Tecfidera (BG 12) And PML

If you are currently taking Tecfidera, please take part in my Tecfidera patient poll (click here).

Over the last month or so, there’s been a rising crescendo of concern among MS patients about the possible link between the newly approved oral MS drug Tecfidera (formally known as BG 12) and the deadly brain infection PML (Progressive Multifocal Leukoencephalopathy). I’ve received many anxious emails on the subject, and Internet MS forums and Facebook pages are rife with alarm over the perceived recent spate of bad Tecfidera news.

As long-time readers of this blog know, I’m not a big fan of Big Pharma, to say the least. In fact, I hold them in regard only slightly higher than the New York Yankees, who I am convinced are the essence of evil incarnate on earth. But I am also not a big fan of fear mongering, and when reviewed objectively, the facts behind the alleged link between Tecfidera and PML simply don’t warrant the level of anxiety recent reports have fomented. In fact, it seems that rivalries in the Big Pharma sandbox may be playing a role in all the hyperbole, but more on that later.

As most MSer are aware, PML is a brain infection that most often occurs in patients experiencing severe immunosuppression, such as those suffering from HIV/AIDS. In the context of MS, the infection is most closely linked to the drug Tysabri, whose mechanism of action often reduces immune system surveillance of the central nervous system quite drastically, opening up the possibility of opportunistic infection by the JC virus, which causes PML. Of course, it is this same mechanism of action that makes Tysabri so effective (the latest figures indicate that Tysabri therapy results in an 81% reduction in relapses, a 64% reduction in disease progression, and one in three RRMS patients appear to be free of disease activity for a prolonged period of time – click here for an exhaustive breakdown of Tysabri, its effectiveness, and PML). Despite Tysabri’s efficacy, PML is a real concern for those taking it, as 347 Tysabri patients have contracted the potentially deadly infection (approximately 120,000 patients are currently taking the drug).

Recently, it was revealed that four cases of PML occurred in German patients taking the psoriasis drug Fumaderm, from which Tecfidera was derived. It’s important to note that although the two drugs are similar, they are not identical. Fumaderm is a compound of dimethyl fumarate and three other related chemicals. Tecfidera is made only of dimethyl fumarate. Fumaderm has been used to treat psoriasis in Germany and some other European countries for about 20 years, with much success (click here), and is generally considered to have a benign side effect profile.

Both Tecfidera and Fumaderm do have immunosuppressive properties. In Tecfidera’s phase 3 DEFINE trial, it was found that the drug reduced lymphocyte counts in treated patients by about 28%. Lymphocytes are immune system cells whose mission it is to combat infection. These same cells are implicated in the MS disease process, and it is this depressive effect on lymphocytes that could well account for Tecfidera’s abity to fight the symptoms of MS. However, 4% of trial subjects (1 in 25) experienced a more severe form of lymphopenia (the medical name for a reduction in lymphocyte counts) which could make them vulnerable to opportunistic infections, requiring them to cease taking the drug. Recovery of lymphocyte counts after cessation of Tecfidera should be quite robust, based on  years of experience with Fumaderm. (Click here for the entire DEFINE trial report)

A look at the four Fumaderm PML cases is quite revealing (click here.-site requires free membership, well worth it). In one case, the patient was not actually taking Fumaderm, but a version of the drug made by a compounding pharmacy which included a chemical not found in Fumaderm, which could have resulted in a formulation more potent or otherwise problematic than the factory produced drug. Another patient had sarcoidosis, a potentially deadly autoimmune disease, and had previously been treated with powerful immunosuppressive drugs. A third Fumaderm PML patient had cancer, and had been treated with Efalizumab, a drug in the same family as Tysabri that has a known risk of PML.

Two of the Fumaderm PML patients had severely depressed lymphocyte counts for two and five years respectively before developing PML. In Germany, the prescribing guidelines for Fumaderm require that patients get blood tests done to check cell counts every month for the first six months they are on the drug, and then every two months thereafter to check for depleted lymphocyte counts. If patients are found to have significant lymphopenia, the guidelines call for dosages to be adjusted or the drug stopped altogether. Apparently, this regimen was not followed in these two cases, as the patients’ lymphopenia was somehow allowed to persist until they developed PML. It’s quite likely that had the lymphopenia been addressed far earlier, neither patient would have contracted PML.

So, what should concerned patients take away from all of this? Tecfidera does depress white blood cell counts, and this effect quite likely plays a large role in its therapeutic value. However, 4% of treated patients can be expected to experience a more severe drop in lymphocyte counts, which could open them up to opportunistic infections like PML if left untreated for an extended period of time. That’s the bad news. The good news is that this drop in cell counts is easily detected by standard blood tests. Once such a decrease is detected, the drug can be stopped and any potential danger averted.

For reasons that I can’t explain, the FDA guidelines for Tecfidera only require blood tests done before treatment is initiated and then once yearly for the duration of treatment. Based on the Tecfidera trial data, as well as the experience gathered from the 20 year history of Fumaderm use in Europe, the requirement of just one blood test a year seems misguided. I’m currently waiting for my insurance company to give me the okay to start Tecfidera, and my neurologist is requiring blood tests every other month for all of his Tecfidera patients. As noted above, two of the Fumaderm PML patients had severely depressed lymphocyte counts for two and five years, so blood testing every other month should provide more than ample opportunity to catch any potential problems well before they become very real concerns.

I am by no means a doctor, just a well educated patient, but I would strongly advise all patients starting Tecfidera to insist that the neuro’s test their blood for lymphocyte counts at least every other month. Doing so should largely eliminate any chance of PML and set many a mind at ease. Despite its similarities to its cousin Fumaderm, Tecfidera is a brand-new drug, and although all signs point to it being a very safe medicine, I think it prudent to err on the side of caution. If your neuro resists, print out the DEFINE trial results and show him/her the data on lymphopenia, which can be found on the ninth page of the study. I always urge patients to educate themselves and to self advocate. Here’s the perfect opportunity to do both.

In short, all of the recent concerns about Tecfidera and PML appear to be hugely overblown. To put things in context, Tysabri has seen 347 cases of PML in approximately 260,000 patient hours of drug exposure. Fumaderm has seen four cases of PML in approximately 180,000 hours of drug exposure. It’s been noted that Fumaderm is not generally given as a long-term therapy. However, at least one study researched psoriasis patients who have taken the drug for up to 14 years, with no apparent added risk associated with long-term use (click here). Based on the DEFINE trial results, the large majority of Tecfidera patients, 96%, should experience no problems whatsoever with lymphopenia. Regular blood testing should ensure that patients who do experience clinically significant drops in lymphocyte counts avoid any potential problems.

The fact that Tecfidera is an oral drug that appears to be almost twice as effective as the injectable CRAB drugs, and may have neuroprotective properties to boot, should make it a very valuable weapon in the arsenal against MS. Like all of the current MS drugs, it is not a cure, but it will hopefully bring many patients some significant relief from this terrible disease. Using all of my self-control, I'll refrain from going on my usual rant about how the focus of pharmaceutically funded MS research on immune system suppression and modulation does absolutely nothing whatsoever in the effort to find a cure for the disease, but it doesn't. And that sucks. There, I said it. I couldn't help myself.

Oh, I almost forgot. About those shenanigans in the Big Pharma sandbox: it appears that the reports of potential problems with Tecfidera were first brought to the attention of the FDA and the general public by Teva Pharmaceuticals, makers of Copaxone, one of the CRAB drugs that are currently considered the first-line drugs given to new MS patients (click here). Guess which MS drugs are most threatened by the potential success of Tecfidera? Yup, the CRABs, of which Copaxone is currently the most prescribed. With Copaxone sales of $4 billion (yes, billion) in 2012, Teva has about 4 billion reasons to try to delay Tecfidera’s entry into the market, or to stir up concern among the drug’s potential consumers. Not that I would ever accuse any Big Pharma players of partaking in such underhanded behavior. Gee, I sure hope the Yankees win the World Series…

Not.

(For a comprehensive overview of the how's and why's of Tecfidera, please see my previous post on the topic, by clicking here)

Can Anti-HIV Drugs Stop MS?

Animation of the structure of a section of DNA. The bases lie horizontally between the two spiraling strands. (Photo credit: Wikipedia)

(Readers who receive these posts via email are advised that this essay contains a video, which cannot be viewed in the email version. Please go to the Wheelchair Kamikaze website (click here) to view the video…)

I imagine the above headline might have furrowed a few eyebrows and crinkled some foreheads when first viewed by readers. HIV (the virus that causes AIDS) has nothing to do with MS, does it? Has Marc finally lost his last marble? Don’t MS patients have enough to worry about without having to contemplate AIDS?

Yes, MS patients certainly do have enough to worry about, and no, the virus that causes AIDS has nothing to do with multiple sclerosis. HIV, though, is a retrovirus, and, strange as it might sound, there is increasing evidence that ancient retroviruses that have become incorporated into the human genome through millions of years of evolution may play a key role in the MS disease process. This might seem like something out of a science fiction novel, but this discovery of prehistoric viral material in human DNA has the potential to completely change the way we understand and treat MS and other diseases (including cancer), and could potentially lead to – dare I say it – a cure.

There are currently two clinical trials underway attempting to shut down these ancient retroviruses in MS patients, and one of them uses a currently available anti-HIV drug. More on these trials a bit later, but first a little background, starting with a quick overview of virology. I know the mere prospect of “a quick overview of virology” is apt to make eyes glaze over throughout the Internet, but please bear with me, I’ll try to keep it as painless as possible.

We’re all familiar with viruses, the little buggers that cause influenza, the common cold, and a many other diseases. Of course, bacteria also cause diseases, but viruses and bacteria, though both infectious agents, are very different beasties. Bacteria are living organisms, and when someone suffers a bacterial infection they can usually be treated with antibiotics, drugs which kill the guilty bacteria and thereby cure the patient. Antibiotics have no effect on viruses, though, because viruses aren’t alive, and therefore can’t be killed. Viruses are kind of like the zombies of the pathogen world, undead infectious agents that exist only to infect living things. The fact that viruses are “undead” is what makes viral diseases so hard to treat, and why we still don’t have a cure for the common cold.

Unlike living bacteria, which can reproduce all on their own, undead viruses replicate by hijacking their victims’ cells and then using the resources within those cells to reproduce themselves. Most viruses kill the cells they invade by replicating to the point where the infected cells burst, releasing the reproduced viruses and thus spreading viral infection throughout the body. Another type of virus, though, called a retrovirus, actually inserts itself into the host cell’s DNA, and in effect become part of the organism they have infected, commandeering the host’s genetic material and cellular mechanisms to replicate themselves without destroying the cells they have invaded. This makes retroviral diseases (such as AIDS) extremely hard to treat, and coming up with ways to neutralize retroviruses has presented medical science with one of its most daunting challenges.

Now, here comes the really strange part. When the Human Genome Project (click here) completed the incredibly complex task of mapping all of the genes contained in human DNA, it was discovered that 8% of our genetic material is comprised of the remnants of ancient retroviruses, many of which inserted themselves into our genetic material tens of millions of years ago during the evolutionary process, before humans were even human. These retroviruses were at one time in the distant past infectious, but have long since been rendered dormant, and it was initially thought that they were nothing more than “junk DNA”, left over genetic material that plays no role whatsoever in the development or functioning of a human being. These ancient retroviruses that are now part of the human genome were named Human Endogenous Retroviruses, or HERVs. They are a part of all of us, genetic remnants of our evolutionary history.

Recent research into HERVs has provided tantalizing clues that rather than always remaining dormant, in certain circumstances these ancient viruses can be activated and may play a key role in many diseases, including multiple sclerosis, many autoimmune diseases, some cancers, and even schizophrenia (click here, here, here and here). The mechanism by which HERVs are activated are not fully understood, but the prevailing thought is that the presence of other viruses and environmental agents, such as Epstein-Barr virus (click here), the human herpesviruses (click here), and other environmental triggers, or a combination of these elements, may “wake” these bits of ancient viruses that are part of our DNA. Once activated, this ancient retroviral DNA can cause our own cells to secrete proteins and antigens that may identify the host cell as a hostile invader, or otherwise initiate critical disease processes.

Within the last five years or so, it’s been established that virtually every MS patient is infected with Epstein-Barr virus (click here), which is best known for causing mononucleosis/glandular fever. I know, many of you are saying, “but I never had mononucleosis or glandular fever, so I don’t have EBV!” The fact is that in the majority of cases infection with Epstein-Barr virus does not result in Mono, but rather can present as a bad cold or flu, or can even be completely asymptomatic. Over 90% of the general population is infected with EBV, but, remarkably, it appears that 100% of MS patients carry the bug. MS researchers have long puzzled over the role EBV might play in the MS disease process, since EBV infection alone certainly can’t be the sole cause of MS, otherwise far more people would have multiple sclerosis. The link between EBV and HERVs could finally clear up this mystery, for if a long-term EBV infection can turn on ancient retroviruses embedded in the DNA of genetically susceptible people, the connection between EBV and MS might finally be understood (click here).

Though the connection between HERVs and MS has yet to be proven, more and more evidence appears to be pointing in that direction (click here), and the hypothesis does pull together some of the “wildcard” factors that have confounded MS researchers for decades. Among these factors are indicators that there is an infectious component to MS, such as the existence of “MS clusters”, geographic locations where MS appears to run rampant among the local population (click here), and migratory studies which show that migration from areas of high MS to areas of low MS before the age of 15 decreases the risk of getting multiple sclerosis, with the reverse being true as well (click here). Through the years many possible infectious candidates have been proposed, to no avail, but if the HERVs theory is correct, it’s a combination of infectious agents, including some hiding in a patient’s own DNA, that may be responsible.

Both EBV (which is itself a human herpesvirus) and retroviruses have proven to be extremely difficult to eradicate, as can be illustrated by the fight against HIV. HIV is a retrovirus, and although medical science has made great strides in developing drugs that keep HIV infection under control (deaths from AIDS have plummeted in the last decade), there is still no way to completely eradicate the virus from the body of an infected person. One anti-HIV drug, Raltegravir (brand name Isentress) (click here) has proven to be quite effective in combating HIV, though, and also shows promise as an anti-EBV weapon.

A clinical trial now underway at Queen Mary University in London, England, called be INSPIRE trial (click here), is attempting to use Raltegravir to treat MS patients. Researchers hope that the drug will deactivate any activated retroviral material in the DNA of MS patients, while perhaps also combating EBV, and thus stop multiple sclerosis in its tracks. Another group of researchers in Switzerland are trying to accomplish the same outcome using an experimental drug that targets a protein on a specific HERV that is thought to be directly connected with MS, which has been dubbed the Multiple Sclerosis Associated Retrovirus, or MSRV (click here). This is a small, 10 person Phase 2 trial whose primary goal is to establish the safety of the experimental drug being tested. Results from the INSPIRE trial, which is just getting underway, are not expected until August, 2014, and the results from the Swiss trial are expected in July of this year.

It’s impossible to overstate the potential that this research has to completely reshape the multiple sclerosis landscape, with vast implications impacting the quest to wipe out many other horrendous diseases as well. If indeed prehistoric viruses embedded within our own DNA are at work driving the MS disease process, shutting down these viruses could amount to a cure. Yes, a cure for multiple sclerosis! Though it may be hard to believe, there is precious little work being done elsewhere to uncover the roots of MS, as so much research time and money is devoted towards finding newer and more effective (and more profitable) ways to suppress the aberrant immune response that is seen in the disease, a response that is in fact a symptom of some as yet unknown underlying cause. All of the current crop of MS drugs, and the vast majority of those in the experimental pipeline, either modulate or suppress the immune system, a mechanism of action which can sometimes dramatically improve the quality of life of RRMS patients, but will never do anything to cure multiple sclerosis. The research going on in London and Switzerland at last holds out hope for a cure, and represent a radical rethinking of the cause of many of the diseases that plague mankind.

My intuition and instincts tell me that these research scientists are onto something, and it’s something potentially huge. It’s long been known that genetics play a role in MS, and it has also long been suspected that infectious agents are at work. The idea that Human Endogenous Retroviruses, bits of viruses that are in a very real way a part of us, encoded into our DNA, could play a key role in the MS disease process ties together both of these observations, as well as several others. The evidence to support this idea is mounting, and to me this hypothesis feels right in a way that no other MS related theory I’ve come across has before. Of course, you can (and probably should) take my “gut feelings” with a grain of salt, but I find myself brimming with enthusiasm that the science of treating MS is finally moving in the right direction. Of course, as I’ve often cautioned before, it’s vital not to let hope eclipse reason, and this research might well lead to nothing. But, somehow, I just don’t think that it will…

Here’s a terrific video presentation by one of the lead researchers involved in the INSPIRE trial, which does a great job of explaining the research and the ideas behind it in a very accessible, easy to understand manner. I urge all readers to watch this video, as the information it contains has tremendous potential…