Patient Taking Tecfidera Develops PML, Later Dies – Outlier or Harbinger of Things to Come?

Last week, in disclosing the company’s quarterly financial report, pharmaceutical giant Biogen revealed that a patient taking its oral MS drug Tecfidera had developed the dreaded brain infection PML and later died of pneumonia (click here). This news understandably created much anxiety in the MS population, particularly among those patients currently taking Tecfidera and those considering starting the drug. Let’s take a careful look at the details of this unfortunate news and try to properly assess its impact.

In the roughly 18 months since it was first approved by the FDA, Tecfidera has become a blockbuster drug, generating nearly $2 billion in sales over the last nine months alone (click here). The tremendous financial success of Tecfidera is in large part due to its ease of use (it’s a pill), relatively high efficacy rates, and a perceived low risk of serious side effects. Until this case of PML was reported, the Tecfidera side effects receiving the most attention were flushing and gastrointestinal distress, both of which subside after 6-8 weeks in the majority of patients taking the drug. Obviously, adding the risk of PML to the equation could change this calculus significantly, so it’s vitally important to parse this new information as best as possible to try and appreciate the true risk posed by PML in the Tecfidera MS population.

It’s essential to understand just what is PML, and how Tecfidera’s mechanism of action might increase the risk of contracting the disease. PML (Progressive Multifocal Leukoencephalopathy) is an infection of the brain and central nervous system that is caused by the JC virus, a pathogen that is present in about 50%-60% of the general population (click here). Under normal circumstances, those carrying the JC virus are completely without symptoms and the virus is kept in check by the human immune system. In patients whose immune systems have been compromised (for instance, people with AIDS),  the JC virus can lead to PML, an infection that destroys myelin in large portions of the brain, leading to significant disability, and, in many cases, death. PML is a much-publicized potential side effect of the intravenous MS drug Tysabri, which profoundly suppresses immune system activity in the central nervous system of patients taking the drug, thereby leaving those carrying the JC virus potentially susceptible to the infection. This is why strict testing for JC virus antibodies has been instituted for all patients on Tysabri therapy. PML has also been seen patients with MS as well as other diseases taking other immunosuppressive drugs, as these drugs can, by their very nature,  compromise the body’s ability to keep the JC virus under control.

Tecfidera (whose chemical name is dimethyl fumarate) is purported to work through a variety of actions. The drug is thought to have anti-inflammatory and antioxidant properties, but studies have definitively shown that one of the drug’s primary actions is immunosuppression. In trials, Tecfidera was demonstrated to reduce the amount of lymphocytes (infection fighting white blood cells) by about 28% in treated patients (click here, the pertinent information is on page 9). While this level of lymphocyte suppression is not considered to put patients at any kind of serious risk, it could very well account for Tecfidera’s efficacy in treating multiple sclerosis, as the disease is, at least in part, driven by an aberrant immune response.

These same studies also found that about 4% (1 in 25) of patients treated with Tecfidera develop a more serious drop in lymphocyte count, resulting in a condition known as lymphopenia. Severe lymphopenia can indeed open the patient up to opportunistic infections, and for this reason FDA guidelines call for regular blood testing to monitor for the condition in Tecfidera treated patients (click here). Currently, the FDA suggests patients have their blood counts checked once a year, but in practice many neurologists are being far more diligent in testing their Tecfidera treated patients. This recent news about PML and Tecfidera could very well result in more stringent blood testing requirements, but even without such a mandate it seems wise that patients be tested quite regularly to check that their lymphocyte counts remain at safe levels.

Although there currently aren’t many available details on the PML Tecfidera case reported last week by Biogen, it is known that the patient in question had been on Tecfidera for nearly 5 years (she started taking the drug during the approval trials), and had been experiencing severe lymphopenia for 3 ½ years. Logic would seem to dictate that a patient be taken off the drug as soon as their lymphocyte counts drop into dangerous territory, so the fact that this unfortunate soul was left with severe lymphopenia unaddressed for years on end is, to my mind, completely inexplicable. Indeed, it would seem that given the circumstances, her neurologist was courting disaster. Again, I am basing this assessment on scant details, but I have a hard time imagining any scenario that would warrant keeping a patient on a medication that was suppressing their immune system to dangerous levels for such an extended period of time. If the specifics of the case are as originally reported, the fact that the patient was kept on Tecfidera for three and half years after she first tested positive for severe lymphopenia quite frankly boggles the mind.

If anything, this case would seem more to underscore the importance of diligent patient monitoring than any inherent potential danger posed by Tecfidera. Ceasing the drug in the face of troubling blood test results should be a no-brainer. Patients experiencing severe lymphopenia in the Tecfidera trials saw their lymphocyte counts increase significantly within four weeks of stopping the drug. It is currently not known how long is required for lymphocyte counts to return to pre-Tecfidera levels.

While it would be extremely concerning if the patient in question developed PML while her lymphocyte counts remained at acceptable levels, the facts as now known indicate that this simply was not the case. Given the immunosuppressive properties of Tecfidera, it would appear to be vitally important that patients be regularly tested to check their white blood cell counts. It would seem that the FDA suggestion of once yearly blood tests is insufficient, and I know many neurologists are checking their patients much more frequently, more on the order of at least once every three months. Monitoring for JC virus might make sense if PML were to be seen in Tecfidera patients not experiencing severe lymphopenia, but at this point the available evidence doesn't seem to merit the taking of this extra step. Then again, any extra bit of information is valuable, and I'd imagine that some neurologists might Institute testing for JC virus in their Tecfidera patients on their own. Tecfidera is proving to be quite effective in reducing relapse rates and the formation of new brain lesions when used to treat RRMS (click here), and with proper monitoring it would appear that the drug is actually quite safe.. Of course, the drug has only been on the market for a year and a half, and only time will reveal the true long term efficacy and safety of Tecfidera.

As this tragic PML case demonstrates, the fact that Tecfidera can induce severe lymphopenia in 1 out of 25 patients taking it should make both patients and doctors alike keenly aware of the need for proper blood count monitoring. Patients shouldn’t be shy about requesting such tests if their neurologists don’t currently require them. Knowledge is power, folks, and patients need to equip themselves as best as possible with the most accurate data available and take an active role in making treatment choices. The doctor-patient relationship should be a partnership, not a dictatorship. It’s terribly unfortunate that PML has entered the Tecfidera picture, but the case in question seems much more like the exception than the rule. This is not to say that this recent news shouldn’t be cause for concern, but it certainly shouldn’t induce panic among those currently taking the drug or those considering Tecfidera therapy.

It is my fervent hope that future MS therapies will turn away from immunosuppression and find some other more effective, more benign mechanism for fighting the disease. But, as the current crop of drugs are generating billions and billions of dollars in profit for the companies that make them, it will likely be quite some time before my hopes are realized. For now, it is imperative that patients as much as possible use their heads, and, armed with accurate information, work in tandem with their physicians to best beat back the beast that is MS. At this point, Tecfidera appears to be a valuable tool in this quest, but like all tools it needs to be used intelligently and with care.

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)