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)

Latest MS Drug News; Much of It Bad…

Image by mtsofan via Flickr

There’s been a spate of news in the last two weeks regarding existing and proposed MS drugs, much of it on the negative side. Several drugs have been rejected by the European regulatory agencies, and another has seen the specter of its deadly side effects continue to rise.

Although much maligned by the MS activist community, many of the drugs prescribed for MS have in fact improved the quality of life for many of the patients taking them. Although exorbitantly expensive, not targeted at the root cause of the disease (which remains unknown), and of help to only a portion of the MS population, the approved drugs have been shown to reduce the rate of relapses in some RRMS patients, though there is much question over whether they actually slow the insidious progression of the disease.

The injectable CRAB drugs (Copaxone, Rebif, Avonex, and Betaseron) have been demonstrated in clinical trials to significantly reduce relapse rates in about one third of patients taking them. Copaxone has a relatively mild side effect profile, but the other three compounds, all forms of beta interferon, often make those taking them suffer flulike symptoms for a day or two after dosing. For the patients in whom they work, though, a significant drop in relapse rates can substantially lessen the impact of the disease on their lives. Unfortunately, after over a decade of use, it's still not clear whether or not these drugs have any influence on the progression of disability. A recent report out of Great Britain challenged the notion that the CRAB drugs positively impact progression (click here), but other studies (click here, here, and here) seem to support the claim that these drugs do at least something to slow progression.

A newer generation of MS drugs, including Tysabri, Rituxan, and the recently approved (by the FDA) Gylenia offer a marked uptick in efficacy in both the reduction in relapse rates and MS symptoms, as well as the proportion of the patient population for whom they are beneficial . Unfortunately, along with this increased efficacy comes an increased severity in their potential side effects, which can include deadly brain infections and cancer. These drugs, too, do nothing to address the underlying cause of MS, and work by profoundly altering the workings of the very complex and little understood human immune system, the consequences of which, over the long-term, have yet to be seen. Still, the sometimes dramatic improvements experienced by some patients taking these drugs have led many to be extremely reticent to give them up. In the case of Tysabri, I personally know several patients who, after several years on the drug, have tested positive for the virus that causes PML, a ghastly brain infection, but still refuse to come off Tysabri because of the positive impact it has had on their lives.

Unlike some other MS voices on the Internet, I'm unwilling to label the current crop of MS drugs "snake oil", simply because of the positive influence they do have on the lives of many patients. Certainly, they do nothing to cure the disease, and I do doubt their ability to significantly impact the progression of MS, but I know of enough patients whose lives have remained relatively productive in large part due to these medications that I can't help recognize their value. The actual financial cost of these drugs is mind-boggling, with the price of the newly approved Gylenia (the first oral medication approved for MS) coming in at almost $50,000 per year, and I abhor the fact that MS has been turned into the goose that continues to lay the golden egg for many pharmaceutical companies, but the apparent positive effect of these compounds shouldn't be ignored. Before the introduction of the CRAB drugs, MS was known among physicians as a "diagnose and adios" disease, one with very little that could be done to combat it. The advent of these drugs, no matter how flawed they are, has at least put some arrows in the quiver of those trying to fight MS.

Unfortunately, all of the drugs currently approved for MS have only been shown to work on patients suffering from the relapsing remitting form of the disease; those of us suffering from the progressive forms remain shut out from any even nominally effective treatment. Very few drugs have even been trialed for use on progressive MS patients, but recently at least some attention has been turned to the plight of those suffering from SPMS and PPMS (click here).

Okay, enough of my bloviating about the current state of MS drugs. Here's a rundown of the latest news regarding MS pharmaceuticals. The fact that many of the articles linked to come from financial websites speaks volumes as to the sad state of affairs regarding MS as Big Business:

• Biogen, the makers of Tysabri, released its monthly report on the rate of PML (a devastating brain infection) in patients taking the drug (click here). When first starting Tysabri therapy, patients in the United States are enrolled in what's called the TOUCH program, designed to carefully track them for signs of the infection. The risk of PML infection as a result of Tysabri therapy has long been touted as 1000:1. The statistics released earlier this month show that the infection rate for patients taking Tysabri for less than two years falls well within that figure, but starts to rise dramatically once patients surpass the 24 month mark. The incidence of PML in long-term therapy is now stated at 2.13 per 1000, and the trend suggests that the longer patients are on Tysabri, the higher their risk of infection. After first being introduced in 2005, Tysabri was quickly withdrawn from the market when the threat of PML became known. It was reintroduced in the second half of 2006; therefore, the majority of patients taking it have yet to reach the "danger zone". As I stated previously, many patients are loathe to stop Tysabri after experiencing sometimes dramatic relief from their MS symptoms while on the drug. As the PML count increases, many patients now on Tysabri will have to grapple with some very difficult decisions.
• The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended against the approval of the oral drug Fampyra (click here), which in North America is called Ampyra. Ampyra, approved by the FDA in 2010, is the only drug thus far approved strictly for the symptomatic relief of MS. The compound increases walking speed in approximately 1/3 of the patients who take it. Some patients on Ampyra also report an overall increase in muscle strength. In recommending against the drug, the CHMP said that it "was not convinced that Fampyra’s small effect on the walking speed was a meaningful benefit for patients. The effect on speed could not be linked to meaningful improvements such as better coordination, balance or stamina or increased range of action. The Committee was of the view that the medicine’s uncertain benefits did not outweigh its side effects which included pain, dizziness, paraesthesia (unusual sensations like pins and needles) and problems with balance, as well as symptoms similar to those of multiple sclerosis that could impair the patient’s ability to walk. The Committee also noted the lack of adequate long-term data on the medicine’s benefits and safety as well as data on some groups of patients, such as the elderly and patients with epilepsy or heart problems. The CHMP concluded that the benefits of Fampyra did not outweigh its risks and recommended that it be refused marketing authorisation."
• The CHMP also recommended against the approval of the experimental oral MS medication Cladribine (click here), marketed by the giant drug company Merck. Cladribine has been used in IV form as an anticancer agent since the mid-1990s, with known possible severe side effects. Reformulated in an oral form and named Movectro, the drug went through a full trial regimen for use in RRMS patients, and was shown to reduce the rate of MS relapses and possibly impede the speed of disease progression. In deciding against the drug, the CHMP had concerns about the medicine’s safety. "An increased number of patients with cancer were observed in trials with Movectro, which may indicate an increased risk of cancer over time and with increasing doses. The Committee also noted that the benefits and the most appropriate dosage for treatment had not been fully established in patients who were expected to use the medicine. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Movectro did not outweigh its risks and recommended that it be refused marketing authorisation." The drug will be up for FDA approval later this year, and it will be interesting to see if the FDA follows their European cousins’ decision.
• The CHMP recommended for the approval of the oral MS drug Gylenia, formally known as Fingolimod or FTY 720 (click here). This drug has already won approval from the FDA, and should be hitting the market sometime in the first half of this year. Gylenia is a powerful drug that greatly alters the workings of the human immune system. The compound traps the immune system's T cells in the lymphatic system, thereby keeping them out of not only the central nervous system, but the rest of the body as well. As one neurologist told me, "Tysabri keeps the cops out of a certain neighborhood, but Gylenia keeps them locked in the police station". While many patients relish the thought of giving up their injections or monthly infusions for the simplicity and pain-free action of taking a daily oral tablet, the mechanism of this drug should give pause. Though it has not yet reached the market, it is believed that neurologists will initially be quite careful in prescribing the drug. Interestingly, Gylenia is being tested as a possible neuroprotective agent, so the drug may have a double-barreled effect. It would be wonderful if science could isolate Gylenia's neuroprotective properties and develop a compound that shields nerve cells from the MS disease process, but that development seems far off in the future.

As an MS patient, I find it incredibly frustrating that millions upon millions of dollars are being spent researching, developing, and marketing pharmaceutical compounds that do absolutely nothing to actually cure the disease, but in effect turn patients into indentured servants of Big Pharma. Unfortunately, our medical research model has evolved into a highly dysfunctional beast, one which all too often ignores real patient benefit in favor of the possibility of huge financial gain. The aberrant immune reaction seen in MS is essentially a symptom of an as yet undiscovered disease cause. If even a fraction of the research dollars spent by Big Pharma on drugs designed to suppress or modulate the immune system were instead spent on finding this unknown cause, we might actually be on the road to a cure for this damned disease.

One can only hope that the beliefs of the most fervent CCSVI advocates hold forth, and vascular abnormalities do prove to be a vitally important part of the MS disease process. At the very least, may investigations into CCSVI finally wrench the focus of MS research away from the concept of autoimmunity and onto a model of MS as disease in which an immune system gone awry signifies greater ills still hidden, and at long last brings those hidden ills to light.

Can I get an Amen?