Monday, March 27, 2017

MS Research Roundup-HSCT, Ocrevus, MS Blood Test, and More

Longtime Wheelchair Kamikaze readers will remember that I used to post articles comprised of veritable potpourris of MS related info on a fairly regular basis, and that I’d title those posts “Bits and Pieces”. I’ve kind of fallen down on the job in that regard lately, but over the last month or so a bunch of MS research related articles caught my eye, so I figured I compile them here. Came up with the snappy and uber-original title “MS Research Roundup” since any readers new to the blog wouldn’t know what in tarnation I was talking about with the “Bits and Pieces” rigmarole. And what’s the use of a rigmarole if people find it befuddling? A befuddling rigmarole defeats the whole purpose of rigmaroles, and that would put me and my readers in a quandary wrapped in a conundrum. Who the hell needs that?

So, without any further bandying about willy-nilly, here are some items I hope you find of interest:

♦ First up, a bit of self-congratulations. The UK-based website Stairlift Reviews (click here) has named Wheelchair Kamikaze one of the 100 Best Blogs for Disabled People and Carers. Much thanks to them, and I must say they’ve done a really good job compiling the list as there are lots of really, really good blogs on there. Pretty sure Wheelchair Kamikaze got in by way of clerical error.

♦ Ocrevus (ocrelizumab) has its much awaited date with destiny on March 28, as it goes up before the FDA for approval. The new MS drug was originally scheduled for FDA review this past December, but the review was delayed due to manufacturing issues. Ocrevus is up for approval for the treatment of both relapsing MS and progressive MS, and if approved for the latter would be the first drug on the market for this form of the disease. Based on the trial results, I’d say the odds of the FDA giving the drug the go-ahead are excellent, especially for relapsing MS. I’d say Ocrevus has at least a 90% chance of approval for relapsing MS. Probably closer to 95%, as a rejection for this form of the disease would really be a shock given the robust trial results. Things aren’t quite as sure for progressive MS, but I’d still peg the odds of approval here at about 70%. I’d say there is probably a 20% chance that the drug is only approved for progressive patients who have enhancing lesions, and a 10% chance that it is rejected outright, most likely because of the higher cancer rates seen versus placebo in the progressive MS trials. I’ll put up a quick post on these pages after the results of the FDA review are announced on Tuesday.

♦ HSCT, the type of stem cell therapy that first wipes out the immune system using chemotherapy drugs and then reboots it by way of bone marrow transplant, has once again been making waves. The results of two trials were recently released, both showing that the treatment is remarkably effective in completely shutting down the disease for years long periods of time in many patients. In one 24 person trial, comprised exclusively of RRMS patients and sponsored by the National Institutes Of Health, 69% of trial subjects experienced no MS progression, relapses, or central nervous system lesions 5 years after undergoing HSCT (click here). Some of them even regained lost function. Pretty damned impressive.

A second study looked at the long-term results of HSCT using retrospective data gleaned from 25 treatment centers around the world (click here). The study looked at 281 patients treated between 1995 in 2006, and found that just under half of the treated patients showed no sign of progression 5 years after treatment. The patient population looked at in this study was about 70% progressive MS patients (the overwhelming majority of these SPMS), which accounts for its lower rate of efficacy than the smaller NIH sponsored study cited above.

Through some physician friends of mine I was able to get my hands on a copy of the actual paper, which revealed that when the numbers were broken down according to disease subtype, 73% of RRMS patients, 33% of SPMS patients, and less than 20% of PPMS patients were progression free after 5 years. It should be noted that there were very few PPMS patients included in this study (only 24 out of the original 281 trial subjects, and only one PPMS patient was tracked through 5 years). The authors of the study conclude by saying that these results warrant serious further trials of HSCT as first-line or second-line treatment in “patients with highly active relapsing MS… Furthermore, our results raise the question whether HSCT may attenuate the progression of disability in patients with progressive forms of MS, a possibility that is more plausible in patients with MRI evidence of central nervous system inflammatory activity before transplant.” Evidence of “central nervous system inflammatory activity” means enhancing lesions as seen on an MRI, and many other HSCT studies have also concluded that the treatment works best on patients exhibiting these types of lesions.

The results of these 2 studies further strengthen the case for the use of HSCT in MS patients who have enhancing lesions. It is beyond absurd that over 20 years since the testing of HSCT on MS patients started, we still haven’t had an actual placebo-controlled trial on what appears to be a highly effective treatment, perhaps the most effective MS treatment to date. This probably has to do with the fact that the pharmaceutical companies can’t make gazillions of dollars on HSCT, since the drugs used to knock out the immune system are all older drugs that have come off patent. Combine this with the fact that HSCT puts patients into long-term remission for years at a time, during which they have no use for the hyper expensive MS drugs marketed by the pharmaceutical companies, and the reasons why HSCT remains understudied becomes a bit less cloudy. MS patients and those who love them deserve more.

I’m working on getting an interview with a prominent HSCT researcher, so hopefully I’ll be able to bring some “straight from the horse’s mouth” info to Wheelchair Kamikaze sometime soon.

♦ For those interested in the history of multiple sclerosis, here’s really good article entitled “The Story of Multiple Sclerosis And Its Major Milestones” (click here). Lots of fascinating stuff here, including the fact that in the 19th century MS was often treated with bloodletting, leeches to the temple, an all meat diet, arsenic, or injections of silver or gold. Heck, if someone showed me some halfway convincing proof that any of these treatments were of use in treating my non-inflammatory progressive MS, I’d go for it in a heartbeat. Leeches to the temple? Bring. Them. On. Couldn’t be any less effective than all of the other crap I’ve tried in the 14 years since my diagnosis, and at least for a little while I’d have a couple of new pets.

♦ Looks like a blood test that will diagnose MS is going to be released in May, 2017 (click here). Not sure why this hasn’t been major news, since if this is true it’s a really big deal. Multiple sclerosis is notoriously hard to diagnose, with many patients waiting months if not years to get a definitive diagnosis. Damn, I’ve had this thing for at least 14 years and the doctors still aren’t sure if it’s actually MS. According to this article, the blood test is supposed to be 90% accurate. The test looks at a patient’s RNA and genetic profile to make it disease determination. I’ll have to do more poking around on this…

♦ Finally, here’s a New York Times article from 2016 detailing just how misleading some of the prescription drug TV commercials can be (click here). This article focuses on the drug Opdivo, which is targeted at a form of lung cancer. It’s hard to miss the Opdivo commercials here in The States. I’m sure many if not all of the yanks reading this post know exactly which ads I’m talking about. They are the ones that show hardy looking cancer patients looking up at claims of the drug’s effectiveness projected on the buildings of a city. Turns out that Opdivo only works in about one in five Stage IV non-small cell lung cancer patients, and in those patients it extends life for about 11 months. Of course, an extra 11 months for a patient dying with lung cancer are priceless, but the ad makes it sound like the drug makes lung cancer just a few notches more serious than a sore throat.

I’m not going to go off on a rant here, I promise, but WHY THE HELL ARE DRUG COMPANIES ALLOWED TO ADVERTISE PRESCRIPTION MEDICATIONS ON TELEVISION?!?! The United States and New Zealand are the only two countries that allow such lunacy, and even the American Medical Association has stated that this practice must be stopped. Maybe if the drug companies stopped spending more on marketing than they do on research (click here) we’d have some drugs for MS that don’t carry with them death as a possible side effect. One thing I’ll say for those leeches to the temples, they didn’t cost $80,000 per year and didn’t cause PML. Of course, they didn’t do anything for MS, so there’s that. But if the leeches were effective, they’d make for some great TV commercials:

Setting: An extreme roller coaster in a giant amusement park. We open with a wide shot of the park, bustling with men so handsome, women so beautiful, and children so adorable that they put to shame the Nazi ideal of human perfection. Amidst the laughter and merriment we find our two thirty-something female protagonists, a stunning redhead and a willowy blonde, energetically climbing into a car on the roller coaster and getting ready for the ride. Both glow with radiant health. The blonde has leeches stuck to her perfect temples, with drops of blood trickling down her almost impossibly high cheekbones.

MS Patient’ s Friend (laughing): “Jane, you’ve got some horrible bloodsucking monsters stuck to your temples!”

MS Patient (cutely giggling): “Oh Susan, don’t be silly. They’re not bloodsucking monsters! They’re Leechabri, my new MS treatment. Last week I couldn’t swallow or get out of bed, but tomorrow I’m climbing Mount Everest!”

The roller coaster then takes off, and the shot widens to follow our heroes as the coaster does a loop the loop. Quick cut to a close-up of our MS patient, laughing hysterically as her leeches flap in the breeze.

And with that image stuck in your mind, I’ll take my leave. I’ll be back with a quick post just as soon as the FDA decision on Ocrevus is announced…

Tuesday, February 28, 2017

Man On The Wire

Of late I find myself in uncharted waters, my creeping paralysis taking me to places in mind and body that I could never have imagined I’d visit. It’s simply getting harder and harder to do everything, and as a result my contacts with the world outside of my apartment grow fewer and farther between. As my disabilities progress and my abilities regress, the familiar patterns and rhythms of everyday life fall further and further away, my healthy days now so for behind me that the memories of them often seem false, the stuff of imagination. Strangely enough, even as my old reality seems to vanish into the ether, certain incidents and instances do suddenly pop into mind with crystal clarity, richly detailed and full of life, decades old events recalled as if I’d lived them only yesterday. This juxtaposition of the old and the new, cast in such stark relief, reveals just how obsolete the rules that governed my old life have become in the context of my new reality.

As my existence has shifted more and more from the physical to the mental, certain truths about myself and my fellow inhabitants of this planet have become clear. Almost from birth we are taught the constructs and customs of the societies in which we live. Now more than ever the mass media plays a tremendous role in shaping our ideals and expectations, and in defining the parameters of social interaction. Along with reading, writing, and arithmetic our 12+ years of formal schooling provide us with a variety of  behavioral templates for daily life. In combination, these ever-immersive entities imprint within us a library of scripts that cover almost every situation we might encounter, almost every part life might call on us to play.

We are taught that our destinies are largely a function of free will; in reality, though, most people live lives that fit neatly within the confines of predefined boundaries, which fall into a daily routine permeated with sameness. We each flesh out our roles with our own particular quirks and peculiarities, but rare is the person who shatters the restraints and expectations of social norms. Some of the people that do so with audacity become rich and famous as a result, but many others who can't or won't comply struggle through life on the fringes of society. Woody Allen famously said that 80% of success is just showing up; this is largely true due to the fact that most human beings can fake it till they make it, falling back on sets of learned behaviors until they can grow into the roles they are expected to play.

Our DNA provides us with the basic programming that defines our individuality – our operating system, if you will – but the process of socialization we undergo as we mature applies layers of scripts and apps that inform the way we function in a diverse array of situations. Just as lines of code allow our computers or cell phones to become spreadsheets or image editors, the scripts and apps we learn through  years of schooling and constant exposure to mass media allow us to navigate life playing a variety of parts, some much more suited to our basic needs and wants than others.

Looking back on my own life I can clearly discern when certain sets of scripted behaviors kicked into gear. In my childhood I was a dreamer, very intuitive, sensitive and emotional, at times to the point of being overwhelmed during what in retrospect was very disjointed upbringing. As an older teenager and young adult in New York and Boston I fancied myself a creative rebel, eagerly immersed in a punk rock subculture filled with other nonconformists who somehow looked almost precisely the same as me. I felt comfortable within the confines of this group dynamic, it’s brand of nonconformity easy for me to adopt, and the lifestyle it afforded fit my natural tendencies towards a nocturnal existence and a general aversion to all things 9-to-5. Though many of the aspects of this role meshed well with my core predispositions, I still never found any long-lasting satisfaction in this guise, my high strung nature always finding reasons to be unhappy.

As I grew older, a series of unpredictable events found me living in a place (South Florida) and assuming roles (corporate cog) that ran absolutely counter to any path I had previously envisioned for myself, and in fact had sworn I would never travel. Still, for a time I survived and sometimes even thrived, falling back on a library of skill sets and behaviors I’d assimilated despite myself. Regardless of the pretzel like contortions required of my natural predilections to adapt to such circumstances, adapt I did, to a degree that I sometimes still find implausible. Over time, and to varying degrees, I was aware that I was living the life of an imposter, and I attribute the perpetual stress of living such a life as being at least partially responsible for my eventually falling ill. Engaging learned scripts can allow one to exist in uncomfortable circumstances, but there is a gaping divide between existing and living.

After far too long I wised up and hightailed it back to New York, whose familiar embrace felt as comfortable as slipping into a favorite old pair of jeans, and skill sets much more familiar than those used in Florida were easily reengaged. For several years I flourished, finding a high profile job in a "glamour" industry and marrying a woman too wonderful for words, until one day during a miles long stroll through the city with my furry best friend Stella I suddenly noticed I was limping. A few months later I was diagnosed with multiple sclerosis, likely the progressive kind, and my existence shot off on another unexpected tangent. About three and half years after I was diagnosed I was forced at age 43 to “retire”, and a year and a half after that a wheelchair became a permanent part of my life.

For many people, leaving work and going on disability can lead to an existential crisis, their divorce from the workforce shattering their very sense of self. This is especially true of folks in the professions, many of whose identities are tied closely to their life’s work. I had no such problem, as even though I attained a respectable amount of success in a highly competitive field, I never fully identified with what I did for a living. I liked saying I was the Director of DVD Production for a huge multinational entertainment company much more than I enjoyed the day to day routine of doing the job. In fact, after a short period of adjustment, I found retirement exhilaratingly liberating, particularly so after I got the wheelchair (which I most assuredly did NOT welcome with open arms) and could scoot around the city and explore all of the nooks and crannies of Central Park to my heart’s content.

I found that even though my circumstances were unfortunate, I no longer needed to fire up any script or program other than those which suited my core desires, many of which had been subjugated for years by the expectations and responsibilities of adulthood. With a camera attached to my wheelchair I started shooting photos and videos, expressing creative impulses that dated way back to my childhood. And then this blog was born, and people I didn’t even know started responding to the words I put to the page. I even discovered a hidden talent for understanding complex medical gobbledygook and translating it into understandable English. In a bizarre turn of fate the fact of my getting sick and its subsequent consequences wound up fulfilling many of the dreams I’d had as a youngster. Yes, certainly a case of be careful what you wish for, but any dream realized, no matter the price, is a precious and wonderful thing.

Now, though, as the disease continues to chop away at my abilities, slowly turning my appendages into useless clumps of tissue – at times robbing me of the dexterity to manipulate a fork much less a camera – and my illness steals from me of the energy to do much of anything at all, I find that I have no script to fall back on. The combined forces of the mass media and years of schooling somehow left out any instructions on how to deal with a decade and a half of creeping paralysis, with its encroaching decrepitude that strips away every sense of normalcy, batters the body and soul with an ever-mounting pile of indignities, and leaves one forced to watch themselves slowly wither away. What cues am I to take, what lines am I to speak, what thoughts am I to think?

So now I enter a realm of improvisation, an ad-libbed world to be negotiated with no map, no signposts, no headlights to help navigate the blind curves ahead, with only my wits and whatever wisdom I’ve accrued to help me feel my way forward. Friends and loved ones are of tremendous comfort, keeping me tethered to the world of the healthy, and my fellow members of this club that no one would ever wish to join can empathize with my tribulations, but this is a journey that ultimately leaves one traveling solo. I suppose the bigger truth is that everyone, sick and healthy alike, ultimately winds up alone. I’ve never heard of a casket built for two.

Not that I am abandoning hope, as for reasons I can’t quite figure this illness has yet to pry optimism from my grip, and I’ve certainly no plans to go quietly into the night, though I’ve also no plans to allow this disease to turn me into a brain trapped within a useless prison of flesh and bone. No, I’ll continue to castigate the powers that be who seem ever more inclined to put profit before patients, I’ll put a spotlight on reasons for hope, and I’ll comment on the human condition from the peculiar vantage point afforded by a life lived in the company of heinous, unrelenting illness. I’ll do so, though, feeling like a man on a wire with no net beneath him, winds gusting furiously beyond anything his training and experience has prepared him to defy. With no script to follow, no application to engage, I suppose there’s nothing left to do than to just make it up as I go along, and to understand that if I fall from the wire, the very act of falling itself may be filled with its own kind of wonder.

Given that setting, there may yet be interesting times ahead.



Tuesday, January 31, 2017

Ocrelizumab Commentary: A New MS Drug With Breakthrough Potential And A Complicated History.

(What follows is my analysis of the potential promises and pitfalls associated with the experimental MS drug ocrelizumab. For those who have not already done so, I urge you to read – or at least scan – the interview I conducted with Dr. Peter Chin, one of the pioneering researchers who worked on this drug. Dr. Chin is the Group Medical Director of Neuroscience at the pharmaceutical company that makes ocrelizumab, Genentech – click here for the interview)

Ocrelizumab, a new MS drug scheduled for review by the FDA on March 28, 2017, has garnered breathless headlines in both the mainstream and medical press as a breakthrough medicine which has the potential to change the MS treatment landscape. Particularly heralded is the drug’s success in clinical studies in treating Primary Progressive Multiple Sclerosis (PPMS), a pernicious subtype of MS that currently has no approved therapies.

Assessing the overall potential of ocrelizumab is more difficult than with most new drugs, as the therapy has a complicated history that must be considered when synthesizing informed views about it. Ocrelizumab, which will be marketed under the brand name Ocrevus, is a close sibling of the much older drug Rituxan (rituximab), whose mechanism of action ocrelizumab closely mirrors. Rituximab, which is manufactured by the same company that makes ocrelizumab, is already being used in many parts of the world as an effective MS therapy, even though it was never officially approved for this purpose. The reasons why ocrelizumab rather than rituximab was advanced in studies as an MS therapy are somewhat controversial; complicating matters further are ocrelizumab’s failure in trials for use in treating other autoimmune diseases (lupus and rheumatoid arthritis). Therefore, when attempting to make a sober assessment of ocrelizumab, one must look not only at the drug itself, but also at how it currently came to be on the verge of FDA approval.

First, let’s look at ocrelizumab itself, in terms of how the drug works and what recent clinical trials reveal about its effectiveness in the treatment of both relapsing and primary progressive multiple sclerosis.

Ocrelizumab is the first B cell therapy for MS proven to be effective in late stage clinical trials. In very simplistic terms, the human immune system is comprised chiefly of 2 types of cells, T cells and B cells, which each use different mechanisms to attack and kill invading bacteria or viruses. Until very recently, the vast majority of MS researchers, who see MS as an autoimmune disease in which the immune system turns against the body’s own cells, considered the multiple sclerosis disease process to be driven almost exclusively by T cells. MS drugs such as Tysabri and Gilenya were designed to specifically target these cells. B cells were given short shrift, and were largely dismissed as having no real relevance in the MS disease process.

The success of ocrelizumab – a drug which destroys B cells – in treating MS has upended these prior assumptions and has forced researchers to rethink their multiple sclerosis disease models. In clinical trials, ocrelizumab, an intravenous drug administered approximately every 6 months, proved to be remarkably effective in treating relapsing multiple sclerosis, and even had a modest effect on PPMS. Let’s look at the actual trial results.

Two separate trials were conducted testing ocrelizumab against the interferon drug Rebif in patients with relapsing multiple sclerosis. These two trials were called OPERA 1 and OPERA 2 (click here). Both two-year trials involved one group of patients taking ocrelizumab and another taking the interferon drug Rebif, and comparisons were made as to the overall effectiveness of ocrelizumab versus the interferon drug. The results were very impressive. Compared to the Rebif treated patients, the ocrelizumab trial subjects experienced a reduction in relapse rates of 46% and 47% in the two trials. Additionally, there was a 40% reduction in confirmed disability progression and a 95% reduction in new enhancing lesions. These results rival or surpass any of the other MS drugs currently on the market. There were no significant differences in the number of adverse events (bad side effects) between the ocrelizumab and Rebif treated patient populations in the relapsing multiple sclerosis trials.

The ocrelizumab PPMS trial was named ORATORIO (click here). This trial lasted 2 ½ years, and randomly assigned 732 patients in a 2 to 1 ratio to receive either ocrelizumab or a placebo. In other words, twice as many trial subjects received ocrelizumab than received placebo. The highlight of this study was that the ocrelizumab treated patients experienced a 25% reduction in time to progression when compared to their placebo-controlled counterparts. Specifically, 29.6% of ocrelizumab treated patients and 35.7% of placebo treated patients experienced a measure of disability progression over the course of the study. This is the first time in a placebo-controlled scientific trial that any multiple sclerosis drug has displayed effectiveness in slowing down the progression of disability in Primary Progressive patients. Ocrelizumab also displayed efficacy over placebo in a number of other outcome measures as well, including the timed 25 foot walk.

As I discussed with Dr. Chin during our interview, it’s important to understand that ocrelizumab did not reverse or even stop the progression of disability in trial subjects. It slowed progression by about 25%. What does this mean for patients in a real-world setting? Well, speaking strictly in a broadly hypothetical basis, if an individual PPMS patient left untreated might need a cane four years after diagnosis, that same patient, if responsive to ocrelizumab, might not need a cane for five years. Again, this is strictly a hypothetical case; PPMS effects patients in widely varying degrees of severity. Additionally, the ORATORIO trial only lasted 2 and half years. How the drug's effectiveness manifests over longer periods of time is not yet understood.

Unlike the relapsing multiple sclerosis ocrelizumab trials, the PPMS trial did reveal some potentially troubling adverse events. Opportunistic infections (mostly respiratory infections and oral herpes) were more common in ocrelizumab than placebo, and the rate of cancer in ocrelizumab treated patients was approximately 3 times that found in placebo treated patients, 2.3% versus 0.8%. Though Genentech says that no direct causal relationship between the cancers in ocrelizumab treated patients could be established, the fact that slightly more than 1 in 50 trial subjects on the drug developed cancer is sure to raise eyebrows, but since similar cancer rates were not seen in the relapsing multiple sclerosis trials these numbers are surely open to question.

There are also some concerns regarding the design ORATORIO study. Back in the mid-2000’s, Genentech conducted a PPMS trial using rituximab, which at first was deemed a failure. Later review of the trial data revealed, though, that a subset of PPMS patients did appear to gain benefit from rituximab therapy (click here). These patients were generally younger than 50 years old, were less disabled, and had enhancing lesions on their MRIs. It’s generally thought that patients fitting this description account for between 10%-15% of the overall PPMS population. The ocrelizumab PPMS trial, though, included about 26% of patients fitting this profile, or approximately double that seen among real-life PPMSer’s. This means that the ORATORIO trial was heavily weighted with patients who were likely to respond to ocrelizumab, since the drug acts in much the same way as rituximab. The ocrelizumab PPMS trial was not designed to discern differences in the effectiveness of the drug between patients with enhancing lesions and those without, but Genentech says there was a “directional consistency” to the trial results, suggesting that the drug was effective in all patient subgroups to one degree or another. Still, the fact that the trial was frontloaded with likely responders is another eyebrow raiser, and may be something that the FDA looks at when making its approval decisions.

Okay, now that we’ve looked at the ocrelizumab MS trials themselves, let’s dive into the history of the drug. Back in the early 2000’s, some MS researchers began investigating whether therapies that destroy B cells might be effective in treating MS. As mentioned earlier, at the time this with a rather radical idea. The drug that was chosen for study was Rituxan (whose generic name is rituximab – click here), a drug developed by Genentech years earlier that had been approved in 1997 for use in fighting non-Hodgkin’s lymphoma and certain types of leukemia. Rituximab, like ocrelizumab, works by zeroing in on a protein found on most types of B cells, called CD20, and then killing the cells on which this protein is located. Though both drugs target and kill B cells, they do so in slightly different ways, and these differences may result in variances in safety and efficacy. Think of the drugs as two hitmen; one likes to slit his victims throats, the other prefers to strangle them. Both get the job done, but their differing killing techniques might effect witnesses differently. In the case of ocrelizumab and rituximab, these differences may effect the actions of other immune cells, thus accounting for possible differences in the safety and efficacy of the drugs.

In the mid-2000’s, MS researchers put rituximab to the test by using it in “proof of concept” trials in patients with RRMS and PPMS. When the trial results were revealed in 2008, the drug proved itself to be extremely effective in treating relapsing remitting MS, but not effective in treating PPMS (click here and here). It’s important to note that the RRMS trials were small, early stage trials, but the PPMS trial was larger and later stage. As mentioned earlier, later parsing of the PPMS data did reveal a subgroup of patients on whom the drug appeared to have some positive effect.

Given the success of the rituximab RRMS trials, the fact that a subset of the PPMS trial population appeared to benefit from the drug, and rituximab’s long history as a successful oncology drug, it’s reasonable to assume that the drug would have been greenlighted for further development as an MS treatment. Instead, all development of rituximab as an MS treatment was halted, and the focus shifted instead to ocrelizumab, a new experimental Genentech product that also targeted B cells via the CD20 protein. While there is some perfectly valid scientific rationale for this choice, many facts and circumstances point to financial motivations playing an oversized role in the decision to advance ocrelizumab rather than rituximab as a potential treatment for MS.

The scientific rationale for choosing to proceed with ocrelizumab is that the drug is comprised primarily of human proteins (the drug is a “humanized” monoclonal antibody), while rituximab contains a mix of mouse and human proteins (making it a “chimeric” monoclonal antibody, meaning that it contains proteins from more than one species). Theoretically, a humanized molecule should be better tolerated by patients than a chimeric drug, especially when used for treating chronic diseases which require continued administrations of the drug. That said, rituximab did have a very good safety profile in its role as an oncology drug, and very few adverse effects were seen in the early rituximab MS trials.

Genentech’s financial motivations for switching from rituximab to ocrelizumab were many. First and foremost was the fact that rituximab was due to come off patent in 2015, meaning that other drugmakers would be free to come in and market their own versions of the drug at that time. As ocrelizumab is a brand-new product, Genentech will have exclusive rights on it for decades to come. In addition, several corporate partnerships were also at play which made ocrelizumab the preferred candidate for further development. Here’s an explanation of the situation, from an article that appeared on the biotech industry news site Genetic Engineering and Biotechnology News in 2010 (click here). Keep in mind that Roche is the parent company of Genentech:

“The operating profits for Rituxan are currently split 60–40 between Roche and Biogen Idec, respectively. But profits for Ocrelizumab would be split 70–30 in Genentech's favor, accounting for Genentech’s enthusiasm to move ahead with the development of Ocrelizumab in MS, at the expense of Rituxan, which loses patent protection in 2015.”

Of course, there is no direct proof that the switch from Rituxan to ocrelizumab was driven primarily by financial considerations (except, perhaps, in files tucked away in the executive offices at Genentech), but I’ve learned through my years researching and writing about these topics that one can never be too jaded in assessing the motivations of the upper echelon decision-makers of Big Pharma. These are publicly traded companies whose officers are, by law, mandated to be beholden to their shareholders, not to the patients taking their products. Welcome to the realities of the medical industrial complex, in which diseases have been transformed into multibillion-dollar a year industries.

Whatever the circumstances, plans for further studies into the use of rituximab in treating MS were abandoned, and early trials using ocrelizumab to treat MS were initiated. In addition to the MS trials, ocrelizumab trials were also started on patients with rheumatoid arthritis (RA) and lupus erythematosus (LE). It’s interesting to note that rituximab was approved for use in treating rheumatoid arthritis in 2007, and has been used effectively and safely in that role since then (click here).

Genentech’s grand plans for ocrelizumab were almost completely disrupted in 2010, when the trials in RA and lupus were halted due to patient deaths and the occurrence of opportunistic infections (click here ). In the parlance of medical research, the risk versus benefit analysis in these trials did not warrant further study. In the parlance of everyday people, dead patients suck. It should be noted that patients in the ocrelizumab rheumatoid arthritis trial were also taking other immunosuppressive drugs, but then again so are most of the patients who have been using rituximab to treat their RA since its approval in 2007.

Ocrelizumab studies in MS were continued because these disastrous infections and patient deaths were not seen in early ocrelizumab MS trials, and also because it’s generally assumed that MS patients and their doctors have a higher tolerance for risk due to the potentially catastrophic nature of the disease (click here). This assumption is borne out by the MS community’s acceptance of drugs like Tysabri, which has a proven link to the deadly brain infection PML. Hundreds of MS patients have contracted this infection due to their taking Tysabri. Other MS drugs, such as Gilenya and Tecfidera, have also been linked to opportunistic infections such as PML. MS certainly isn’t a disease for the faint of heart.

In the years since the rituximab MS studies were shelved by Genentech, MS neurologists have been using the drug on an “off label” basis due to the obvious potential of the drug displayed in those early trials. “Off label” refers to the fact that doctors are free to prescribe any FDA approved drug for any indication whatsoever, even if the drug has not been approved for that purpose (click here). Many MS neurologists here in the USA as well as in Europe have been using rituximab to treat MS patients safely and effectively for years. The use of rituximab in MS is especially prevalent in Sweden, and a recent study out of that country that took a retrospective look at MS patients treated with rituximab found that the drug was startlingly effective and had an excellent safety profile (click here). As noted earlier, rituximab has also proven safe and effective in treating rheumatoid arthritis. Remember, the RA trials for ocrelizumab had to be halted due to opportunistic infections and patient deaths.

It should be noted that over its 20-year history rituximab has been linked to some cases of PML, but to a far lesser degree than drugs like Tysabri. In rheumatoid arthritis patients, it appears the rate of PML in Rituxan treated patients is on the order of 1 in 25,000 (click here). Rituximab has also been linked to other opportunistic infections, but again, at a lower rate than is seen in most other MS drugs. Let’s face it, any drug that profoundly changes the highly evolved human immune system is bound to open patients up to infections they wouldn’t otherwise contract. Ocrelizumab and rituximab both destroy B cells, one of the major components of the human immune system. No one knows what the long-term effects of living without any B cells might be. We do know, though, that the long-term effects of living with MS can be harrowing. Such is the state of the current MS treatment paradigm.

In conclusion, while the excitement generated by the impending approval of ocrelizumab for relapsing multiple sclerosis and primary progressive multiple sclerosis is certainly warranted, expectations, especially for those with PPMS, should be kept realistic. Ocrelizumab will likely slow the rate of disability progression for some progressive MS patients, and even though this isn’t the revolutionary change patients battling PPMS are so fervently hoping for, it is a start. Relapsing multiple sclerosis patients can expect ocrelizumab to be among the most effective disease modifying drugs on the market.

The fact that rituximab, a very similar drug with a proven record of efficacy and safety, is an available and very viable option should play into treatment decisions, as should the failed ocrelizumab trials in RA and lupus, and the increased cancer rates seen in the ocrelizumab PPMS trials (again, these rates could be aberrations). These factors need not make patients shy away from ocrelizumab, but there is every reason to explore them with your neurologist. Don’t be afraid to ask your doctor why they might favor one drug over another. This holds true when deciding on any MS treatment. Remember, the doctor-patient relationship should never be a dictatorship, but a partnership. Here’s to hoping that ocrelizumab proves itself worthy of the buzz it’s generated in advance of its anticipated FDA approval.

And here’s to more desperate hoping that MS researchers soon come up with methods other than profoundly kneecapping the human immune system in their search for ways to treat MS.

Tuesday, January 17, 2017

Ocrelizumab Exclusive: Interview with Pioneering Researcher Dr. Peter Chin

Dr. Peter Chin
Late last month I was contacted via email by a representative for the pharmaceutical company Genentech, asking if I would like to interview one of the researchers who played an instrumental role in the development of the new MS disease modifying drug ocrelizumab. At first I assumed I must’ve received the email as the result of some sort of clerical error, what with my being a mere blogger and all, but I figured if they’re offering, I’m accepting.

Thus, I present the below interview with Dr. Peter Chin, the Group Medical Director of Neuroscience at Genentech. Dr. Chin has been involved with the development of ocrelizumab for well over a decade, and was a pioneer in the study of the role of immune system B cells in multiple sclerosis. This line of thinking has upended much of what had previously been thought about the disease, as the working theory up until very recently was that immune system T cells were the primary culprits that should be targeted when developing drugs aimed at alleviating multiple sclerosis. Ocrelizumab is a very close cousin of rituximab, also known by its brand-name Rituxan, another Genentech product which many neuros have been using off label to treat their MS patients.

Ocrelizumab, an intravenous medication requiring infusions approximately every 6 months, has garnered a tremendous amount of attention of late, as it is the first drug ever to show efficacy in treating progressive MS in a late stage clinical trial and is in the process of being considered for approval for the treatment of PPMS (as well as relapsing multiple sclerosis) by the FDA. The drug has generated blaring headlines and hyperbolic chatter in the medical and mainstream press, and talking directly to Dr. Chin presented a valuable chance to cut through the clutter and get the pertinent info straight from the horse’s mouth. Not to insinuate that Dr. Chin is a horse; au contraire, he proved to be an extremely erudite gentleman during our extensive talk. He was also quite generous with his time, as our scheduled 30 minute interview lasted for nearly an hour.

The following interview is filled with a tremendous amount of important information. It’s been lightly edited for readability. I’ll publish it here without commentary and follow-up next week with my take on the potential promises and pitfalls of ocrelizumab, an intriguing new MS medication.

As you read through the interview, you’ll notice a brand-new feature on these pages called “WK notes”. These are explanations in everyday language of some of the more esoteric medical terminology that cropped up during the interview. And, if anybody’s wondering, “WK” stands for Wheelchair Kamikaze, not Wicked Kool.



WK: Dr. Chin, let me thank you for taking the time to do this interview. To start, could you explain the importance of the relatively recent research into the role of B cells in the Multiple Sclerosis disease process? I understand that when this research first started, it was not in the mainstream of general Multiple Sclerosis research.

Dr. Peter Chin: Genentech started collaborating with leading academic researchers at major universities to look into the possibility that B cells might be important in MS about 15 years ago. To some degree this was not the mainstream line of thinking, but there were researchers who had a scientific hypothesis and believed that B cells might be important because they are the cells that differentiate into cells that secrete antibodies, and antibodies are implicated in the disease pathogenesis (WK note: pathogenesis refers to the conditions that lead to the development of a disease). They are found in lesions and in the cerebral spinal fluid as oligoclonal bands (WK note: more commonly referred to as O-bands, these are one of the primary diagnostic indicators that neurologists look for when examining the spinal fluid of potential MS patients). So there was some rationale, and I think it was an exciting time when the first proof of concept studies unblinded, showing that B cells may play a more important role than anybody thought.

WK: Just to be clear, before this time it was assumed that this was a T cell mediated disease, is that right?

Dr. Chin: That’s correct. The vast majority of efforts in developing new medications up until that point were directed towards T cells.

WK: Genentech was the first to study the use of B cell therapies in MS with the drug Rituxan, whose generic name is rituximab, which was the precursor to ocrelizumab, correct?

Dr. Chin: Yes, that’s right. Genentech developed rituximab a long time ago for oncology, and we learned a lot about the medication from there. Rituximab provided a proof of concept that B cells might be important in MS, but we advanced another molecule that we believe has the best potential for long-term treatment from both the safety and efficacy standpoints for people living with MS, and that’s ocrelizumab. Ocrelizumab is a humanized molecule which is different from rituximab because rituximab is what we call a chimeric antibody, which has a portion of its protein sequence that is derived from mice. (WK note: a chimera is a mythical beast made up of the parts of different animals, such as a winged lion. Chimeric drugs are those that include the DNA of both humans and animals.) Ocrelizumab is a humanized molecule, meaning most of its protein sequence is human. That becomes important, particularly in a chronic disease, because ocrelizumab is hypothetically less likely to generate an immune response against the drug itself than a drug that includes more non-human DNA.

WK: Can you tell us a bit about the proof of concept studies that used rituximab to treat RRMS?

Dr. Chin: Yes, it’s important to recognize that these were small proof of concept studies, with a single dose of rituximab against placebo. It did show a reduction in MRI enhancing lesions, which was the primary endpoint, and also showed about a 50% reduction in relapses against placebo, in a six-month period. So it did provide some preliminary information that targeting CD20 positive B cells might be effective (WK note: CD20 is a protein that appears on the surface of a variety of different types of B cells). Around the same time, ocrelizumab was being studied in rheumatoid arthritis in a dose ranging study. One thing we looked at was multiple doses of ocrelizumab and their effects on B cells as well as efficacy and safety. We also looked at immunogenicity (WK note: immunogenicity is the ability of a substance to provoke a response in the immune system) and found that this was a molecule that had potential for chronic autoimmune conditions, and decided to advance ocrelizumab for Phase II development in RRMS, which led to the Phase III development program which was just published in the New England Journal of Medicine.

WK: PPMS trials were also done with rituximab about 10 years ago, too. Since I am suspected of having PPMS, I was tremendously interested in that particular trial. Can you talk a little bit about that trial?

Dr. Chin: The rituximab PPMS trial is a trial that I was involved in, actually, and it was a Phase II/III study of 439 patients comparing rituximab versus placebo. It was a single study, and it was a negative study. Meaning that the primary endpoint, which was the time to 12 week confirmed disability progression, was not significantly different than placebo.

WK: My understanding is that even though the trial as a whole was negative, when the data was looked at retrospectively there was a subset of patients – primarily those who were younger, less disabled, and had enhancing lesions – that did appear to gain benefit from the drug. Is that correct?

Dr. Chin: That’s right, although this finding was hypothesis generating rather than confirmatory, meaning it was not proven in the study.

WK: Okay, let’s talk about the ocrelizumab MS trials, which are creating chatter all around the MS community. Starting with the RRMS studies, some of the results reported were pretty astounding. Could you describe those results?

Dr. Chin: The phase III RMS studies were called OPERA 1 and OPERA 2 (WK note: RMS refers to both RRMS and Relapsing SPMS). These were two, two-year trials – double-blind, double dummy studies – comparing ocrelizumab head-to-head to the interferon beta 1a drug Rebif. Here the relapse reductions were 46% and 47% compared to interferon. There was also a 40% reduction in confirmed disability progression, and approximately 95% reduction in gadolinium enhancing lesions compared to interferon. These are very promising results from an efficacy standpoint, and have the potential to really change the way that MS is treated.

WK: Yes, those are extremely impressive results. Were there any instances of PML, the potentially fatal brain infection that has been seen in patients taking some of the other MS disease modifying drugs, in any of the patients in the Ocrelizumab trials?

Dr. Chin: No cases of PML have been observed in any of the ocrelizumab development trials.

WK: Okay, let’s move onto the PPMS trial, which is really generating tons of buzz. Could you please summarize the studies and their findings?

Dr. Chin: The ORATORIO study is the Phase III double blinded study, lasting more than 2 and half years, comparing ocrelizumab to a true placebo. The primary result of this study indicated a 24% reduction in the risk of 12 week disability progression. Importantly, there was also a 25% reduction in the risk of 24 week disability progression, which is generally considered a more robust outcome measure for disability progression.

That 25% reduction is the reduction in risk over the entire timeframe for all the patients that were included in the trial, and that’s at least 120 weeks, but there were patients who entered the study early in the treatment period that were on the drug for a longer period of time. So the 25% reduction in the risk of disability progression is the figure for the entire cohort for the entire length of the trial.

WK: Okay, so the data from the trial tells us that this new drug for people with primary progressive MS is not reversing disability or stopping the progression of disability, but it is slowing the accrual of disability. Is that a fair assessment?

Dr. Chin: Yes, the primary result of the study is the 24% reduction in 12 week confirmed disability progression. So that is not a measure of improvement, and you’re correct, it shows a delay in the progression of disability as measured by EDSS (WK note: EDSS is a scale that measures the level of disability in MS patients).

WK: Realistically, then, PPMS patients on ocrelizumab can expect that they probably will keep progressing, but it would be at a slower rate than if they were left untreated?

Dr. Chin: That’s a hard question to answer for any individual, but the overall results for the population of the study show a slowing of disability production as measured by EDSS, there is a slowing of the worsening of the timed 25 foot walk, which is another major end point in progressive MS trials. This is literally a measure of how long it takes to walk 25 foot feet. There is a slowing in the rate of brain volume loss, and, at least over the course of the trial, there appears to be a stabilization of the accumulation of T2 lesion accumulation. On this end point the placebo treated patients continue to accumulate T2 lesion volume and patients on ocrelizumab experienced a small decrease that was stable over the course of the two and half years or more.

WK: You previously noted that ocrelizumab was tested in trials for the treatment of rheumatoid arthritis. Weren’t those trials halted because of opportunistic infections and patient deaths?

Dr. Chin: There were opportunistic and serious infections observed in the Phase III program in rheumatoid arthritis. What’s important here is that rheumatoid arthritis is a different treatment paradigm. These are patients that are also on concurrent immunosuppressants in addition to ocrelizumab. (WK note: many of the rheumatoid arthritis patients in the ocrelizumab trial were taking other immune suppressing drugs in addition to ocrelizumab.)

WK: And ocrelizumab was also being trialed for treating lupus, and those trials also had to be halted for similar reasons, correct?

Dr. Chin: There were 2 studies in lupus. Ocrelizumab was studied in systemic lupus erythematosus (SLE), and that was discontinued primarily because the expectation for efficacy was low based on another study involving B cell targeting. The other study was on lupus nephritis, and there were serious infections that were observed, but the decision to halt was based on an assessment of potential benefits versus risks.

The same is true for the Rheumatoid Arthritis program. The potential for benefit/risk improvements over existing therapies, based on the data that were already on hand, was deemed not to be promising. So the studies were discontinued.

WK: Were any of these same problems – opportunistic infections and patient deaths – seen in either the RRMS or PPMS ocrelizumab trials?

Dr. Chin: The ocrelizumab Phase III safety results for MS overall were very favorable. This is the data that was just published in the New England Journal of Medicine. The proportion of patients in the relapsing study with any adverse event were similar to those who were on beta interferon, and the proportion of patients with any serious adverse event, including serious infections, were also similar to interferons. The same is true with the primary progressive MS trial, which was a slightly longer trial. When compared to placebo the proportion of any adverse event, any serious adverse event, or any serious infection was comparable to placebo.

WK: In looking over the ORATORIO PPMS trial results, it appears that there were higher rates of cancer among the ocrelizumab treated population when compared to the placebo population. I believe the numbers were 2.3% of the ocrelizumab population developed cancers, while .8% of the placebo group developed cancers. Is that of any real concern?

Dr. Chin: There is a numerical imbalance in the number of cases observed, but the overall numbers are small. This is not a confirmed risk, but I will say that patient safety is important to us and we do continue to monitor this in ongoing clinical trials. We don’t believe that the totality of the data supports a causal relationship, but we will continue to monitor this in our ongoing Phase III open label extension studies. So far, in the additional data we’ve accumulated, there is no increase in the rate of cancers being seen.

WK: The earlier rituximab trials demonstrated that there was a subset of the PPMS population on which the drug appeared to be effective – primarily younger patients who were less disabled and had enhancing lesions. In the ocrelizumab PPMS study this group made up about 26% of the test subject population, whereas in the general PPMS population the number of patients displaying those characteristics is thought to be somewhere between 10%-15%. So it would appear that the ocrelizumab study was populated with a higher percentage of patients who might be high responders than are present in the real-life PPMS population. Can you comment on this possible disparity?

Dr. Chin: The first thing I would say is that the study results are designed to assess the efficacy in the entire study population. So this was not a study only of patients of a certain younger age or only of patients who had enhancing lesions or did not have enhancing lesions. I say that because when you look at subgroup results, it’s important to recognize that these studies are not designed to address the efficacy in the subgroups. Also, I would note, that in data that we presented earlier this year that there is a directional consistency, meaning that there is still a reduction in disease worsening in patients who both had enhancing lesions and did not have enhancing lesions at baseline. This was presented at the ACTRIMS meeting in February 2016.

WK: Are there differences between the mechanisms rituximab and ocrelizumab use to eradicate CD20 B cells?

Dr. Chin: There are differences in how they bind to CD20 molecules on the B cells. And there are differences in what we call effector function, and that’s the portion of the antibody that interacts with other elements of the immune system to remove the cells. So, yes, there are differences in the functions of the two molecules.

WK: The mechanism of ocrelizumab in PPMS patients that do have enhancing lesions – which indicate active inflammation within the central nervous system – would presumably be much the same as you would see in the RRMS model, in that the drug clearly reduces inflammation by targeting B cells. Can you propose a mechanism of action for ocrelizumab that would be beneficial for the vast majority patients with PPMS who don’t have signs of enhancing lesions or any other signs of active inflammation in their central nervous systems?

Dr. Chin: That’s a very challenging question, and a good question. I think what you’ve hit on is an area that the entire research community in MS is thinking about. It’s not a question that anyone can answer definitively at this point, because the mechanism of progressive MS and the evolution of progressive MS over time isn’t completely understood. I think there’s a recognition in the research community that the biology has become very complex and how intervening in one way will impact the disease is hard to predict. Genentech is a member of the Industry Forum of the International Progressive MS Alliance, a coalition of organizations that has formed to address the kinds of questions that you’re asking, so we contribute what we can to the understanding of progressive MS. But that’s a really big question that you’re asking.

I think our understanding of B cells currently, which I will acknowledge is ongoing and evolving, is that B cells do interact with T cells, and by removing B cells from circulation we may be breaking that interaction. We also know that B cells differentiate into plasma cells and plasmablasts which create antibodies, which might also be involved. (WK note: plasma cells and plasmablasts are among the more mature types of B cells circulating in the human body.) B cells also create a number of cytokines that also impact and potentially stimulate other parts of the immune system. (WK note: cytokines are chemicals secreted by cells that trigger actions in other cells.) There may be multiple ways that selectively targeting b-cells might be leading to efficacy.

WK: Just a couple of weeks ago we learned that the December 28, 2016 date for and FDA decision on the approval of ocrelizumab had been delayed until March 28, 2017. Can you shed some light on the reasons behind that postponement?

Dr. Chin: We did have an announcement about this extension of the date, and yes it’s March 28, 2017, which is the expected action date by the FDA. The FDA needs more time to review additional data that was submitted during the review, regarding the commercial manufacturing process. What I want to stress is that this is not related to the review of safety or efficacy data. It’s about the manufacturing process and the data regarding that process. This extension of the action date by the FDA is a commonly used procedural tool and they use it to allow more time to evaluate additional information. It’s not uncommon for questions that come up during the review, and as a result of those questions additional data get submitted. It’s just the nature of the process.

WK: As a final question, as a scientist who has devoted a large part of your career to studying MS and progressive MS, what do the trial results from the PPMS ocrelizumab studies indicate to you about the disease, and what can we look forward to in the future for what had previously been an untreatable and rather terrible malady?

Dr. Chin: I think the first thing I’d say is that the data that we just published in the New England Journal are really landmark data for a number of reasons. One, they highlight and confirm that B cells are important in MS, which is still a relatively new concept. That’s a major area of science that Genentech has contributed to that the entire community is continuing to work on. From a clinical trial results standpoint, this is the first molecule that has shown efficacy in both relapsing MS and primary progressive MS. It’s the first molecule under consideration for approval by the FDA for both RRMS and PPMS. It’s an exciting time and an exciting potential new medicine to be working on.

Particularly in regards to primary progressive MS, I want to make the note that Genentech is the only company that has actually done two Phase III studies on primary progressive MS. It’s something that we’ve been very committed to because of the unmet medical needs and the fact that there are no approved therapies. My great hope is that people will start to see that maybe we can do something about primary progressive MS, and build upon this first step with ocrelizumab, which is a very meaningful one.

WK: On behalf of all Wheelchair Kamikaze readers, I’d like to offer a tremendous thank you for doing this interview. On a more personal level, I’d like to thank you for devoting your career to unraveling the mystery of this dreadful disease. It’s tremendously important for a lot of people who suffer from all forms of MS, but especially those who have been without any proven treatment options for so long, who are stuck living with the misery that is progressive MS.

Dr. Chin: Thank you for that, Marc. I think it’s important for you to know that there are hundreds of people at Genentech and Roche who have worked on these primary progressive trials and the RMS trials for many years. I think I can speak for all of them that they do it with a passion for making a difference, understanding the degree of unmet need that’s out there.


I hope readers have found real value in the above interview. I’d love to hear your thoughts in the comments section.

As I stated earlier, I’ll follow this up next week with an essay on my thoughts about all things ocrelizumab, touching on many of the points that I discussed with Dr. Chin. A big thanks goes out to Genentech and Dr. Peter Chin for allowing me the chance to conduct this rather expansive interview.

Until next time…

.

Thursday, January 5, 2017

New Year's Eve Through MS Eyes (repost)

(This essay was first posted about one year ago. Guess this makes it a golden not so oldie, but it's timely and the sentiments expressed will hold true as long as MS remains my unwanted life partner…)

Back in in the days before I got jumped by MS I always loved New Year’s Eve. While many of my fellow habitual night crawlers derided the night’s festivities as “amateur’s hour”, a time when those less accustomed to nocturnal hijinks were apt to get sloppy and make fools of themselves, I embraced the ringing in of the new year con mucho gusto. Never content with just one party for the duration of the night, my friends and I would go on a kind of New Year’s Eve tour, hitting four or five shindigs and nightclubs before heading home well after dawn on January 1. The sentimentality of the holiday, with its tacit promises of sins forgiven and futures bright with hope held me in its thrall, for though I seemed to live in a state of perpetual neurotic dissatisfaction, I also brimmed with expectations that bigger and brighter days were waiting just over the horizon. New Year’s Eve was the one night a year that this heady brew of emotions and expectations were codified into celebration, to be shared with friends and strangers alike.

I suppose my fondness for the holiday has its roots in my early childhood. My mom and dad divorced when I was three, and for several years after the split my mom and I lived with my grandmother and my unmarried aunt. On New Year’s Eve my young, single mom – who herself loved the nightlife – would head out with her friends into the NYC of the swinging 60s, and my grandmother, aunt, and I would watch Guy Lombardo and his Royal Canadians playing old timey big band hits for the well-heeled crowd at the Waldorf Astoria Hotel, broadcast live to our ragged black and white console TV. We didn’t have much money and lived in a building in the Bronx that was closer to a tenement than a high-rise, but our lack of means did nothing to diminish the excitement and expectations of the evening.

Though I was maybe only four or five years old, on New Year’s Eve I was allowed to stay up till midnight to take part in a family tradition that stretched back decades. We didn’t have any fancy noisemakers or horns, but at the stroke of midnight, as confetti and balloons floated down on the well to do at the Waldorf and Guy Lombardo’s boys played “Auld Lang Syne”, my grandmother, aunt, and I grabbed sturdy but well-worn metal pots and pans, and, using big spoons as drumsticks, burst into the hallway of our apartment building, banging with joyous intensity on those old, scarred cooking implements, creating a raucous racket and shouting at the top of our lungs “Happy New Year’s!” Most of the other residents of the building joined us in creating a jubilant and low rent but somehow defiant cacophony, delirious and intoxicating stuff for the very young me. I daresay that for those few moments we had a lot more fun than the swells at the Waldorf.

When I grew older, as a young adult I fully embraced the revelry of the holiday. I had quite a few memorable New Year’s Eves in my late teens through my mid 20s, from seeing the new wave band The Waitresses playing a show at 5 AM at the famous Peppermint Lounge to bumming cigarettes from a then barely known Howie Mandel at an MTV “after party” that rollicked on and on as if it might never end. I recall with great fondness stumbling out of a nightclub with a group of deliriously intoxicated friends and madly howling at the moon as the last seconds ticked away on one long ago year. As I transitioned into full adulthood, mixed in with raucous annual celebrations were the occasional intimate, more romantic New Year’s get-togethers with lovers and close friends. No matter the circumstances, though, the night never passed without champagne and good cheer, and always kindled within me expectations of bigger and better things to come.

Now, nearly 13 years since I was diagnosed with Primary Progressive MS, the night carries with it a much more complex and troublesome mix of emotions. For the first several years after my creeping paralysis struck, while I was still relatively able bodied, my wife and I would host New Year’s Eve parties, more sedate than my revelries of the past but good times nonetheless. Now, with my body increasingly compromised and my stamina waning, even a small gathering of friends can prove taxing. This New Year’s it was just my wife and me watching celebrations from around the world beamed into our living room in high definition on our big-screen TV, images so crisp and detailed it seemed as though I could step right into them. That is, if I could step.

Despite my best efforts to stay fixed in the moment, I soon found it impossible to watch millions of people celebrating without enviously contrasting their situation with my own. With nary a thought given to their tremendous good fortune at simply having limbs and senses intact, the televised multitudes danced and sang, drank and strutted, laughed and hugged and mingled and voiced exuberant expectations about a future brimming with possibilities. Lubricated by flowing booze and the magic of the night, all could convince themselves that the coming days held good fortune that would far eclipse those which now belonged to history.

For the healthy masses, New Year’s Eve encapsulates the reality that the future is but a blank canvas, the images to be painted on it not predetermined but subject to the will of each individual. All but the most intransigent of difficulties will give way to effort, ingenuity, and discipline. Reality is but a construct of the human mind and the emotions it creates, and as such can be born anew once the self-defeating habits of the past are no longer allowed to dictate actions in the present. Not that these kinds of changes are easy, but with sound body and mind anything – anything – is possible. Sadly, it took my getting sick for me to fully understand this, but there is no greater truth.

And there I sat in a wheelchair – a wheelchair, goddamnit – trying my best to not begrudge the healthy, to vicariously share in at least some of the delirium, to laugh along with them and not let the sneaky tears that kept making their way to the corners of my eyes expose the turmoil that roiled within. There is indeed a reason they call progressive disease progressive. Physically, this last year has been a rough one, with old symptoms getting noticeably worse and new ones breaking the surface. Activities that could be accomplished with relative ease just a year ago are now at times tortuously difficult, and some of those that had been difficult have become damn near impossible. And by activities I don’t mean anything as devilishly complicated as walking or tying a shoe, but rather firmly gripping a fork, or struggling into a sweater, or on bad days, even just staying out of bed for more than four or five hours at a time. My strange and thus far indecipherable mix of endocrine dysfunctions, creeping paralysis, and hideously painful deteriorating joints (courtesy avascular necrosis, a very rare side effect of the intravenous steroids once used to try to beat back the creeping paralysis) has become more intractable than ever, defying all efforts, mainstream and alternative alike, to slow things down.

Unlike those healthy New Year’s Eve revelers on TV, no amount of willpower or change of habits will arrest this bitter physical decline. I continue to fight my disease on all fronts, employing a dizzying array of supplements and medicines to lessen the impact of some symptoms, and undergoing treatments both holistic and traditional at which my condition seems simply to sneer. Though for the most part my spirit stays strong, in the face of this insidious physical onslaught and its accompanying indignities I find it impossible to not at times give way to the weight of it all, having my breath taken away daily by the shocking realization that this is no dream that I can wake from, but instead a concrete reality in which I am being forced to watch myself slowly wither away. My mantra of “staying in the moment” does still help to keep me grounded, but there are also times when the moment just sucks, no two ways about it. Though I can and do fantasize about a future free from illness, my utter conviction to stare this bastard straight in the eyes lands such fantasies well into the realm of the far-fetched, right there alongside my old dreams of becoming the next Mick Jagger or Philip Roth.

New Year’s Eve is a time to look back and project forward, and for the healthy this shedding of the old and embracing of the new can be cathartic, if even just for a few hours. This New Year’s brought me no such respite, though, as a look back illuminated the losses suffered these past 12 months, and peering too deep into the future can be perilous, a glimpse at the dark at the end of the tunnel, a glance at an unthinkable void.

Yet I am not without hope. I keep myself immersed in the latest research and MS news, and though much of it is, quite frankly, garbage, there are approaches that do show promise. Perhaps I am delusional, but even through this morass of illness and increasing disability my resolve to not back down sometimes bends but doesn’t break, even as I acknowledge that merely stabilizing my disease state is at this point quite a longshot. But I know for a fact that sometimes longshots do come in. After all, I’m a guy who once won $15,000 in the Florida lottery, so I’m proof positive that you’ve got to be in it to win it.

And even as I sat there watching the partiers on TV, wrestling with my complicated and disconcerting mass of emotions, when the clock struck midnight I chugged some champagne and kissed my wife, while my inner five-year-old banged on pots and pans and screamed at the top of his lungs, “Happy New Year’s!”…



Wednesday, December 28, 2016

So Long, 2016…

(For those who receive this via email, this post contains a video, which can be viewed on the Wheelchair Kamikaze website – click here)

Just a few things to wrap up it up as we bid adieu to 2016, a year that has seen much tumult and turmoil for so many. My Spidey senses are telling me that 2017 may make 2016 look like a powder puff, but then again, three decades ago my Spidey senses told me that I would be the next Mick Jagger, so what the hell do they know? Stupid Spidey senses.

On a much more upbeat note, on Tuesday, December 27, 2016, Wheelchair Kamikaze received its 2.5 millionth page view, according to statistics provided by Google. All I can say to that little factoid is – mind blown. When I first started the blog I never expected more than a couple of dozen people to look at the thing, and even though I strongly suspect that at least 2.45 million of those page views are directly attributable to my mother, I’m still gobsmacked.

Wheelchair Kamikaze hit 1 million page views back in January 2014, about 5 years after I started the blog. Now, we’ve added another 1.5 million page views in only 3 years. Again – mind blown. All I can say is thank you thank you thank you thank you thank you thank you thank you thank you thank you thank you 2.5 million times to everybody who has ever laid eyes on these pages. Though my stupid Spidey senses never saw the unfortunate circumstances that led to Wheelchair Kamikaze coming down the pike, I am eternally grateful to everyone who has animated these pages with their comments, input, and presence. 

We are all in this together, folks, and the only way out is through. You’ve all helped me stumble my way through the body and mind twisting experience of multiple sclerosis, and if I’ve been able to help some of you shoulder the burden even just a little bit then at least there has been some method to the madness. Okay, all together now – MS SUCKS!

For those who might want to read a bit more about yours truly and the back story of the blog, Healthline.com has published a very nice article about WK in conjunction with the blog taking 2nd place in the website’s Best Health Blog contest (click here). I’d like to profusely thank the writer who penned the article, Elea Carey. She somehow managed to wrangle the veritable deluge of self-indulgent verbosity I sent her way in response to some simple interview questions into a succinct and elegant piece of writing. Maybe I should hire her as the full-time editor of this blog. Lord knows I need one. Stop me before I compound sentence again.

Okay, enough about me, I’ll end this last blog post of the year with an actual MS related item. The much anticipated FDA review of Ocrelizumab, the first drug that has a chance to be approved for the treatment of PPMS (along with an almost guaranteed approval for RRMS), has been delayed. Although the drug was initially slated for FDA review on December 28, that date has now been pushed back to March 28, 2017, due to “manufacturing issues” (click here). I’ve previously written fairly extensively on Ocrelizumab and its late stage trials (click here), and I’ll certainly have more to contribute in the coming weeks. 

Although the medical press is practically hyperventilating about the first drug that stands a very good chance at being approved for use in people with PPMS, there are some valid reasons for concern regarding this product. I’m hoping to interview a representative from Genentech, the manufacturer of Ocrelizumab, which, if it happens, should be pretty interesting. I’m also working on getting some interviews with other prominent figures in the MS world, so stay tuned…

All righty then, here’s to a happy new year to all, and may 2017 bring each of us much more good than bad. I’ll leave you with the following tune from a band I’ve loved ever since I first saw them as a high school sophomore in the late 1970s. To hell with my tingling Spidey senses, how about some unabashed optimism to ring in a brand-new year…

Thursday, December 22, 2016

Happy Holidays, and Results from Our Donation Poll

 

Ho ho ho, Merry Christmas, Happy Hanukkah, Good Festivus, and Happy Kwanzaa. And for anybody not covered by the previous salutations, I wish you a joyous winter solstice.


Okay, folks, the votes are in for our holiday donation contest, and it looks like the Tisch MS Research Center of New York has won in a landslide victory. The Tisch Center garnered 63% of the votes in our poll to determine which MS nonprofit should get the $500 donation derived from the prize money Wheelchair Kamikaze won in Healthline.com's "Best Health Blogs" contest.


Ultimately, over 210 people voted in our contest, with about 130 of them voting for the Tisch Center, so a resounding victory all around. This takes nothing away from the other nonprofits I offered up for votes: The Accelerated Cure Project, The Buffalo Neuroimaging Analysis Center, and The Multiple Sclerosis Association of America. All of these organizations are doing great things for the MS community and are certainly deserving of your own holiday gifts if you are so inclined. You can read more about all of them by (clicking here).


Oddly, the blog post soliciting votes for these groups was viewed almost 1200 times in the past week but only slightly more than 200 people voted in the poll. Not sure why somebody would read the post and not vote, but c'est la vie. Maybe it had something to do with Russian hacking or some other nefarious goings-on. Sad.


I will be making the donation to the to the Tisch Center as soon as I receive payment from Healthline.com, which is on its way. This past week I visited with Dr. Sadiq, the lead researcher of the Tisch MS Research Center, and he was extremely excited about the prospects for The Center's upcoming Phase 2 regenerative stem cell trial for MS patients, the first such trial to receive FDA approval. In preparation for the upcoming trial, The Center is about to start construction of the world's largest MS stem cell laboratory in the world, and is also about to publish the results of the first phase of the trial. The Phase 2 trial is currently scheduled to start in June, 2017. In addition to stem cell research, The Tisch Center is also delving into many other aspects of the MS mystery, and Dr. Sadiq had some very encouraging things to say about the whole of the Tisch Center's research efforts. He feels that his researchers are closer than ever before to unraveling some of the core mysteries of Multiple Sclerosis.


Not sure if I'll get a chance to put a post up next week, so let me take this opportunity to wish everybody a happy and healthy 2017. Here's hoping that the new year brings only good things to each and every one of us!


Thanks for reading Wheelchair Kamikaze, and for breathing life into this blog. My appreciation for all who visit these pages is beyond words…


Here's some Christmas cheer from The Godfather of Soul…





Friday, December 16, 2016

WK Takes 2nd Place in "Best Health Blogs" Contest!


Hey folks, thanks to your votes Wheelchair Kamikaze took 2nd place in Healthline.com’s “Best Health Blogs” contest! This is really a terrific honor, particularly because of the fierce competition – 382 other blogs were nominated to participate in the contest. Big congratulations to the two 1st place winners who apparently tied in the voting, “Lizzie’s Lungs” (click here) and “ALS and Wellness” (click here), as well as 3rd place winner “Early Onset Alzheimer’s” (click here). And of course, a huge thank you to Healthline.com (click here) for running the contest. Although Wheelchair Kamikaze has been honored as among the top MS blogs in the past, I believe this is the first time it’s been recognized as one of the best health blogs in general. BTW, Healthline's graphic department came up with the above image. I'm not THAT much of an egomaniac…

Healthline has generously awarded Wheelchair Kamikaze $500 for its second-place finish. I’d like to donate this prize money to a worthy MS nonprofit, and I’d like Wheelchair Kamikaze readers to pick which organization should get the big bucks. We’ll do this via an online vote, much the way Healthline’s contest winners were chosen. I’ve taken the liberty to nominate four worthy organizations from which to choose. Here’s some brief background on the chosen organizations to help inform your vote. I’ve arranged the candidates in alphabetical order.

  • The Accelerated Cure Project (click here) – The ACP is the organization administering the iConquerMS project (click here), a patient-centric research project in which MS patients can take a personal stake in advancing the cause of MS research by completing a series of online questionnaires, suggesting research topics of importance to them, and providing their feedback on research studies. By “crowdsourcing” a massive amount of data supplied by MS patients themselves, iConquerMS is compiling an unprecedented database on all aspects of MS that is open to researchers worldwide. This huge pool of information should reveal trends and insights into and about the disease that otherwise would have been missed by looking at smaller pools of data. I strongly encourage all readers to visit the iConquerMS website to sign up and begin participating in this tremendously important project. Your information has power, and together we can conquer MS. (Full disclosure: I am a member of the iConquerMS engagement committee).
  • The Buffalo Neuroimaging Analysis Center (click here) – BNAC is a research organization devoted to shedding light on the mysteries of multiple sclerosis and other neurologic diseases through the use of innovative imaging techniques and advanced analytic tools. The group did some of the first rigorous scientific research on CCSVI when Dr. Zamboni’s vascular theory of MS first made headlines, producing findings that cast some doubt on the causative role of venous abnormalities in MS. Their research has expanded to include the role that vascular abnormalities might play in exacerbating a wide range of neurological disorders. Lead researcher Dr. Robert Zavidanov directs a team of medical researchers and scientists of a variety of disciplines, who, among many other projects, have probed the role that gray matter lesions and inflammation of the tissues that surround the central nervous system play in the MS disease process. BNAC has pioneered many revolutionary imaging techniques. Their work promises to change in a fundamental way our understanding of Multiple Sclerosis. (Full disclosure: I’m on the patient advisory board of BNAC).
  • The Multiple Sclerosis Association of America (click here) – The MSAA provides vital services and support to MS patients throughout the United States. Programs include a Helpline with trained specialists; award-winning educational videos and publications, including MSAA’s magazine, The Motivator; safety and mobility equipment distribution; cooling accessories for heat-sensitive individuals; educational programs held across the country; and Lending Library among other services. For MS patients in financial need, the Association provides assistive equipment and cooling garments free of charge, as well as financial assistance for those who cannot afford to get MRIs. The scope of services and information provided by the Multiple Sclerosis Association of America is truly astounding, and even includes a smart phone app that helps patients manage their MS. Their website is a terrific resource for information on all things MS. I encourage all Wheelchair Kamikaze readers to visit the MSAA website and poke around, it’s a veritable treasure trove of information and vital services.
  • The Tisch MS Research Center of New York (click here) – The Tisch Center is a worldwide leader in cutting-edge multiple sclerosis research, and is currently in preparations to begin the first FDA approved Phase 2 regenerative stem cell trial in MS patients ever conducted, expected to get started this June. The Center is building the largest stem cell research laboratory in the world, and its staff of world-class researchers has developed proprietary methodologies that transform raw mesenchymal stem cells into cells specific to the central nervous system, which should prove to be much more capable of repairing the damage done by MS than the raw cells themselves. Under the guidance of Dr. Saud Sadiq, the Tisch center is involved in a wide variety of transformative MS research projects, from identifying new disease biomarkers to understanding the mechanisms behind disease progression. The Tisch MS Research Center is totally devoted to finding the cure for Multiple Sclerosis, which is of course the ultimate desire of every MS patient and all those who love them. (Full disclosure: Dr. Sadiq is my personal neurologist).

Please take a thorough look at all of the above candidates, and vote for whichever organization you would like to see receive the $500 awarded to Wheelchair Kamikaze by Healthline.com. The poll is located at the top of the left-hand column of this page. I’ll leave the poll open for 7 days, so the results can be determined just before Christmas. Of course, all of these organizations are great candidates for your own charitable giving, should you be so inclined. Ho Ho Ho…

Once again, thanks so much to everyone who voted for Wheelchair Kamikaze in the best health blog contest…

Friday, December 9, 2016

Shingled Out – Updated

(A quick thank you to all who have voted for Wheelchair Kamikaze in Healthline.com's "Best Healthcare Blog" contest. Voting continues until December 12, (click here) to cast your vote…)


Note – this is an updated version of this post, which was originally published earlier today. This update includes further information on the shingles vaccine, added at the end of the essay, due to some concerns raised by readers over the safety of the vaccine when used in MS patients. Just wanted to ensure that these issues were addressed. 

Well, it looks like the holidays have come early to my house, and rather than Santa bringing me that 1956 Porsche I've always wanted, I instead got the shingles. Yay. Guess I was on St. Nick's "naughty" list…


About two weeks ago I started feeling vaguely unwell, suffering from the kind of symptoms one typically gets before the onset of the flu. Just generally achy, no appetite, and a tremendous amount of fatigue, even for an MS patient. A few days later I was assaulted by the worst headaches I've ever experienced, jolting bolts of excruciating pain that felt as if somebody was trying to impale my skull with a red-hot stiletto behind my right ear. The pain, which exploded from the bottom of my skull forward to the area above my right eyeball, came in waves about every minute or so, and was breathtakingly debilitating. I have a lot of experience with pain due to a degenerative bone condition called Avascular Necrosis, but the searing, twisted agony I was suddenly stricken with was beyond anything I'd ever felt or even imagined.


As I sat cradling my head in my hands, trying desperately to keep my skull from blowing apart, my wife quickly googled the symptoms I was experiencing. She came up with a condition called occipital neuralgia, which can develop in MS patients. The ailment involves inflammation or damage to one of the occipital nerves, which run from the base of the skull up through the scalp, and its symptoms seemed to precisely match what I was feeling. As this was all occurring on a Saturday night, there was little I could do but suffer through it. I was absolutely not going to go to a hospital emergency room, as I long ago resolved that before I would put myself through the existential, soul crushing misery of sitting in a New York City emergency room on a Saturday night I'd have to be suffering from something no less serious than a severed limb. Much better to lay moaning in bed waiting for my skull to combust.


The next morning I called my neurologist and told him what was going on, and he agreed that my symptoms sounded like occipital neuralgia. He phoned in a prescription for gabapentin, a drug also known as Neurontin, which is used treat nerve pain. The Neurontin did indeed reduce my pain level substantially, but also made me feel completely loopy and dumb as a box of nails. Still, not a bad trade-off, all things considered. Better stupid with a dull headache than smart with a skull trying to contain a thermonuclear blast.


Later that day I noticed a slight rash on my right forehead, an area in which I sometimes get a bit of psoriasis. For reasons that doctors really can't explain, many patients with nervous system diseases also get skin conditions like psoriasis or eczema. Ask a doctor about this strange correlation and they'll likely answer you with a string of polysyllabic mumbo-jumbo, because most physicians would sooner poke their own eyes out than utter the words "I don't know", but the truth is this connection has long been observed but is little understood. In any event, the skin on the right side of my forehead became more inflamed as the day went on, and started getting very tender as well. By that night I noticed little blisters appearing in the rash, and I started thinking "shingles".


The next day, Monday, I called my neuro's office and told them I suspected I had a case of shingles, and they told me to come right in. After a brief examination, the neurologist I saw confirmed that I probably had shingles, but advised me to see a dermatologist ASAP to nail down the diagnosis. I saw a dermatologist the following morning, and she concurred that I did indeed have shingles. I told her that I would rather have a spiral staircase, and she just stared at me blankly. I hate doctors with no sense of humor. She did say that the severe headaches I had experienced were typical for people developing shingles on their forehead and scalp, so that at least explained the pain I was feeling.


Shingles is a condition caused by the varicella zoster virus, also known as the herpes zoster virus. This is the virus that causes chickenpox, which was very common among children of my generation, back before most kids were given the chickenpox vaccine. I had chickenpox when I was six years old. The varicella zoster virus is a human herpes virus (click here), a family of viruses that also includes Epstein-Barr virus and the viruses that cause oral and genital herpes. In total, there are eight known human herpes viruses, which all share a common trait: once a person is infected with them, they are infected for life.


In the case of the varicella zoster virus, after causing chickenpox the virus goes into deep hibernation, taking refuge in the root cells of nerves. Later in life, usually when a person is older than 50, the virus can suddenly wake up and migrate down the path of the nerve to the skin, where it causes the painful rash that is the hallmark of shingles. There is now a shingles vaccine that can greatly decrease the chance of a person infected with herpes zoster to develop shingles, but I never asked for the shot. I'd seen countless commercials for the vaccine, and had thought to myself, "self, you should probably get that vaccine", but as I am generally nauseated by prescription drug advertising I refused to be swayed by the pharmaceutical companies' slick efforts to hawk their product. Stupid me.


While I did know that shingles involve a painful rash, I didn't know that the condition also commonly makes patients feel like absolute crap for weeks on end. Those initial flulike symptoms I was experiencing in the days before I developed the searing headaches and then the rash have blossomed into full-fledged misery, leaving me feeling like I just tried to kiss the "A" train between stops. I still have a dull headache, my muscles hurt, I feel feverish (even though I have no fever), and I'm so fatigued that I could easily sleep 20 hours a day. I'll be on antivirals for the next 30 days, which supposedly will shorten the duration of these symptoms. The blistering rash on my forehead is starting to crust over (yum), which is the first sign of healing. And, of course, as with any bug that strikes an MS patient, all of this has only made my neurologic symptoms much worse. My compromised extremities are less functional than ever, a frightening preview of what my continuing progression has in store.


I've been told to avoid contact with people until at least the end of this week, since there is a chance I could pass the virus on to folks who either never had chickenpox or were never vaccinated against them. The weird thing is that if I did pass the virus on to someone they would develop chickenpox, not shingles, since the first stage of varicella zoster infection is always chickenpox, no matter when you contract it. Avoiding people shouldn't be much for problem, as I can barely make it from my bedroom to the living room in my wheelchair. And who wants to see people anyway, when you've got a disgusting crusty rash on your forehead. Children would run screaming…


Please, take my advice – if you had chickenpox as a child, go get the shingles vaccine. I wouldn't wish what I'm currently going through on a dog. Actually, I wouldn't wish anything bad on a dog. I like dogs. Dogs are better people than most people.


Woof.


Addendum: numerous readers have sent notes advising me that because the shingles vaccine contains live virus they've been told it's a no-no for MS patients. Others, though, have reported getting the vaccine with no problems.


Here's more info on the shingles vaccine and MS, from the National Multiple Sclerosis Society Website:


"Zostavax is a live-virus vaccine to prevent shingles. MS neurologists do not recommend live-virus vaccines for people with MS because these vaccines can lead to an increase in disease activity. However, Zostavax is an exception because most people have had chicken pox earlier in their lives and therefore already have the virus in their bodies. Each person needs to discuss the potential benefits and risks of this vaccine with her or his healthcare provider."


For further info, a very comprehensive article about the shingles vaccine and its use in MS patients can be found at the Multiple Sclerosis Association of America's website (click here).


Bottom line, there seems to be some conflicting information out there regarding the safety of MS patients getting the shingles vaccine. This appears to be due to the complex nature of Multiple Sclerosis and the drugs used to treat it. Each patient is different, and no one-size-fits-all approach will cover all bases. Given my horrible experience with shingles, I'd say it's definitely worth a conversation with your neurologist to discuss whether or not you're a candidate for the shot.



(Warning, shameless self promotion ahead: Wheelchair Kamikaze has been nominated for Healthline.com's "Best Healthcare Blog" contest. If you feel WK deserves such an honor, please cast your vote on the contest webpage (click here). Just scroll down at the contest webpage until you see the blog name, Wheelchair Kamikaze is currently in fourth place).