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)

Don't Believe Everything That You Read

Unless you read it here, of course...

As somebody who keeps a close eye on MS related news, literally each and every day I come across news articles and press releases touting some amazing new medical breakthrough or groundbreaking drug therapy that promises to smite the MS beast. These bits of news are quickly gobbled up by the various Internet MS message boards, and generate all kinds of excited chatter in the virtual MS world.

The e-mail inboxes of MS patients are often filled with notes sent by well-meaning family members and friends, breathlessly announcing these findings. Now, there's nothing wrong with hope and optimism, as we'd be doomed without them, but it's important that patients learn to keep things in perspective, if only just to keep from suffering repeated disappointments.

The truth of the matter is that most of the breakthroughs generating these headlines amount to far less than meets the eye. Just today, there is news about a group of scientists who have identified two genes that seem to be vital in determining the severity of MS. Reading a little bit deeper, though, reveals that this discovery was made on mice, and the genes in question are mouse genes. I like mice as much as the next guy (as long as they stay the hell out of my house), but the simple fact is that MICE DON'T GET MS.

Scientists induce mice to get diseases that kind of resemble MS (most often, an allergic reaction called EAE), and then test all kinds of things on these mice to see if they'll affect the phony MS that the mice have been given. Quite often, the drugs and therapies being tested prove to have a dramatic effect on the mouse MS imposter. So often, in fact, that I've come to believe that staring intently at a stricken mouse, or talking lovingly to it, will cure it of this MS pretender (note to self: get some mice, make them gimpy, apply for MS research grant, tell mice that you love them, schedule press conference). Unfortunately, the same benefits rarely carry over to humans, because, as I mentioned before, MICE DON'T GET MS.

Another flavor of MS news item that often creates a frenzy are early-stage drug trial results, typically released by the pharmaceutical company developing the drug in question. In order to meet FDA approval, experimental drugs must go through a three stage trial process. Each of these phases are usually double blinded, placebo-controlled trials, in which one group of patients is given the actual test drug, and the other a placebo. The trial process generally takes about 8 to 10 years.

Very often, the results of successful early Phase 1 or Phase 2 trials are loudly announced to the world, setting off a wave of excitement among MS patients starving for optimistic news. Tellingly, these announcements are usually found in the financial or business pages of newspapers or Internet news sites. Why is that, you might ask? The answer is simple, but somewhat disheartening. The primary motivation behind the release of such results is not to give MS patients hope that they can hang their hats on, but rather to pump up stock prices (in the case of the big public pharmaceutical companies) or generate investor cash (in the case of smaller, startup firms). Very early in my MS career, my neurologist, Dr. Big Brain, warned me to not take any of these reports too seriously, as the primary motivation behind them is financial.

One must never forget that the pharmaceutical business is a mega-industry in this country, and that the fortunes, both literally and figuratively, of pharmaceutical company executives rise and fall with the stock prices of the companies they run. In fact, as public companies, the big pharmaceutical companies are mandated to place the interests of their stockholders before the interests of the patients taking the drugs they produce. These companies must generate ever-increasing profits, or risk the calamity of falling stock prices.

There have been recent revelations of pharmaceutical companies burying unfavorable trial results data, and sometimes even misrepresenting such data (in other words, lying about it). Even when data is not actually misrepresented, the methods used to statistically analyze it can influence the favorability of the data one way or another. Naturally, drug companies choose to analyze the data in the fashion most favorable to the outcomes they desire, but very often, this does not result in the most accurate assessment of a drug's effectiveness and/or risk to patients. Unfortunately, the reported results of these giant shell games often toy with the emotions of desperately ill patients hungering for a little good news.

All in all, it's best to take much of the news generated about MS with several grains of salt. Between mice that don't get MS, and the financial wheelings and dealings of the pharmaceutical industry, much of the information out there just isn't very reliable. Don't get me wrong, I believe that there are great strides being made in battling the disease, but if even one quarter of the positive news reported about MS were true, the illness would have been cured years ago...