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

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

A Little History

If Ampligen has failed to gain approval at least it and the company have been entertaining. Ironically, given its long and rather harrowing path through the FDA, Ampligen's first use in an ME/CFS patient was prompted by none other than the FDA. After an ME/CFS patient with culture evidence of HHV-6 infection significantly improved clinical trials began.Problems occurred early on, however, when Hemispherx Biopharma, the drug's maker, cut the trial duration in half, and ME/CFS patients sued at one point to get access to the drug. The early Ampligen trials in chronic fatigue syndrome ultimately sparked the publication of a hilarious novel by Floyd Skloot, Patient 002.The company came under fire early. In the early 1990's CAA President Kim Kenney (McCleary) said “Ampligen is a good drug in the wrong hands”.  Daniel Hoth, then head of the National Institutes of Health’s AIDS drug program, went further when he told the Wall Street journal that “no professional drug company with any degree of professionalism would ever develop Ampligen the way it was developed by HEM.”

Difficult Path

Hemispherx Biopharma, though, has never had an easy time of it. In what surely must be a record for frustration for a drug company, Ampligen was moved to a different section of the FDA four times; each move eliciting a new review and different findings.The FDA panel's rejection of Ampligen in 2013 provided more head-shaking moments when two ME/CFS experts  unexpectedly voted against it, and several non- ME/CFS experts (citing the community's urgent needs) voted to approve it.Hemispherx felt blindsided at the hearing by safety issues it been told had been addressed years ago, and which it didn't feel it was given adequate time to respond to.  (Since then FDA officials have said safety is not a major issue). It's no wonder the company has felt at times that the deck has been stacked against them.With the FDA asking for large drug trials that HB lacked the funds to produce, Ampligen finally seemed to be dead, but a new push to understand ME/CFS at the NIH may be producing a sea change for the drug.

Patients Push FDA To Approve Drug

More than anyone, ME/CFS patients know of the cost of having no FDA approved drugs.  Patient outcry at the FDA denial of Ampligen in 2013 - including an 11-day hunger strike by patient Robert Miller, 5,000 signatures petitioning the FDA to reconsider, and thousands of emails from patients and Congresspeople flooding the FDA - prompted the FDA to conduct a Drug Development Workshop in 2014 and publish guidance for the industry on ME/CFS drug development.The FDA's effort to spur drug company interest in ME/CFS appears to have failed, however, leaving Ampligen still the only drug candidate within short-term reach of drug approval for a disease that the FDA acknowledges urgently needs approved treatments.With NIH director Francis Collin's commitment to reinvigorate  chronic fatigue syndrome (ME/CFS) research and mentioning the possibility of an NIH funded Ampligen trial, it's time to take another look at the "first" drug for ME/CFS.

Renewal

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

Ampligen

Ampligen is an immunomodulator that targets a portion of the immune system that fights viruses.  Ampligen's producer, Hemispherx Biopharma, was surely cheered by  the assignment of a major NIH study  to a neuroinfectious disease specialist, Dr. Avindra Nath.Ampligen's use in ME/CFS is predicated on the idea that viruses and/or immune issues are playing havoc in the disease. Ampligen is a toll -like receptor three (TLR-3) inducer. The receptor it binds to are found on antigen presenting cells such as dendritic cells that have been exposed to pathogens.The binding of the receptor activates hundreds of genes in a cell. The side effects from most TLR inducing drugs limits their effectiveness, but Ampligen is unique among these drugs in that it does not cause cells to produce large amounts of pro-inflammatory cytokines.

Efficacy

Reports of Ampligen's ability to dramatically improve the health of some people with ME/CFS abound.The 90,000 doses given safely through Hemispherx Biopharma's compassionate care program to ME/CFS patients by a handful of doctors in the U.S. have produced some startling stories of improvement and recovery.Anita Patton, Mary Schweitzer, Bob Miller and Kelvin Lord have all documented their Ampligen success stories. Several experienced significant improvement while on it only to relapse while off it.  Anita Patton essentially went from bed bound to normal functioning on Ampligen, back to being bed bound off of it, and then again to normal functioning when back on the drug.Kelvin Lord's story was perhaps most representative. He's provided the most complete (and funniest) review of an ME/CFS patient's experience with Ampligen in a series of blogs titled "The Ampligen Chronicles".  Faced with rapidly deteriorating health, Ampligen was Kelvin Lord's last shot at health. To his surprise and delight it worked.It didn't return this businessman, flight instructor, skier and parasailor to complete health, but Kelvin did progress from being barely able to walk to be able to work 6 hours and do 45 minutes of resistance exercises a day. His brain fog, orthostatic intolerance, canker sores and extreme fatigue disappeared. He was back to being a productive human being for a major part of his day - a huge jump. (Read about it here.)  Going from bed bound to productive is probably a bigger jump, it should be noted, than most FDA approved drugs provide.(Find other stories in Health Rising's Ampligen Resource Page.)Of course, examples of Ampligen's lack of efficacy can be found as well, but this is to be expected given the  heterogeneous nature of ME/CFS.  Until the subsets in ME/CFS can be targeted with treatments unique to them, treatment efficacy even for most effective treatments, is probably going to be fairly low - perhaps around the 30-40% mark found in Ampligen.

Studies

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

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

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

Thirteen Ampligen trails have been done over the past 20 years or so.  Nine occurred in severely ill prior fatigue syndrome patients; three of these were large multisite trials and five were open label trials measuring safety and efficacy.  All told over 830 different ME/CFS patients have received over 90,000 doses of Ampligen. Most of the patients in the studies had been ill for at least 6-9 years.The results of the trials have been positive. The first 92 person trial found significant increases in Karnofsky performance scores (p<.001), quality of life, exercise tolerance and oxygen utilization during exercise. Ampligen receiving patients also used significantly less drugs to alleviate their symptoms than placebo receiving patients.The number of patients seeking emergency room care demonstrated how severely ill the patients in the study were, and how helpful Ampligen might be if it were available.  Ampligen cut the number of patients visiting the emergency room in half (from 15% to <8%). The placebo patients stayed an average of eight days at the hospital, while the Ampligen receiving patients stayed an average of less than three days.(In how many diseases would 15% of the patients in the clinical trial spend an average of 8 days at a hospital over the duration of the trial? This was a very severely ill cohort.)The primary endpoint of next  234 person trial was exercise intolerance. The results, which barely reached the minimum standard of significance (p< .05/ p<.048), indicated that exercise tolerance increased on average about 22%. Overall Ampligen improved VO2 max results on the exercise test by 5.5%, and Ampligen receiving patients were able to stay on the treadmill for about nine minutes longer than placebo receiving patients.Further analyses found 3 cohorts of patients with regards to exercise tolerance; high responders, mild responders and no responders. Overall patients on the drug improved significantly more than patients given placebo (p<.001).As in the first study, hospital visits were significantly reduced in the Ampligen receiving cohort and Karnofsky performance scores were significantly increased.The two clinical studies suggest that 30-40% of people with severe ME/CFS can be expected to get "clinical benefit" from Ampligen.The trials were mostly successful, but did have their problems.  The company stopped the first trial early and then modified the second trial in midstream. Even though the second trial was successful a great deal of discussion at the FDA hearing involved why the trial was modified.  Records could have better kept as well.From the ME/CFS communities perspective, though, the success of both trials  was paramount. Many felt the lapses should have overlooked given the urgent need for treatments in such a large and often disabling disease.  Many also felt that the positive testimony by doctors who had been using the drug for years should have been given more weight.

Conclusion

While there were some problems with the trials the drug did meet several important endpoints including increasing time on a treadmill and increased oxygen utilization. It should be noted that Ampligen has tried to move the needle on probably the most difficult factor of all to budge in ME/CFS: oxygen utilization during exercise.Any drug providing clinical benefit to 30-40% of a population which has no approved drugs should be a slam dunk. (Less effective drugs have been readily approved in other illnesses). Hopefully, with new leadership, Hemispherx's twenty plus year journey to bring Ampligen to market will end successfully, and the ME/CFS community will finally get its first drug approved.