All posts by Cort Johnson

Dr. Peterson Calls for “Therapeutic Strategy” to Develop Drugs for ME/CFS

“We’re Ready”

Dr. Peterson had 2 minutes to get to the point. And he did.

After 30 years of treating approximately 9,000 patients and tired of the ‘therapeutic stagnation’ in this disease, he called on the FDA to ‘execute a therapeutic strategy’ that would pave the way for drug development. No doubt speaking not just to the FDA but to drug company reps listening, he gave them good pragmatic reasons to do so; 1,000,000 sick people in the US, a $9 billion hit to our economy yearly, a market for a diagnostic marker yielding potentially $250 million a year, a drug therapy possibly bringing in billions….PetersonPhoto right

“I implore the esteemed committee to develop a therapeutic strategy for ME/CFS” Dr. Dan Peterson to FDA

Listen to Dr. Peterson at minute 92:00 of this VIDEO.

He didn’t ask the federal government to do it all  on their own. The ME/CFS physician community he asserted is ready to do its part.  They’re already using objective markers such as NK cell functioning, MRI’s, SPECT scans, low VO2 max tests to inform their therapies and they have formed the consortia and networks needed to take on pilot studies and multi-center Phase I, II and III clinical trials.

He was backed up by his longtime colleague, Dr. Nancy Klimas later in the meeting when she said ” much of what is needed to develop drugs for ME/CFS is ‘already in hand'; we have, she said, the ‘clinical trials groups’  who have ‘many, many years of  experience with these…instruments we’ve been talking about’. “There’s really no reason to delay any further”

“There’s  really no reason to delay any further” Dr. Nancy Klimas on targeted clinical trials for ME/CFS at the FDA Stakeholder’s meeting

The key problem is the large heterogeneous population that makes up the ME/CFS community.  Dr. Slagle of the FDA noted that the heterogeneity of the ME/CFS patient population made it necessary for researchers to  define and target specific subsets, but both  Dr. Klimas and Dr. Peterson asserted they’re ready, right now, to bring targeted therapies to bear on just those subsets.

This is all about one thing; scientifically redefining ME/CFS … wherever that takes us … and as long as it leads to treatments.

Scientifically Redefining ME/CFS SR Facebook logo new

Dr. Peterson’s report of Vistide’s success in a retrospective study of severely ill ME/CFS with herpesvirus infections constituted not just an attempt to provide better treatment options but to redefine this illness using biological variables; in this case a subset of patients with active  cytomegalovirus infections who responded to Vistide.

The Chronic Fatigue Initiative’s Hornig/Lipkin pathogen study will, with the addition of Simmaron’s spinal fluid samples, contribute to this process if they illuminate a distinct subset of patients with active viral infections, as suggested by Madie Hornig in Florida.  (Results are due within the next two months.)

Now comes convincing the pharmaceutical industry that it’s worth their while to invest in this disorder, and that’s where Dr. Peterson’s request for a ‘therapeutic strategy’ that will compel pharma to enter the market comes in.  That therapeutic strategy will involve the FDA  identifying endpoints for subpopulations and study designs that industry will have confidence in.Food_and_Drug_Administratio

Is the FDA ready to do that?

We’ll bring you more of the FDA meeting in coming blogs.

Your Brain on Viruses: Study Finds Even Common Viruses Cause Cognitive Declines

The ‘Manhattan Project’

The Northern Manhattan Study is an immense project that’s taking a deep look at health in Northern Manhattan, New York . The project consists of  analyzing basic health characteristics of several  thousand people over time and it’s spinning out studies at a dizzying rate.  The project is not on chronic fatigue syndrome, but because it’s  looking at factors that have shown up in ME/CFS it may shed  some  light on what’s happening there.  In fact it may shed a lot of light.

Manhattan

The ‘Manhattan Project’ is examining health issues in a wide swath of the population. Several findings may have relevance to ME/CFS/FM

For instance, each of the studies below looked at a factor that’s been found (in at least some studies) in ME/CFS and  each of the findings seemed to make sense what we know of ME/CFS.

Increased IL-6 levels were associated with cognitive declines in one study, and increased  soluble tumour necrosis factor receptor 1 (sTNFR1) levels were associated with increased  mortality in another.  Increased levels of daytime sleepiness in the elderly were associated with increased risk of stroke, heart attack and vascular events in another.   Metabolic syndrome was associated with cognitive declines in another. Eating a Mediterranean diet was associated with  reduced ‘white matter hyperintensity volume’ a marker of small blood vessel breakage in the brain and reduced vascular events such as stroke.

Infectious Burden

Neurology. 2013 Mar 26;80(13):1209-15. doi: 10.1212/WNL.0b013e3182896e79.Infectious burden and cognitive function: The Northern Manhattan Study. Katan MMoon YPPaik MCSacco RLWright CBElkind MS.

The most applicable study to ME/CFS, however, is clearly the latest one which determined if infectious disease burden was associated with cognitive declines.  In this study the researchers tested  blood from a broad swath of the population in New York  for antibodies to common bacteria and viruses (three of them herpes viruses) and gave the participants  cognitive tests.  Then they created an index of infectious burden (IB) and determined if more infections meant more problems with cognition…and found they did; the more active infections present, the  worse the cognitive impairment.

Infections

This study suggested that having more infections, active or latent, are associated with reduced cognition.

No ME/CFS studies have attempted to associate pathogen load with cognitive declines but given the increased  rate of infections Dr. Peterson and other immunologically oriented ME/CFS  doctors have found and the documented cognitive impairment in ME/CFS, the finding made sense. Cognitive impairment is  associated with brain issues but the researchers didn’t zero in on the brain; instead they focused on cardiovascular problems which interfered with blood flows to the brain.

It turns out that studies have linked common infectious agents to inflammation, coronary artery disease and stroke and a past ‘Manhattan project’ study found  that high infectious burdens  were associated with an increased risk of stroke and increased carotid plaque buildup.

Many viral pathogens in the herpesviridae family, characterized by latent or persistent infection, were implicated in increased stroke risk.

It appears that chronic infections often play havoc with cardiovascular functioning. Infectious organisms can impact cardiovascular functioning in various ways. They can directly invade the vascular walls. C. pneumoniae and H. pylori DNA was found in aetherosclerotic lesions in 26%  and 37% of cardiac bypass patients in one study.  With regards to pathogens commonly found in ME/CFS, high rates of active HHV6 infection  found in Italian cardiac patients who did not have aetherosclerosis suggested the virus may play a role in heart patients who have idiopathic heart disease.

Cardiovascular Issues

At the 2008 HHV6 Symposium in Baltimore, a German researcher, Dr. Lassner reported that heart biopsies he’d done in German heart patients commonly revealed parvovirus B-19, HHV-6, enterovirus and/or Epstein-Barr Virus infections.  He noted that HHV-6 infection of the blood vessel walls results in the production pro-inflammatory cytokines which can constrict the blood vessels, impair capillary production and reduce heart blood flows. HHV6’s ability to trigger blood vessel wall constriction is intriguing given studies suggesting it may play a key role in ME/CFS.

Blood vessels

Pathogens can affect the cardiovascular system and cardiovascular problems appear to be rife in ME/CFS.

Lassner, interestingly, found antivirals (IVIG-parvovirus, interferon-enterovirus) to be effective in virus infected heart patients, but reported much the same treatment response  pattern found in many ME/CFS patients; improvement while on antivirals followed by relapse when off them.

Infections can also turn on the macrophages which help create the dangerous plaques, they can confuse the immune system into attacking parts of the body and they can help an inflammatory state that is damaging, etc.

These observations, along with the results of this current study lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, may be an important etiologic factor of atherosclerosis.

Simply the presence of active herpesvirus or other infections  can contribute to an inflammatory mileu that can be detrimental.  Katan reported that an inflammatory state could lead to aetherosclerosis, ‘subclinical stroke’ and dementia. Subclinical strokes (ie transient ischemic attacks from which patients recover) primarily effect executive functioning, one of the cognitive processes known to be impaired in ME/CFS.  Changes in mood and  the ability to organize and take on multiple tasks could be a sign of a ‘subclinical stroke‘.  Other symptoms can include feelings of numbness or weakness, double vision, dizziness/vertigo, confusion, inability to speak, loss of balance or coordination.

Cardiovascular issues have been found in ME/CFS and more and more attention is being given to this area. Cardiovascular control is impaired,  reduced cardiac vagal tone is associated with cognitive declines, impaired blood pressure variability,  reduced cerebral blood flows, reductions in stroke volume and cardiac output (all this in the past year and a half)  provide ample evidence of impaired cardiovascular functioning in this disorder.  Interestingly autonomic nervous system issues similar to those found in ME/CFS were correlated with cognitive declines in fibromyalgia.

All in all the finding of decreased cognitive functioning with increased infectious burden in the  Northern Manhattan Study findings may not be surprising for many people with ME/CFS. At the most recent HHV6 Conference in Paris Dr. Peterson reported on several ME/CFS patients who’s cognitive abilities rebounded remarkably following Vistide infusions for herpesvirus infections and Dr. Lerner has reported similar results in his herpesvirus infected patients.

Conclusions

The latest Manhattan project study should be helpful in highlighting not only the cognitive declines but the cardiovascular risks that are associated with common or  chronic latent or active infections. Since active infections are part and parcel of ME/CFS, this study’s important association of decreased cognitive function with increased infectious burden suggests that measuring both those factors in ME/CFS should be routine, and may offer objective measurements of treatment efficacy.

Report From Paris: Peterson Reports Antiviral (Vistide) Effective in Treating Herpesvirus Infected Chronic Fatigue Syndrome (ME/CFS) Patients

PetersonPhoto right

“These results show objective endpoints, subset selection, and recovery. There were complete responders and partial responders among severely ill CFS patients with HHV6 or CMV. These are encouraging results for this subset and further well-designed trials should be pursued to confirm them.” Dr. Dan Peterson

At the HHV6 Conference in Paris, France today Dr. Peterson reported on the results of a retrospective study following 65 severely ill chronic fatigue syndrome patients given a course of Vistide from 2005-2012 for HHV6 and/or HCMV infections.  Despite the interest in pathogens in ME/CFS, antiviral studies are rare and this is the first one reported for this drug.

Virus from vistide presentation


Dr. Peterson has three decades of experience treating immunologically challenged ME/CFS patients.

Vistide (Cidofovir) gets a lot less press than other antivirals and immunomodulators (Ampligen, Rituximab, Valcyte,  Valtrex) used in this disorder  probably because the drug requires a  complex infusion protocol,  frequent blood tests because of the rare but real possibility of  serious kidney side effects and is expensive  (although it can be covered by insurance).

This combination – infusions, frequent blood tests and expense – requires close physician follow-up. With Dr. Peterson’s specialized focus on patients with dysfunctional natural killer cells, however, he may be most consistent about testing for herpesviruses, which are known to be active in ME/CFS patients.

After three decades of focusing on immunologically challenged ME/CFS patients, Peterson may be more experienced at pathogen detection and treatment than any other practitioner in the field, and so it’s not surprising to find the first Vistide study coming from his office.  In an interview, a former patient of his said, ‘he leaves no stones unturned'; when he finds something he goes after it ‘aggressively’.

In his presentation he stated  almost 30% of  his patients test positive for  active HHV-6 or human cytomegalovirus (HCMV) (PCR, rapid culture, antigenemia), and a whopping 50% test positive for active Epstein-Barr virus (EBNA) infection.

Serious Drug For A Serious Illness

Vistide (Cidofovir) is  FDA approved for the treatment of cytomegalovirus (CMV) in patients with AIDS. (Cytomegalovirus is a member of the herpesvirus family.) and it’s been used off-label to treat  human papillomavirus, BHK virus, herpes simplex virus, vaccinia virus infections. The Black Box warning on Vistide speaks for itself

 ‘Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with  few as one or two doses of Vistide. The “recommended dose, rate, frequency of Vistide injections must not be exceeded.”

The Study

A positive response was denoted by a negative pathogen test, improved fatigue and cognitive functioning determined by an interview with Dr. Peterson and  the patient’s self reports after the trial.

Response

  • Full Responders - Patients were deemed to be full responders if they were able to completely return to work or to work-related activities
  • Partial Responders – demonstrated significant improvement of symptoms but were unable to return to work or work related activities.
  • Non-Responders – Did not demonstrate any measurable improvement post-treatment

Results

Seventy percent patients improved

Seventy percent of ME/CFS patients with HHV6 and/or HCMV infections improved significantly on Vistide

Dr. Peterson reported that seventy percent of patients were full  (able to return to work) or partial (significant increase in functionality) responders; a very high rate of success in a illness characterized by a poor response to treatments.  Only thirty percent of Vistide recipients did not have a significantly positive response to the drug. No serious side effects were seen; ironically the minor side effects seen were attributed to a drug, Probocenid, used to ensure Vistide was safe.

It’s not clear what percentage of ME/CFS patients will test positive for HHV6 or cytomegalovirus in other practices but this type of response suggests the drug may be  being under-used. With the FDA Stakeholder’s meeting  coming up in three weeks and the Chronic Fatigue Initiative’s pathogen discovery study results due to be published later this year, Dr. Peterson’s presentation is timely. (Unfortunately, Dr. Peterson was not invited to present at the FDA Stakeholder’s Meeting.)

Dr. Peterson called for placebo-controlled, double-blinded multi-center studies that address Vistide’s efficacy, examine its effects on the immune system and study the mechanisms of increase in VO2 max scores in ME/CFS.

Sample Cases

Dr. Peterson reported on several cases, all of whom were men – something Dr. Peterson has said he likes to do to break up the notion that only women get this disorder.

  • A 27 year old college graduate  unable to work because of  constant flu-like symptoms, weakness and marked cognitive decline (math!) presented with low NK functioning, low VO2 max and HHV6 and cytomegalovirus infection. He was able to return to work after 24 weeks of bi-weekly infusions. His VO2 max on the exercise test went up went up 23%,  his NK cells a remarkable 400% and he tested negative for both viruses at the end of treatment. He had had ME/CFS for three years.
  • A 54 year-old former high school teacher unable to work due to extreme fatigue, flu-like symptoms and cognitive problems severe enough to keep him from being able to grade his students papers presented with active HHV6 and cytomegalovirus infections and low NK cell functioning and VO2 max. He was able to return to work after 24 weeks of bi-weekly infusions. His VO2 max increased 47%, his NK function test went up 20% and he tested negative for both viruses. He had had ME/CFS for five years.
  • The third patient had classic, acute onset ME/CFS which progressed to seizures. Both serum and cerebral spinal fluid tested positive for HHV6. At the end of the Cifodovir trial the  viral load in his cerebral spinal fluid dropped from 3670 copies/ml to undetectable levels. Serum HHV6 was dramatically reduced (47,000 copies/ml to 3,000 copies/ml). Still symptomatic and experiencing cognitive problems, he was nonetheless able to return to work.

Conclusions

The retrospective study indicated Vistide (cifodovir) can have dramatic effects on functional capacity in HHV6 and/or HCMV infected ME/CFS patients.

Increasing VO2 max appeared to be critical to increasing functionality as the partial responders did not increase their VO2 max while on Cifodovir. At the FDA Advisory Meeting for Ampligen Dr. Bateman noted that VO2 max test results probably were, given the exertional problems in ME/CFS, the most difficult to ‘move’ test result in this disorder.

VO2 max levels in Dr. Peterson’s patients prior to Vistide administration were exceedingly low; they appeared to in the ‘very low’ range even for people for 65 years of age and older. Vistide moved those test results about 20% on average; leaving them still, it appeared, below normal but sufficient enough for a significant increase in functionality.

A Vistide Example

Vistide_CFSThe VO2 max tests suggested most patients had not returned to full health and Dr. Peterson has said he knows of few complete recoveries. I interviewed a former patient of Dr. Peterson’s several years ago. Faced with the loss of his career and the ability to care financially for his family Vistide turned out to be a godsend.

Cut down by acute onset ME/CFS, his VO2 max score topped out at an unbelievably low 15 (which qualified him for heart disease) and he was a ‘2’ out of 10 on his own energy scale (had trouble sitting up to eat).  Within a month on Vistide he was at a ‘4’; the next month he was a ‘5’ and sleeping soundly for the first time since he’d gotten sick. The next month he was a ‘7’ and his VO2 max tests had doubled to 28; still far below the 44 expected at his age, but an amazing increase, never the less.  Three months later he was at ‘90%’, back at work and able to do everything except exercise.

CMX001 – The Future Vistide? 

Dr. Peterson didn’t report on CMX001 in Paris, but sitting in the background of all this is a analogue of Vistide called CMX001 which appears to be a safer and more effective,  if not yet available, version of it. A  2012 review named CMX001 as one the ‘ten hot topics’ in antiviral research.

Chimerix Pharmaceuticals modified Vistide so that it can easily be taken up into the  tissues. That means no need for infusions, no worries about kidney problem and according to Chimerix, dramatically increased effectiveness.

CMX001 has been in development for  some time but just this March the FDA awarded the drug ‘fast track’ status for the prevention of cytomegalovirus infection.  Phase II trials are finished  and Phase III trials will get underway this year.

Given Dr. Peterson’s success with Vistide, FDA approval of CMX001 could be very good news for ME/CFS patients with HHV6, HCMV and/or possibly EBV infections.

Wrap Up

In a retrospective study Vistide proved to be  effective  in treating severely ill ME/CFS patients with HHV6 and HCMV infections. Dr. Peterson called for double-blinded, placebo-controlled studies to further study Vistide’s efficacy and mechanism of effect.  The CFI’s pathogen discovery studies due out this year should shed light on what percentage of ME/CFS patients could benefit from Vistide.

A Vistide analogue under development called CMX001 which does not require infusions and does not effect the kidneys could be boon for ME/CFS patients with herpesvirus infections if it is approved by the FDA. CMX001 was given fast-track status by the FDA earlier this year.

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Simmaron Research Mobilizes Unique Assets to Push ME/CFS Field Forward: A Look Back at the First Year

April 4, 2013

We envision a world where ME/CFS is treatable and well-understood. To get there, we are scientifically redefining ME/CFS.

Simmaron focuses on chronic fatigue syndrome research

Simmaron has moved quickly in the past year and half and is involved in a variety of potentially groundbreaking studies.

The latest addition to the ME/CFS Research Foundation scene, the Simmaron Research Foundation started off small. There were no huge endowments, no connections to major academic centers; in fact, Simmaron was located in little Incline Village off of Lake Tahoe, a locale rich in chronic fatigue syndrome (ME/CFS) history but definitely not known for its medical resources.

What Simmaron did have was Dr. Daniel Peterson, a practitioner whose deep experience and extensive biobank is unparalleled in ME/CFS. Since the early days of the Incline outbreak in the early 1980’s Dr. Peterson has been immersed in chronic fatigue syndrome.  Now with the Simmaron Foundation’s support he had the opportunity to put his experience and samples to the test. It turned out that the ME/CFS research community was very interested in what he had to offer.

After just a year and a half, the Simmaron Foundation is making its mark.With studies underway that will help to redefine ME/CFS and how it gets researched and treated, Simmaron has quickly become perched on the front lines of ME/CFS research.

A Vital Resource – Finally Hitting Stride

Dr. Peterson quickly knew something had gone very wrong with the sick patients crowding his  door in Incline Village in the 1980’s, and early on  he began collecting samples for the studies he felt had to come.  It took decades but that time has come, and given the technology and the quality of the researchers  he and Simmaron Foundation are working with now, it was probably worth the wait.

Chronic Fatigue Initiative Pathogen Study

Simmaron Research provided 40  patient and 40 control samples to the biggest, most  rigorous and comprehensive ME/CFS pathogen study ever –  the Chronic Fatigue Initiative’s Pathogen Discovery project. Lead by Dr. Mady Hornig and Dr. Ian Lipkin, this project will set the stage for pathogen research in this disorder for years to come.

Simmaron’s eighty samples will join samples from four other ME/CFS clinics in a search that will:

  1. screen for 18 viruses, bacteria or protozoa  already associated with ME/CFS. If that hunt proves unsuccessful they will
  2. sequence everything in the blood to look for known and unknown viruses
  3. then develop tests for any new pathogens they find as well as
  4. look for unique protein signatures and
  5. analyze 50 markers of immune activation/inflammation/oxidative stress

The well-characterized, rigorously documented samples Simmaron is providing will play a key role in this study.  Of all the clinics in this project, Dr. Peterson’s stands out in its focus on immunologically challenged patients.  If the Lipkin/Hornig team finds pathogens, they will likely show up in the Simmaron samples.

The results from these studies are coming in and  by the end of this year we’ll finally have some answers to one of the biggest questions facing ME/CFS researchers and patients for over twenty years – what role pathogens play in this disorder.

ME/CFS Cerebral Spinal Fluid Samples – Meet Top Pathogen Experts in the World

The large pathogen discovery study funded by the Chronic Fatigue Initiative will dramatically increase our knowledge of the role pathogens play in ME/CFS but, for all the tissues it was studying (tears, saliva, blood and fecal samples), it was missing an important one – perhaps the major one – until Simmaron stepped in.

Cerebral spinal fluid circulates around the brain stem and the outside margin of the brain. When it’s collected, down near the tailbone, it bears traces of its path through the brain. If pathogens, unusual proteins or inflammatory markers are present in the brains, as so many believe,  the CSF is the best way, short of an autopsy or biopsy, to find them. CSF fluid analysis is used to assist with diagnosis in a number of neurological disorders.

Watch Cerebral Spinal Fluid Circulate Around the Brain

The Director of the HHV6 Foundation, Kristin Loomis, considers the Simmaron spinal fluid samples critical to the CFI project’s success because many of the viruses suspected in chronic fatigue syndrome simply don’t show up in the blood, the saliva, etc.  She noted that several theories suggest the pathogens present (HHV6, EBV, enteroviruses) have assumed unusual forms that make them difficult to trace in the blood.

It wasn’t just the size of Simmaron’s spinal fluid contribution – 60 of these difficult to collect spinal fluid samples – something Dr. Mady Hornig called ‘unparalleled’ – but who they’re from that makes them so special. Dr.  Peterson doesn’t routinely do spinal fluid tests; these samples are from patients -often the illest of the ill – he suspected had neuro-inflammatory problems and his superb diagnostic skills means the CFI can have confidence in what kind of patients they’re looking and that’s unusual in ME/CFS research.

This study is not just about pathogens; the Center for Infection and Immunity will be looking cytokines and other biomarkers that could tell us more about the health of ME/CFS patients’ brains. Recent successes documenting  unusual proteins in ME/CFS patients cerebral spinal fluid suggest  the spinal fluid may indeed be the place to look.

Dr. Hornig, the leader of the CFI’s pathogen discovery effort, called the Simmaron spinal fluid samples ‘a really unique opportunity’. It’s no surprise Simmaron made funding this study a top priority.

ME/CFS Cerebral Spinal Fluid Samples –  Meet the Top Natural Killer Cell Experts

natural killer cells

The extensive immune analysis given to Simarron’s spinal fluid samples will provide insights into the immune status of the brain in ME/CFS

We journey halfway across the world down to the Southeast coast of Australia for Simmaron’s next spinal fluid study where the ME/CFS research group led by Sonya Marshall-Gradisnik, PhD, now centered at Griffith University, will be digging deep into the immune profile of the same samples CFI researchers are analyzing for pathogens.

Griffith is now ground zero for  natural killer cell research in ME/CFS.  Griffith researchers recently contributed a chapter on natural killer cell dysfunction in ME/CFS and at the Ottawa conference they  documented the NK cell dysfunction present in ME/CFS,  identified miRNA’s contributing to the NK cell  dysfunction, documented the same dysfunction in T-cells, and identified cytokine abnormalities in the blood. Now they’ll look for these abnormalities in Simmaron’s spinal fluid.

These two studies put the Simmaron Foundation’s spinal fluid samples at the heart of a  double-barreled research effort.  CFI researchers will  determine whether pathogens/markers they’ve found in the blood, saliva, etc. are also in the spinal fluid, while Griffith researchers will determine whether their immune abnormalities show up in the  spinal fluid.  At the end of this process not only will we know a lot more about the brain in ME/CFS, we’ll know much more about where to look for the biomarkers this disorder needs so badly to move forward.

A Multi-Site Clinical Assessment of ME/CFS

CDC multi-site CFS study

Dr. Peterson’s unique focus on immunologically challenged patients will pay dividends in the CDC multi-site definition study.

How to define properly  Chronic Fatigue Syndrome is another issue that’s plagued the field for decades. Perhaps no issue is more important to the field. Inadvertently involving different types of patients, for instance, in research studies could explain the inconsistent research and treatment trial results that have stifled interest in this disease for decades. Drug companies are reluctant to enter into treatment trials for an  illness they don’t feel has a real definition.  The list of negative effects from having a vague definition goes on and on.

With their participation in the Center For Disease Control’s Multi-Site Assessment study, however, the Simmaron Foundation and Dr. Peterson’s Sierra Internal Medicine, will be helping to provide answers to this perplexing and important question.

In this study led by the Open Medicine Institute, Simmaron joins seven other clinical sites to provide electronic data on diagnostic procedures, test results, treatments and outcomes on over 800 patients to the CDC for analysis. The project will, for the first time, produce statistically based analyses of the different subsets ME/CFS practitioners are likely seeing and will bring  the practices and insights of ME/CFS professionals to the fore in scientific publications for the first time.

Once again, Dr. Peterson’s unique focus on immunologically dysfunctional patients will play a vital role in highlighting this significant subset of patients. Promising first results have lead the CDC to refund and expand the project to include more physiological measures.

Charting Long term (gulp) ME/CFS Prognosis

Few studies have looked at a vital subject for most ME/CFS patients; what they can expect in the future.  Is ME/CFS progressive and, if it is, what does it progress to? Some researchers believe ME/CFS may progress to range of other disorders and a recent study found significant fatigue predated the development of multiple sclerosis in many patients. This study will catch up with patients seen at least 10 years ago in Dr. Peterson’s practice and see how they are doing.  The results could profoundly effect our understanding of ME/CFS and will provide physicians important clues how to best manage it.

Post-Infectious Cardiomyopathy Study

Simmaron’s identification of  four  patients in its surrounding community with mysterious  heart problems (cardiomyopathy) provides a new opportunity learn more about the possible role of infection in this heart condition.

Simmaron has recruited the Centers for Infection and Immunity at Columbia University to dig into these patients serum, plasma and other biological samples to see if they can figure why they developed this unusual form of heart disease.  Possible infections will be given a particularly close look.

This study should be published this year.

Conclusion

Dr. Peterson’s years of experience and his extensive data bank have brought new opportunities for Simmaron and for the ME/CFS research field. With collaborative efforts ranging from New York to Atlanta to Australia, the Simmaron Foundation, located in little Incline Village, has developed world-wide connections and is engaged in studies that could redefine ME/CFS, provide vital insights into its longterm prognosis and its neuroinflammatory nature.  Simmaron has been indeed been rising.

 

Infection, Autoimmunity and PANDA’s: Dr. Hornig on Chronic Fatigue Syndrome at Dr. Klimas’ NSU Conference

Quite the Resume

Dr Mady Hornig comes with quite a resume. She and Dr. Ian Lipkin MD direct the Center for Infection and Immunity at Columbia University in New York, and Dr. Hornig is directing the Pathogen Discovery and Pathogenesis Program at the Chronic Fatigue Initiative (CFI).

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

An MD and immunologist with a background in neuropsychiatry, Dr. Hornig’s been focused throughout her career on uncovering immune dysfunctions associated with mood and developmental disorders such as autism, PANDA’s, ADHD and schizophrenia. Her current work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project constitutes the largest examination yet of the role the immune system and viruses play in mood disorders and schizophrenia. She’s currently a lead investigator for  the Autism Birth Cohort study determining how development, genes and environmental factors combine to produce autism.

Dr. Hornig has quickly become a major chronic fatigue syndrome investigator and said she and Dr. Ian Lipkin were using all the tools available to them including gene expression studies, immune and stress markers and proteomics using mass spectroscopy.Check out the ME/CFS studies her lab is or has been involved in….

Chronic Fatigue Syndrome Studies at Dr. Hornig’s Laboratory

  • 200/200 Cases and controls with Chronic Fatigue Initiative  – 18 pathogens identified, then unbiased high throughput sequencing – pretty much tell us anything that is in there
  • 150/150 cases/controls in XMRV study
  • 400/400 cases/controls in huge Montoya Stanford study
  • 60 cases/60 controls Simmaron Spinal Fluid Study

Dr. Hornig focused in on the Simmaron Institute spinal fluid study calling it ‘really intriguing’, calling the number of well-characterized spinal fluid samples  ‘unparalleled’, and stating the study was a ‘unique opportunity’.

We’ll get another chance to see her at the 2013 Invest In ME Conference in May.

The Talk – Infection, Autoimmunity and Illnesses

Placing chronic fatigue syndrome into the category of ‘neuropsychiatric disorders’ (disorders that effect cognition and mood among other things) Dr Hornig started off her talk demonstrating how attacks of insanity seem to have swept over populations, not suggesting that she’s studying a group of insane people, but demonstrating how infections can generate symptoms we don’t generally associate with them.

Mom???

Dr. Hornig believes three factors, timing – a window of opportunity,  a genetic predisposition, and an environmental insult probably come  together to cause chronic fatigue syndrome.  That window of vulnerability could have occurred at any time but Dr. Hornig zeroed in on pregnancy:  a time, it appears, when many chronic disorders are  set into motion.

Mom? The roots of some chronic illnesses appear as far back as pregnancy

Mom? The roots of some chronic illnesses appear as far back as pregnancy

She suggested, but did not say, that chronic fatigue syndrome could be triggered as early as pregnancy and then not show up for 20 or  40 or 50 years until  another window of vulnerability opens up – perhaps during a stressful period, another infection, toxic overexposure. (She noted that the stress response is similar in all these cases).   Indeed, that model of disease, she said,  could apply to outbreaks of autism and ADHD in early life, multiple sclerosis, schizophrenia and ME/CFS in middle life and Parkinson’s and Alzheimer’s disease in later life.

Cannabis triggered schizophrenia during adolescence is an example of the three factors combining in a perfect storm to cause a devastating  disease.  It turns out that bringing together one form of a COMT gene (the COMT gene, oddly enough is implicated in ME/CFS), the tumultuous physiological time of  adolescence, and an environmental factor (cannabis) you get an increased risk of (gulp) schizophrenia.  Basically smoking pot when you’re an adolescent increases your risk of  schizophrenia (it happened to one of the my best friends) but smoking it when you’re an adult – even if you have this particular form of this gene- doesn’t increase your risk at all.

She described an incredible and rather frightening study in which researchers examined pro-inflammatory cytokine levels (IL-6 and IL-1b) in the blood of mothers collected 40-50 years ago. Skipping  forward they found that women whose mothers had high cytokine levels during pregnancy  tended to be depressed and have reduced  brain activation in middle age. This suggested those high levels of pro-inflammatory cytokines changed the circuitry of female fetus’s brain enough to make those women more vulnerable to depression later on.  She noted that some of the same stress-circuitry showing up  in those women is implicated in ME/CFS as well.

The Immune Side of Neuopsychiatric Disorders

Hornig is an immunologist and she  explained that many ‘neuropsychiatric disorders’ may be explained by immune problems; the list  she presented was not a particularly pretty on; besides fibromyalgia and ME/CFS it included Tourette’s syndrome, autism, obsessive compulsive syndrome, ADHD, anorexia nervosa, narcolepsy, major depressive disorder, bipolor disorder and schizophrenia (and probably should have included irritable bowel syndrome, interstitial cystitis and other disorders that co-occur with ME/CFS. ).

There are several  groups in here; the heavy psychiatric disorders – depression, bi-polar disorder, compulsive obssessive disorder and schizophrenia; the CFS-like disorders (ME/CFS, FM….IBS, IC, etc.) and then autism and ADHD.

The Infection Autoimmune Connection

The infection/autoimmune connection is a strong one with many autoimmune disorders showing up shortly after infections…but..(there’s always a but :))  she noted that other autoimmune disorders  can take years to show up making it difficult to determine the trigger.  If it was a pathogen, it could’ve  and may very well have done it’s damage and then disappeared, leaving a chronically disrupted immune system in its wake.

PANDAS – A Possible  Model for ME/CFS

“Several studies suggest autoimmunity may play a role…”

PANDA's - a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

PANDA’s – a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

Hornig  then described an infection triggered neuropsychiatric disorder called PANDAS that could be a model for ME/CFS.  Children with PANDAS don’t eat eucalyptus leaves for lunch, but they do display dramatic changes in behavior including obsessive-compulsive behavior, tics, mood swings and anxiety soon after a staphyloccus infection. They also display the kind  of ‘ vigilance’ and arousal that shows up in some people with chronic fatigue syndrome.

Hornig has become deeply involved in PANDAS. Much is controversial about PANDAS but it’s believed to be an autoimmune disorder that targets the basal ganglia in the brain (which is, yes, also under consideration in ME/CFS…). Working with Dr. Lipkin, Dr. Hornig found that mice injected with strep   engage in obsessive compulsive behaviors (they flip themselves over backwards again and again) and that simply injecting  antibodies to streptococcus  into mice caused problems with learning and memory, coordination, and social interactions.  Then, in a nice Koch-like test, they found that  removing the antibodies from the mice  resulted in the return of  normal behavior.

General Stress Response Affected

That made it pretty clear  it’s the antibodies; eg. the immune response that’s the problem and what they found next confirmed that; they found that the antibodies to strep mistakenly cross-react (ie  target  for destruction) two important parts of  the  immune system; C4 complement and heat shock proteins.

Why would we, with ME/CFS, be interested in these factors?  Because both  appear, Dr. Hornig said, to be general responses to infections and stressors of all sorts, with all its different triggers, chronic fatigue syndrome could be associated with a basic derangement of the stress response (to  infection, trauma, etc.).

Dr. Hornig didn’t mention it both C4 and heat shock proteins  have (yes, yes, yes :)) been implicated in chronic fatigue syndrome at one time or the other

Dr Hornig noted that children with  PANDAS can respond to IVIG, antibiotics and other immune agents.  That’s a bit controversial (no surprise there) with  the American Heart Association (AHA)  recommending that strep not be tested for in children with PANDAS or that they attempt IVIG  treatment despite the fact that one preliminary  study has found IVIG effective.

It’s more of the old, we need more studies before we do or recommend anything without providing the money to do them leaving potential helpful treatments on the shelf while patients suffer (sound familiar?). (PANDAS is way down on the NIH’s priority list.

Key Partners – The Stress Hormone-Immune System Interactions

Hornig noted the immune- stress response connection with PANDAS and now she enlarged on it. Proper central nervous system functioning is dependent on having  balanced immune and stress responses; throw those responses in just one part of the system-  tryptophan degredation – into disarray can cause you to not be able to lay down a memory. Tryptophan is a possible candidate with ME/CFS but she was most interested in the biggest bundle of nerves outside the brain – the enteric nervous system or gut….

Getting Down With The Gut

Hornig then directed us out of the brain and downwards into the gut.  On a very, very basic level this makes sense since  everything  that our bodies run on (except for the gases) comes from our food which means we better be able to digest it well. Stopping the flow of anti-oxidants  (selenium, cysteine, glutathione) from our food out of the gut into our body, for instance, results in increased levels of oxidative stress,  pro-inflammatory cytokines and auto-antibodies  (autoimmune reactions).

Get increased auto-antibodies and you can have problems showing up in literally any part of the body. Just to get our attention, Dr. Hornig noted that an  autoantibody attack of folate receptors could show up in problems with  metabolism,  methylation and B-12.

Then she shifted upwards – back to the brain.  So far our dysfunctional gut has left us with low levels of anti-oxidants, high levels of pro-inflammatory cytokines,  and high levels of autoantibodies in our blood.  Send all that stuff up to the precious (and fragile) blood-brain barrier  protecting our brain and….you have the possibility of a rip exposing the brain to all sorts of bad actors. Depending on which part of your brain gets attacked there goes your  sex drive, appetite, motivation, energy levels, etc….and to think it all could have started with bad flora in your gut.

More Floral Than Viral?

Lest we think this is some researcher’s fantasy, Hornig described her work with autistic kids.  Hornig’s group did not find evidence of measles in autistic children but they did find levels of digestive enzymes so low to be almost non-existent. The autistic kids couldn’t break down milk products because they were lacking the enzyme for that but that hardly mattered as their guts were so deficient they couldn’t have gotten the milk protein into their bodies even they could have broken it down.

Not only was their gut flora massively different but they also they harbored a rare bacteria called Sutterella not present at all in the healthy controls.  Sutterella was not just present,  it was flourishing, accounting for up to  7% of all gut bacteria. Usually a very minor component of the gut microbiome, Suttarella was the third most common bacteria found in these kids.  That really raised some eyebrows.

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Still, it’s not clear if Sutterella itself is whacking the kids or if its crowding out good gut flora or if its doing nothing but  we do know that Sutterella thrives in low oxygen  environments and has been linked to inflammatory bowel disorder, Crohn’s disease and ulcerative colitis. (It  can also, though, sometimes be found in healthy individuals.) Hornig’s ability to find an antibody to Sutterella in about 50% of the children indicated they had mounted an immune response to it.

Bacterial imbalances in the gut have been observed in gut disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease but its become clear that  bad gut bacteria could wreak havoc far outside the gut. The first non-gut disorder associated with bad bacteria appears to have been arthritis.  (Check out a horrifying and fascinating New York Times story of  young child’s battle with rheumatoid arthritis.)  Cesareans appear to  put children at increased risk for asthma because they prevent children from picking up important gut bacteria as they pass they through the birth canal.   Bacterial imbalances in the gut appear to be associated with increased obesity in people with  type two  diabetes .

Researchers have identified three main types of gut composition in humans and they know that diet can influence gut flora. They know that  cutting out sweets and processed foods and using prebiotics and probiotics can help some people reduce or eliminate  inflammation.  Fecal transplants may actually be more effective because they contain more of the bacteria that’s actually populating our guts.

Hornig noted how  important the small intestine is for so many different type of phenomena – for cognition, anxiety and even for sleep. Did you know that if you’re not getting peristalsis (small gut movements pushing the food along)  during the night then you’re missing some sleep enhancing molecules.

Major Chronic Fatigue Syndrome Gut Study Out This Year

The Shukla CFIDS Association gut metagenome study is looking more exciting all the time. This study, which study started several years ago and should be published soon, sought to characterize the entire  gut microbriome before and after exercise in people with ME/CFS.

By studying the gastrointestinal microbiome, Shukla’s work will determine if the ratio of normal to pathogenic (illness-causing) bacteria is off-kilter in CFS patients and if exercise causes harmful bacteria to travel into the body from the gut, creating the postexertional symptoms that are such a prominent feature of the illness. The results have the potential to yield microbial biomarkers for CFS as well as targeted treatments aimed at rebalancing the ratio of bacteria. From CFIDS Chronicle Winter 2009

  • Xafaxan: Gut Rebalancer Extraordinaire –  Suffering from gut issues? Check out a new page Health Rising has on Xafaxan, a gut antibiotic used to snuff out small intestine bacterial overgrowth (SIBO) problems. One person with ME/CFS ended six years of gut turmoil with one short course of Xafaxan…

 Q & A Period

Is Chronic Fatigue Syndrome Infectious?

She thought perhaps, but if so probably mostly during the initial stage of the illness, and that it was highly unlikely it was  infectious in later stages of the illness.  Hornig is following the same model as Klimas in her research; she’s  looking for an infectious agent but finding  immune and stress response factors indicative of a pathogenic attack (at some point) is a major focus.

With a kind of immune system hypervigilance twist she stated its possible an initial infection sensitized the system so that further infections, even very mild ones, might be  throwing it  into a tizzy.   If ME/CFS patients have a problem with infection in general; that is, if any infection has the potential to trigger a kind of overwrought immune response, then she felt it was more important the source of that than to look for a specific virus.  With all the known infectious triggers for ME/CFS she believes some genetic susceptibility/immune issue was present.

One reason for Hornig’s interest in ME/CFS may be due to her work in autism. Hornig believes innate immune system problems during maternity may play a role in the development of autism, and the innate immune system  – the early immune response system involving NK cells, dendritic cells and others – is getting more and more attention in ME/CFS.  Interestingly, Hornig found that infection induced inhibition of the same Toll-like receptors (TLR3) Ampligen effects lead problems with sensorimotor gating responses as adult.  Check out this blog for a treatment of sensory gating issues in chronic fatigue syndrome.

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Clin Invest Med. 2008 Dec 1;31(6):E319-27. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndromepatients and matched healthy controls. Thambirajah AASleigh KStiver HGChow AW.

J Intern Med. 2009 Aug;266(2):196-206. doi: 10.1111/j.1365-2796.2009.02079.x. Epub 2009 May 19.Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. Jammes YSteinberg JGDelliaux SBrégeon F.

Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. Jammes Y, Steinberg JG, Delliaux S. J Intern Med. 2012 Jul;272(1):74-84. doi: 10.1111/j.1365-2796.2011.02488.x. Epub 2012 Jan 4.

Mol Psychiatry. 2010 Jul;15(7):712-26. doi: 10.1038/mp.2009.77. Epub 2009 Aug 11. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G, Lipkin WI.

J Allergy Clin Immunol. 2003 Aug;112(2):397-403. Complement activation in a model of chronic fatigue syndrome. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF.

Mol Med. 2009 Jan-Feb;15(1-2):34-42. doi: 10.2119/molmed.2008.00098. Epub 2008 Nov 10. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Sorensen B, Jones JF, Vernon SD, Rajeevan MS.

Great Start – Big Plans Ahead: Dr. Klimas at her NSU Coming Out Party

Dr. Klimas has big plans for her new Institute on Neuroimmune Research at NSU

Dr. Klimas has big plans for the new Institute on Neuroimmune Research at NSU

A Coming Out Party

The coming out party for Dr. Klimas Institute for Neuroimmune Research at Nova Southeastern University (NSU) on January 26th was a year in the making.   In 2011 NSU had made her an offer she couldn’t refuse –  the opportunity to break down what she called the  silo’s that separated researchers, clinicians and educators  – and in  Dec 2011 she announced, after decades or work at the University of Miami, she was leaving to  create a new Institute at NSU.

In the Institute’s first public event, a  Patient Conference,  she brought together members of the Institute to talk about it. After the Dean’s short introduction, Dr. Klimas  gave the first presentation.

The Big Plan : Finding Effective Therapies

 (Warning…I frequently take riff’s on  the presentations (see Waziry and EBV below) ; if something in these blogs turns out to be incorrect, it’s probably due to  my riff :))

Dr. Klimas’  presentation was titled a BIG PLAN and it’s a plan  that is  focused towards one goal…”Finding Effective Therapies”. Dr. Klimas’ effort is fundamentally oriented towards finding effective therapies and we’ll see how that’s going to work in a later presentation.

The mission statement pointed out just what kind of disorder Dr. Klimas believes chronic fatigue syndrome is…a “neuro-inflammatory” disorder; a nervous system disorder involving inflammation; ie  immune activation.

Dr. Klimas emphasized that the reason she came to NSU was to create an integrated program that has the  clinicians, researchers and educators  all working together in a tightly knit group.  Each person, she said is  engaged in all of it; the doctors are talking with the researchers who are informing the educators.  In fact the way the building is structured they have to communicate; everyone eats and meets in the same central meeting/ conference room.

The Institute focuses on two groups, people with chronic fatigue syndrome and people with Gulf War Illness (GWI)

Gulf War Illness (GWI)

Introducing Gulf War Illness Dr. Klimas stated the  remarkable fact that fully 1/4 of the Gulf War Vets (that’s 200,000 people and some estimates are higher)  returned with a chronic, often disabling multisystem illness ….(sounds like ME/CFS?)…that looks like ME/CFS but is biologically very  different.  What happened? It appears that a  toxic cloud of elements from gas fires, pesticides, vaccines, uranium etc.  with the major contributor probably being something we’ve all been exposed to at times;  pesticides.

  • Dig Deeper: Check out a  recent fascinating New York Times article  suggesting that contaminated dust and  Sarin, a close cousin of organophosphate pesticides, were  key factors in GWI.

That toxic insult is probably long, long gone but that initial insult  appears to have reset many GW participants systems permanently and Dr. Klimas is trying to figure out how to reset  the reset button.

Chronic Fatigue Syndrome (ME/CFS)

Dr. Klimas’s test results suggest an insult is still present in ME/CFS. (More on that later). Calling it a terrible illness Dr. Klimas noted that 1/4 or more of people with ME/CFS are fully disabled and many more are partially disabled and that the disease with the funny name is as debilitating  as heart disease, end stage kidney disease, AIDS (AIDS !!!) and MS.

She laughed at one idea she  come across at times; that people with ME/CFS  want to be on disability and the poverty level income that provides them instead of having access to their income they enjoyed previously; yes, she laughed , what a great tradeoff that would be.

The People

Dr Waziry will focus on determining what pathogens are doing to the cells of people with chronic fatigue syndrome

Dr Waziry will focus on determining what pathogens are doing to the cells of people with chronic fatigue syndrome

Thus  far the Institute has on board researchers specializing in  gene expression (Nathanson),  viral effects (Waziry), clinical research (Dr. Klimas) and two computational biologists,  (Broderick and Cradock) and, I’ve been told, may be adding an animal modeler.

Pathogens

Waziry specializes in a key, key area – detecting how  viruses muck up how cells operate. If  viruses are present you, of course,  want to get at them but if the viruses are gone or are hard to find  then finding some sort of viral fingerprint could inform you how the damage occurred, where to target treatments and  what viruses to look for would be very helpful and that’s what Waziry is doing.

Given the common infectious trigger in this disorder  this slant makes  sense; something, after all, happened way back when and for many people it involved a pathogen.  If  Waziry finds a signature unique to cells that  Epstein Barr Virus mutilated, for instance,  you’d know your pathogen without having to resort to expensive and not always accurate blood tests.  It’s also possible, given the many  infectious triggers documented in ME/CFS (EBV, parvovirus, coxsackie, West Nile Virus, Giardia, etc.) that they’re all tweaking the system in the same way.  If that’s what’s happening then  finding a common immune signature will allow the team to develop simple diagnostic tests for a significant portion of ME/CFS patients.

Computational Biology

The computational biologists are trying to stop the illness cascade in its tracks in chronic fatigue syndrome

The computational biologists are trying to stop the illness cascade in its tracks in chronic fatigue syndrome

Dr. Klimas has fully  embraced a new branch of  biology called computational biology that uses sophisticated data mining techniques to analyze  how our internal  systems operate.  In fact Dr. Klimas has so fully embraced this type of research that her computational biologists are doing cutting edge work not being done in any other disease.

The computational biologists (Broderick and Crawford) play clean up. Every piece of  research and clinical data gathering ultimately ends up in their hands. They’re trying to do something unique in medicine;  using data mining techniques to target the molecular source of this disease in time.  Think of it as isolating the pebble the started the snow slide that ended creating an avalanche.  This isn’t about symptom amelioration anymore; this is about getting at the very beginnings of the system-wide ‘collapse’ that occurred and is still occurring  in people with ME/CFS.

The computational biologist are the ones, Dr. Klimas explained, that will ultimately be able to tell her that  tweaking this  patients HPA axis here, and prodding their  immune system over here and here,  should stop the cascade of system-wide dysfunction that  causes chronic fatigue syndrome…Essentially she wants to cut a relapse or flare  off at it’s …er…..start.

We’ll learn more about this approach in Broderick’s talk.

Speeding Up the Process

Dr. Klimas wants to move quickly. No more of this  waiting two years for the NIH to respond;  Dr. Klimas – through a process Dr. Broderick will outline later – hopes to produce multiple small-scale, phase-1 type clinical trials in house to get the  data needed to get pharmaceutical companies interested in drugs that will help ME/CFS patients.

The Institute

At this point the Neuro-immune Institute has  11 staff members including 6 researchers/research assistants, a research coordinator, a Director of Medical Education, two Nurse Practitioners (one of whom has ME/CFS) plus researchers from the University of Miami, University of Alberta, Wright State,  and the CDC . And they’re busy with no less than seven different active studies going on at the moment.

Accomplishments of the Past Year

Dr. Klimas announced two encouraging signs; (a)  they’d achieved more in the past year than expected and (b) Nova kicked in more than she expected.

In the first year the Institute for Neuroimmune Research has been involved in

Research

  • a really large DOD grant
  • Genomic studies
  • Gene expression and immune regulation study
  • Gene expression exercise study
  • GWI animal modeling
  • CDC – multisite ME/CFS physician study
  • Chronic Fatigue Initiative Pathogen Study – Dr. Klimas stated that the CFI, which  is the most well-endowed ME/CFS research foundation,  is motivated to come up with answers quickly as well, and that the pathogen samples in the big Lipkin/Hornig study are being analyzed now. She stated the Institute would  continue their work with CFI, suggesting that further studies are around the corner.
  • Epidemiological Study – stating this has never been done before, this study has tracked people back as far as  10 years and asked them how they’re doing now; thus far 1,000 people have answered the questionnaire. Smiling broadly she said they did it on student stipends; $8,000 (a site?) – a ridiculously low figure  – and they’re getting important, never before seen data.
  • Ampligen Study

Treatment

  • Doubled the clinical space at their  Kendall clinic
  • Created a  new clinic at Davie

An Effective Team – Dr. Klimas mentioned how effective she and  Mary Fletcher, whom, she said does not sleep and works weekends (we’ll see evidence of that later :)), were at writing and getting NIH grants. That’s very true; while other ME/CFS researchers have given up on the NIH and few get grants, these two always seem to be in the mix at the NIH.   Their ability to consistently get grants for this  disorder is extraoardinary and is partially because of the interest in the cutting-edge computational biology approach they’ve taking.

Goals for this Year

Next Dr. Klimas went over their goals for this year.

We’re going to be able to collect huge mountains of data on normal care and make the evidence happen….Dr. Nancy Klimas

 Turn the Clinical Database into A Research Database (and then analyze the heck out of it)

The plan, is to integrate her clinical databases into her REDCAP  research database, providing her sophisticated  tools to analyze treatment effectiveness in her patients, past and present. If you’re part of her clinic (with your permission) you’ll become a research partner as well.

Integrating her clinical database into her research database could allow Dr. Klimas to answer many question about treatment effectiveness

Integrating her clinical database into her research database could allow Dr. Klimas to answer many question about treatment effectiveness

This is big stuff. By putting her patients into  a research database made for, well, research and analysis – Dr. Klimas is opening up thousands of records and patient outcomes to  analysis. Over time this will bring  treatment outcomes  out of the fog of individual guesswork and intuition into the clarity of statistically derived analysis.  No more waiting for for someone spend two years convincing the NIH to fund a small treatment trial….those trials have effectively been underway in ME/CFS specialists offices for decades; they’re just waiting to be uncovered.

Doxepin elixir is commonly used to aid sleep in chronic fatigue syndrome but how effective is it really? Are there certainly types of patients it works better in?   Would some patients do better with Ambien? Nobody really knows the answers to these questions but given the staff and funding  they are answerable with this technology.

If this really works, this work, and Dr. Kogelnik at the Open Medicine Institute has similar plans, would be a bonanza for both patients and doctors. Since the CDC doesn’t seem to be able to handle non evidence-based data, we could anticipate an entirely new CDC Toolkit, for example, coming out of  this work.  Dr. Klimas said they were  going to try and sell the project to Medicare.

The ability to do this kind of work is one of the dreams of the electronic digital revolution spreading across the medical field.  Only time will tell but hopefully it will deliver on its promise.

How did Dr. Klimas get this project up and running? She walked into an NSU office…and asked them “Do you think we could????” and it was borne. That’s the difference between working in a pro-active environment that is eager for you to succeed and in an institution (my words, not hers) that tolerates your existence but isn’t going to go out of its way to support you.

Other Goals

  • Establish a Translational Research Program
  • Begin the DOD modeling studies (see later presentation)
  • Establish a Nanostring (Gene Expression)  Laboratory
  • Integrate DOD and NIH programs at the new lab
  • Apply to NIH for Program Project Funds to Pull Everything Together
  • Train Young  Researchers

Five Year Goals

  • Be a self sustaining unit without the need for extra University funding
  • Develop funded training program for young faculty
  • Creating an endowment that supports the program
  • Broaden international collaborations
Dr. Klimas goal is to create a environment that fosters communication and innovation

Dr. Klimas goal is to create a environment that fosters communication and innovation

Conclusion

Dr. Klimas is getting good support, the Institute is growing rapidly, it’s involved in many studies and it’s got big plans. 2012 was a good first year for the Institute for Neuroimmune Research.

Next up: Dr. Hornig on Autoimmunity and ME/CFS

FDA Advisory Meeting on Ampligen and Chronic Fatigue Syndrome (ME/CFS) Pt I: Dueling Presentations Set the Stage For Critical Vote

Food_and_Drug_Administration

The Great Room

We were in the ‘Great room’ and it was  a great room; an impressive  room able to seat several hundred people with large screens covering the sides of one wall so that everybody had a clear view of what was going on.  With the FDA often following FDA Advisory Committee recommendations this was where many drugs got approved or not and it felt like it.

The meeting starting out with the FDA rep emphasizing that  they ‘got it'; that they understood chronic fatigue syndrome is a serious and sometimes devastating disorder that vitally needs treatment options.  Announcing that they were both  ‘delighted’  and ‘overwhelmed’ by the 750 testimonials from ME/CFS patients,  their servers promptly crashed under the weight of the large online crowd watching the proceedings.

One had the feeling they weren’t used to this level of patient participation.

Just two days prior to the hearing, the FDA made public  a highly critical 220 page document outlining the FDA’s concerns on the safety and efficacy data. Hemispherx employees, however, appeared confident they could answer the FDA’s queries.

The Meeting

Hemispherx presented first with its President Dr. Carter flashing Dr. Klimas’ famous quote that she’d rather have HIV than chronic fatigue syndrome and emphasizing that ME/CFS can be life-threatening  and is as debilitating as multiple sclerosis, rheumatoid arthritis and lupus.

Safety

A good part of Dr. Carter’s presentation was focused on safety.  The FDA’s background information and questions posted  just two days  earlier had made it clear safety was going to be a major issue; something that clearly flabbergasted Dr. Carter, who noted at one point, that it was not until this year that substantial safety issues had been raised.

One problem Hemispherx faced was that Ampligen is not just a new drug; it’s (a) a drug that affects the complex and powerful immune system, (b) it’s the first of a new class of immune drugs  to get this far at the FDA, and (c)some other drugs in this class have had substantial safety issues.  The FDA noted that autopsied rodents given Ampligen possibly indicated signs an overheated inflammatory response and they posed questions about the reliability of the safety data.

Sign the Petition to Approve Ampligen Here

Stating that Hemispherx had ‘irrefutable evidence’ the drug was not sparking a strong inflammatory response , Carter laid out why. The chemical structure of the drug  was distinctly different from the other drugs in its class  that had safety concerns. In contrast to those drugs Ampligen quickly metabolized into natural molecules indicating it was giving the immune system powerful but transient nudges – hardly the type of activity that would promote a sustained inflammatory response.

The first of a new class of drugs to come under review at the FDA, Ampligen's safety record got special scrutiny.

Hemispherx argued that Ampligen’s chemical makeup, it’s quick metabolism in the body and years of clinical data indicated that Ampligen was safe.

The rodent data was simply irrelevant ;  unlike humans rodents were slow metabolizers of the drug – which meant the drug sat around in their systems for long periods of time – a danger not faced by humans. Only primates, Dr. Carter asserted,  were acceptable test animals for this drug.

Plus 95,000 doses of the drug had been given safely  since 1997. Whatever issues FDA had with the original study data, dating back 20 years in one case, subsequent use had shown the drug to be safe.  Hemispherx’s  174 safety reports indicated the drug was safe, the drug was being safely used outside the country, no evidence of autoimmune illnesses had ever been reported  and  with some irritation Carter stated the drug’s safety concerns had been dealt with 18 years ago.  Carter also tried to allay cancer concerns by noting  Ampligen’s anti-cancer effects were currently being studied at academic centers.

Hemispherx’s chief researcher, Dr. Strayer reported that the no evidence of the FDA’s chief concern, an autoimmune response,  had ever been reported and then examined the case of one participant with transient liver problems (another FDA concern)  who’s health ended up improving greatly on the drug.

Indeed, the study data indicated the drug appeared to be safe with only minor symptoms (eg flu-like issues, nauseas, abdominal issues)appearing significantly more commonly  in Ampligen treated compared to placebo treated patients.  The FDA, though, was most interested in the outliers; the few  patients who reported severe illnesses while on Ampligen even if  they couldn’t be statistically traced to Ampligen.

Efficacy

Lecturing a bit, Carter moved on to assert the FDA had not done the proper type of analyses in their background review. He noted that   the drug’s five  moves from division to division in  the FDA, the company been given different instructions from each.  Hemispherx would also refute the FDA’s assertion they had not prepared a statistical plan until after a study was done.

Ampligen;s ability to raise endurance levels, one of the other most difficult things to achieve in this disorder, suggested the drug was getting at core features of the disease.

Ampligen’s ability to raise endurance levels, one of the other most difficult things to achieve in this disorder, suggested the drug was hitting core features of the disease.

(This will be a central theme for the FDA; researchers are not ‘allowed’ to examine data later and then highlight what works; they are expected to devise a plan  of attack and then stick to it.  Hemispherx will argue that they did this and the FDA will argue that they didn’t.)

Following close on Dr. Carter’s heels Dr. Lucinda Bateman told the panel her clinic had been involved in some 30  drug trials for chronic fatigue syndrome and fibromyalgia.  Emphasizing the community’s  needs for good treatment options,  she reported that  available treatments tended to be poorly tolerated and generally had modest or no benefits.  She posted a report from Dr. Lapp, a  long time Ampligen provider,  that he’d seen from modest to remarkable results in his patients on Ampligen and had seen no serious side effects .

In response to a question,Dr. Batemen noted that the chief endpoint in the trial, increasing endurance, was a particularly difficult  thing to  achieve in chronic fatigue syndrome as endurance was one of the last things to improve as patients got better.

Dr. Strayer  showed that  Ampligen increases endurance much more than the five other drugs approved to do that in other diseases had done, that it significantly increases functionality (average Karnofsky score increases from 50-60) and  it allows patients to reduce the use of potentially damaging drugs.

Declaring that I am not a statistic, Bob Miller ended Hemispherx’s presentation with a powerful, personal review of the drug’s promise.

Hemispherx felt the treadmill endurance test results would be both pivotal to their case and difficult for the panel to understand and brought along an expert, Dr. Chris Snell of the Pacific Fatigue Lab,  to answer questions.  The panel, however, got swept up in other issues.

FDA Presentation

The FDA presentation was unremittingly critical. Using chart after chart, they pointed out  irregularities in the data and noted that several times the company changed course in midstream. At one point, for instance,  Hemispherx stopped its 1991 trial at 24 weeks instead of continuing it for a year as they’d promised.  Another time the company started a trial, recognized that the exercise protocols were too harsh and wiping out the patients, then revised it and eliminated the first 7 patients from the final data set.  That seemed to make sense, but every change bothered the FDA and considerable  discussion ensued about the significance of those 7 patients.

The FDA's presentation was critical of Hemispherx's safety and efficacy data.

Hemispherx evoked surprise at the FDA’s recent emphasis on safety data. The Agency was highly critical of what they felt were lapses in the data.

The FDA said that 41% of the people listed as responders no longer could be categorized as such as they continued on the drug in the post-trial cost-recovery period.  (Most of the original participants in  the trial continued on with the drug after the trial was over – itself a strong commendation for the drug. ). They stated that most of the statistical significance came from just a few patients who improved remarkably on the drug and from patients on placebo who fell apart.

Safety turned out to be a huge issue and the FDA brought up numerous small irregularities; an lupus flare reported for a patient although people with lupus  were supposed  to be excluded from study, abnormal liver tests in the raw data that didn’t show up in the final report, different numbers for patients who discontinued the study…

The FDA clearly took great affront at these irregularities; it wasn’t necessarily that they altered the results…it was that they were there in the first place. There was no doubt that this was a data set with problems and if you were watching Hemispherx’s stock you would have seen it rise after Hemispherx’s presentation and then plummet after the FDA’s.   Hemispherx would have to answer for them in the discussion period to follow. After lunch they appeared ready to do so.

In the end few disagreed that the data indicated  that Ampligen was effective at least a subset of patients. The disagreement was whether Hemispherx  should be allowed to move forward at that point or whether new studies should be done to target that subset.

Log Transformation

To “log transform” or not to was one of the major issues the FDA raised in their background report; the fact that log untransformed data  had shown that Ampligen had a significantly positive benefit while log transformed data indicated the drug (almost did but) didn’t have that effect.

This technical question would dog Hemispherx throughout the hearing; and they would ultimately answer it but  one had the feel that it was too late…that the damage had been done. Hemispherx’s statistician, with years of FDA experience under his belt, showed instructions from the FDA stating that log transformation should not be used unless necessary because it could skew the data, and then

Sign the Petition to Approve Ampligen Here

The FDA officials were focused on something else, though, when and why Hemispherx decided to log transform or not the data.  The big question was whether Hemispherx  saw the data before it decided whether or not to transform the data.  The statistician appeared to argue that Hemispherx had to check the variance to determine if transformation was warranted but in the end stated the biostatistician who prepared the data was no longer with the company and they didn’t know. That was a huge blow…

Never mind that Hemispherx had demonstrated that the log transformation data was not warranted or that non transformed data was appropriate …the FDA was mostly interested in whether the biostatistician had ‘followed the rules’.  It was a bizarre thing as a patient  to watch a drug that could help  ill people be held up on procedural issues but there it was.

Discussion Period

This is how the FDA approves drugs?  More impromptu debate  than rigorous analysis the discussion session kind of flowed along from topic to topic with a pro-FDA moderator calling the shots.  In fact, an actual debate, with each side arguing pro’s and con’s of each issue would have been much better.

The FDA's sloppy and rather ad hoc process which often felt hurried did not inspire confidence

The FDA’s sloppy and rather ad hoc process often felt hurried and did not inspire confidence

Instead of issues being  drawn up,  presented on the screens and then discussed in an organized manner with each side given equal time, the conversation lurched from topic to topic with the Hemispherx reps being frustrated spectators  too many times.

After lunch, Hemispherx had  appeared confident even after the morning pummeling they’d taken from the FDA team.   They felt they had answers to the FDA’s concerns but after the meeting, several members of the team felt they simply were not provided the opportunity to produce them.  The moderator did call on Hemispherx  several times but, for the most part, the FDA personnel to  held  the floor.

The short early discussion period  clearly left many questions hanging at a time when the issues were fresh in the reviewers minds but the later discussion period felt hurried as well.

Given the ad hoc nature of the discussion period drugs companies must shake in their boots and investors must tremble when they approach these meetings.  Then again, this is an FDA that gives companies 220 pages of background materials and a list of questions to be answered  two days before the meeting.  The FDA  team clearly has the upper hand in these hearings and that’s apparently how they want it.

Process vs Result

The hearing was largely a contest between those focused on  process and those focused on the  results.  The FDA stated months ago that changes in protocols as studies were underway meant the study was now a hypothesis gathering expedition not a validation study. If Hemispherx found out their exercise protocols were too harsh they should have stopped the study , redo their protocols, cleared them with the FDA, enrolled another group of patients and then redo the study. That’s not a process a small drug company will find easy to accomplish.

Sign the Petition to Approve Ampligen Here  

Hemispherx acknowledged that yes, at times, we had to change things   – but when we did, that data showed this drug helps ME/CFS patients. Given the needs of this  community we think that should be enough.

Indeed, the needs of the community loomed large in the minds of several panel members who stated that, however irregular the study follow through, they felt Hemispherx showed that the drug helps patients and that was the paramount issue for them.

Several of those who voted against the drug also agreed that Hemispherx did show efficacy at least for a subset of patients but they wanted standard protocols followed and felt  there were too many irregularities with the data. They encouraged Hemispherx to do another study.

Harsh FDA Report…Good Committee…Which Way Ampligen?

December 20, 2012

PastFuture

A once in a 20 opportunity for the ME/CFS community presented itself at the FDA hearing on Ampligen

The meeting webcast can be accessed at the following web address:   https://collaboration.fda.gov/aac122012/  At the access page  sign in as a guest. No password is required. For more info click here.

Agenda

  • 8:00 AM EST: Meeting Opens
  • 8:20-9:50 – Hemispherx Presents
  • 10:20-12:00 – FDA Presents
  • 1-2:30 Public Presents
  • 3-5:00 – The Committee answers the FDA’s questions and then votes.

THE FDA

The FDA released its background report and its list of committee members and, if you want to compare the two, the Agency was even-handed; the report was highly critical and the committee members they picked boded well for Ampligen chances..

REPORT

Harshly Critical Analysis

We knew FDA Advisory Meetings can be intense, rough environments. With the FDA background report on Ampligen you can count that as confirmed. This is not going to be easy for Hemispherx..

The FDA analysis of the Ampligen trials, focusing on methodological issues, mistakes and what it believes are inadequate efficacy and safety data does not, on the face of it, appear to bode well for Ampligen and the market agreed with the stock shaving off half its value the day the report was released.

FDA reports do tend to highlight negatives, not positives which makes sense given the way the meetings are set up; the sponsoring drug company presents its data in its best light, then the FDA does its best to poke holes in it, and then the independent review committee decides.

In the meantime be prepared for a difficult hearing. These FDA Advisory hearings have been described as ‘blood baths’ from which few companies and drugs escape unscathed.

Background

Review

A harsh FDA report presented two days before the meeting did not bode well for Ampligen

The  long and rather tattered history of Ampligen at the FDA since 1988 is outlined. The first interagency transfer to a new department occurred in 1992. The long gap between the first proof of concept trial (1990-1991) and the confirmatory trial (1998-2004) probably demonstrated how difficult it was for Hemispherx to raise the money needed to carry out the second trial.

Ampligen’s  New Drug Application (NDA) submitted on Oct, 2007 was refused filing because  it was missing  study reports, ECG and laboratory data, case report forms, ‘dose ranging’, ‘inconsistent statistical plans’, clinical pharmacology data, carcinogenicity data and had database discrepancies.  This was a long list but Hemispherx fixed some of the problems and explained others, and in the first third of 2008 quickly resubmitted the application and it was allowed to move forward.

In Nov 2009, however, citing inadequate effectiveness and safety data, drug-drug interaction data, carcinogenicity data, anti-drug antibody information and inadequate analytical methods the FDA told Hemispherx, among other things,  to conduct a new clinical trial; something which was beyond Hemispherx’s means.

“Your two main studies (AMP-502 and AMP-516) do not provide adequate evidence of effectiveness or safety.”

In 2012, after being moved to another branch of the FDA, Hemispherx requested to be allowed to  re-analyze the data from the second, larger, confirmatory  trial. The agency was leery about this approach stating “It would be unusual for this type of data to provide adequate evidence of efficacy.” but allowed the process to continue forward  stating the efficacy issues would be addressed at the final review..

Two Trials

The FDA will be relying on evidence from two trials; AMP-502 and AMP-516.  (The agency is, unfortunately, not using confirmatory data generated from patients who continued on the drug after the trial because that data was not placebo-controlled.)

First Trial (1990-1991) – The first study (502) involving 92 patients demonstrated significant increases in functioning (Karnofsky Performance Score (KPA)) and ETT (time on treadmill).

Problems had occurred. After finding that the original exercise protocol was too difficult, however, Hemispherx changed the protocol and eliminated the first seven patients from the analysis. ( If those patients are included in the analysis the significantly positive effects disappeared. )

The trial was originally supposed to last for a year but after an interim analysis it was stopped after 24 weeks. The FDA drew attention to the fact  that the statistical analysis plan was written and dated 16 years after the completion of the study and later noted ‘multiple protocol violations’ including patients restarting their other medications during the trial had occurred.

Second Trial (1998-2004) – The second larger trial (516), designed to confirm the first trials results, failed to show significant increases in self-reported  functioning or ETT.  Recently Hemispherx re-analyzed the data using patients with lower disease duration (1-10  years)  and dichotomous branching  techniques and received significantly positive ETT results but still no significant changes in self-reported functionality, daily living, SF-36  or symptom scores.

Hemispherx found that the percent of  patients reaching 25% and 50% increases from baseline was  significantly increased  in patients receiving Ampligen and that patients with lower duration illness (<10 years) were more likely to benefit. Despite reports in the literature that lower duration patients (< 2 years) do tend to respond better  the FDA found ‘no scientific rationale’ for the lower duration analysis and advised caution in interpreting them.

Several issues were reported including using median KPS values  for some patients and minimum median values for others.  Hemispherx also chose to use any response (ie the best response recorded)  during the duration of the trial for its endpoint instead of set responses at the end of the trial.

The re-analysis was helpful but the FDA questioned whether these types of re-analyses are suitable for  determining efficacy  suggesting they  are better suited for ‘hypothesis testing’.

 Due to the nature of analyses conducted after data unblinding, the Agency generally considers post-hoc analyses to be hypothesis generating rather than forming the primary basis of efficacy for an application.

Hemispherx was caught in the first study with an exercise protocol that was apparently wiping the participants out. In the second , larger ‘confirmatory’ study Hemispherx had to analyze the results differently to get positive results in the exercise testing but not significantly positive results in self-report tests.  Changes in protocols and analysis are often red flags to reviewers and questions were raised why a protocol and analysis would work in one trial and not the other.

It was rough stuff but a Hemispherx rep appeared unflustered and confident that the company was ready to respond to the FDA’s report.

Tough Subject – With its subsets and its vague definition, ME/CFS is a difficult field to test any drug in, and drugs that practitioners say have positive results in some patients have failed to achieve them in placebo-controlled trials.  If the disorder is larded with subsets then the results of any major trial of a drug that works probably should appear like Hemispherx’s did; that is, it should have weakly significant results because of the patients in the trial who have a different type of disorder altogether.  We should also know of people who had excellent results (we do) and doctors who prescribe the medication to targeted patients should have good results (they do).

Subsets-chronic-fatigue-syndrome-ampligen

Subsets will inevitably complicate matters in any clinical trial for chronic fatigue syndrome (ME/CFS) as its defined now

The FDA must realize that it’s facing an unusual challenge in a disorder that is so poorly defined.  The background report did not take into account the possibility of subsets watering down the study results but the Committee is made of several members who are well aware of this problem. Dr. Unger of the CDC, for instance, has publicly stated she is sure this is true and is engaged in a study that should help ferret them out.

Indeed a recent analysis suggested the subset problem meant Hemispherx started its trial with one of its hands tied behind its back. Throw in the fact that it’s a small company with limited resources and you probably get what we see; midstream changes that attempt to account for new information and re-analyses to target possible subgroups.

One analyst stated:

 

Ampligen’s trials had no way to account for this meta-population problem beyond looking for interesting trends within the data set. And that is what they did… No one seems to know what an appropriate biomarker for the general CFS population is, but the FDA is holding Ampligen up to an unrealistic standard nonetheless. In the end, HEB did find statistical support that Ampligen provides a biologically meaningful impact on the lives of at least some patients with CFS.

The problems facing Ampligen-or any putative therapy for CFS for that matter, is that the underlying cause(s) are unknown. As a result, there are quite possibly distinct sub-groups within any potential CFS study population with markedly distinct pathophysiologies, and hence

Safety

Hemispherx has reported that tens of thousands of doses of Ampligen have been given without issue but the FDA will rely on the results from  ‘only’ 567 patients  of which ‘controlled data’ are available for only 162. The FDA stated that for drugs intended for long-term treatment they would like at least 1,500 people exposed to the drug for short term periods and 100 for over a year.

Here, too, the FDA cited numerous issues including serious adverse events not reported, marked  laboratory abnormalities not reported, miscoding of adverse events and reasons for patient discontinuation of the trial and incomplete/misleading data presentation.  Some serious adverse events  that resulted in hospitalization were not reported. The discrepancies were enough for the FDA to call into question the data from all the trials.

On the other hand, the side effects that showed up more in patients receiving Ampligen  (flu-like symptom, chills, vasodilatation, shortness of breath ) were not particularly significant.  Other more serious side effects did occur but not more significantly in patients receiving Ampligen but the Agency expressed concerns about them.

Overall, the Agency has concerns regarding the reliability of the safety database for Ampligen, based upon lack of appropriate documentation and reporting. While review of the safety database for Ampligen suggests that the drug induces a systemic inflammatory reaction with a number of serious events of concern, the lack of reliable reporting prevents any accurate assessment of frequency. The key safety issue for discussion at the advisory committee meeting is whether conclusions can be drawn from the data as it stands …

Hemispherx will explain why the safety data is sufficient and why oversights, omissions, etc.  occurred and why they shouldn’t bear negatively on the review.

COMMITTEE MAKEUP – the Good News

 

Taking the committee makeup into account one analyst predicted a close but positive vote. At least six people have history with chronic fatigue syndrome and I would be very surprised if Komaroff, Marshall weren’t strong yes votes and the others strongly leaning towards yes. If those six vote yes they’re two votes away from a tie vote and three from a majority vote.  For me, I think Marshall can be very persuasive once he gets going J.

  • Dr. Philip Bautista
  • Dr. Robert Lahita – Rheumatologist – research focus: lupus; latest article – novel treatments for lupus
  • Dr. Tuhina Neogi – Rheumatologist, Epidemiologist – research focus: osteoarthritis and gout
  • Dr. Peter Peduzzi – Biostatistician
  • Dr. Irwin Russell – Rheumatologist associated with Fibromyalgia Research and Consulting in San Antonio, Texas – research focus- fibromyalgia; one study on duloexetine
  • Dr. Larry Borish – NIH grant recipient – allergic reactions in CFS
  • Dr. Lenore Buckley
  • Dr. Ralph D’Agostino (Ph.D)
  • Dr. Jacqueline Gardner (Ph.D)
  • Dr. Anthony Komaroff (MD) – ME/CFS expert
  • Dr. Gailen Marshall (MD, Ph.D) – CFSAC representative
  • Alaine Perry (MPH) – Patient representative – CFSAC representative
  • Dr. Mathew Rudorfer (MD)
  • Dr. Sean Hennessey (Ph.D)
  • Dr. Elizabeth Unger (Ph.D) – Chief of CDC CFS research
  • Dr. James Ware (Ph.D)

Conclusion

The harsh FDA report was produced by statisticians with little knowledge of the disorder but the FDA also produced a committee with a core of members with extensive knowledge of ME/CFS. The Committee vote is the key. Will Hemispherx and the patient advocates be able to convince the committee members to overlook a harsh FDA report? We’ll see.

The vote will come at the end of the day. The committee members will be asked to vote all at once so that the members are not influenced by the others votes.

The FDA will take everything into account and release its decision on Feb 2nd. They could approve the drug outright (not likely to happen), approve it with conditions, ask for more studies or just slam the door on the drug.

Dec 20th: High Noon for Ampligen and Chronic Fatigue Syndrome

December 16, 2012

Decades of hope and work for Ampligen, still the only drug ever produced for CFS, will culminate on Dec 20th.

by Cort Johnson

Ampligen’s time is finally here.  Twenty years of effort and hope  will culminate on the early evening of Dec 20th, when, following an  all-day hearing,  an FDA Advisory committee  will determine  Ampligen’s fate. Palms will be sweating and hearts will be pounding that evening as patients, physicians and their supporters and researchers with decades of work on the line  await what will be a momentous  decision.

Produced by Hemispherx Biopharma, Ampligen is and has been the only drug under development for chronic fatigue syndrome for over twenty years.  No other drugs are waiting in the wings and no other companies appear interested in  putting  years of effort  and millions of dollars into producing or even testing a  drug for this disorder.

It’ll all come down to 6-10 or so independent ‘experts’ opinions on whether this drug is safe, effective and worth putting on the market.

Prior to  the big decision we’ll see presentations from Hemispherx, the FDA and ME/CFS patients.   Dr. Bateman, Dr. Snell and Hemipherx representatives will present for Ampligen.

LOCATION: Open to the Public

Anybody can come and we hope as many people as possible  come and if they wish, give testimony.  Patient Testimony will be given in 3-minute slots  from approximate 1pm to 2:30

December 20, 2012: Arthritis Advisory Committee Meeting Announcement

Center Date Time Location
CDER December 20, 2012 8:00 a.m. to 5:00 p.m. FDA White Oak CampusBuilding 31Great Room (Rm. 1503)White Oak Conference Center10903 New Hampshire Avenue Silver Spring, Maryland

 

For Directions and other Info

Hemispherx is likely to face tough questioning at the FDA Advisory Committee meeting for Ampligen

TOUGH ENVIRONMENT

According to someone who’s been there, FDA Advisory Hearings  tend to be in-your-face type affairs in which tough questions  and a critical attitude are the norm. If Hemispherx  is getting whacked around at the hearing don’t attach too much significance to it;  every pharmaceutical company gets hammered at these hearings – even those that get their drugs approved.

My understanding is that there will be two presentations; the FDA will present its interpretation of the data and Hermispherx  with Dr. Bateman, Dr. Snell and its own raft of professionals will present its case. The FDA Advisory Board, made up mostly of rheumatologists  will pepper each group with questions and come to a decision on three questions.

      • Does  Ampligen work ( efficacy)?
      • Is Ampligen safe?
      • Do Ampligen’s benefits outweigh its risks?

Each member will answer each of these questions live and we’ll get  their decision in public  that day. From there the FDA will take their reports into account and submit their final ruling on Feb 3rd, 2013. They almost always follow the decisions of the Advisory Board.

Still Some Unknowns

There’s still quite a bit about this meeting that we don’t know and that the FDA probably won’t share until 2 days before the meeting. Take no offense at this – this, for some reason,  is standard FDA procedure. (The FDA states they will provide the information at least two day before the meeting, which everybody is taking to mean it will happen two days prior. )

At Least Two Days Before the Meeting..We Will Know

      • Panel Makeup – The final makeup of the panel.  We do  know that the panel will be made up of persons from the Arthritis Advisory Committee and perhaps others but we’re not sure who.  The FDA website states the  committee is made up of 12 slots, six of which are vacant (including the Chair :) ). Of the six persons  listed on the website one of them, Dr. Irwin Russell, is director of the Fibromyalgia Research and Consulting Clinical Research Section of South Texas. Another is an immunologist; none of the others, at first glance, have any indirect connections with CFS or FM.
      • Patient Advocate – the identity of the ‘Patient Advocate’, who presents the needs of the patient community to the panel will be listed.
      • Discussion Points/Questions – Hemispherx will want to rest up beforehand because the FDA may list a series of questions  they want information on just  two days before the epochal hearing takes place. Hemispherx may  be cramming all the way up to the hearing..
      • Webcast Link – We’ll  get the link for the webcast.

The information will be available here or maybe here; it’s not entirely clear from the notice..

STAR ALIGNING? 

Ampligen has been under review of one sort or the other since the nineties, but after  a surprisingly good year for Ampligen there is  good  reason to hope for a successful outcome.   In July the FDA reversed a devastating 2009 decision requiring Hemispherx to produce new  expensive studies which  appeared to  put Ampligen out of reach for good.  With chronic fatigue syndrome gaining more prominence, though, and with  the FDA being given a  new mandate to give  serious, underserved  illnesses a foot up,  Ampligen was  back in the mix in 2012.

Key Legislation Provides An Opening

The 2012 FDA Safety and Innovation Act (FDASIA) passed in July appears to  have played a key role in reversing Ampligen’s fate. The FDASIA encouraged the FDA to use a process called ‘accelerated approval’ which allows the Agency to conditionally approve drugs  for ‘serious and life-threatening illnesses’ while  drug companies worked on proving efficacy. This is a perfect mechanism for small drug companies like Hemispherx which would be allowed to market the drug and use the profits to fund further studies it couldn’t otherwise undertake.

Have the pieces come together for Ampligen and Hemispherx?

Coming just two days after the passage of FDASIA, the FDA turnaround  on Ampligen might indicate the FDA  is using the drug to make a statement regarding its willingness to follow FDASIA guidelines.  Indeed, Sue Sutter, a noted business/pharmaceutical journalist suggested  the FDA’s change of direction on Ampligen may have been directly  influenced by the  FDASIA.

More groundwork was laid on Sept 13th when FDA Deputy Director, Sandra Kweder, M.D. publicly stated on an ME/CFS Teleconference that the  FDA considers ME/CFS to be a “serious and life threatening disorder”.  An FDA notice for the meeting  that specifically mentioned ‘accelerated approval’ and ‘unmet medical needs’ with regard to drugs for ME/CFS indicated that the FDA, again, was specifically drawing attention to FDASIA guidelines.

The FDA’s decision to hold an  ME/CFS  advocacy teleconference and use ME/CFS  to produce it’s first Stakeholders Meeting for  a disorder in decades next year  also suggests a positive stance by the FDA.  (One FDASIA provision calls for more patient involvement.)  Sue Sutter  called these efforts “a major step in the FDA’s efforts to raise the profile of CFS as a drug development target”.

Finally a Jan 2011 decision to consolidate, after being bumped around to six divisions,  oversight of CFS treatments in the Division of Pulmonary, Allergy and Rheumatology Products, suggested the Agency was trying, finally, to get its arms around this disease and its challenges.

THE PLUS’S

The Drug

  • Ampligen out-performed a placebo in exercise trials
  • Patients on the drug were able to reduce their use of other medications, some of which can  be harmful
  • Over 1,000 patients have been administered over 90,000 doses of the drug safely
  • Even long term use of Ampligen appears to be safe (ie does not cause disease)
  • Significant buy-in from physicians who have administered the drug and patients who have taken it.  (See Dr. Peterson talking about Ampligen in the past   Read Kelvin Lords experiences on Ampligen here).

The Disorder

  • Chronic fatigue syndrome is a relatively common disorder with no FDA approved drugs (and no other drugs in sight) which presents high economic costs to people who have it and to the  nation as a whole
  • CDC figures suggest that chronic fatigue syndrome is functionally as disabling as multiple sclerosis and 10 times as common
  • Other disorders with few FDA approved drugs have been given more latitude with regard to drug efficacy at the FDA; ie if no other treatments are available the FDA is willing to relax its efficacy requirements.
  • FDASIA passage supports accelerated approval in cases where serious unmet needs are present and the drug is safe.

The MINUSES

  •  The biggest hurdle Hemispherx has to deal with is the age and number  of its studies.  In 2009 the FDA wanted a brand spanking new study with lots of bells and whistles.  The FDA relinquished that stance earlier this year but Hemispherx could be penalized for not being a billion dollar pharmaceutical company with resources to burn. Hemispherx’s re-analysis of its original data had Ampligen performing better. Will that be good enough?
  • Controversial Disease – with a poor definition. Will the disorders negatives trump its positives and the community’s needs? No federal agency has ever made the CFS communities needs a priority. Will the FDA be the first?

DECISION TIME

Taking Responsibility – The FDA rarely does not follow the decisions of its independent reviewers but the responsibility for the final decision is theirs.  They, of course, contributed to Hemispherx’s dilemma by moving the drug around to six regulatory teams.  Frustrated with these kind of bureaucratic bottlenecks and the slow pace of drug approvals, Congress acted in 2012 to make the FDA work more effectively for chronically ill people in the U.S.

It’s hard to see what the FDA has to lose by giving Ampligen Accelerated Approval status. They know the disorder is serious, they realize the community has huge unmet needs, they have proof of efficacy and most of all, they know the drug is safe.

POTENTIAL GAME CHANGER

Ampligen approval would change how ME/CFS is viewed leading to more respect and more funding

If approval occurs patients will get access to a drug that’s worked well for many, doctors will view ME/CFS as more of a treatable disorder and immune research will heat up.  Future studies examining Ampligen’s effects could very well pave the way for a biomarker and uncover subsets.

FDA approval would also give pharmaceutical companies the message the FDA is serious about finding ways to get drugs to this community and that it will work with them where it can to do. A thumbs down could suggest the opposite.

Maybe the biggest change, though, would be a change in context for ME’/CFS.  If you can change the context in which a thing occurs opportunities that were denied to it come naturally. An FDA approval would make this disorder more real as a disorder thus giving it more access to the opportunities other ‘real’ disorders have. The FDA does not approve drugs for figments of the imagination; it approves drugs for HIV, pneumonia and cancer.  Ampligen approval would begin to thrust chronic fatigue syndrome into that realm and  disorders like that  get respect, they get interest and they get funding.

The final decision for Ampligen will come on Feb 2nd.