studies that published those results continue in an effort to characterize the neurological levels of inflammation and immune response and move us closer to treatments.

Several studies suggest that increased oxidative stress and vascular characteristics of people with chronic fatigue syndrome may put them at increased risk of cardiovascular issues.  Improperly functioning mitochondria can produce massive amounts of free radicals and thus inflammation, which in turn furthers hampers mitochondrial functioning.

A Mitochondrial Immune Connection?

Any discussion of “exhaustion” has to touch on the mitochondria.  It turns out that immune exhaustion may very well be linked to mitochondrial problems.

Early on Ron Davis suggested that energy problems in ME/CFS could be affecting the immune cells in particular. Immune cells typically don’t use a lot of energy until they come upon a pathogen, at which point they use enormous amounts of energy to transform themselves into fighting machines that attack the defender and pump out scads of cytokines.  If mitochondrial dysfunction is present it might very well show up in the immune cells in spades.

Armstrong and McGregor’s metabolomic findings suggested that ME/CFS patients were in energy depleted states similar to those found in inflammatory, sepsis-like conditions or starvation.  Their work suggested that energy depletion (immune exhaustion?) may be associated with inflammation in ME/CFS.

Naviaux believes the mitochondria provide our first and perhaps most precise reflection of immune health.  His insights into the mitochondria/immune interface has guided much of his work.

SMCI Tackles Mitochondrial-Immune Connection

The Solve ME/CFS Initiative is exploring the intersection between the immune system and the mitochondria in a slate of studies. In the “The Bioenergetic Health Index of NK Cells as a Diagnostic Tool for Chronic Fatigue Syndrome” Isabel Barao – an ME/CFS researcher who’s also worked with the Simmaron Research Foundation – will assess the energy index of NK cells in ME/CFS.  This new test, called the “Bioenergetic Health Index,was developed at the same University Jarred Younger is working at (University of Alabama at Birmingham).

low energy chronic fatigue

ME/CFS researchers are determining if low energy production is affecting immune performance

Another SMCI study “Metabolic Analysis of B-Cell Maturation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” will assess whether mitochondrial problems are affecting the B-cell problems that Rituximab may be fixing in ME/CFS.  Fluge and Mella – the originators of the Rituximab treatment regimen in ME/CFS – believe autoimmune processes may be attacking the mitochondria in ME/CFS.

A third study “HHV-6 Mediated Mitochondrial Modulation and Its Association to ME/CFS” will determine if HHV-6 infection is affecting mitochondrial energy production in ME/CFS.

The Stanford immune responsiveness test is not available yet. Too expensive for clinical use, researchers are trying to find ways to lower its cost. When the Stanford test becomes available it might not be surprising to find ME/CFS and FM patients scoring very low.

In the meantime ME/CFS researchers are avidly exploring the intersection between the immune system and the mitochondria.

Simmaron

Is Chronic Fatigue Syndrome (ME/CFS) a Brain Disease? The 2016 IACFS/ME Conference Pt. III

December 23, 2016

brain chronic fatigue syndromeRemember:  $100,000 Year End Matching Gift Opportunity: A generous donor will match your gift to Simmaron between now and December 31, 2016, doubling your impact!

Chronic fatigue syndrome (ME/CFS) may be many things: an autonomic nervous system disease, or a disease involving the mitochondria, or an immune disease, but the IACFS/ME conference made one thing crystal clear – this disease effects the brain. Given the recent metabolomic findings suggesting that a low energy or hypometabolic state is present it makes sense that the most energy intensive organ of all – the brain – might  be affected. Plus, recent evidence suggesting that the brain’s immune system may be particularly affected suggests that brain might just be where it all comes together for ME/CFS.

In Part III of our 2016 IACFS/ME Fort Lauderdale Conference Overviews check out what the Conference told us about brain in chronic fatigue syndrome (ME/CFS).

Dr. Natelson: The Bad News / Good News Presentation

Dr. Natelson was in surprisingly good spirits given that he was delivering what must have been some wrenching news.  His recent study indicated he could kiss about a decade of work and one really interesting hypothesis goodbye.

A number of his studies had suggested that ME/CFS patients without mood disorders had more brain abnormalities (MRI’s, spinal taps, neuropsychological testing, lactate levels) than ME/CFS patients with mood disorders. It was an unexpected and exciting finding that was backed up by several studies, but the crucial larger study found no difference at all.

It’s certainly a cautionary tale regarding the small, generally underpowered studies that permeate this disease. Dr. Newton appears to have gone through a similar process; a stream of publications on muscle and mitochondrial issues were unfortunately later negated by a larger follow up study. It shows we can’t count on findings until they’re nailed down by bigger studies.

The news wasn’t all bad. Natelson’s latest study validated the fact that the major antioxidant in the brain – glutathione (GSH) – is lower in ME/CFS (we can accept that finding) and ventricular lactate levels are higher than in healthy controls (we can accept that one as well). Both findings would seemingly fit in well with studies showing that aerobic energy production is blunted and that neuroinflammation is present.  (We can’t accept the neuroinflammation finding yet.)

Dr. Natelson, a neurologist,  believes pro-inflammatory cytokines are probably whacking glutathione in ME/CFS. He also believes that reduced cerebral blood flows are a solid finding.

Occult Patients. About half the ME/CFS patients in his study also had two or more brain abnormalities – a condition Natelson called an “occult encephalopathy”. Occult refers to hidden or concealed abnormalities that take special tests to uncover. Encephalopathy is a broad term that refers to a syndrome that affects brain functioning. Natelson, then, has evidence (in what appears to be a fairly large study) that a hidden brain disorder is present in about half the ME/CFS patients.

Now that Natelson has evidence that a brain encephalopathy is present in about half the ME/CFS patients, he hopes to use proteomics to find a biomarker in the cerebral spinal fluid (CSF).  He’s preparing a grant proposal. This won’t be his first go-around in the proteomics field. Natelson was the senior author of the 2011 Schutser proteomics study which cast doubt on the idea that chronic Lyme disease is a subset of ME/CFS.

Natelson has high hopes for proteomics – a technology that he believes will help uncover unique biomarkers. In fact, Natelson, neurologist that he is, believes the hunt for a biomarker should begin in the cerebral spinal fluid, and then move to the blood. Because ME/CFS is, more than anything, a brain disorder, the best biomarkers are going to show up in the fluid that bathes the brain. They’re present in the blood too, but are being obscured by all the other factors in the rich broth that the blood is. His plan, then, is to locate them in the CSF and then find them in the blood.

POSTER – Zeineh Replicates Stanford Study

Zeineh’s arcuate fasiculatus results made a big, big splash when they came out in 2014. It was just a small pilot study, but it was Stanford, and that was enough for media outlets from CNN to Bloomberg News, the San Francisco Chronicle, and WebMD to lead with the news that ME/CFS is real.

I vividly remember Dr. Hyde, who knows of what he speaks regarding brain imaging, standing up at the Stanford Symposium and saying that was the best presentation on brain imaging in ME/CFS he had ever seen.

The Zeineh findings were exciting for a number of reasons. One, Zeineh used cutting-edge imaging technology called diffusion tensor imaging (DTI) that had not been used in ME/CFS before.  (One of the benefits of working at Stanford, Zeineh stated, was access to the best technology in the world.) We’ve always hoped that as medical testing gets more precise it will uncover issues that haven’t been seen before, and that’s what happened here.

The arcuate fasciculus is a connective fibe

The arcuate fasciculus is a connective fiber.

We know that the gross nerve damage present in multiple sclerosis isn’t present in ME/CFS, but we also know that the Simmaron Research Foundation’s cerebral spinal fluid study suggests that immune issues in ME/CFS patients’ brains may be almost as severe as those in MS patients.  Zeineh examined the brain’s microstructure, and his findings suggested that atrophy in the wiring that connects the different sections of our brain together had occurred. That kind of damage would impede the free flow of signals across the brain – making it more difficult to think and process information.  (Many brain diseases are now considered primarily diseases of connectivity.)

After his first study was released Zeineh pointed to its potential importance stating

“Most CFS patients at some point in time have been accused of being hypochondriacs and their symptoms dismissed by others. And there is still skepticism in the medical community about the diagnosis. That’s one of the reasons these findings are important.” – Michael Zeineh

Zeineh’s findings also suggested reduced white matter and problems with the thalamus and basal ganglia were present.  He attributed the fasiculatus results to inflammation.

Leptin Again..…Not only did Zeineh replicate his past results, but his ability to correlate them (in a preliminary analysis) with cytokine levels suggested that inflammation was indeed responsible for the damage he found. The real surprise, though, was the cytokine that popped up; it was leptin. With all the different cytokine results floating around (See the IACFS/ME Conference Immune blog) it was shocking to see a familiar cytokine pop up – and leptin at that.

Nobody had connected leptin to ME/CFS until Jarred Younger’s Good Day /Bad Day study suggested a couple of years ago that it was driving the immune problems in ME/CFS.  (Younger is in the middle of a larger validation study now.) Younger believes that leptin could play a key role in the neuroinflammation believed to be present in chronic fatigue syndrome.  Now Zeineh’s (preliminary) analysis suggests that leptin may be causing the brain injury he’s found. Although these results are preliminary, these are the kind of results this field could really use.

Zeineh has moved fast; he published his first study in 2014 and he presented the results of this study in 2016.

POSTERS:  The Zinn’s Damaged Connectome

Talk about connectivity:  the Zinn’s and Lenny Jason’s latest study found problems with connectivity in spades in what must be one of the most damaged brain networks of all in ME/CFS –  the attention network.  (Talk about a good fit for fatigued, concentration-challenged ME/CFS patients.) The Zinn’s found that the different brain-wave bands in this network were not in sync; while two were increased, another was decreased. Their small study also found significantly increased activation of three brain-wave bands in the attention network during a task relative to healthy controls. That actually wasn’t good news; it suggested that ME/CFS patients had to work VERY hard to maintain their attention during that task.

Connectivity issues came to the fore in the Zinn’s next poster as well. We know that information processing is slowed in ME/CFS. We also know that different regions of the brain have to work together to process information.  Put those together and it raises the possibility that the slowed information processing in chronic fatigue syndrome could be the result of bad connections.

transmission line

Reduced connectivity was the theme of several studies

Again, the Zinn’s small study suggests it just might be. Their EEG results pinpointed one brain-wave band that was inhibited across the occipital (rear), parietal (top) and temporal (front) lobes (i.e. a good chunk of the brain). Even worse the signaling “hubs” most effected in ME/CFS constituted “the most electrically active” regions of the brain.

A regression analysis also suggested that the longer you’ve had this illness the less well connected these parts of the brain are. The Zinns referred to their findings as “widespread functional dysregulation in the connectome”.

At the conference, Marcie Zinn pointed out someone vigorously talking to a group clustered around their posters. “That’s Rex Cannon, she whispered. It turns out he actually wrote THE BOOK on the type of EEG analysis they’re doing. The Zinn’s and Lenny Jason had apparently invited him down to the conference and he was interested; in fact he was so interested in their findings that they’re now collaborating with him.

Byron Hyde – the Pioneer

The “father” of brain imaging research in ME/CFS, Bryon Hyde, didn’t present but he was there and provided a nicely illustrated booklet on his findings. Hyde said he had a new book coming out on ME/CFS soon.

Hyde has been using SPECT scans to diagnose and treat patients for decades; his experience indicates that hypo perfusion or low blood flows to different parts of the brain is common in ME/CFS. Furthermore be believes that low blood flows to certain parts of the brain are causing many of the major problems in ME/CFS.  Simply by assessing a SPECT scan he can probably tell you what kind of patient you are.

In the booklet he demonstrated how he’s able to tie certain SPECT scan findings to distinct problems ME/CFS patients face.

  • Autonomic dysfunction – patients with autonomic dysfunction always, in his experience, demonstrate reduced blood flows in an area above the insular cortex called the operculum. The insula regulates homeostasis; e.g. the autonomic nervous system. Damage to this area is associated with orthostatic intolerance, blood vessel problems and problems with heart regulation.

Hyde, long associated with ME/CFS and critical of exercise therapies, is able to find middle ground with regard to activity. The damage to the insula and therefor to the autonomic nervous system is too significant, he believes, for these patients to benefit from graded exercise therapy (GET), but he also believes that patients shouldn’t let fear keep them in bed forever either. Depending on how severely ill a person is, Hyde states that “a gradual, patient regulated increase in activity is necessary, both for the body and the soul”.

  • Muscle dysfunction – Patients with muscle dysfunction show low blood flows to the motor cortex (Brodman’s area 4 of the posterior lobe).
  • Cognitive problems  – Patients’ problems with information processing (which included everyone), speech comprehension, and processing visual and auditory information – all have left anterior temporal lobe injuries. These are found in all ME patients.
  • Lots of Stuff –  Patients with problems in a host of areas including learning, complex motor skills (driving?), sleep, alertness, multi-tasking, emotions, etc. demonstrate low blood flows to the anterior and posterior cingulate lobes. Most patients have injuries in both these areas.

Hyde believes the 1984 Incline Village/Lake Tahoe outbreak investigated by the CDC was a classic enterovirus epidemic. He asserts in the booklet that Stephen Straus’ blockage of a publication about this outbreak in the New England Journal of Medicine by Dr. Peterson and others had tragic consequences.  Hyde believes that pure ME is an enteroviral disease diagnosed using disease history, gastric or GIT biopsy and a SPECT scan.

If Hyde is right about enteroviral infections, some hope may be on the horizon.  Enteroviral infections are so difficult to treat given our limited pharmocopia that most doctors don’t even test for them. Hyde reported, though, that several new enteroviral drugs (Pirodavir, Vapendavir, Pocapavir, Plecoaril and Rupintivir) are in the early stages of being tested.

Hyde has a new book coming out on ME soon.

Brain Research Heating Up!

A gateway to the brain - the cerebral spinal fluid

A gateway to the brain – the cerebral spinal fluid. (See the arrows)

Interest in neuroinflammation in chronic fatigue syndrome (ME/CFS) is growing, and that means more emphasis on the brain. The problems Natelson and Shungu have described (increased lactate, decreased glutathione and reduced cerebral blood flows) are likely the result of increased inflammation and oxidative stress. At the IACFS/ME conference Dane Cook demonstrated that exercise not only impairs cognition a day later but that it also puts a whopping damper on ME/CFS patients’ brain activity.

After Zeineh’s mighty diffusion-tensor machine uncovered microstructural damage in one of the main connective pathways in the brain, his preliminary analyses suggest that inflammation (via leptin) was the cause. Meanwhile, different issues with “the connectome” in the brain showed up in the Zinn’s (soon to be published) studies. Their tagging of the alertness network made perfect sense.

The brain research is heating up! Quite literally. The Solve ME/CFS Initiative just funded Jarred Younger’s attempt to assess neuroinflammation in the brain using a new heat scanning technique. Younger believes areas of the brain associated with fatigue are going to be red hot (figuratively speaking) in ME/CFS patients.

All these interesting results mean an increased interest in examining our best gateway to the brain (short of a biopsy): the cerebral spinal fluid (CSF). As was noted, Dr. Natelson is eager to get underway with his proSR_Donate_6.9.14_1teome CSF study. Dr. Baraniuk is currently examining the exosomes – small fluid vesicles that contain inflammatory factors – in the CSF of ME/CFS patients to see if they’re adding to the inflammatory milieu there. The Simmaron Foundation’s new spinal fluid study, which is incorporating Dr. Naviaux’s metabolomic results, aims to duplicate and expand on its past CSF study.

That study showed a degree of immune dysfunction almost equal to that found in multiple sclerosis. Remarkably, almost half the cytokines in the ME/CFS patients were abnormal. No exercise was needed to tweak them. There was no need to filter for duration or severity either. Even at rest those cytokines were off, off, off.  That suggested that major and readily identifiable immune issues exist in the brain. It also suggested, as Dr. Natelson proposed, that the brain might just be the first place researchers should go to look for immune problems in ME/CFS.

Given the variable cytokine results often seen in this field, it was stunning to see the Simmaron Foundation’s CSF cytokine results essentially duplicate those found in the Lipkin/Hornig blood study. That got Ian Lipkin so excited that he flew all the way to Incline Village to promote it last year. Simmaron is raising money for that project right now.

Remember:  $100,000 Year End Matching Gift Opportunity: A generous donor will match your gift to Simmaron between now and December 31, 2016, doubling your impact!

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Is Chronic Fatigue Syndrome An Inflammatory Disease? The 2016 IACFS/ME Conference Overviews Pt II

immune-systemThe immune system’s complexity reared its head again at this conference as Dr. Montoya showcased some of the findings coming out of his large immune studies at Stanford.  Montoya’s assertions that chronic fatigue syndrome (ME/CFS) is similar to systemic inflammatory response syndrome and should be called an inflammatory disorder were intriguing indeed. It’s still, however, hard understand what is going on in the immune system in ME/CFS.

This is a long blog; if you just want the main findings a quickie overview is given at the end of it.

IMMUNE SYSTEM

Montoya’s huge (584 person!) and impressive immune studies –  the largest ever done in this disease – dominated several presentations.  The studies are bit unusual in that they contained about twice as many healthy controls (n=392) as patients (n=192).  Montoya posted an impressive list of 30 researchers he’s collaborating with at Stanford and elsewhere.

He spoke of a complex immune situation often characterized by both up and down immune activation, but which strongly suggested chronic fatigue syndrome is an inflammatory disorder.

Cytokine Study

Cytokines are molecules produced by immune cells that regulate immune functioning in many ways. Montoya tested many cytokines (51) but only two popped out in the first run of this study. That was surprising; large studies are particularly good at finding small but still significant differences, but this study found few differences between the ME/CFS patients and healthy controls than some smaller studies.

Lipkin and Hornig enhanced their cytokine study results by controlling for duration. The key for Montoya was severity. When he added severity to the picture, the immune findings popped out. In the more severely ill patients a rather eye-popping third of the 51 cytokines tested (leptin, CXCL-1, CXLC10, GM-SF, IFN-Y, GM-CSF, IL-4, IL-5, Il-7, IL-12p70, IL-13,  IL-17F, NGF, TGF-b, CCLI, SCF and TGF-a) – most of them pro-inflammatory in nature  – significantly increased.

Montoya proposed that TGF-b, traditionally thought of as anti-inflammatory, may have been acting as a pro-inflammatory cytokine. That cytokine has shown up in several ME/CFS studies before.

Interlude: Cytokine Results Still All Over the Map

The results were encouraging, but cytokine results in this disease are still all over the map. For years researchers have thought they MUST be involved in ME/CFS, but cytokine results have been stunningly inconsistent.

For example, while a 145 person Australian study did, like Montoya’s study, find increased levels of cytokines (IL-10, IFN-γ, TNF-α), none of those cytokines showed up in Montoya’s results.

igg-antibodyA 99 person study from the Klimas group measuring 16 cytokines found significant alterations in 10 of them (increased – LT-a, IL-1a, IL-1b, IL-4, IL-5, IL-6, and IL-12; decreased – IL-8, IL-13 and IL-15.) IL-4/5-were increased in Montoya’s severe ME/CFS group, but IL-13 was decreased in the Klimas study and increased in Montoya’s.

Wyller’s recent large study of ME/CFS adolescents found no cytokine differences between those diagnosed with the Fukuda criteria cytokine and healthy controls. A Japanese/U.S. study found no evidence that either sleep deprivation or exercise effected cytokine levels as well.

The large Landi/Houghton 179 person study of longer duration patients found mostly cytokine reductions instead of increases (reduced levels of IL-7, IL-16, VEGF-a, CX3CLI, CXCL9; increased CCL24). If most of Montoya’s group were early-stage ME/CFS patients, that might help explain the differences, but we don’t know that they were. (Montoya did state that he is going to filter for illness duration.)

The Lipkin/Hornig cytokine study found increased levels of 16 cytokines in early or late duration patients vs healthy controls (IL-1a, IL-1ra, IL-4, IL-12p70, Il-13, CXCL8, TNFα, SFASL, CCL2, CCL3, CD40L, MCP1, TNFSF10, SCF, CFS1, and resistin).  Only three of those (IL-12p70, Il-13, SCF) were found elevated in the Montoya study; thirteen were not.

An Australian study that tracked for severity in a different way from Montoya suggested that more severe patients do have higher cytokine levels. It found reductions in IL-1b, and increases in IL-7, IL-8 and IFN-y. Of those, IFN-y was increased in the Montoya study.

In a much (much) smaller cytokine study published earlier this year, Dr. Fletcher’s study suggested that dramatic shifts in immune functioning may occur over time. IL-a plays an important role in early ME/CFS and then declines. IL-8 levels were abnormally high early on but declined to lower than normal levels after a few years. Il-6 levels were low early on and elevated later. Ironically, the Montoya study didn’t find any of these cytokines elevated in his severely ill patients.

Conclusion (?)

Until cytokine results achieve more consistency they’re clearly not going to get traction in the medical world.  The inconsistency seems surprising as most of these studies are from good labs. It’s possible, though, that subsets are mucking up the issue. Filtering for duration is clearly needed, and Montoya’s study suggested that filtering for severity is as well. The Klimas group’s Gulf War Syndrome study suggested that  gender may need to be accounted for as well.

Dr. Peterson’s atypical patient subset may throw another loop into cytokine results. Peterson’s atypical ME/CFS subset group so dramatically affected cerebral spinal fluid results that it had to be excluded from the study altogether.  Could  this group be effecting blood cytokine results as well?

Researchers are not going to stop studying cytokines – they’re apparently too enticing – and it’s possible that studies underway may help us understand what is going on.  If Lipkin/Hornig can, in their study underway, replicate their cytokine results in different duration patients – that will be something. Ditto with several good day bad day studies underway. If Montoya can duplicate the Lipkin/Hornig duration results that would really be something. Time will tell.

It’s also possible that cytokine levels per se aren’t as important as we might think. Broderick’s models suggest that context is key; in the right context a factor can be important even if it’s levels are not raised.  His models suggest that treatments targeting just two cytokines might be able to enable ME/CFS patients to exercise again. (See upcoming IACFS/ME treatment blog).

Montoya’s network analysis indicated that Il-1B – an important regulatory cytokine associated with increased pain – was the most important factor 24 hours after exercise.  That certainly makes sense given what we know about exercise and pain.

Another possibility is that cytokines in the nervous system are more important than those in the peripheral blood. It’s thought, for instance, that cytokines must contribute to central sensitivity syndromes (CSS’s) such as fibromyalgia as well, but a similar issue with consistency apparently applies there. Staud has suggested that cytokines probably play a major in CSS, but only within the central nervous system.

No Biomarker Yet – An immune signature that shows up only in the more severely ill gives us clues about the illness but obviously isn’t going to work as a biomarker.  But what would happen if Montoya essentially shoved those people into a more severe state by having them exercise? Would adding exercise to the mix make the more moderately ill patients look like more severely ill patients?

Montoya’s Exercise Study

Would exercise make moderately ill ME/CFS patients in the throes of post-exertional malaise look like severely ill patients? The answer to that question was no.

Montoya’s maximal exercise test produced opposite results from the cytokine study done in patients at rest.  This time, exercise reduced the levels of four cytokines (TNF-a, IL-8, CCL4, ICAM-1) while increasing the levels of only 1 (CXCL-10).

Both TNF-a and IL-8 increase during exercise in healthy people, however. The fact that both went down in ME/CFS patients may be notable.  If immune exhaustion is present then perhaps one might expect cytokine levels to drop when the body is faced with an exercise stressor.

A 2014 review of exercise studies reported that while exercise does appear to effect the complement system and gene expression and increase oxidative stress in ME/CFS, it does not appear to effect cytokines. Montoya’s results suggested the opposite.

Genomics Study Suggests Chronic Fatigue Syndrome is an Inflammatory Disorder

At the Stanford Symposium, Montoya announced that the gene expression results indicated that ME/CFS was similar to a disease called systemic inflammatory response syndrome or SIRS. He repeated that assertion again; this time stating that ME/CFS was a “100% match” to SIRS.  (The abstract was a bit more cautious, stating that the gene expression results were “very similar” to it and similar diseases).

SIRS

SIRS has been called a
“cytokine storm”

The concept of SIRS came out of ten years of work at a Toronto trauma lab by Dr. William Nelson. SIRS is  a kind of cytokine “storm” – a term sometimes used in ME/CFS – which refers to a positive feedback cycle that results in higher and higher levels of cytokines.  SIRS also effects both pro and anti-inflammatory cytokine levels as well.

SIRS refers to a state of systemic inflammation after infection or some other insult and can result in organ dysfunction and failure. Intriguingly, given the Australian metabolomic group’s suggestion that the metabolomic results in ME/CFS are similar to sepsis, it’s closely related to sepsis.

SIRS has other manifestations that some may find familiar. Increased heart rates, lower or higher than normal body temperatures, rapid breathing rates, and low white blood cell counts found in SIRS have also been found in ME/CFS. The rapid breathing rates, by the way, are associated with either increased metabolic stress due to infection or inflammation or may signal inadequate perfusion because of the onset of anaerobic cellular metabolism.

Other possible links include fibrin deposition, platelet aggregation, and coagulopathies aka Dr. Berg’s findings in ME/CFS some years ago. Dr. Montoya’s immense gene expression study almost couldn’t have uncovered a more interesting disease to link to ME/CFS.  How serendipitous as well – if this all turns out – that Ron Davis and some members of his Open Medicine Foundation team have done an enormous amount of work on sepsis.

How is SIRS treated? In some ways (blood volume enhancement, anti-anaphylaxis drugs, selenium, glutamine, eicosapentaenoic acid, and antioxidants) that can be helpful in ME/CFS.

Epigenetic Modifications Point at Immune System and HPA Axis

Montoya’s epigenetic study suggested an infection (or some other insult) had indeed occurred in ME/CFS. Greatly increased rate of methylation in ME/CFS patients’ immune regulatory genes suggested some infection or other environmental insult had occurred.

Other epigenetic modifications were found to affect HPA axis genes.  Given the strong interaction between the HPA axis and the immune system, it wouldn’t be surprising at all to find that some event had tweaked both the HPA axis and immune genes in many ME/CFS patients. (The Montoya group is currently engaged in a promising HPA axis study.)

Other gene groups affected by methylation (epigenetic modification) include genes that play a role in, yes, metabolism.  One gene highlighted in a whole genome polymorphism study has been implicated in lactic acidosis (NUFS7). A polymorphism in this gene, which transfers electrons from NADH to CoQ10, could result in increased oxidative stress and reduced mitochondrial output.

Is Chronic Fatigue Syndrome an Inflammatory Disease?

Finding increased immune activation in severe ME/CFS patients, and with gene expression results a close match to SIRS, Montoya asserted that ME/CFS is an overactive immune disease and proposed that its new name should include the word “inflammatory.” Montoya results suggest this, but it’s hard to see how any consensus can be reached until we get more consistent results from the cytokine studies (???).

Pathogens

When asked about retroviruses, Montoya suggested there was no cheese down that tunnel. In several of his newsletters Montoya promised “exciting” new findings regarding pathogens but none were presented at this conference.

Allergy Study Reveals Intriguing Subset

Dr. Levine’s allergy study was, for me, one of the surprise highlights of the conference. This nice big study demonstrated how valuable a resource the multi-site ME/CFS experts centers are, and how valuable a tightly integrated network of research centers will be.

In one of the bigger ME/CFS studies to date, Levine queried 200 patients in five sites regarding the incidence of allergic symptoms/conditions and found that the presence of sinusitis and hives distinguished ME/CFS patients from healthy controls.  (My guess is that the presence of sinusitis is overlooked and understudied in ME/CFS).

allergy subset ME/CFS

An allergy subset appears to have increased pain sensitization as well

The fact that having either of those conditions resulted in patients experiencing more pain suggested that an immune process was ramping up their pain levels.   That hypothesis was strengthened when Levine found that this group also had a much, much higher incidence of migraine, tension headaches, back pain, neck pain, and fibromyalgia.  Plus they had more gut and inflammatory symptoms. Something clearly appeared to be driving a pain sensitization process in these patients.

What is the tie that binds these findings together? Levine suggested it might be mast cell activation. Plus, Dr. Levine noted that both mast cells and neurons secrete two factors: nerve growth factor and substance P, known to increase pain. Then there’s tryptase to consider. A recent study suggested that modification of a tryptase gene could be behind some cases of EDS, POTS, IBS, ME/CFS and FM. Another suggested mast cell activation may be occurring in ME/CFS

This is the kind of study that makes you wonder why the heck it hasn’t been done before. The study was surely not expensive, yet it might illuminate much about ME/CFS.  It was funded by the Hitchens Foundation.

POSTER: RNase L Returns? Novel Isoform of Ribonuclease L Shows up in Fibromyalgia

The idea that an important immune enzyme called RNase L had been broken into pieces and was not only no longer working properly but was actually causing channelopathies and other issues raised a great deal of interest in ME/CFS the 2000’s. At some point work on the enzyme stopped but RNase L was not forgotten.

In a surprise a Spanish group looked for and found the broken-up bits of the enzyme in fibromyalgia. The results were too variable for the 37 dKA form of the enzyme to be considered a biomarker but they did suggest that a subset of FM patients carried it.

Even more surprising was their finding of another broken up bit of RNase L (70 kDa) which was almost totally associated with the FM patients (p<.0001). They’ve create custom-made antibody to identify it and will apparently keep working on it.

PATHOGENS

POSTER: EBV Rides Again

We’ve heard so much about EBV over the years that we forget what a special virus it is. It’s’ true that almost everyone has been infected with EBV, and most have no problem with it, but EBV is no walkover.

When one is exposed to EBV later in life, it causes infectious mononucleosis (glandular fever) and is associated with several forms of cancer (Hodgkin’s lymphoma, Burkitt’s lymphoma, gastric cancer, nasopharyngeal carcinoma, central nervous system lymphomas). Evidence suggests that EBV infections result in a higher risk of many autoimmune diseases including dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis. Lastly, while hardly mentioned in the medical world (ME/CFS is not even mentioned in the Wikipedia article) but foremost in ME/CFS patients minds, EBV is a well-known trigger of ME/CFS.

EBV must have a multitude of tricks up its sleeve to contribute to so many illnesses. The idea that it plays a major role in ME/CFS has risen and fallen over the years. Right now, that idea seems to be more in its descendant phase, but as Dr. Klimas’s study shows, it ain’t over until it’s over; EBV may still very much figure in this disease.

Micro RNA’s – small bits of RNA – regulate which genes get expressed. It turns out that EBV, tricky virus that it is, encodes viral miRNA’s of its own. (EBV was the first virus found able to do this. Given the immense amount of EBV research being done (over 25 studies published in November alone) that was perhaps no surprise.)

HHV-6

HHV-6 appears to contribute to symptoms in ME/CFS

Peripheral blood mononuclear cells (PBMCs) were collected from ME/CFS patients and healthy controls before, during and after exercise, and various tests were done to assess EBV miRNA’s.  Preliminary results suggested that ME/CFS patients’ cells express higher levels of EBV proteins than normal and thus might be more likely to support EBV reactivation.

Plus some strange features emerged. The immune cells in ME/CFS tended to be smaller and have less volume (Ron Davis has found something similar). Instead of forming a classic “pump” shape the ME/CFS nuclei take on a puckered and wrinkled look as if they were aged. Plus, when a key immune transcription factor called STAT I gets activated, presumably by the virus, it ends up in the wrong part of the cell – a pattern indicative of viral reactivation.

All of this suggests that EBV may be tweaking ME/CFS cells in strange ways and that the virus may still play a part in ME/CFS.

POSTER: A Better HHV-6 Test

It’s clear that herpesvirus tests leave something to be desired and Nancy Klimas’ group is attempting to find a way to improve the diagnostic effectiveness of the Elisa test. The current test are provide only  yes-infected or no-not infected answers and are particularly unreliable at the high and low ends of the spectrum.

This study, involving Dr. Govindan from Tufts University and four Florida researchers, used various statistical tests to see if they could develop a truly “quantitative” Elisa for HHV-6.

The intercept they developed allowed them to accurately stratify patients, and showed that the HHV-6 intercept they produced was negatively associated with physical functioning; i.e. the higher the intercept – the worse the ME/CFS patients physical functioning was. This suggested that a) HHV-6 does contribute to the symptom burden in ME/CFS, and b) that this new test could aid doctors in determining when to apply antiviral therapies.

POSTER: Enterovirus Brain Infection Found

Dr. Chia’s work to get the medical world to take enterovirus infections in ME/CFS seriously continues. He gave a workshop on enteroviruses and seemed to be in demand; every time I saw him he was engaged in conversation with a group of people.

His poster highlighted the possible effects of enteroviruses in the most dramatic way. It told the story of a young man who first developed gut problems and then severe ME/CFS. Tests for herpesviruses were normal, but his Echovirus antibody levels were sky-high.  Stomach and colon biopsies stained positive for enteroviruses but enterovirus RNA was not detected in his blood (it often isn’t).

Unfortunately, the young man failed to respond to either alpha or gamma interferon or to SSRI’s, benzodiazepines or acid suppressants. Repeated MRI’s of his brain and spinal chord were normal. Six years into his illness, at the age of 29, he committed suicide.

His ending was tragic, but his story was not over. His harvested brain provided clues as to what may have happened. Neither a brain culture nor an RT-PCR picked up signs of enterovirus, but a western blot found protein bands which were similar to those found in the young man’s stomach biopsies (but different from those found in tuberculosis and lymphoma).

Dr. Chia concluded that this finding replicated a similar finding dating back to 1994.  He concluded that the

“finding of viral protein and RNA in the brain specimens ….is consistent with a chronic, persistent infection of the brain causing debilitating symptoms. EV is clearly one of the causes of ME/CFS, and antiviral therapy should be developed for chronic EV infection.”

Like herpesviruses, most enteroviral infections are passed off quickly, but like herpesviruses, enteroviruses are also associated with serious disorders including polio, meningitis, myocarditis, hand, foot and mouth disease and others. According to Wikipedia, treatment for enterovirus infections is primitive, consisting mostly of relieving symptoms such as pain as they occur.

One hopes at some point an independent lab will take up Dr. Chia’s work and give it the replication it needs and he deserves.

Conclusions

The cytokine findings are disappointingly inconsistent, but the immune system is a vast place and gene expression, epigenetic modeling and other studies continue to point a finger at it.  The Montoya studies should tell us much, plus the entry of noted researchers such as Ian Lipkin and Mady Hornig,  Maureen Hanson, Derya Unutmaz, Michael Houghton and Patrick McGowan into the field ensure that we’ll be learning much more about the immune system in the years ahead.

Marshall-Gradisnik’s NCNED team is churning out immune studies at a rapid rate, Broderick’s early modeling  studies suggest an immune focused 1-2 punch may knock out post-exertional malaise, and Fluge and Mella are testing another autoimmune drug, cyclophosphamide, in clinical trials.

Both Fluge/Ron Davis believe an immune process may be targeting energy production in our cells, the same may be true for ion channels, and it’s now clear that an autoimmune process is producing POTS in some patients. Every microbiome study thus far suggests altered microbial diversity and/or gut leakage into the blood could be sparking an immune response.

The Simmaron Foundation’s expanded spinal fluid study should give us a better handle on what’s happening in the brain just as new techniques to measure the amount of neuroinflammation present in the brain come online.

Finally, it’s encouraging that researchers are getting serious about subsets – and finding them when they look for them.

Major Findings

  • Increased levels of pro-inflammatory cytokines are associated with increased severity in ME/CFS;
  • Exercise, on the other hand, appears to down-regulate cytokine levels in ME/CFS including several cytokines that are typically increased during exercise in healthy people;
  • Gene expression results suggest ME/CFS is very similar to a sepsis-like condition called systemic inflammatory response syndrome (SIRS) which shares some other characteristics with ME/CFS;
  • Epigenetic modifications suggest that events may have altered the expression of genes involved in both the HPA axis and immune systems in ME/CFS;
  • One subset of ME/CFS with sinusitis and/or hives also falls prey to other pain sensitization type disorders such as migraine, fibromyalgia, headache and back pain. Mast cells could be implicated;
  • A broken up form of RNase L, an important enzyme involved in fighting pathogens, showed up in fibromyalgia;
  • Higher levels of EBV proteins in ME/CFS patients’ cells plus structural abnormalities in their cells suggest EBV reactivation may occur more frequently in ME/CFS;
  • A quantitative Elisa test suggests that HHV-6 contributes to the symptoms of ME/CFS as well;
  • Enteroviral proteins in the brain of a young man with ME/CFS who committed suicide suggested that enteroviruses have infected the brains of some people with ME/CFS.

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The Pridgen Revolution? Dr. Pridgen on Bringing His Antiviral Approach to Fibromyalgia To Market

The Pridgen Revolution?

Almost three years ago, Dr. Pridgen threatened to turn the world of fibromyalgia treatment on its head. Few had connected fibromyalgia with viruses or even immune problems when Pridgen announced that a) FM is caused herpes simplex virus reactivation and b) that it could be treated with antivirals. Then he shocked a chronic fatigue syndrome community (ME/CFS) well acquainted with antivirals with his assertion that one antiviral drug was not enough.  (Pridgen believes the same process is going on in ME/CFS). Pridgen wasn’t done, though, instead of using the usual anti-herpes virus drugs he used an anti-inflammatory (Celebrex) that had antiviral properties as his second antiviral.

pridgen_skipPridgen was knocking down received wisdom at every turn. One would not have been remiss to think that he and his unusual protocol would, as other supposed cures have, disappear at some point, but he hasn’t.

Instead, touting his success with the drug combo, Pridgen embarked on the long and difficult task of bringing a new treatment to market. After joining up with a University of Alabama virologist, Dr. Carol Duffy, Pridgen formed a biotech company aptly named Innovative Med Concepts, hired an ex-Pfizer vice-president, put together a strong scientific board, raised the money for a Phase 2 trial, and embarked on toxicology testing.

The Phase II trial was successful enough for the drug combo to move forward. Then Innovate Med Concept got a break when FDA granted fast-track status to its IMC-1 formulation, allowing the drug combo to move forward as quickly as possible.  (Fast-track status is granted to serious diseases that have “substantial impact on day-to-day functioning.”)

Now comes the real work – raising money for some very, very expensive Phase 3 trials. It’s been about a year since we checked in. In an interview, I asked Pridgen how it was going.

The Pridgen Interview

The Phase II trial results were certainly quite good, but they weren’t spectacular.  How did the Phase II trial inform the Phase III trial and how will it be different?

We wanted to prove the concept first with a dose that we knew would be effective.  Additionally, we chose this lower dose, as it would allow us to begin without first performing the very expensive and time-consuming toxicology studies. We will be beginning the final 2 toxicology studies necessary to be Phase 3 ready, this month, and we expect to have these completed late this winter or in early spring 2017.

This was a year to prep for the big Phase III trials. How much money do you need to raise? Do you need to do one or two trials and how big does the trial or trials need to be? How much money do you need to raise?

Typically, two Phase 3 studies are required, the studies require 500-1000 patients per study, and these studies cost $25-50 million each.

One report suggested that some pharmaceutical companies have shown interest. Can you say anything about that?

drug-developmentWe have met with a dozen different pharmaceutical companies. All knew that we would be either forming a strategic partnership, or continuing the drug development ourselves once we near Phase 3 readiness. We will meet with these pharmaceutical companies to discuss a possible partnership at the upcoming JP Morgan meeting Jan 2017 in San Francisco.

We’ve seen a couple of high-profile Phase III trial failures recently. One may have been due to doctors misidentifying a side effect as something else and using a drug that interfered with the results. Another got excellent results in the Phase II trial but then didn’t meet its primary endpoint (but did meet some of its secondary endpoints) in the Phase III trial.  In another trial a very high placebo rate surfaced. What can you do to ensure that IMC-1 trial goes as well as possible?

We have actually been using a variant of this combination at my office for 2-3 years, so we are extremely confident in, not only its efficacy, but also know the combination is quite well tolerated and safe. Though providing the necessary optimal dose is incredibly time-consuming for the office staff, and complicated for the patients, we endure this hardship because of the dramatic improvement they experience.

Dr. Pridgen remains very, (very) confident in the effects of his protocol; he’s so confident that he anticipates raising the bar for the primary endpoint of his Phase 3 trials. Drugs have failed because they chose the wrong primary endpoint or too difficult of a primary endpoint, but Pridgen reports the study will use the most difficult primary endpoint to attain of any fibromyalgia trial to date:

Finally, because IMC-1 is so effective, we will use a primary endpoint that represents the highest bar ever used for any of the drugs previously studied for FM. We feel that this will negate to some degree the placebo effect.

We can see from studies and patient comments that the fibromyalgia population is pretty heterogeneous one. Some people do well on Lyrica – others do terribly. Low dose naltrexone works very well for some and others do poorly on it, etc., etc. The heterogeneity seen in the reactions to pain medications, in general, is pretty daunting. Is there any way you can target FM patients who are more likely to do well on the drug?

Again, Pridgen waxed confident in how efficacious this drug combination is. He believes his is the only protocol that gets at the source of fibromyalgia.

We believe IMC-1 is targeting the possible cause of fibromyalgia, not just modifying the body’s perception of pain.

Emedicine lists four antivirals (Famvir, Valtrex, Acyclovir, Penciclovir) used to treat herpes simplex infections. You’ve found that you need to add Celebrex to Famvir to get the best results in FM. Why do you think this is?

Penciclovir is not available in the PO form because it is not well absorbed, so it is a better topical agent.  Actually, Famvir turns into the active form, penciclovir, once it is acted on by human and viral enzymes. Celebrex is effective as an antiviral also. Herpes viruses are known to up-regulate the Cox-1 and Cox-2 enzymes to maximize viral activation. Though Celebrex (celecoxib) is known as a Cox-2 inhibitor, it actually has substantial Cox-1 inhibition.

viral-attack-cfsAre the herpes simplex infections harder in FM harder to get at than in other diseases? Do you need to reach into the central nervous system?

Essentially all adults have HSV-1, but we believe there is an immune defect in place in some patients, which results in an inability to force the virus into dormancy after an acute infection. In other words, patients with FM, have an ongoing HSV-1 infection, which we feel results in a chronic stress response. The meds can act centrally, however, the virus lives in the Trigeminal, and Nodose ganglia which are intracranial, but technically not in the CNS. The dorsal sacral root ganglia are the third major site (in the pelvis) where the virus resides.

Note: The herpes virus is known to hide out all three of these ganglia or cell bodies.

  • Trigeminal ganglia – is the largest and most complex of the 12 cranial nerves. The trigeminal ganglia provides sensations to the face and other parts of the head. It also sends signals that allow us to chew and even helps with balance. People with trigeminal neuralgia can experience high levels of pain when doing things like brushing their teeth or putting on makeup.
  • Nodose ganglia – are sensory ganglia or nerve cell bodies of the vagus nerve that are found near the top of the spine..
  • Dorsal sacral root ganglia – are associated with vertebrae in the pelvic area. The nerves emanating from them impact all areas of gut and pelvic functioning. In between bouts of genital herpes virus reactivation, the herpes simplex virus hides in these ganglia.

Like the other herpesviruses, almost everyone is infected with HSV-1, and when reactivated these infections can be pretty harmful. They’ve been shown to cause gastrointestinal and esophageal disorders, acute viral encephalitis, and approximately 25% of all genital herpes infections. Fibromyalgia is a bit different; it causes widespread pain, fatigue, sleep and sometimes mood problems as well as other symptoms- and is thought more of as a central nervous system disorder than anything else. Can you explain what the herpes simplex virus is doing differently in FM to cause this extraordinary range of symptoms?

The ongoing stress response affects nearly every system in the body. The immune response to this stress response over time affects sleep, mood, anxiety, thyroid, adrenal function, GI tract, HA’s and much more.

Dr. Duffy was reportedly writing up a paper on her gut findings. Can you tell us that the status of that is?

We have one last sample (of 60 total) to obtain to complete the study.

(At a conference Duffy was reported to find HSV-1 in 100% of FM gut biopsies and a protein found only in cells that are actively infected with HSV-1 in 80% of patients.)

With another year under your belt have you learned anything new treating FM using Famvir and Celebrex?

We have found that anything that was previously part of the functional somatic syndrome will improve on this treatment. At the risk of sounding like a snake oil salesman, we have patients who have chronic non-seasonal sinusitis, HA’s, brain fog, and even libido issues who swear by IMC-1.

Dosing – I also asked Dr. Pridgen about dosing information. He replied that the dosing information has to be proprietary right now. This is because pharmaceutical companies or other funding sources would not back a product composed of already approved drugs if the dosages were put in the public realm. Given the enormous costs of the Phase 3 trials, Pridgen’s drug combo would never make it to market without their backing.

That means FM patients will have to wait before Dr. Pridgen publicly reports on the appropriate dose. For many people this conversation is moot – their doctors would not prescribe antivirals now anyway. People seeing Dr. Pridgen or people seeing doctors in touch with Dr. Pridgen will obviously get the right doses.

If the trials are successful and the FDA approves the IMC-1 formulation everyone should be able to get a shot at these drugs.

Can you give us a timeline regarding the Phase III trial(s)?

They will start next year.

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For more on Dr. Pridgen’s antiviral approach to fibromyalgia:

Simmaron’s Fifth Anniversary Event Updates ME/CFS Community on Dynamic Research Underway

5th-birthday-258x300

Simmaron recently held a patient update session with its Scientific Advisory Board and key collaborators in Incline Village, Nevada. The event celebrated the Simmaron Research Foundation’s fifth year anniversary.  I don’t know if anyone would have predicted five years ago that patients would be hearing from the likes of Mady Hornig, Maureen Hanson, Konstance Knox and Elizabeth Unger but here they were in little Incline Village talking about their work.

CDC Collaboration

The surprise guest at the event was Elizabeth Unger. Dr. Unger was a fitting guest at the Simmaron’s 5th year anniversary meeting; it’s been, after all, just over five years since she took over the helm of CDC’s Chronic Fatigue Syndrome (ME/CFS) program.  Who would have thought five years ago that the head of CDC’s CFS program would show up at a Simmaron information meeting.

Certainly not Dr. Peterson. About five years ago I asked him if the CDC  had ever shown interest in his work,  and he just laughed.  His relationship with the CDC was frosty to say the least. That’s not true any longer.Dr. Elizabeth Unger

Under Dr. Reeves, the CDC developed a definition in-house that received zero support from researchers (and patients). Under Dr. Unger, the CDC has made ME/CFS experts a core feature of its work, is meeting with patient groups, has worked with CFSAC on its website, and is engaging with patients and experts in its educational materials.

Instead of a stumbling block, Dr. Unger turned out to be a collaborator who’s committed an enormous amount of time, energy and her (limited) budget to learning about ME/CFS doctors and their patients.  What a shift that has been.

Dr. Unger threw all the definitions out the window in the multisite ME/CFS expert study. Realizing that doctors, most of whom had decades of experience in this disease, were a better source of what ME/CFS was than any definition, she cleared the decks; anyone the expert doctors believed had ME/CFS, whether they met x or y definition or not, she would study. They were, by default, ME/CFS patients. Dr. Peterson thought it was a brilliant move.

At Dr. Peterson’s invitation, Dr. Unger stayed following a routine site visit to hear the presentations from Simmaron’s Scientific Board and attend the patient gathering.  At the patient meeting she had some good news; the first paper from the ME/CFS experts multisite study was finally under review for publication.

It had been a long time coming. Simmaron and Dr. Peterson are already deeply immersed in the greatly expanded second phase of the trial, and had just gotten a contract for the third phase of the study. The study was already slated to continue at least into 2017 and now will continue further.

This now immense study involving over 800 patients and controls will surely supplant the infamous PACE trial as the largest and longest ME/CFS study ever done. With a third phase slated to begin shortly, it’s going to provide an unprecedented look at a very large group of ME/CFS patients, and how they are tested and treated by doctors over time.

Dr. Unger quickly went over a few of the highlights; the greatest heterogeneity, surprisingly, was found within the ME/CFS expert’s sites, not between them. By and large, the practitioners are not seeing different kinds of patients; instead each is seeing a similarly wide variety of patients. How wide? The standard functional tests being done, for instance, indicate that some people with ME/CFS experience high rates of pain while others experience no pain at all.

The constant is that ME/CFS is producing high reductions in vitality and physical functioning but has relatively little effect on mental or emotional functioning.  Dr. Unger said the multisite studies will go a long way to helping the public understand how severe a disease ME/CFS is.

Konstance Knox  

Konstance Knox, PhD, is collaborating with Simmaron on her insect infection study at Coppe Healthcare. She posited the interesting idea of ME/CFS having a similar trajectory to Lyme Disease. Lyme Disease,she noted, first showed up in pediatrician’s offices in children with arthritis in Old Lyme, Connecticut in the 1970’s.  Eventually the children were found to be infected with bacteria carried by ticks.

KKnox

ME/CFS patients have been showing up in doctor’s offices with unexplained fatigue, post-exertional malaise, pain and debilitating symptoms for years. Could a similar scenario prevail for at least a subset of ME/CFS patients? Knox thinks it might. Her large study, using samples from 300 ME/CFS and healthy controls gathered in the NIH’s XMRV study, is looking for evidence of pathogens that aren’t always tested for in chronic fatigue syndrome (ME/CFS). They include three different kinds of Borrelia bacteria, the Powassan and Dengue viruses, and the most widespread insect borne disease in the U.S., West Nile Virus.

Each demonstrates how rapidly insect borne pathogens can invade a country. Borrelia was identified as the cause of Lyme in 1981, and according to one estimate, is believed to effect 300,000 people a year.  West Nile Virus was first found in New York in 1999 and has spread across the country.  Now the Zika virus is beginning to touch upon our southern shores in Florida as well.

In Dr. Knox’s mind, the Powassan virus is the big mystery. Carried by the same ticks that cause Lyme disease, Powassan is similar to tick-borne encephalitis virus which has long been shown to cause serious illnesses in Eurasia.

Unlike the Lyme bacteria, which needs the tick to be attached for quite some time for the bacteria to get transmitted, the Powassan virus can be transmitted in just 15 minutes. Knox found that 11% of the 2,000 ticks she studied in Wisconsin  carried Lyme disease and 6% carried the Powassan virus.  She found 55% of people infected with Lyme disease also were infected with the Powassan virus.

Dr. Knox’s preliminary data of ME/CFS patients with an acute flu-like onset found a low incidence of Lyme disease (3%) but a pretty high incidence (11%) of people who had antibodies which looked like they might be to TBEV; i.e. the Powassan virus. The NIH samples offer an opportunity to study these infections in well characterized patients and controls from multiple clinical sites.

Dr. Mady Hornig

The Hornig/Lipkin team at Columbia’s Center for Infection and Immunity (CII) isn’t just looking at ME/CFS to understand the disease. It’s mining clues from a wide range of disorders – from autism to narcolepsy – to try to understand the disease processes that are occurring. They believe the “omics” revolution – which attempts to understand diseases in terms of their genomics, proteomics, metabolomics (and probably other “omics”) – holds the key to understanding and finding the subsets present in ME/CFS.

Mady Hornig sits on the Simmaron Research Foundations Board. She and the Simmaron Research Foundation are frequent collaborators. Until they get to a cause, Dr. Hornig is unwilling to rule out any possibilities. ME/CFS could be caused by an immune response to a wide range of pathogens (which may be present or not) or to an as yet undiscovered agent. That statement suggested that Dr. Hornig doesn’t consider the earlier CII study which found little or no evidence of pathogens to be the end of the story.

Of course few researchers have looked in the tissues. Dr Chia believes he’s found enteroviruses and Dr. Duffy herpesviruses in the gut tissues of ME/CFS and/or fibromyalgia patients. Hornig and Lipkin have looked in the blood but they’re also raising money to do analyses of the flora in the stool and saliva over time. (Check out the Microbe Discovery Project  for more.) Plus, as we’ve seen, a Simmaron/Konstance Knox project is looking for evidence of insect borne illnesses that have not been tested for before.

If  pathogens are involved, the heterogeneity in the disease could reflect genetic differences in how each person responded to them, how old the person was when the infection occurred, the state of each person’s microbiome at the time, etc.  The take-away message was that different symptoms don’t necessarily mean different diseases.

The CII is doing a lot, but Dr. Hornig started out by focusing on a hot topic these days – metabolomics.  The CII team believes that metabolomics may provide the link between what’s happening in the microbiome and the rest of the body. Metabolomics uncovers the breakdown products of metabolism. If a substance, say tryptophan is not being metabolized properly in the gut, it can leave a metabolic signature in the blood that can be picked by metabolomics tests.  From the blood it’s apparently a pretty straight shot to the brain.

Marrying gut (microbiome) and blood (metabolomics) data would be the cat’s meow, and it’s begun to happen. Several small studies have been able to link altered gut bacteria to the presence of gut metabolites in the blood.  A small Solve ME/CFS Initiative study carried that idea one step forward by adding exercise to the mix. It suggested that exercise could, probably by increasing leaky gut issues, result in increased levels of gut metabolites in the blood.

Dr. Hornig believes that aberrant tryptophan metabolism in the gut could provide a major clue for ME/CFS patients.  These metabolic by-products have already been associated with several neurological diseases and are known to cause symptoms similar to those found in chronic fatigue syndrome (ME/CFS). If she finds problems with tryptophan metabolism in the gut and then can pick up their metabolic by products in the patient’s blood she can make a strong case for a gut-brain connection in ME/CFS.

While she was at it, she also noted that these bacteria can affect NAD+ and energy production.  To sum up, Dr. Hornig is gathering data on a process that could be affecting cognition, the gut and energy production in ME/CFS.

No Mady Hornig talk it seems is complete without an emotional moment. Every event I’ve seen her at has left her and others in tears at some point, and it happened again. I watched an older gentleman come over and clasp her hands. Five minutes later there they were hugging each other and sobbing away.

Top Poop Crew

Dr. Peterson and Simmaron won the top poop collector award

Dr. Peterson and Simmaron won the top poop collector award

While on the microbiome she noted, with a smile, that of all the groups they were working with, Simmaron was the best poop collector; Dr. Peterson gathered more stool samples (hundreds of them apparently) from more patients than any other doctor they were working with. (Go Simmaron :))

Maureen Hanson

Maureen Hanson, PhD, presented some  interesting news recently when she announced during an SMCI webinar that her small metabolomics had duplicated the Naviaux study’s core finding that ME/CFS was a disorder of reduced metabolism; i.e. it’s a hypometabolic disorder.

Maureen Hanson

That finding helps us understand her Simmaron talk a bit better. Hanson explored the subset question more deeply than anyone I’ve seen before.  Chronic fatigue syndrome (ME/CFS), she said, could be a bunch of different diseases, or one core pathology could be driving it.

Whatever it is, the diversity of symptoms found in the disease has produced a credibility problem because diseases which produce lots of symptoms have long been considered “psychosomatic”. The many different triggers ME/CFS and outbreaks has been associated with, and the many different bodily systems it effects, have been confusing as well.

Hanson thought it was intriguing that the symptom presentations seen in different locales appears to be similar! If ME was the result of different agents producing different diseases in different places then the locales should look very different but they don’t.  Hanson then fished out a bevy of factors which could affect symptom preSimmaron Research | #ShakeTheCFSstigmasentation; the age at which ME/CFS occurred, gender, genetic background, co-infections present, pathogen variations, treatments tried, degree of exercise attempted – all of these could conceivably tweak one disease into producing different symptoms. (Consider what happens to some people who collapse and appear to revert to a different state after overexertion or after using the wrong drug.)

She noted that her mitochondrial DNA study suggested that slight alterations in ME/CFS patients’ mitochondrial DNA could result in different symptoms. That sure presents just the tip of the iceberg with regards to genetics.  (Ron Davis and the Open Medicine Foundation will be attempting to marry genetic data and metabolomics in one of their studies.)

Hanson’s microbiome project was powered by a small NIH grant and took place in a Cornell lab famous for its microbiome work.  The project was a small one but it made a big splash and was picked up by over 50 media outlets.

The study’s finding – a reduced diversity of bacterial species (about 20% less) similar to that found in two potentially devastating gut diseases (Crohn’s and ulcerative colitis) gave Hanson the opportunity to tell the media again and again that ME/CFS is a real disease.  The study also found that ME/CFS patients’ gut bacteria tended to be more dominated by a smaller number of bacteria.

Bacteria of the Ruminococcaceae family –  important in fighting inflammation  – were significantly reduced in ME/CFS.  The representatives of another bacterial family called Enterobacteriaceae – which contains some rather nasty pathogens but hundreds of other species – doubled in ME/CFS patients.

At the genus level, Faecalibacterium prausnitzii, a butyrate bacteria, which produces an anti-inflammatory protein and protects the intestine was reduced in ME/CFS. A similar finding is found in irritable bowel syndrome.

The low butyrate findings in both Hornig and Hanson’s microbiome studies suggest they are both on the right track. That’s actually a big win given how complex (and new) microbiome analysis is, but perhaps it is not surprising given the pedigree of the labs doing the analyses.

As did a Solve ME/CFS Initiative study, Hanson also found evidence that gut materials were leaking into the blood of ME/CFS patients – a process that could spark an inflammatory process that makes its way all the way up to the brain.

[Butyrate – One neurobiologist calls butyric acid – which is produced by butyrate bacteria – “an ancient controller of metabolism and inflammation”. He reports that butyrate is the primary source of energy for the lining of the large intestine. Butyrate is such an effective anti-inflammatory that butyrate enemas (which reportedly smell horrible) and oral supplements are being used to combat inflammatory bowel diseases like Crohn’s and ulcerative colitis.  Butyrate also appears to reduce intestinal permeability – which Hornig’s/Lipkin’s and Hanson’s studies suggest many be happening in some people with ME/CFS.

Butyrate may also increase the levels of T regulatory cells which help reduce inflammation and autoimmune processes.

Hanson is a careful researcher and she spoke carefully regarding treatment. She noted that the inability of researchers at this point to clearly determine which gut species are present hampers them from recommending treatments. They can determine which families are present but because bacterial families can contain many different kinds of gut species -some of which have opposite functions – the study’s impact on treatment recommendations is not clear.

Atypical vs Typical Patients – the Peterson Subset

For many years Dr. Peterson has speculated about what he calls typical vs atypical ME/CFS patients. It’s not clear to me what the groups consist of but my sense is that  typical ME/CFS patients tend to plateau over time and they tend to have familiar co-morbid disorders such as fibromyalgia, migraine, IBS, etc. Atypical ME/CFS patients, on the other hand, tend to have other serious disorders and/or have really serious cases of ME/CFS. Whitney Dafoe and Corinne Blandino are two examples of atypical patients; Whitney because he’s so ill and Corinne Blandino because she has a strange spinal lesion.

Dr. Peterson

Dr. Hornig reported earlier that a cerebral spinal fluid (CSF) tests results had found dramatically different results.

At another event, Mady Hornig talked about the dramatic differences found in the CSF of classical versus atypical patients. Virtually all the immune factors tested were higher in the complex atypical vs the classical patients. In fact, the findings in the two subsets were so different that the atypical patients had to be removed from a study comparing healthy controls and ME/CFS patients. Simmaron and the Center for Infection and Immunity have taken a deeper look at the cerebrospinal fluid in these two types of patients.

I asked Dr. Hornig if she thought the atypical patients had a different disease or were an offshoot of more typical patients? She simply said that she thought that the atypical patients needed to be more closely watched.  Later Dr. Peterson suggested, however, that they may be profoundly different biologically.

We should know more about the similarities and differences between these two subsets soon. A Simmaron/CII spinal fluid study comparing the two in greater detail has wrapped up. The metabolomics data from the Ron Davis/Open Medicine Foundation severely ill patient study and the Naviaux study examining more typical ME/CFS patients will give us some guidance as well. Plus, the CDC will be comparing the test results of severely ill patients and healthy controls in the third phase of its multisite study.

A talk with Dr. Peterson found him in a more optimistic frame of mind than I’d seen before. While the promised funding package at the NIH hasn’t shown up yet, he was clearly impressed by the Nath Intramural study, the continuing work of the CDC, and the work Ron Davis is doing at the Open Medicine Foundation.

We didn’t talk about Ampligen and Rituximab but advances with both those drugs may make his job easier. Peterson’s stated that his patients have about a 70% response rate to Ampligen. That high percentage probably reflects two things: Dr. Peterson’s feel for who will respond to the drug, and his ability to dose this drug optimally for each patient.

At the IACFS/ME Conference, Hemispherx Biopharma will report a breakthrough in their understanding of the drug effects in ME/CFS. It appears that they’ve found a way to identify which ME/CFS patients respond to Ampligen – a finding that should help doctors and patients decide whether to try the drug, and make their next clinical trial that much easier. Dr. Patrick of Canada appears to have done the same with Rituximab – a very expensive powerful drug that many doctors are probably leery of trying in their patients without more guidance.

  • Dr. Peterson will be co-leading a session with Drs. Fluge and Mella on Rituximab and Emerging Treatments, and will be a panelist on a session devoted to diagnosing difficult cases of ME/CFS, and will be highlighting a fellowship opportunity with Simmaron, at the International IACFS/ME Conference at the end of October.

With groundbreaking spinal fluid publications, more collaborative studies lined up, and additional findings on their way to publication, the Simmaron Research Foundation (SRF) has made pivotal contributions to the rising science of ME/CFS in its first five years. The Simmaron Research Foundation is committed to translational research efforts that produce solid gains for patients. With collaborators like these, the next five years promise much.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS

Post Lyme Disease and Chronic Fatigue Syndrome (ME/CFS) – Are They The Same?

August 6, 2016

Post treatment Lyme disease syndrome (PTLSD) occurs when someone is treated for Lyme disease but never recovers. This mysterious illness has all sorts of possible interconnections with chronic fatigue syndrome (ME/CFS). Symptomatically it’s quite similar, and of course, as so often occurs in ME/CFS, it’s triggered by an infectious event, from which one never recovers.

The list of possible infectious triggers for chronic fatigue syndrome is a long one (Epstein-Barr virus, parvovirus-B, enteroviruses, Giardia, Ross River virus and others). (With the Simmaron Research Foundation involved in a study looking at the incidence of insect borne diseases in ME/CFS more infectious triggers may be added to the list.)

lyme disease

Is chronic Lyme Disease the same as chronic fatigue syndrome (ME/CFS)

Some think Borrelia burgdorferi – the pathogen causing Lyme disease – should be on that list. Lyme disease is transmitted by a tick carrying the Borrelia burgdorferi bacteria. Early on the bacteria can cause a red spreading rash and fever, muscle aches, headaches, fatigue etc. If untreated it can cause some horrific problems but even if treated it can cause lifelong problems in some.

That suggests that a problem with the immune response may be involved. Like ME/CFS the symptoms of post treatment Lyme disease syndrome (PTLSD) very much look like immune symptoms. Typically when researchers assess immune functioning they measure cytokines and other immune factors but these researchers and others like them are more and more taking a different route.

Cytokines can help us understand what’s happening in the immune system but they don’t tell us what is causing the problem. Examining the genes that turn on those cytokines (and many other genes) might. At the very least it provides researchers with a much wider inquiry.  The upside to this kind of inquiry is lots of information – and so is the downside; researchers have to filter through that information to figure out what is relevant and what is not – not an easy task.

It is a task, though, that more and more researchers inside and outside the chronic fatigue syndrome field are embracing.  In this case a look at the gene expression of people who came down with Lyme disease and then were treated for it proved to be quite illuminating.

The Study

Using “next-generation” techniques this study examined the gene expression of the PBMC’s in the blood

  1. just after people got Lyme disease
  2. three weeks after they get treated for it
  3. and then six months later.

This same kind of study has been done twice in ME/CFS to mixed results. In this case the results were exciting enough for the Director of the NIH, Francis Collins, to devoted one of his recent blogs to it.

Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease. Jerome BouquetaMark J. SoloskibAndrea SweicChris Cheadleb, Scot FedermanaJean-Noel BillauddAlison W. RebmanbBeniwende Kabrea, Richard HalpertdMeher BoorgulabMBio. 2016 Feb 12;7(1):e00100-16. doi: 10.1128/mBio.00100-16.

The Results

The study revealed the startling fact that even after antibiotic treatment almost half the patients (13/29) had lingering effects (new-onset fatigue, widespread musculoskeletal pain involving ≥3 joints, and/or cognitive dysfunction) from the infection six months later. Four met the new criteria for post-treatment Lyme Disease Syndrome (PTLDS). (See the new criteria which is similar to some ME/CFS and FM criteria here. )

The infection initially caused a massive change in gene expression involving over 1200 genes. Surprisingly three weeks of antibiotic treatment, which presumably had wiped out the bacteria, the gene expression was still greatly altered with over 1,000 genes acting up (or down) in the Lyme disease patients.

A pathway analysis indicated that the types of genes one would expect to get involved with an infection did; the inflammatory, immune cell trafficking, and hematologic system pathways were all upregulated.

lyme-gene-expression

Lyme triggered a massive and possibly permanent change in gene expression

The big surprise, though, came in the last blood draw which showed that six months after treatment the gene expression of the Lyme patients (well and ill) and the healthy controls was still quite different.  The researchers clearly expected that six months after the antibiotic treatment, with many former Lyme patients fully recovered, that they would look, once again, like the healthy controls but they didn’t.

Some important immune genes had been turned off; genes associated with the toll-like receptors which alert the body to a pathogen, for instance, were no longer activated. Almost 700 other genes, however, were still significantly upregulated or downregulated in the Lyme disease patients.

This suggests, as we’ve seen before, that significant infectious events can have long term consequences.

The gene expression analysis, unfortunately, provided no clues why some people with Lyme disease recovered after antibiotic treatment while others remained ill. That was probably due to the fact that only four Lyme patients meet the criteria for post treatment Lyme disease syndrome (PTLDS); i.e. the sample size was very small and that small sample size brings up a question.

A Missing Group?

Where to draw the line symptomatically between a disease and non-disease state has dogged ME/CFS researchers since the disease began. A more stringent criteria has the benefit of ensuring that a more ill patient group is identified but it can also cut out those who are still ill. That may have happened with this Lyme study.

In the beginning of the article, the authors asserted that Lyme patients who remained ill after antibiotic treatment were a) a minority and b) unusual. They stated that these patients tended to have more severe symptoms in the beginning, had greater spread of the pathogen through their body, and had had delayed antibiotic treatment. The vast majority of Lyme patients (about 90%) who were treated appropriately with antibiotics, on the other hand, tended to “recover rapidly and completely”. 

This study, however, found that almost half (13/29) the Lyme disease patients, all of whom were presumably appropriately treated with antibiotics, said some of their symptoms persisted at six months.  Because they didn’t meet the PTLDS criteria they weren’t included in the analysis between recovered and non-recovered patients. (Apparently they were included in the recovered group.)

Nor would they be included as post-Lyme disease patients by a doctor using the PTLDS criteria, and might very well be considered depressed, malingerers or whatever. This not to say the PTLDS criteria is a bad one; it’s designed to produce a group of quite sick post Lyme patients for studies, but that criteria – particularly any criteria based on symptoms – is going to have problems.

Disease Similarities

The study indicated that the gene expression responses to an infection can vary dramatically  and in unexpected ways. The researchers compared their gene expression results to those of five other infections.

Early in the disease, for instance, Lyme disease looks more like viral influenza than other bacterial infections such as Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. (Even with influenza, though, the response at the gene level is far different with the two infections sharing just 35% of activated/downregulated genes.)

pathogens chronic fatigue syndrome

This study indicates that infections can cause surprising results at the gene expression level.

All five of the infections analyzed did trigger the upregulation of two immune pathways (TREM1,TLR) involved with infection but interferon signaling pathways – often believed to be active in viral infections – were upregulated only in Lyme disease and influenza.

Genes identified with activated B-cell pathways were prominently featured in the early phases of all the infections except for Lyme disease.

Plus, Lyme disease was the only disease to exhibit a down-regulated EIF-2a (cellular stress response) pathway. Because that pathway was down-regulated at all three blood draws it could play a major role in Lyme. The fact that the same pathway is down-regulated in lupus suggests Lyme disease could have something in common with autoimmune disorders and the authors suggested a lupus treatment might be helpful in Lyme. )

The takeaway message is that the body’s response to an infection is probably unique to that infection. That suggests that the many infections that trigger ME/CFS may produce very different gene expression responses – and that many different pathways to ME/CFS may exist. Whether they all merge upstream at some point to produce ME/CFS or if a bunch of entirely different pathways to ME/CFS exist is a question that can’t be answered at this time.

The Chronic Fatigue Syndrome (ME/CFS) Connection

At the gene expression levels Lyme disease appears, at this point, anyway, to be little like ME/CFS. While some similar pathways were seen in the two diseases in the end only 18% of the same genes and about a third of the same pathways showed up in both diseases.

At this point Lyme disease looks much more like lupus (60% of pathways in common) than ME/CFS, and the authors suggested that circulating immune complexes might be a tie that binds those two diseases together.

I found two ME/CFS studies with a similar design; each assessed gene expression during an infection and then afterwards and then determined if the results varied between those who recovered and those who got ME/CFS.

An early small Lloyd study (2007)  found significant gene expression differences in those who developed ME/CFS after infectious mononucleosis compared to those who recovered. A 2011 gene expression study (n=36) by the same group, however, that compared ME/CFS patients with infectious onset (EBV, Ross-River, Coxiella virus) and healthy controls over time, found so little difference over time between still sick and recovered patients the papers ended stating that “further investigation of the peripheral blood transcriptome is not warranted.”

Some researchers beg to differ. Five years later with several groups (Ron Davis – Open Medicine Foundation, Derya Unutmaz – Bateman-Horne Center,  Lipkin/Hornig – Center For Infection and Immunity, Nath – Intramural NIH Study and Dr. Montoya – Stanford ME/CFS Initiative) are mounting major efforts to understand the ME/CFS “transcriptome” and other “omes” using better techniques.

genomics chronic fatigue syndrome

Genomics and other “omics” studies will provide new and probably unexpected insights into ME/CFS and other diseases

Unutmaz, for instance, proposes to use gene expression and other technologies to uncover immune subsets that he believes will irrevocably alter how ME/CFS is viewed and studied. Some time ago, he threw some samples from the Solve ME/CFS Biobank into his big immune machine. The data that popped out was enticing enough for him to spend a considerable amount of time working up an NIH grant proposal. That work paid off and he recently scored a major grant from the NIH.

While the Lyme disease study didn’t help researchers understand what goes awry in people who are still sick after getting an infection (and after being treated for it) – which is what we really want to know – a larger study is underway to determine that.  Researchers were also working on identifying 50-100 genes they hoped could finally produce a early diagnostic test for Lyme disease.

The study demonstrated the power of this technology to reveal new things about disease. Several things popped out in this study that weren’t expected:

  • Every infection probably triggers a unique response
  • a Lyme infection may irrevocably change how our genes are expressing themselves (even after treatment)
  • Early in the course of the disease Lyme looks more like viral influenza than other bacterial infections
  • Lyme disease has some important similarities to lupus and rheumatoid arthritis that could suggest new treatment possibilities
  • That some commonalities exist between ME/CFS and Lyme disease but the diseases appear more different than similar

Seeing gene expression differences emerging between different infections suggests this work provides a kind of precision that we very much want to see.  That precision, though, requires an enormous amount of data, and with that ironically, can come some muddiness.  Where gene expression has generally let us down in ME/CFS has been the difficulty of  consistently identifying the specific genes on which the disease may turn.

Hopefully the more powerful machines and analytic techniques being used by ME/CFS researchers will help provide the diagnostic biomarkers and new treatment options that other research efforts have not been able to. If this study is any indication, as researchers dig more deeply into the molecular underpinnings of ME/CFS, we’ll probably be in for some surprises.

The Other MEGA Chronic Fatigue Syndrome (ME/CFS) Project: Dr. Hornig Talks

June 29, 2016

Three MEGA chronic fatigue syndrome (ME/CFS) projects (The OMF’s Severe ME/CFS Big Data project, NIH’s Clinical Center Study, The UK’s Grand Challenge) were recently discussed on Health Rising, but another “mega” project exists.

They all have some similarities. Like the others, the mega project underway at the Center for Infection and Immunity (CII)  is attempting to get at the molecular roots of chronic fatigue syndrome (ME/CFS). Like the others it’ll be searching through vast amounts of data in an attempt to uncover the unique biological signature(s)

personalized medicine

The CII hopes to develop a molecular signature of ME/CFS

Like the Open Medicine Foundation and NIH Clinical Center projects, some of the technology has been developed in-house. We’re blessed with the attention of some of the most innovative researchers in the world.

Let’s take advantage of a recent talk by Simmaron Researcch Foundation Scientific Board member Mady Hornig in Sweden and check out the CII’s big plans for ME/CFS. (A transcript of the talk is provided  on the striking, new Microbe Discovery website).

We learned recently that the internationally renowned Ian Lipkin is all in for chronic fatigue syndrome (ME/CFS); that his bucket list includes just two diseases: ours and autism.  Mady Hornig certainly didn’t skimp on her vision for ME/CFS at the talk either; she wants to create a Center of Excellence for ME/CFS at the CII, and hopes that the large array of studies the Center is engaged in will lay the foundation for that.

You can’t have research centers without funding, though. The NIH has been very responsive recently, and the big Clinical Center study is very exciting, but extramural funding is where it’s at and little money thus far has flowed to outside researchers. Last year Ian Lipkin and Mady Hornig in one of the weirdest grant awards ever received money for sampling but no money for analysis (?) –  and then had to drop in 500 K in to complete their sampling. It’s no wonder then that Mady Hornig (six months ago) referred to a “crisis” in funding. This, of course, is a crisis that’s been present for over 20 years.

Times are changing, though, and hopefully we’ll get some good news soon about the Trans NIH Working Group’s”strategy to reinvent ME/CFS at the NIH.

Even with this dearth of federal funding the CII, with the help of the Chronic Fatigue Initiative (funding metabolomics, proteomics, immune signatures, pathogen discovery projects), the Microbe Discovery Project, the (microbiome), the Stanford program (pathogens), the Simmaron Research Foundation (spinal fluid) and others, has put together a megaproject – a diverse, multidimensional attack focused on getting at the molecular underbelly of ME/CFS.

Check out the different stabs at ME/CFS the group is taking.

pathogens chronic fatigue syndrome

Dr. Montoya said last year to prepare for some exciting results in the pathogen study.

The Pathogen Slant  – in a very large study, the CII using PCR, Mass Tag PCR  (developed in Lipkin’s laboratory) and high throughput will scan for 1.7 million agents in, if I’m reading it right, 800 patients and controls. In his Spring 2015 and 2016 newsletters, Dr. Montoya said to expect some exciting results. They’re looking at viruses, bacteria, and for the first time ever in ME/CFS, fungi.

The Gut Plus Slant – (n=100) -The CII expects their microbiome analysis of the bacteria and fungi in gut will tell them a lot about immune functioning. It turns out that no less than 60% of our immune cells travel through and get altered by bacterial metabolites in the gut before they make it to the blood. They’re also looking at the throat area to see what this common collection point for pathogens might tell them. The CII has finished their first analyses of their initial gut study: the results were apparently good enough for the team to expand their study and begin taking multiple samples from the same patient over time.

It’s this kind of rigorous, dogged, longitudinal approach to ME/CFS – which no one by the way as ever done before – that they hope will put them first in line for a Center of Excellence. I don’t think anyone, ever, has watched the immune and microbiome systems over the length of time (12-18 months) the CII is. It would be very hard, indeed, to discount any pattern that consistently showed up over that period of time.

Plus, they’re building quite a biobank of samples at the same time. The CII will surely be at the top of the NIH’s list of potential ME/CFS research consortiums.

The Autoimmune Slant – Autoantibodies could conceivably be behind everything that happens in ME/CFS. The CII will be looking for autoantibodies to human cells and  pathogens including viruses, bacteria and fungi. This will allow them to dig up evidence of past infections that may have triggered ME/CFS. Their search will also include those adrenergic autoantibodies recently found in POTS patients that dysregulate their heart rates.

genes

Genetic, immune and pathogen data could come together to form a model for ME/CFS

The RNA Seq / miRNA – Gene expression Slant – Gene expression tells  us which genes are doing what. This study will determine what’s happening with the immune genes in ME/CFS. Right now we might guess they’ll see increased immune gene expression early in the disease and reduced gene expression.

Since studies have shown that unique patterns of gene expression or genetics predispose people to prolonged courses of illness after an infection, this study is ripe with promise.  (If I’m reading this right a paper should be out in the not too distant future.)

The CII could end up identifying:

  1.  pathogens that kick off the illness
  2. a pattern of gene expression that makes ME/CFS patients particularly vulnerable to that pathogen and
  3. the autoimmune reaction that grew out of an inadequate immune response that failed to quickly dispatch the pathogen.

Itraq / MRM Metabolomics ( amino acids, kynurenine, serotonin) Slant – The CII is particularly interested in how metabolomics (the search for metabolites in the blood) may be able to tell them what’s happening in gut.

tryptophan-kynurenine pathway

Some results suggest the kynurenine pathway has gotten turned on in ME/CFS

The L-tryptophan and the kynurenine pathway is a particular focus.  L-tryptophan should metabolize into serotonin, a feel good chemical involved in sleep, sex drive, vigilance and mood regulation. L-tryptophan, however, can also be captured by the kynurenine pathway which metabolizes it into some nasty products (bye-bye good feelings). The kynurenine pathway has popped up in an array of neurological and neuropsychiatric diseases.

Dr. Hornig noted their metabolomic analyses suggest the kynurenine pathway is alive and well in some ME/CFS patients. In a prior talk, she reported that their early data suggests that a subset of people with ME/CFS with low serotonin have increased immune activation ( IL-1 beta, TNF alpha, IL-12p40, and L-17F) as well.

Interestingly, interferon gamma (IFN-y) (see below) – an antiviral and proinflammatory activating cytokine, and TNF-a – a powerful pro-inflammatory cytokine, both of which may have become activated early in the disease, both push tryptophan metabolism into the kynurenine pathway.

Dr. Hornig said they were “very keen” to understand tryptophan’s role in ME/CFS.

Cytokine and Immune Arrays Slant  – They are or will be examining a wide array of cytokine levels over time to pluck out the most consistent contributors to ME/CFS.  Many people are interested in the role the autonomic nervous system plays in ME/CFS but the Lipkin/Hornig group may be the first to examine the role the immune system plays in causing  the ANS  issues and/or problems with orthostatic intolerance.                                                                                                                                                                                                                                                                               Allergy related cytokines (IL-4, IL-13, IL-17A, IL-10, Eotaxin) that can affect histamine production and alter blood pressure have popped up in their studies (and eotaxin has popped in other studies). Histamine, of course, can have devastating effects of blood pressure and circulation.  Dr. Hornig believes some of the “systemic fatigue” in chronic fatigue syndrome could originate here.

Simmaron

Similar results in spinal fluid and blood tests would provide a powerful validation for immune dysregulation in ME/CFS

The Spinal Fluid Slant – The Simmaron/CII study was not only the first study ever to document similar immune changes in the blood and spinal fluid, but it also introduced two new subsets; Dr. Peterson’s typical / atypical patietnts.  Dr. Lipkin was so high on expanding the spinal fluid study that he flew out to Lake Tahoe for the first time in 20 years to rally support for it.

An expanded Simmaron/CII spinal fluid study with more participants and more testing is underway. Should testing reveal similar findings in the spinal fluid and the blood again, a powerful message would be sent that ME/CFS is a immune disease.

Treatment

People with shorter duration illnesses could possibly benefit from  antibodies to IL-17A or interferon gamma that could  reduce their hyperactive response to these cytokines. Many commercial antibodies, in fact, are now available. If Hornig/Lipkin can validate upregulated IL-17A or interferon gamma is present those treatments could become available to people with ME/CFS.

For the longer duration patients Dr. Hornig suggested that increasing the immune response by using Ampligen or [ an IL-1 receptor antagonist could be helpful.

Networking

The immune system doesn’t just poop out in the longer duration patients – it kind of goes bananas. An immune networking comparison in short vs longer duration patients suggested  a very focused and active immune network existed in short duration patients. In the longer duration patients, though, a much more complex immune network featuring many down-regulated immune pathways was present. It’s the stark a portrayal of these two subsets that I’ve seen.

surprise results

These big data studies may result in some surprises popping out.

Biomarker? – Despite the fact that interferon gamma levels were not particularly high they were incredibly predictive of short duration patients. That suggested, as Jarred Younger’s and Gordon Broderick’s work has suggested, that context is the key. It’s possible that increased IFN-y in the context of ME/CFS has unexpectedly strong effects.

Remember This – A big surprise in the longer duration patients spinal fluid was the almost complete disappearance of IL-6, a cytokine needed for memory storage and retrieval.  The IL-1 receptor- antagonist (IL-1ra) was very low as well. That was an intriguing finding given that (a) the network analysis suggested that IL-1ra was a key down-regulating element in ME/CFS and (b) drugs such as Anakinra could boost it back up – and presumably stop the central nervous system down-regulation.

Conclusion

The Center for Infection and Immunity, led by Dr. Lipkin and Dr. Hornig, is engaged – largely thanks to the Chronic Fatigue Initiative as well as the Simmaron Research Foundation – in the third mega study of ME/CFS under way. Among the unique elements of this project are it’s continuing spinal fluid component, it’s strong focus on the gut and the kynurenine pathway, and it’s long term longitudinal study that could prove pivotal in validating ME/CFS as a disease.

The CII’s strong blood immune and spinal fluid studies last year probably helped the NIH agree to reinvigorate ME/CFS research. Hopefully, that’s just beginning of the role the Center will play in deciphering ME/CFS. Boasting one of the most extensive research efforts on ME/CFS, it surely it’s a strong candidate to be one of the ME/CFS research consortiums we hope will get funding.

Next Up – the Center for Infection and Immunity Replies to the NIH’S Request for Information on the next steps for ME/CFS

 

Making the Case for Ampligen in Chronic Fatigue Syndrome (ME/CFS)

Ampligen has been in the FDA pipeline for so many years that it almost seems like a mirage at this point. The ME/CFS community has been praying, hoping, believing that Ampligen will be its first FDA approved drug for over twenty years. For a lot of people that hope may have died, but the drug has gotten new life recently.

A Little History

If Ampligen has failed to gain approval at least it and the company have been entertaining. Ironically, given its long and rather harrowing path through the FDA, Ampligen’s first use in an ME/CFS patient was prompted by none other than the FDA. After an ME/CFS patient with culture evidence of HHV-6 infection significantly improved clinical trials began.

Ampligen has trod a difficult path at the FDA over the past twenty years.

Ampligen has trod a difficult path at the FDA over the past twenty years.

Problems occurred early on, however, when Hemispherx Biopharma, the drug’s maker, cut the trial duration in half, and ME/CFS patients sued at one point to get access to the drug. The early Ampligen trials in chronic fatigue syndrome ultimately sparked the publication of a hilarious novel by Floyd Skloot, Patient 002.

The company came under fire early. In the early 1990’s CAA President Kim Kenney (McCleary) said “Ampligen is a good drug in the wrong hands”.  Daniel Hoth, then head of the National Institutes of Health’s AIDS drug program, went further when he told the Wall Street journal that “no professional drug company with any degree of professionalism would ever develop Ampligen the way it was developed by HEM.”

Difficult Path

Hemispherx Biopharma, though, has never had an easy time of it. In what surely must be a record for frustration for a drug company, Ampligen was moved to a different section of the FDA four times; each move eliciting a new review and different findings.

The FDA panel’s rejection of Ampligen in 2013 provided more head-shaking moments when two ME/CFS experts  unexpectedly voted against it, and several non- ME/CFS experts (citing the community’s urgent needs) voted to approve it.

Hemispherx felt blindsided at the hearing by safety issues it been told had been addressed years ago, and which it didn’t feel it was given adequate time to respond to.  (Since then FDA officials have said safety is not a major issue). It’s no wonder the company has felt at times that the deck has been stacked against them.

With the FDA asking for large drug trials that HB lacked the funds to produce, Ampligen finally seemed to be dead, but a new push to understand ME/CFS at the NIH may be producing a sea change for the drug.

Patients Push FDA To Approve Drug

More than anyone, ME/CFS patients know of the cost of having no FDA approved drugs.  Patient outcry at the FDA denial of Ampligen in 2013 – including an 11-day hunger strike by patient Robert Miller, 5,000 signatures petitioning the FDA to reconsider, and thousands of emails from patients and Congresspeople flooding the FDA – prompted the FDA to conduct a Drug Development Workshop in 2014 and publish guidance for the industry on ME/CFS drug development.

The FDA’s effort to spur drug company interest in ME/CFS appears to have failed, however, leaving Ampligen still the only drug candidate within short-term reach of drug approval for a disease that the FDA acknowledges urgently needs approved treatments.

With NIH director Francis Collin’s commitment to reinvigorate  chronic fatigue syndrome (ME/CFS) research and mentioning the possibility of an NIH funded Ampligen trial, it’s time to take another look at the “first” drug for ME/CFS.

Renewal

Equels-Thomas

Thomas Equels has vowed to make the company attractive to investors

The Board of Hemispherx Biopharma (HB) responded to the new climate of interest by replacing its longtime President and CEO, William Carter, with its Chief Financial Officer, Thomas Equels. Equels vowed to whip company into better financial shape in order to attract investors who could help get Ampligen FDA approval. FDA approval of Ampligen, he declared was HB’s number one priority, and he would work arm in arm with the FDA to achieve that.

Ampligen

Ampligen is an immunomodulator that targets a portion of the immune system that fights viruses.  Ampligen’s producer, Hemispherx Biopharma, was surely cheered by  the assignment of a major NIH study  to a neuroinfectious disease specialist, Dr. Avindra Nath.

Ampligen’s use in ME/CFS is predicated on the idea that viruses and/or immune issues are playing havoc in the disease. Ampligen is a toll -like receptor three (TLR-3) inducer. The receptor it binds to are found on antigen presenting cells such as dendritic cells that have been exposed to pathogens.

The binding of the receptor activates hundreds of genes in a cell. The side effects from most TLR inducing drugs limits their effectiveness, but Ampligen is unique among these drugs in that it does not cause cells to produce large amounts of pro-inflammatory cytokines.

Efficacy

Reports of Ampligen’s ability to dramatically improve the health of some people with ME/CFS abound.

The 90,000 doses given safely through Hemispherx Biopharma’s compassionate care program to ME/CFS patients by a handful of doctors in the U.S. have produced some startling stories of improvement and recovery.

success

Ampligen’s success stories attest to the drugs effectiveness in some people

Anita Patton, Mary Schweitzer, Bob Miller and Kelvin Lord have all documented their Ampligen success stories. Several experienced significant improvement while on it only to relapse while off it.  Anita Patton essentially went from bed bound to normal functioning on Ampligen, back to being bed bound off of it, and then again to normal functioning when back on the drug.

Kelvin Lord’s story was perhaps most representative. He’s provided the most complete (and funniest) review of an ME/CFS patient’s experience with Ampligen in a series of blogs titled “The Ampligen Chronicles”.  Faced with rapidly deteriorating health, Ampligen was Kelvin Lord’s last shot at health. To his surprise and delight it worked.

It didn’t return this businessman, flight instructor, skier and parasailor to complete health, but Kelvin did progress from being barely able to walk to be able to work 6 hours and do 45 minutes of resistance exercises a day. His brain fog, orthostatic intolerance, canker sores and extreme fatigue disappeared. He was back to being a productive human being for a major part of his day – a huge jump. (Read about it here.)  Going from bed bound to productive is probably a bigger jump, it should be noted, than most FDA approved drugs provide.

(Find other stories in Health Rising’s Ampligen Resource Page.)

Of course, examples of Ampligen’s lack of efficacy can be found as well, but this is to be expected given the  heterogeneous nature of ME/CFS.  Until the subsets in ME/CFS can be targeted with treatments unique to them, treatment efficacy even for most effective treatments, is probably going to be fairly low – perhaps around the 30-40% mark found in Ampligen.

Studies

“The drug has not received a marketing approval despite the lack of proven efficacious agents in the treatment of this disease that can be severely debilitating and is estimated to effect over one million persons in the US.” The author

W.M. Mitchell, a Vanderbilt pathologist and HB Board member, recently published an overview of Ampligen in a pharmaceutical journal. (Mitchell recently co-authored a study which reported finding a significantly more accurate blood test for prostate cancer.)

Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me). Mitchell WM. Expert Rev Clin Pharmacol. 2016 Apr 5.

Thirteen Ampligen trails have been done over the past 20 years or so.  Nine occurred in severely ill prior fatigue syndrome patients; three of these were large multisite trials and five were open label trials measuring safety and efficacy.  All told over 830 different ME/CFS patients have received over 90,000 doses of Ampligen. Most of the patients in the studies had been ill for at least 6-9 years.

The results of the trials have been positive. The first 92 person trial found significant increases in Karnofsky performance scores (p<.001), quality of life, exercise tolerance and oxygen utilization during exercise. Ampligen receiving patients also used significantly less drugs to alleviate their symptoms than placebo receiving patients.

The number of patients seeking emergency room care demonstrated how severely ill the patients in the study were, and how helpful Ampligen might be if it were available.  Ampligen cut the number of patients visiting the emergency room in half (from 15% to <8%). The placebo patients stayed an average of eight days at the hospital, while the Ampligen receiving patients stayed an average of less than three days.

(In how many diseases would 15% of the patients in the clinical trial spend an average of 8 days at a hospital over the duration of the trial? This was a very severely ill cohort.)

exercise

Ampligen reduced exercise intolerance and increased oxygen utilization

The primary endpoint of next  234 person trial was exercise intolerance. The results, which barely reached the minimum standard of significance (p< .05/ p<.048), indicated that exercise tolerance increased on average about 22%. Overall Ampligen improved VO2 max results on the exercise test by 5.5%, and Ampligen receiving patients were able to stay on the treadmill for about nine minutes longer than placebo receiving patients.

Further analyses found 3 cohorts of patients with regards to exercise tolerance; high responders, mild responders and no responders. Overall patients on the drug improved significantly more than patients given placebo (p<.001).

As in the first study, hospital visits were significantly reduced in the Ampligen receiving cohort and Karnofsky performance scores were significantly increased.

The two clinical studies suggest that 30-40% of people with severe ME/CFS can be expected to get “clinical benefit” from Ampligen.

The trials were mostly successful, but did have their problems.  The company stopped the first trial early and then modified the second trial in midstream. Even though the second trial was successful a great deal of discussion at the FDA hearing involved why the trial was modified.  Records could have better kept as well.

From the ME/CFS communities perspective, though, the success of both trials  was paramount. Many felt the lapses should have overlooked given the urgent need for treatments in such a large and often disabling disease.  Many also felt that the positive testimony by doctors who had been using the drug for years should have been given more weight.

Conclusion

While there were some problems with the trials the drug did meet several important endpoints including increasing time on a treadmill and increased oxygen utilization. It should be noted that Ampligen has tried to move the needle on probably the most difficult factor of all to budge in ME/CFS: oxygen utilization during exercise.

Any drug providing clinical benefit to 30-40% of a population which has no approved drugs should be a slam dunk. (Less effective drugs have been readily approved in other illnesses). Hopefully, with new leadership, Hemispherx’s twenty plus year journey to bring Ampligen to market will end successfully, and the ME/CFS community will finally get its first drug approved.

 

 

 

 

 

 

 

 

 

New Hemispherx Prez Says Getting Ampligen Approval Top Priority

It seems like Hemispherx Biopharma – the maker of Ampligen – has been the under the gun for years.  Last year it settled a 2012 class action lawsuit alleging it made false and misleading claims about Ampligen. It endured another lawsuit in 2009 for more alleged federal securities violations. Last year it was called “a penny-stock firm with a penchant for hype” by Damien Garde at Fierce Biotech.

decline

Hemispherx Biopharma’s financial resources have declined recently

According to Investor Wired Hemipsherx’s net loss including non-cash effects, averaged about $12 million or $(0.05) a share in the first nine months of the last two years.With regards to cash, cash equivalents and marketable securities the company lost about $4 million in the first nine months of 2015  ($16,108,000 – $12,375,000).

The news has not been all bad, though. Hemispherx Biopharma was rated the ninth best performing health care stock of 2012. Citing Hemispherx’s ability to achieve additional patent protection for Ampligen in Europe through 2029, Investor Wired put Hemispherx Biopharma on its “Biotech Stocks to Watch List” at the end of last year. It’s all more of the roller-coaster for Ampligen and Hemispherx Biopharma.

The fact that Ampligen is even still around may be something of a small miracle.  It’s hard to envision a more difficult drug pathway than for a small drug company producing a drug for a controversial disease like ME/CFS.

It’s a telling sign of drug company wariness towards ME/CFS that decades after Ampligen was introduced, it’s still the only drug to go through the FDA approval process for the disease, and no other drugs are in sight. Until FDA approves the first medicine for ME/CFS, no significant investment in this disease will likely come from the pharma industry. Ampligen represents an important logjam in ME/CFS treatment that has to be solved.

For all the difficulty surrounding Hemispherx, it should be noted that the company managed to keep Ampligen alive long enough to hopefully take advantage of the changed landscape for ME/CFS.

Change at the Top

A new era for chronic fatigue syndrome (ME/CFS)  appears to be dawning at the NIH. With Francis Collins, the head of the NIH, taking the lead in the fight to understand and treat ME/CFS, a window of opportunity has opened for Ampligen.

Equels-Thomas

Equels declared that Ampligen is Hemispherx’s number one priority

Hemispherx Biopharma’s first move to capitalize on that opportunity was to fire its long time CEO and Chairman, William Carter (and two of his relatives) and elevate Thomas Equels, former Chief Financial Officer and Executive Vice Chairman to the Presidency.

Stating that it was re-examining its fundamental priorities, Hemispherx Biopharma’s (HB’s) board pledged it would implement a “strong financial austerity plan”.  (In 2014, Carter made $2,364,874 including about $2,000,000 in cash and a $894,000 bonus.)  Equels was given a mandate to “strengthen internal controls, achieve enhanced governance, and create an environment for greater stockholder value.” Equels was brought in, in other words, to institute a new era of efficiency and productivity in order to appeal to investors.

In an interview Equels stated that “commitment, integrity and cooperation” were to be the new bylines for Hemispherx. He made it clear – in fact, he repeatedly emphasized –  that Hemispherx Biopharma’s number one goal was getting FDA approval for Ampligen for chronic fatigue syndrome (ME/CFS). To that end, Hemispherx was developing an “overarching strategy” to pull in public and private investors to move the drug forward. Acknowledging that Hemispherx’s resources were limited at this point, he said he’d be pulling the plug on all non-priority activities.

That overarching strategy includes fixing Hemispherx’s strained relationship with the FDA. There’s been no love lost between the FDA and Hemispherx Biopharma. Several advocates told me they held their breath whenever the sometimes fiery Carter spoke at the FDA hearing. Some felt Hemispherx was treated unduly harshly, and not given the opportunity to respond when safety issues the company thought were resolved came to the fore.

race for Ampligen

Can Equels finally bring Ampligen across the finish line?

The FDA, however, acknowledges that ME/CFS community urgently needs drug options, and FDA officials have said that the safety issues for the drug have been resolved. Some advocates that have met with them believe they are eager to move forward on ME/CFS.

Equels said he’d met with Janet Woodcock at the FDA to understand where the FDA sees the gaps.  He pledged Hemispherx would be there “arms locked with FDA officials” to do what was necessary to move the drug forward.  Hemispherx officials also apparently quickly talked with NINDS chief Dr. Koroshetz  not long after NIH Director Collins announced the NIH would reinvigorate ME/CFS research.

At the end of the day, Equels said, we have a proven therapy – it’s about bringing it across the finish line.

Next up: Making the Case For Ampligen

(Disclosure: Hemispherx Biopharma has contributed funding to a project underway at Health Rising.)