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)

Hype or Hope? Much Touted Oral MS Drug Tecfidera (BG 12) Approved byFDA.

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

Last week, the FDA approved Biogen’s long-awaited oral MS drug, Tecfidera (formally known as BG 12). Naturally, the news was featured most prominently in the financial sections of newspapers/websites (click here), as an uptick in shareholder value is much more newsworthy than a potentially breakthrough drug that could help hundreds of thousands of patients suffering from a heinous disease. Much was also reported about the drug's yearly price of $54,900, which is actually considered reasonable in the demented world of MS drug pricing. Such are the priorities of our whacked out society. Okay, social commentary over…

Tecfidera’s active ingredient is dimethyl fumarate (DMF – click here), a derivative of fumaric acid, a naturally occurring substance that can be found in mushrooms, lichens, and moss. DMF was first used for medicinal purposes in a highly effective anti-psoriasis drug called Fumaderm, which has been marketed in Germany since 1994. It’s important to note that Tecfidera and Fumaderm are not identical compounds, which must be kept in mind when comparing the actions and side effects of the two drugs. Much might be inferred by reviewing the history of Fumaderm, but trying to make precise, direct comparisons could well in lead to erroneous conclusions. More on that later…

The release of Tecfidera has been much anticipated in the MS community, as clinical trials showed the pill to be significantly more effective in reducing relapses and slowing the progression of multiple sclerosis disability than the current frontline MS treatments (Copaxone, Rebif, Avonex, and Betaseron – all injectables), while its side effect profile appears to be quite mild when compared to many of the other MS disease modifying treatments.

Tecfidera joins Gilenya and Aubagio as the only MS treatments currently in pill form. In clinical trials, Gilenya was more effective in terms of reducing relapse rates, but concerns about potentially serious side effects (dangerously low blood pressure and pulse rates, potential for opportunistic infections) have kept the drug from reaching "blockbuster" status. There are some indications that Gilenya may have neuroprotective properties, and it is currently undergoing trials for use against Primary Progressive Multiple Sclerosis (click here). It is one of the few drugs being tested for the progressive forms of the disease. In trials, Aubagio proved to be just about as effective as the CRAB drugs in reducing relapses, and has exhibited some potential in inhibiting disease progression, but the drug comes with two black box warnings (the strongest issued by the FDA) concerning liver toxicity and the possibility that it can cause major birth defects (click here). Tecfidera’s comparatively mild side effect profile, which is comprised primarily of flushing of the skin and gastric disturbances, its high rate of efficacy, and oral dosing have led to the expectation that it will soon be a leader in the multiple sclerosis drug market.

Tecfidera’s mechanism of action, which is not fully understood (something that is not uncommon, the action of many pharmaceuticals are not fully understood), appears to be threefold. The drug exhibits immunomodulatory, anti-inflammatory, and antioxidant properties, the combination of which theoretically affords the compound its potency. In two large-scale studies, called DEFINE and CONFIRM, Tecfidera reduced relapse rates by approximately 50% over placebo, and reduced the progression of disability by about 30%. By comparison, the CRAB drugs reduce relapse rates by about 35%, and Tysabri cuts relapses about 65%. Whether these drugs impact disease progression has yet to be firmly established.

Much of the excitement surrounding Tecfidera involves the prospect that, in addition to its disease modifying characteristics, the drug may be neuroprotective. Neuroprotection is one of the holy grails of MS research. If the cells of the central nervous system can be protected from the ravages of multiple sclerosis, then the progression of the disease can be inhibited. The notion that Tecfidera may be neuroprotective is based on the fact that one of the drug’s supposed mechanisms of action is the activation of Nrf2 pathways in the human body. Nrf2 (click here) is simply a protein that exists within every human cell, inoperative until it is kicked into action by a Nrf2 activator (think of it like a bottle rocket – until lit, it sits there doing nothing, but once lit (activated) it zooms into action). Once activated, Nrf2 migrates into the nucleus of the cell and bonds to the DNA within, initiating the production of powerful antioxidants. If Nrf2 was a bottle rocket, it’s thought that Tecfidera could initiate the process that lights its fuse.

Antioxidants (the good guys) are the body’s defense against free radicals (the bad guys), cell damaging oxygen molecules that are released during the biological process of turning food into energy, much like noxious exhaust fumes are released by an automobile engine turning gasoline into energy. Once free radicals are released they act like wrecking balls, smashing through cell walls and inflicting injury. The process by which free radicals do damage to the body’s tissues is known as oxidative stress, which is believed to be one of the primary drivers of MS disease progression, as well as a factor in many other diseases (click here). Therefore, by combating oxidative stress through Nrf2 activation, Tecfidera may protect central nervous system tissues from damage by free radicals, which would be a very good thing.

Some Facebook pages and websites, including a previous post on Wheelchair Kamikaze (click here), have mistakenly equated Tecfidera with a nutraceutical product called Protandim (click here). In laboratory tests, Protandim has proven to be a powerful Nrf2 activator, a quality it does share with Tecfidera. However, Tecfidera’s mechanism of action appears to be much more complex and wide-ranging, and not confined only to Nrf2 activation. It also effects cytokines (chemical signals that influence the inflammatory process – click here), and down regulates the immune system. This down regulation of the immune system may in fact be the primary driver of Tecfidera’s effectiveness. According to the official report detailing the results of the DEFINE trial (click here), which appeared in the New England Journal of Medicine, “It is difficult to determine whether the therapeutic effect of BG 12 stems predominantly from immunomodulatory mechanisms or from neuroprotective mechanisms.”

Now back to Fumaderm, Tecfidera’s very effective German anti-psoriasis cousin. Fumaderm's efficacy in treating psoriasis, an autoimmune disease, is well documented, with 50% of the patients taking it achieving at least 70% improvement in their condition. Since Fumaderm’s primary component, like Tecfidera, is dimethyl fumarate, its side effect profile is similar to Tecfidera’s. Through 20 years of use, the most prevalent Fumaderm side effects have been gastric disturbances (stomach ache, vomiting, and diarrhea) and flushing of the skin, which, according to a paper prepared by Britain’s NHS (click here), can lead to discontinuance and/or noncompliance in 30% to 40% of patients. In the Tecfidera drug trials, though, dropout rates were negligible, with no significant difference between those patients taking the actual drug and those on placebo. Gastric disturbances and flushing of the skin were the most commonly reported side effects in the Tecfidera trials, but appeared to be manageable and diminished significantly after one month on the therapy. This discrepancy between the patient experience with Fumaderm versus Tecfidera is likely due to the different chemical makeup of the two compounds (Tecfidera is composed only of DMF, while Fumaderm includes DMF and some other derivatives of fumaric acid), and/or to differences in dosing, as patients on Fumaderm generally take a higher dose of DMF than will be given to Tecfidera users. Still, only real world experience will tell us how troublesome these side effects prove to be.

Another effect seen in both drugs is leukopenia, a reduction in white blood cell counts. This condition is accompanied by lymphopenia, a reduction in specific white blood cells, including B and T cells, which are the targets of many of the current MS drugs (Tysabri, Rituxan, Gilenya, Aubagio). This suppression of immune system cells may play a part in the two drugs' effectiveness, but can be problematic if the cell counts get too low, as this might open the patient up to opportunistic infections, although none were seen during the clinical trials. Tecfidera induced lymphopenia and leukopenia are reversible with cessation of drug therapy.

In its 20 years on the German market, comprising over 170,000 patient hours, Fumaderm has been linked to four cases of PML (click here), the opportunistic brain infection associated with Tysabri. While this may initially seem troublesome, it’s important to keep in mind that these cases occurred over a very long time period, and at least one of these patients was using other powerful immunosuppressive drugs. Generally, opportunistic infections are not seen in patients using Fumaderm.

During the Tecfidera DEFINE trial, white cell and lymphocyte cell counts dropped an average of 10% and 28% respectively, which could very well play a role in the drug’s efficacy. Importantly, though, over the two-year run of the trial, no instances of opportunistic infections were reported. It was noted, however, that 4% of trial patients experienced a more serious drop in cell counts (this info can be found on page 1106, paragraph 3 in the NEJM article – click here). In Germany, Fumaderm patients are required to have blood tests once a month for the first six months they are on the therapy, and then every other month thereafter, to keep an eye on cell counts The FDA guidelines for Tecfidera only call for yearly blood tests, and though I’m no doctor, this recommendation seems a bit questionable. Even though no opportunistic infections were noted in the two Tecfidera trials, why not err on the side of caution? We’re only talking about simple blood tests, which could head off potential problems before they get started.

Some other rare but potentially serious side effects noted in the Tecfidera study were liver and kidney events, although most were mild and reversible. There were no reported incidences of kidney failure. Still, I would think, all the more reason for regular blood tests, especially since so many MS patients are on other drugs that can be liver or kidney toxic.

So, what do I make of all this, as an educated patient? Tecfidera seems to be a very promising new drug for MS sufferers, one which might even help those with progressive disease due to its antioxidant, neuroprotective potential. I will very likely begin Tecfidera therapy sometime in the near future, even though my diagnosis is still uncertain and none of the other MS drugs have helped me. I’m encouraged by the fact that Tecfidera is related to a drug that is very effective in treating psoriasis, and has also anecdotally been noted to have a positive effect on a host of other diseases, including sarcoidosis and alopecia. I definitely show signs of some sort of systemic autoimmune activity, a condition against which Tecfidera’s mechanisms of action suggest might make it effective.

Tecfidera’s clinical trials convincingly demonstrate it to be effective in treating RRMS. Whether you believe MS is an autoimmune disease or not, it’s indisputable that the immune system plays some significant role in the MS disease process, and Tecfidera’s combination of immunomodulation, anti-inflammatory action, and antioxidant activation should provide a potent mix to help tame the disease. We’ll have to see just how troublesome the gastric and skin flushing side effects turn out to be, although, as stated above, in the trials they appeared to drop off dramatically after the first month of therapy.

Personally, if and when I do go on Tecfidera, I am going to insist on blood tests every 4-6 weeks, based on the study data concerning leukopenia and lymphopenia, as well as renal and hepatic toxicity. I’m on so many drugs that I rattle when I move, and I’ve learned to take nothing for granted. I’d suggest patients sharing similar concerns print out the New England Journal of Medicine DEFINE trial article linked to above and show the pertinent sections to their neurologist. The 4% rate of serious lymphopenia has not been publicized, as far as I can tell, and that alone should be reason for regular monitoring of blood counts. Better safe than sorry, especially when using a drug new to the market. Of course, that’s just my humble “I'm not a doctor” opinion…

(Update: for more information on Tecfidera and PML, please see my latest post on the topic, by clicking here)

Related articles

• FDA Approves New Multiple Sclerosis Treatment: Tecfidera (fda.gov)
• UPDATED: Biogen Idec rolls up FDA OK for blockbuster multiple sclerosis drug Tecfidera (fiercebiotech.com)
• Biogen Prices New MS Pill At $55K, Prepares For Marketing Battle (forbes.com)

Multiple Sclerosis: The Ugly Truth

(Warning: the following essay contains frank descriptions of the physical ravages that can result from Multiple Sclerosis, and may be disturbing to some readers. Those who are sensitive, or would simply rather not know, should stop reading now. Really.)

For much of the healthy public, the face of MS comes in the form of celebrities who suffer from the disease. At the current time, here in The States the most prominent MS representatives are probably Ann Romney (wife of presidential candidate Mitt Romney), Jack Osbourne, and Montel Williams. Mr. Williams in particular has become a full-time MS activist, bringing welcome publicity to Multiple Sclerosis as he chronicles his struggles to fight the disease. I have nothing but respect for anybody battling this heinous scourge, and I don’t mean to belittle anybody’s misfortune, but I often find myself wishing that the public could see much deeper into the horrors that MS can inflict, beyond the relatively robust Mrs. Romney, the newly diagnosed young Mr. Osbourne, and the charismatic Mr. Williams.

The following snippet of an Associated Press article on Mrs. Romney’s experiences dealing with MS is typical of how the mass media often portrays Multiple Sclerosis:

“The wife of Republican presidential nominee Mitt Romney said Wednesday that her love of horses helped her overcome her fear that Multiple Sclerosis would put her in a wheelchair.”

As frightening as the prospect of being put in a wheelchair may be to the general public, the above quote significantly downplays just how monstrously devastating the effects of Multiple Sclerosis can be. I applaud any publicity that shines light on the disease, and certainly, it takes courage for those in the public eye to speak openly about their illness, but the beast that is MS can do far worse than leave someone reliant on a wheelchair. This public face of MS most often provides only a faint glimmer into the hellish world of those more severely afflicted with Multiple Sclerosis, a reality that can shock even those suffering from lesser ravages of the disease.

As a truly distressing depiction of the dark side of MS, the plight of former Mouseketeer and teenybopper starlet Annette Funicello stands in stark contrast to the sanitized version of the disease that is most familiar to the general public. Mrs. Funicello has been decimated by Multiple Sclerosis, its wicked impact leaving this once vibrant woman — who several decades ago epitomized exuberant youth — trapped in a living nightmare, her body gnarled and fully frozen while her mind presumably remains intact. For those who can bear to watch, Canadian television’s CTV network recently produced a video profile of Annette Funicello’s current condition, and her loving husband’s never-ending struggle to find some treatment to help relieve her suffering (click here for part one, and here for part two). Be forewarned that the content of these videos may scare the living shit out of you. Please don’t watch if viewing the worst that MS can do might have deleterious effects on your own ability to deal with the disease.

The past two weeks have not been kind to quite a few of my MS friends. One dear woman, who is amongst the sweetest souls I’ve ever had the pleasure to know, recently lost the ability to swallow, a development that necessitated the surgical implantation of a feeding tube into her abdomen. She will never again experience the simple pleasure of eating. Another friend, an accomplished artist who uses MRI images to make compelling pieces of visual art, informed me via email that she is now for all intents and purposes a quadriplegic, and can no longer use her own hands and fingers to bring her creative visions to realization. Instead, she “choreographs” a helper, providing verbal instructions to an able-bodied person in an attempt to maintain her artistic output. The anguish came through loud and clear in the voice of a big hearted man who has seen the disease rip apart not only his body but family and fortune too, while he haltingly told me that he had lost the ability to hold himself upright in a seated position, and has suddenly been plagued with fecal incontinence.

Through my many years of actively taking part in online Multiple Sclerosis forums, I’ve borne virtual witness to the steady decline and ultimate demise of more patients than I can bear to recall. The pattern has become hauntingly familiar; the slowly dwindling chronicling of ever mounting indignities and disabilities, and then a silence speaking loudly of total incapacity and sometimes even death. Occasionally, a family member will kindly put up a post informing the deceased’s online friends of their passing, but more often than not the person merely vanishes into the ether. I daresay my own online activities have similarly diminished as my disease (which still defies definitive diagnosis) has advanced, hopefully not a harbinger of things to come.

This is the true face of MS, a face little seen by the public at large. Of course, many patients suffer a far milder course of the disease, but a significant number do not. As much good as celebrity MS ambassadors can do, I fear they don’t convey the true depravity of the illness, and may in fact serve to lull the public into a sense of complacency regarding Multiple Sclerosis. Almost always, mention of the condition is accompanied by assurances of astonishing medical breakthroughs, of researchers on the verge of finding a cure, of proclamations that now is the best time in history to be diagnosed with MS. What’s left unsaid is that forms of the disease remain completely untreatable, and the pharmaceutical remedies available to those that are treatable are hugely imperfect, at best. An actual cure remains a distant dream, as the vast majority of research dollars are directed at developing new and supposedly better ways of suppressing the aberrant immune response allegedly responsible for the devastating effects of MS, resulting in drugs that can improve the quality of life of relapsing remitting patients, while quite possibly doing nothing to stem the actual progression of their illness. These drugs do not a whit to cure the disease, even as they reap huge profits for the companies that manufacture them.

The medical research model that has evolved in the United States is quite simply broken, warped by the corrosive influence of blockbuster drugs generating fantastic profits. Over 75% of medical research done in the US is funded by the major pharmaceutical companies, all of which are publicly traded entities. As such, they are mandated by law to be beholden to their stockholders, not to the patients taking their products. The job of a drug company CEO is to constantly expand his company’s bottom line, by endeavoring to create an infinite stream of ever-increasing earnings. Thus, research dollars flow to projects most likely to result in huge profits, and these projects tend to follow the lead of previously successful ventures. Scientific researchers, in need of steady income, are of course drawn to projects that will receive ample funding, and so a dysfunctional cycle has developed, one in which good people simply doing their jobs perpetuate a system of medical research that has failed to cure any major disease in decades. As the stream of government research funds dries up, due to harsh economic times and shifting political philosophies, the situation becomes even more acute. As the saying goes, the road to hell is paved with good intentions.

Perhaps if the public was privy to the hideous reality of those most severely afflicted with MS, and was made to understand that such cases are not mere outliers, their revulsion would spur an outcry that might shatter the status quo. It’s not as if there are no funds available to fuel the research efforts needed to conquer horrendous illnesses. The US Air Force’s newest jet fighter, the F-22 Raptor, comes in at a cost of approximately $350 million per airplane. The F-22 is a wondrous piece of technology, invisible to radar and able to cruise at supersonic speeds. It was originally designed to fight an adversary that no longer exists, the Soviet Union. The Air Force has 187 of these fighters. Would our nation’s defense be significantly hampered if the Air Force possessed only 184 of them? The roughly billion dollars saved could certainly fund a concerted national research effort that might rid mankind forever of diseases whose cost in human misery is incalculable. It’s simply a matter of priorities, and in the language of World War II GIs, the priorities of our society are FUBAR (Fucked Up Beyond All Recognition).

I’m constantly amazed at the courage, bravery, and fortitude displayed by the MS patients I’ve come to know, whose grit and determination serve to gird my own. If only our national zeitgeist would take its cue from the steadfast heroism of those afflicted with terrible diseases and those who care for and love them, and raise an outcry demanding that our nation flex its immense intellectual and financial muscle to find ways to better human life, rather invent technological marvels intended to destroy it. The generals could still have their high-tech toys, only a wee bit fewer of them. Perhaps if MS and other horrendous diseases were portrayed in their full horror, and not in the sanitized versions commonly depicted by our mass media, a change in priorities might be possible. There is a vast Holocaust happening just beyond the eyes of the public, a Holocaust that will likely continue until that public is forced to look upon the contorted faces of the afflicted, and is made to understand such a fate could very well be their own. As John Donne wrote centuries ago, “Ask not for whom the bell tolls, it tolls for thee…”

Research Roundup: CCSVI, New Drugs, and Other Items of MS Interest

The last two months have brought a deluge of MS research data, much of it coming out of October's ECTRIMS (European Council on Treatment and Research in Multiple Sclerosis) conference, this year held in Amsterdam. While the meeting was dominated by the release of drug study data (naturally), there was also tantalizing research data revealed regarding CCSVI as well as a number of other MS related matters. I'll attempt to provide a broad overview of the recent research goings-on, and will try my best to not put readers to sleep with too much scientific mumbo-jumbo. Just in case, better grab a blanket and a pillow, because I have a feeling this is going to be long…

♦ CCSVI - On the CCSVI front, ECTRIMS appears to have been the latest venue for the ongoing pissing war that's being waged between CCSVI supporters and detractors, featuring dueling research reports, most of which are entirely based on imaging studies finding greater or lesser degrees of venous abnormalities in MS patients. To my mind, the problem with all of these studies, both pro and con, is that the imaging techniques used (MRVs and Doppler sonography) are prone to technical and/or operator error, so the wide disparity in findings may more reflect the failings of the technology then the hypothesis being explored. MRVs are highly subject to artifacting, and sonography is extremely operator dependent. While time and experience has brought more accuracy to both technologies in regards to revealing CCSVI, the fact remains that the only way to assess the state of a patient's veins with a high degree of accuracy is to actually go in and explore those vessels with an invasive (minimally) catheter venography, which so far has proved impractical for large-scale study purposes, especially when it comes to subjecting healthy subjects to a potentially (again, minimally) risky procedure.

While quite a few studies were presented that refute the theory that multiple sclerosis has a vascular component (click here), some others provided intriguing finds that support the CCSVI hypothesis. The most striking of these was a small study out of the esteemed Cleveland Clinic that compared jugular and azygos veins taken postmortem from the cadavers of MS patients and healthy control subjects. This of course begs the question, can a cadaver truly be a healthy control subject? Certainly, healthy though they might once have been, at the very least they'd be terrible guests at dinner parties. But I digress… The unique aspect of this study is that investigators were actually able to hold and examine the veins in question, the only imaging technology utilized being the ever trusty human eye (presumably aided by some type of optical magnification).

Although quite small, limited to only 13 subjects, the study hints at some rather dramatic trends (click here). The researchers looked at the veins of 7 MS and 6 non-MS subjects, and found a variety of structural abnormalities and anatomic variations. Interestingly, vein wall stenosis (narrowing) occurred in equal numbers among the MS and non-MS samples. More prevalent in the MS veins, though, were abnormalities involving malformed valves and anomalous membranes (structures such as webs and septums that shouldn't be there) which could lead to disrupted blood flow. These types of abnormalities would be difficult to spot using noninvasive imaging methods, casting further doubt on studies reliant strictly on traditional MRV in particular, and also Doppler sonography unless the operators were well-versed in protocols specifically designed reveal such anatomic irregularities.

The findings of this study, if borne out by future, larger investigations, could shed light on the wide disparity in benefit (or, often, lack of benefit) experienced by those who have undergone CCSVI venoplasty (click here for a terrific discussion of this, written by Julie Stachowiak of about.com). Many CCSVI treatment procedures, especially those done within the first year or so after knowledge of CCSVI hit the mainstream MS population, concentrated primarily on areas of venous narrowing, which the Cleveland Clinic findings suggest are not as abnormal as first thought. Since these narrowings were seen in equal numbers among MS and non-MS subjects, they may fall within the parameters of normal anatomic variation, and have little actual significance.

The high prevalence of malformed or misplaced valves and other anatomic structures within the veins of MS patients, on the other hand, could very well prove to have considerable import. Although the goal of CCSVI treatment has in large part shifted away from simply expanding narrowed veins and moved more towards clearing malformed or otherwise broken valves, aberrant membranes  would in many cases be difficult to treat using the balloon venoplasty techniques currently employed to address CCSVI. In theory, some of these treatments may have coincidentally alleviated the effects of such abnormal membranes by disrupting them and compressing them against the vein walls of treated patients. If this were the case, and these membranes eventually returned to their original form, this might explain the far too common phenomenon of restenosis experienced by patients treated for CCSVI. The failure to properly treat malformed valves and abnormal and misplaced membranes within the veins might also explain the failure of CCSVI treatment to significantly benefit many of those who have undergone treatment. This of course assumes that the MS-CCSVI link exists, which despite a growing body of anecdotal evidence, still needs to be confirmed by scientifically robust studies.

The Cleveland Clinic cadaver study certainly illustrates how little we still actually know about CCSVI and the proper way to treat it, and that some of the initial assumptions upon which treatment methodologies were based might have been misguided. Certainly, should CCSVI prove to be a vital piece of the MS puzzle, CCSVI venoplasty techniques must be refined, and very likely equipment and devices specifically designed to treat the condition effectively need to be developed and put on the market. As I've mentioned in previous posts, the study and treatment of CCSVI is still in its infancy, and patients and physicians alike need to be careful not to put the cart before the horse, despite the tremendous amount of hope and excitement that CCSVI has generated.

Another interesting CCSVI research project, conducted by the Buffalo Neuroimaging Analysis Center (BNAC) looked at the phenomenon of CCSVI in healthy patients, and attempted to identify risk factors that might be involved in the development of the condition (click here). BNAC has imaged hundreds of MS patients and healthy controls, and found that CCSVI is present in roughly 25% of non-MS subjects. By pinpointing the factors that might lead to the development of CCSVI in otherwise healthy people and cross-referencing these with known risk factors for MS, the relationship between CCSVI and MS might better be assessed.

Since a picture is said to be worth a thousand words, I suppose a video made up of moving pictures would be worth several million words, so, in the interest of saving you pages and pages of reading, here is the head researcher at BNAC, Dr. Robert Zivadinov, discussing the results of this study:






Indeed, the findings of this study are fascinating, in that many of the known risk factors of MS (particularly infection with the Epstein-Barr virus) also seem to be prevalent in healthy subjects who exhibit CCSVI when subjected to noninvasive imaging techniques. As Dr. Zivadinov stated, study findings such as these only emphasize the need for continued, multidisciplinary research into the CCSVI-MS connection. My e-mail inbox sees a steady flow of notes from patients who have benefited from CCSVI treatment, but also a disturbingly high number of reports from patients disappointed in the lack of results they've experienced. The CCSVI story has only started to be written, and with more research results set to be released in the coming months, our knowledge of the condition should expand exponentially.

Perhaps the most well-known MS sufferer to undergo CCSVI treatment is Montel Williams, who recently discussed his experience in this video with the celebrity physician Dr. Oz. Unfortunately, Dr. Oz gets some of the particulars about CCSVI treatment wrong, but there certainly is value in Montel's testimony. Here is Montel's story, in his own words:





♦ Pharmaceuticals -some late stage MS drug trial results have been released recently, most describing extremely positive results. Disparaging Big Pharma is a favorite pastime of mine, and I think the pharmaceutical companies deserve all the disparaging they can get, due to their sometimes devious and deceitful ways of doing business, and their iron grip on most of the medical research that takes place in the USA. Unlike some other MS advocates, though, who disparage all Big Pharma MS products as snake oil, I've come to realize the value of the ever-expanding arsenal of disease modifying drugs. Though none of them offers anything close to a cure, for those patients who find them effective, they do increase quality of life, sometimes dramatically so. Of course, many of them do come with a laundry list of frightening potential side effects, but by reducing relapse rates and in some cases alleviating the burdens of disability, the current crop of disease modifying drugs has been a godsend to the patients on whom they are effective. Hopefully some of the newer compounds on the horizon will be all the more effective while at the same time limiting deleterious side effects.

One of the most promising new compounds is BG 12, an oral MS drug being developed by Biogen. Also known as oral fumarate, BG 12 has been shown in late stage phase 3 trials to not only dramatically decrease relapse rates and the number of lesions seen in the MRIs of treated patients, but also appears to significantly delay the progression of the disease in some patients (click here). Research results showed that BG 12 reduced relapse rates by 50% when compared to placebo, and also reduced the risk of disease progression by 38% over placebo. The drug works in a way very different than any existing MS medication, by suppressing pro-inflammatory factors called cytokines, and possibly providing some protection against nerve cell death. Encouragingly, the drug also appears to have a very benign side effect profile, with the most common side effects being gastric disturbances and diarrhea. The drug does not appear to open patients up to opportunistic infections or cancers, as do some of the other available MS pharmaceutical therapies. Given that BG 12 is an oral drug that seems to be very effective, and carries with it a relatively benign side effect profile, I expect this drug may prove to be very popular with patients and the doctors who treat them.

Genzyme announced the results of phase 3 trials of the drug Alemtuzumab, which was previously known as Campath and will be marketed under the name Lemtrada (click here). This very powerful drug is given intravenously, with infusions once a day for 5 consecutive days for the first treatment and then, a year later, 3 infusions during 3 consecutive days. Lemtrada severely depletes the human immune system, acting on both lymphocytes and monocytes, which are then reconstituted by the body, resulting in permanent changes in the immune systems of patients treated with the drug. In effect, Lemtrada "reboots" the immune system, in the hopes that the reconstituted immune system will no longer attack a patient's own nerve cells. Trial results showed Lemtrada to reduce relapse rates by 49% when compared to patients taking Rebif, along with a 42 percent reduction in the risk of sustained accumulation (worsening) of disability as measured by the Expanded Disability Status Scale (EDSS). Previous trials have shown that the effects of Lemtrada are very long-lasting, with patients showing significant benefit five years after initial treatment ended (click here). However, while these results are very impressive, Lemtrada does carry with it the risk of some serious side effects. About 16 % of treated patients develop autoimmune thyroid disease, and 1% develop a potentially lethal autoimmune blood disorder known as ITP. Because of this, patients using the drug must be carefully monitored, and use of Lemtrada may be limited to patients with highly active disease. Research is currently underway to develop ways to identify patients most at risk for the autoimmune side effects of Lemtrada, to more easily identify patients who should be excluded from this treatment option (click here).

The potential MS vaccine Tovaxin has been granted fast-track status for the treatment of SPMS by the FDA (click here). Fast-track status can cut in half the time it takes a drug to be approved, and if Tovaxin does eventually get such an approval, it will only be the second drug specifically approved for the treatment of secondary progressive multiple sclerosis in the United States. Tovaxin is a compound individualized for each patient, which desensitizes a treated patients immune system T cells to their own nerve cells, thereby stopping the autoimmune reaction (click here). Several years ago, Tovaxin failed to meet the goals of its phase 2 trials (click here), and although it had shown great promise, was left for dead. The company developing it, Opexa, later re-examined the failed trial data and determined that Tovaxin had indeed demonstrated positive effect, and now Tovaxin has risen like Lazarus, giving it (and Opexa's stockholders) new life…

A study done to assess the risk of stopping Tysabri for "drug holidays" showed that this practice significantly increases the risk of patients suffering MS relapses within six months after stoppage (click here). The idea of drug holidays came about because Tysabri is linked with PML, a potentially fatal brain infection, the risk of which increases with the amount of time a patient is on Tysabri. It was thought that taking occasional breaks from Tysabri might allow the immune system to reconstitute itself enough to combat the emergence of PML, but this study suggests that temporarily switching to another MS therapy unfortunately carries with it an increased risk of patients suffering an MS relapse. Kind of a "damned if you do, damned if you don't" scenario…

♦ Miscellaneous Studies - A variety of other MS related research results have also recently been announced. The active ingredient in the spice saffron may prove to be effective in combating MS (click here). In experiments, this ingredient was shown to combat inflammation and cell stress, at least in petri dishes and test tubes. Interestingly, saffron is often used in Asian cuisines, and the incidence of MS is much lower in Asian countries than it is here in the West. The spice tumeric (cumin) has also been shown to have strong anti-inflammatory properties, and this spice too is used heavily in some Asian cuisines. So go out and have some Indian food, it's good for you. Chicken Tikka Masala, yum…

Researchers in Sweden have discovered that young people between the ages of 16 and 20 who work overnight shifts or odd hours are twice as likely to develop multiple sclerosis as those who never worked such hours (click here). The researchers explained the sleep restriction associated with working the night shift has already been shown to increase the risk for certain health problems, including heart disease, thyroid disorders and cancer, likely by interfering with melatonin secretion and increasing inflammatory responses. Kind of an odd finding, but upsetting circadian rhythms has been shown to have an adverse effect on health, so these Swedish meatballs might be on to something…

German researchers have linked gut bacteria to multiple sclerosis (click here). We all have millions of microbes living in our guts, normally to no ill effect. However, more and more research links these bacteria to some autoimmune diseases. The researchers who did this study used mice genetically engineered to develop a Multiple Sclerosis like disease, and allowed some to develop gut bacteria, and others to remain gut microbe free. About 80% of the mice with gut bacteria went on to develop MS like symptoms, while none of the sterile mice did. While it's a far cry to go from mice to humans, this study does demonstrate that intestinal microbes do interact with the immune system, something that has long been suspected. Of course, most of the bacteria are in our guts is harmless, and some even serve a beneficial effect, but these research results certainly warrant further investigation.

Well, let's call it a wrap. There's an astounding amount of MS research being conducted, much of it driven by the huge profits to be made treating MS patients with hyper expensive drugs that tamper with the little understood human immune system. Still, as is evidenced by the last few investigations I mentioned, the breadth of MS research is quite wide, and each bit of knowledge uncovered may hold the key that finally unlocks the puzzle that is MS. Certainly, research into CCSVI has the potential to upend much of the conventional wisdom regarding the disease, and it's of the utmost importance that MS patients themselves drive such research forward, by educating themselves, advocating for energetic and innovative research into the disease, and agitating against those who stand in the way. Power to the people, y'all…

Related articles

• Risk Factors For CCSVI Are Similar To Risk Factors For Developing MS (medicalnewstoday.com)