Thursday, October 30, 2014

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.

Friday, October 17, 2014

My Body, My Self

In Mel Brooks’ 1981 comedy “The History of the World, Part 1”, a scene set during the French Revolution features a member of the aristocracy rushing to tell King Louis XVI, “It is said that the people are revolting!” His Majesty quickly replies, “You said it, they stink on ice”. 

The exchange is an amusing play on words that succinctly and humorously sums up the crux of the social upheaval engulfing France at the end of the 18th century. Substitute me for the King of France and the words “your body” for “the people”, and you’ll get a pretty good idea of what’s going on inside me, both physically and mentally, courtesy my creeping paralysis. My body is in full revolt, increasingly refusing to obey my commands, and I find the situation along with my withering body itself completely repellent. My body is revolting, and it stinks on ice (not literally, I hope, for the sake of those who get close enough to smell me).

The mind-body connection is a strong one, but progressive multiple sclerosis can be a buzz saw intent on breaking that bond. As the disease advances it forces one to separate body from mind, as the “self” becomes more and more divorced from the body that serves as its vessel. Despite lofty ideals about looking beyond the physical to the person within, our sense of self can’t help but be intricately entwined with our physical state; our identities, for better or worse, are in so many ways shaped by our outward appearance, a dynamic that seems ever on the increase in a culture obsessed with beauty.

We live in a society that idolizes physical beauty to the point of absurdity, elevating the utterly talentless but extraordinarily beautiful to fame and fortune and fueling in many an obsession with physical perfection. This incessant quest for beauty has in turn birthed entire industries devoted to indulging this ravenous appetite for youthful good looks which only further feed our insatiable societal lust for flawless appearance. Billions of dollars are made catering to a population infatuated by comeliness, with cosmetics, fad diets, exercise crazes, and plastic surgery all exploding to the sound of cash registers ringing and money changing hands.

Though we pay lip service to the idea that beauty is only skin deep, study after study has shown that in modern Western society those perceived as physically attractive have a quantifiable advantage over those not similarly blessed. There are, of course, exceptions to the rule, and beauty is by no means a sure ticket to happiness. Indeed, for some it can become a curse – think Marilyn Monroe – but our popular culture covertly and overtly continuously pounds home the message that the spoils of life most often go to those deemed gloriously pretty or handsome. I’m not sure that anyone can be immune to this pervasive zeitgeist, and I certainly was no exception back in my healthy days, although my relationship with my body even pre-MS had a long history of discord.

Growing up I was as skinny as they come. I’m not talking merely thin, I’m talking Boney Maroney, stick figure, almost comically scrawny. In addition to earning the nickname “Bones”, until I was 15 or so I was also quite short, and as a skinny little pipsqueak I was often subject to teasing not only by other kids but sometimes by adults as well. While it’s considered bad manners in grown-up circles to talk about a heavy person’s weight, it seems no such taboo exists when it comes to the extremely thin, regardless of their age. Being teased by other kids was bad enough, but in response I quickly developed a smart and scathing wit with which to defend myself from their juvenile barbs. Hurtful comments made by adults, though, always struck home hard, and I can still vividly remember some of the most boorish comments directed my way by adults who should have known better, the combined effects of which spawned massive insecurities that persist to this day.

A sudden growth spurt when I was about 15 years old took care of the pipsqueak part of my problem, but I remained superduper skinny for years to come. When I graduated college I was 6 feet tall and weighed in at a whopping 120 pounds soaking wet. Fortunately, sitting atop that emaciated frame was a face that was kind of cute, and much to my delight and amazement I discovered that there were women who actually like skinny men. I naturally gravitated towards artsy social circles and wound up the lead singer of a punk rock band, a role in which thin was most definitely in. In the underground music scene in the 1980s there was more than a touch of heroin addict chic, and I had the decided advantage of being as thin as a junkie without actually having to take drugs. I’d managed to find a social scene in which my being the skinniest guy around was actually an advantage. Go figure.

My body finally filled out in my late 20s, but I always remained on the thin side. Nobody was ever going to mistake me for Adonis. Although I was considered attractive, and was sometimes even called handsome, the insecurities that first took root when I was a skinny little nebbish lived on and I fought hard to overcome a shyness that at times bordered on social anxiety. I’ve been told that some found me aloof or even standoffish, but in reality I more often than not was quaking in my boots. That scrawny little 10-year-old was never far from the surface, a mind-body connection that persisted far into adulthood even though it no longer reflected my physical reality.

Now an entirely different kind of mind-body connection, or, more correctly, a mind-body disconnection plagues me. Just around the time that I had become comfortable in my own skin – thank you, decades of psychotherapy – a little problem called multiple sclerosis reared its ugly head. While walking my pooch along the Hudson 11 ½ years ago, I developed a slight limp in my right leg. All too soon that limp was joined by a weakening right arm, and whatever dastardly bastard was causing this distress refused to release its grip. Fast forward a decade plus and this beastly disease has just about fully consumed my right side and is gluttonously munching away at my left. My mind reels in horror at the damage that has already been done and can barely stand to contemplate that which may lie just beyond the horizon. But the me that existed before my illness struck still resides within, inevitably changed by the experience but ever yet struggling to maintain itself.

In a situation surreal but all too real, I find myself (and my self) trapped in a body that increasingly not only refuses to obey my wishes but seems to have a mind of its own. I sometimes put my disease to the test, concentrating intently, face contorted with effort, commanding my right ankle to flex, but much to my overwhelming chagrin and frustration, nothing ever happens. Absolutely nothing. Many nights, though, just about the time when I’m ready to go to sleep, my entire right leg will shudder and quake in muscle spasms beyond my control, violent enough to shake the bed frame, the tremors coming in waves every 30 seconds or so for hours on end despite the pharmaceutical cocktail meant to quell them. All the while, inside, buried deep within the emotional maelstrom brought on by my illness, lays a big kernel of the old me, observing it all in utter disbelief.

Since the onset of my disease, the divide between my essence and the body that contains it has grown from a slight fissure into a great chasm. I’ll occasionally struggle from my wheelchair to stand in front of a mirror, trying to strike a pose that suggests some semblance of normalcy, imagining that if someone were to glimpse me at that precise moment they might not guess I was so afflicted. But then I see in my reflection that my right arm has withered, the fingers on my emaciated right hand curl unnaturally inward, and my right wrist and elbow stay unbent only by my precariously lodging them against the side of my body. In shorts my legs reveal themselves to be sticks, as if they remembered who they were back in my skinny youth and decided to reprise the role. My once lean stomach has become a bulbous belly, courtesy years of sitting in a wheelchair. This is not the me that I hold in my mind’s eye, and yet this is the reality of the body I now possess, a body that will become only more and more unfamiliar with time barring some incredible medical intervention.

This decrepit circumstance has forced me to break the mind-body connection that we are so conditioned to accept as reality. Though I struggled to embrace my physical self in my younger days, I must reject the physical decay that now besets me, as for sure this defective mass of flesh and bone does not define me. My mind remains sharp, maybe too sharp, and my sense of self is more pronounced now than ever, albeit in an increasingly disembodied state. I don’t know if consciousness survives our ultimate physical demise, but I do know that the essence of who I am is increasingly independent of the physical form that maintains it.

In a strange paradox, I have become more sure of the person I am these days than I ever was back when my body was whole. I’m privy to insights I likely never would have attained if not for my unfortunate situation. It’s a strange life, this existence within an existence, but it is life nonetheless, not one I ever would have chosen but one in which holds within it not only sorrow and frustration but also still moments of contentment and sometimes even joy. Along with my sense of self those two most vital elements of life, joy and contentment, have by necessity undergone their own bits of revision, reshaped and reimagined by a me that more and more severs the connection between body and mind.

My body is revolting, and yes, you said it, it stinks on ice… Ha!