All posts tagged Celecoxib

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

Big Antiviral Trial Could Usher in New Treatment Era for Fibromyalgia

 A New Approach to Fibromyalgia

Infections are a common trigger for fibromyalgia (FM), and fibromyalgia patients are experience many ‘sickness behavior’ symptoms, but we haven’t usually associated FM with viruses or immune system problems.

woman questioning

So it’s going to be Fibromyalgia that gets the really big antiviral trial ….

That’s been changing  recently. A immune biomarker has been proposed. Small fiber neuropathy - possibly caused by immune dysregulation – has been found. Dr. Dantini has been treating FM with antivirals for years.  The immune system’s starting to get some respect in FM.

Now, in a surprising twist, it’s going to be fibromyalgia rather than chronic fatigue syndrome, that’s getting the big, placebo controlled, double-blinded multi-center antiviral trial.

Last year we heard that Dr. William Pridgen in  Alabama was getting his ducks in a row for a major antiviral trial. Four weeks ago in an email exchange he confirmed that the money – $3.3 million dollars – all gathered from ‘angel investors’ is in  hand, and the four-month 143 patient trial began  in early October.

Pridgen’s Innovative Med Concepts biotech startup is producing the study.

A Different Path

The pathways researchers and doctors take to get to disorders like FM or chronic fatigue syndrome are nothing but diverse, and it’s worth taking a look at how Dr. Pridgen, a surgeon, came to fibromyalgia. (Dr. Julia Newton’s pathway to ME/CFS was through elderly people experiencing dizziness and, to her surprise, a great deal of fatigue.) Dr. Pridgen’s pathway to fibromyalgia was through the gut.

Pridgen saw a pattern emerge in his  treatment of thousands of patients with chronic gastrointestinal issues that intrigued him. A patient would get better, but then experience a stressful event that would send him/her back into the soup.  They would get better, but during the next relapse they would stay sick longer and their recovery period would be shorter. Eventually they would be sick all the time.

virus

Shorter and shorter relapses over time in his patients lead Pridgen to conclude that a virus must be involved.

The problem, he thought, had to be some sort of pathogen that was steadily increasing with every recurrence. Giving his patients antivirals helped, but problems remained. Then he found that adding an anti-inflammatory (which also had anti-viral properties) reduced their fatigue, gastrointestinal complaints, depression and anxiety markedly and improved their energy.

An observational study indicating that the combination drug approach had a 90% ‘efficacy rate’ led Pridgen to start a company, enlist investors and create the large treatment trial.

Pridgen’s theory fits glove and hand with several other fibromyalgia/chronic fatigue syndrome theories. As with Van Elzakkers’ vagus nerve infection theory for ME/CFS, Pridgen’s theory begins with a nerve loving virus that takes up residence – for life – in nerves in the sensory ganglia found across the body.

Instead of HHV6 or EBV Pridgen believes herpes simplex viruses, are the key in FM/ME/CFS. Other than a 1993 theory proposing herpes simplex virus was at play in ME/CFS, interest has been scanty. HSV-1’s ability to affect many of the genes and gene pathways suspected of playing a role in nervous system disorders such as Alzheimer’s, Parkinson’s, depression, chronic fatigue syndrome and autism, however, lead one researcher to propose it could play a role in all of them.

HSV-1 has been found in the esophagus, stomach and duodenum of the gastrointestinal system. In fact, HSV-1 was proposed to  cause ‘recurrent functional gastrointestinal disorders’ such as IBS, as far back as 1996.

Pridgen’s patent application indicates that he believes that stressors and  peptides and hormones released by the sympathetic nervous system and HPA axis  set the stage for herpes simplex-1 reactivation. Pridgen proposes that repeated HSV reactivation can  kill the sensory nerve cells ( small fiber neuropathy?) and destroy part of the nerve ganglion.  (Stress induced HSV-1 reactivation has been documented in laboratory animal studies.)

Once  these neurons and ganglia are damaged, Pridgen believes they send out signals that ultimately muck up the pain processing centers in the central nervous system. The over-generation of neurotransmitters such as glutamate, Substance P, serotonin, norepinephrine, dopamine, brain-derived neurotrophic factor (BDNF) involved in this process then causes central sensitization.

Antiviral Plus

Pridgen proposes to stop the viral reactivation and the central sensitization with antivirals; an approach that’s been tried before in chronic fatigue syndrome, but not in the way Pridgen’s doing it.

connections

Are two ‘antivirals’ better than one? We’ll find out sometime next year.

One of Pridgen’s patent applications suggests that one of his unique insights has been to combine valacyclovir (valtrex) with an anti-inflammatory, Celecoxib (Celebrex) that has antiviral properties.  Other combinations are being tested and Pridgen stated  they have not released the make-up of IMC formulation used in the trial. It’s not clear, then, what drugs at what doses were used in the study or which will prove most effective. 

Celexcoxib (Celebrex) is a non-steroidal antinflammatory (NSAID) COX-2 inhibitor usually used  in the treatment of osteoarthritisrheumatoid arthritisacute pain, painful menstruation and menstrual symptoms. It down regulates the activity of inflammation producing  cells.

Pridgen proposes that the  two drugs hit the virus at different stages of its life-cycle. Pummeling the virus with that one-two punch, he believes, will finally stop the virus from reactivating.

Pridgen and Duffy are looking for herpes simplex virus, but other herpes viruses could be affected by this treatment. We won’t know if they are until further studies are done.

Inflammation Gone Awry

Pridgen and his partner, molecular virologist, Carol Duffy will also attempt to develop a diagnostic test for fibromyalgia using cytokine arrays they believe will document high levels of  pro-inflammatory cytokines and low levels of anti-inflammatory cytokines.

Like VanElzakker, Pridgen believes the body is over-reacting to the virus.

“It’s basically exaggerating its reaction to the virus. Any little stress reactivates the virus, and, rather than the body saying, ‘Oh, this is just a virus I’ve been living with this since I was five,’ the body keeps saying, ‘Oh, my God,’ and throws on all this inflammation, and that gives these people this pain.”

“There is a theory that all pain, one way or another, is inflammation,” Duffy says. “It’s inflammation gone awry.”

Not just Fibromyalgia

Pridgen and Duffy have their eyes on more than Fibromyalgia.  Pridgen’s provisional patent proposes this treatment will work for chronic fatigue syndrome, irritable bowel syndrome, chronic pain, chronic headache, chronic neck pain, chronic back pain, chronic depression, chronic clinical anxiety disorder, post-traumatic stress disorder (PTSD), brain fog, cognitive dysfunction and chronic interstitial cystitis.

Celebrex – The Antiviral?

We don’t hear anything about Celecoxib as a virus fighter in ME/CFS, but some evidence suggests it could be efficacious against herpes simplex virus. The ability of COX-2 inhibitors to decrease prostaglandin production is believed to push the immune system towards a Th1 (antiviral) response and away from the Th2 response often found in ME/CFS.

stop sign

Pridgen believes Celexicob’s antiviral properties, in concert with Valtrex, will knock down the herpes viruses causing FM and ME/CFS

Celebrex was shown to reduce stress induced herpes virus reactivation in the nervous systems of mice.  Another study found that reactivation of HSV-1 in mice was associated with upregulation of COX-2 gene expression in their nerve ganglia.  HHV-6 can also induce COX-2 expression.  Both COX-1 and COX-2 are needed for viral replication.

(One mother found that VIOXX (now off the market) reduced her daughters IL-6 levels and eliminated the ‘panic attacks’  she’d experienced following a central nervous system infection.)

(Aspirin and flavanoids, vitamin E and fish oils also inhibit COX-2. The efficacy some ME/CFS patients experience from using omega-3 fatty acids could be due to antiviral effects.)

Tissue Biopsies

Along with treating the virus, Pridgen and his partner, molecular virologist Carol Duffy, will be using PCR to test for the virus, not in the blood, but in gut tissue samples.

One of the most intriguing aspects of the Pridgen-Duffy study is the search for HSV-1, not in the blood, but in the tissues. We know the Chronic Fatigue Initiative’s Pathogen study  failed to find evidence of viral infection in the blood. Now, Pridgen and Duffy are testing gut samples for herpes virus simplex in their study.

First PCR will be used to search for herpesviruses in both the control and FM gut samples. Then antibodies will be used to determine if an active infection is present.  In subsequent studies, electron microscopy will look for the herpesviruses particles themselves.

In preliminary studies 18/19 fibromyalgia patients with gut issues contained herpes simplex virus DNA in their gut tissues. No other herpesviruses were found. Immunoblot testing indicated that an active infection was present in eight of nine positive biopises.

Dr. Pridgen reported in an email they are still trying to determine  the optimum doses and cautioned everyone to wait until the results of the phase three trial are done before starting this treatment.  He also stated he feels  they are ‘very close’ to helping many people with this condition.  The results of trial will be released mid-year, 2014. 

Conclusion

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A successful trial could usher in a new era of treatment for fibromyalgia and perhaps chronic fatigue syndrome

Pridgen and Duffy’s big multi-center antiviral trial in Fibromyalgia is nothing if not exciting in its scope and approach. Pridgen’s ability to come up with over $3,000,000 in startup funding suggests he and Duffy have got some solid data backing their trial up. .

If they results are positive, Pridgen and Duffy could usher in an entirely new way of treating both fibromyalgia and chronic fatigue syndrome.