Through the "Valley of Death": Dr. Pridgen, Fibromyalgia and the Looming Trials
Skip Pridgen fibromyalgia
First there were the anecdotal reports – FM patients were not just getting better but some, and not just a few, were getting well using something entirely new – an antiviral protocol, of all things, created not by a pain specialist or rheumatologist but by a surgeon. Aside from a few doctors in the U.S., no one was treating FM with antivirals and virtually no research had examined the role of pathogens in the disease. A PubMed search of fibromyalgia and herpesviruses pulled up just two herpesvirus studies - both done over thirty years ago.
But here was Skip Pridgen, a Tuscaloosa surgeon, not just asserting that herpesviruses were the cause of FM, but that an unusual antiviral protocol consisting of a herpesvirus antiviral and anti-inflammatory with antiviral properties (celecoxib) was doing the trick. Plus, he asserted that herpes simplex virus – a virus that has gotten no attention in FM’s sister disease, chronic fatigue syndrome (ME/CFS) – was the culprit.
Pridgen, who’s treated thousands of patients with gastrointestinal issues, came up with the protocol after he noticed that his FM patients with IBS seemed to get better and then relapse. Figuring that a herpesvirus might be responsible, he gave them a herpesvirus drug and was surprised that not only their GI but also their FM symptoms improved.
When celecoxib had the same effect in FM patients with arthritis, the idea of a drug combo – IMC-1 - was born. Pridgen and Carol Duffy – his research partner at the University of Alabama – believe the drug combo is effective because each drug inhibits the virus at different points in its replication cycle and they stop viral reactivation as well. (Hitting a virus at multiple points is a strategy employed to stop HIV.)
Pridgen created a startup Innovative Med Concepts – and put together a pretty hot team (including a past Vice President of Pfizer) and some respected researchers for its Scientific Advisory Board (including Daniel Clauw and surprise, surprise former ME/CFS researcher Dr. Dedra Buchwald) and got a Phase II clinical trial funded and going. (Dr. Buchwald was a surprise because she was so darn conservative in her approach to ME/CFS…)
The clinical trials are where it gets really serious, though. For all the reports of Pridgen helping FM patients, they mean nothing to Pridgen’s hopes of producing an FDA-approved drug. The trials are where the action is, and with the recent publication of Pridgen’s Phase II clinical trial in the Journal of Pain Research, we finally have something we can really get our hands around.
The Trial
A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia. William L Pridgen, Carol Duffy, Judy F Gendreau, R Michael Gendreau. Journal of Pain Research 2017:10 451–460
Pridgen has been almost relentlessly upbeat in his assertions about the effectiveness of his new protocol and he and his co-authors don’t pull any punches in the title of their journal article which boldly states that “A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia”. Because the trial was distributed across twelve sites, it sampled a broad array of FM patients (and doctors). With 143 patients participating, it was a good sized double-blinded, (neither the patients nor doctors/researchers knew who got the drug or placebo), and placebo-controlled 16-week study.
Six questionnaires were used to assess the drug combo’s effectiveness. The primary endpoint – the test the study really had to meet involved two questionnaires – a numerical pain rating scale (NRS) and a past week functional and symptom assessment questionnaire called the Fibromyalgia Impact Quotient (FIQ-R) score.
The first part of the FIQ-R asks how difficult it was over the past week to do things like walk continuously for 20 minutes, vacuum the floor, climb one flight of stairs, go shopping, etc. The second part asks each patient to rate their pain, energy, sleep, depression, etc. The study participants had to be off off a variety of drugs (duloxetine, milnacipran, pregabalin, gabapentin, sodium oxybate, and opioids). Over ninety percent of the participants were women and their average age was 49.
Results
IMC-1 was statistically significantly superior to placebo in most of the tests
Functionality and Symptoms - The FM patients on the IMC-1 protocol showed a statistically significant improvement in their functionality and overall symptom scores on the FIQ-R test relative to the patients not on the protocol. (The average patient showed a 2.2-point improvement on the eleven-point scale.) Functionality, symptoms, and overall impact of FM all showed significant improvement on the drug.
Pain Assessment – Past 24 Hours - With regard to the other primary endpoint – the NSR measurement of pain, only when the data was subjected to “imputation” did the patients report statistically significant improvement in their past 24-hour pain. (Imputation analyses were used to account for missing data.)
Overall Improvement - Another test called the PGIC asked patients about how much they had improved. Patients had to report that they were much or very improved to pass the PGIC test. About 35% of patients on the IMC-1 protocol reported they were much or very much improved at weeks 12 or 16 vs about 18% of those on placebo – a statistically significant result.
Another Pain Analysis - Responder analyses used to assess what percentage of patients received a 30-50% reduction in pain found that about 30% of FM patients reported a greater than 50% reduction in pain over the past 24 hours on the IMC-1 drug combo.
Fatigue - Two fatigue assessments (MFI, PROMIS fatigue short form) had differing results; the older MFI test showed no significant improvements in fatigue while the more recently developed PROMIS test showed that those on the drug combo received statistically significant reductions in fatigue.
Depression – The depression findings were intriguing given that one does not ordinarily link depression with herpesvirus infections. When the imputation analyses to account for missing data were performed, however, IMC-1 produced a highly statistically significant (P=0.003) reduction in depression. (This data was not in the published paper.) Since the HSV-1 virus hangs out in three different nerve ganglia in the body, knocking it down could conceivably affect many symptoms – including depression and anxiety.
Learn more about possible connections between the herpes simplex virus and fibromyalgia and chronic fatigue syndrome - The Devil Is In The Details – A Herpes Simplex Virus Inquiry For Fibromyalgia and Chronic Fatigue Syndrome
Safety and TolerabilityWith more patients off the drug than on the drug reporting side effects, the IMC-1 drug combo passed the safety test with flying colors. That finding was bolstered by the much higher dropout rates in the placebo arm compared to the drug arm.The Phase II clinical trials reported on here is a proof of concept trial done to demonstrate that the drug probably works and is safe. Because these trials are also used to help manufacturers determine the best dose to use in a Phase III trial, Phase II trials are also more experimental.The results were good but not spectacular. I asked Dr. Pridgen if he was satisfied with them. Considering that he felt that Innovative Med Concepts had a hand tied behind its back by the FDA he was:
Given that the FDA restricted our dose to that which we ultimately used, we were thrilled that we met statistical significance with our primary, secondary and even our exploratory endpoints. Being able to show statistically significant improvement in Pain, fatigue, depression, and a dramatic impact on IBS is truly unique. Honestly, I have never seen a proof of concept trial with this broad of an impact. Knowing that the recent toxicology results support our planned ideal dose, as you might imagine, we are incredibly confident in our Phase 3 trial. Dr. Pridgen
Pinpointing the Culprit
One of Pridgen’s and Duffy’s tasks includes demonstrating that herpes simplex one (HSV-1) – the virus they believe is responsible for FM – is, in fact, present. Pridgen reported that Duffy’s analysis of FM patients gut tissue is complete and that the data that emerged “far surpassed” their expectations. They are writing up the manuscript now.
Through the Valley of Death
Pridgen-IMC-1-valley-death
Pridgen reported a couple of factors that may increase IMC-1’s effectiveness in the next trial. A higher dose will be used in the next trial and the screening process for the participants will be tighter to avoid the impact of confounding factors.
The huge Phase III clinical trials required for FDA approval are called the “Valley of Death” by some for good reason. Pridgen said that testing the drug combination – featuring two drugs that are already FDA approved – will require two 500-1000 person drug trials, each costing from $25-50 million.
That’s on top of almost complete animal toxicology testing that’s been done and the large proof of concept Phase II trial. Trials like that take some heavy lifting and Pridgen’s enrolled some top talent to get IMC-1 through the “Valley”. Rick Burch, the President of Innovative Med Concepts and the former Senior Vice President for Pfizer, oversaw divisions employing more than 6,500 employees and had a hand in launching Lyrica. As chief medical and safety officers, Drs. Michael and Judy Gendreau helped usher Savella to FDA approval.Pridgen reported that Innovative Med Concepts met with 14 companies (half pharmaceutical, half companies that could provide financing) at JP Morgan in January of this year. He expects the trials to begin in late 2017.
He’s confident enough of the drug’s success to expect to employ in the next trial what he stated was the toughest primary endpoint ever used in an FM drug trial – a 50% or more reduction in pain.
Will Pridgen’s approach revolutionize our understanding and treatment of fibromyalgia? Could FM really come to be viewed as a herpesvirus-induced disease – and if it is – what would that mean for chronic fatigue syndrome? Intriguing questions all. The rubber will really meet the road for surgeon turned drug developer and the many FM patients looking for better treatment options probably at the end of this year.
More on Dr. Pridgen and His Approach to Fibromyalgia
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