All posts tagged Famvir

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

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

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

Skip Pridgen fibromyalgia

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

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

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

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

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

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

The Trial

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

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

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

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

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

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

Results

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

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

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

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

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

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

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

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

Safety and Tolerability

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

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

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

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

Pinpointing the Culprit

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

Through the Valley of Death

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

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

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

Pridgen-IMC-1-valley-death

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

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

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

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

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

 More on Dr. Pridgen and His Approach to Fibromyalgia

Simmaron

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

The Pridgen Revolution?

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

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

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

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

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

The Pridgen Interview

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

They will start next year.

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