Thursday, April 27, 2017

At Long Last, the Answers I've Been Seeking! (Or, Only His Hairdresser Knows for Sure)

Ever since my diagnosis almost 14 years ago, I’ve been on a single-minded quest seeking not only the cure for the scourge that afflicts me but also answers the intangibles of my disease – the how’s, why’s, and where’s of my predicament. More precisely, just how did I get sick, why did I amongst the masses get stricken with this dreaded creeping paralysis, and just where might I have picked up this curse. Inscrutable questions, yes, and queries a wiser soul would probably have best left undisturbed, but despite my knowing better I have never been able to stop my mind from pondering these imponderables.

I can now breathlessly report, dear readers, that my seemingly quixotic mission to unearth truths that I feared might very well be beyond comprehension has finally been rewarded, the answers now mine – and from the unlikeliest of sources. Before I reveal these precious gems of knowledge, these nuggets of illumination, please allow me some exposition, without which I’m not sure the full magnitude of my discoveries can be appreciated.

I’ve always had a knack for attracting eccentrics into my life, a strange type of gravity that has kept my existence full of oddballs, characters, and cranks. They're almost always of the benign variety, unconventional creatures whose quirks have much more often been a source of delight than offense, whose idiosyncrasies have imbued my time on earth with welcome bursts of color and verve. Who needs normal? Normal is boring. Why just have a peanut butter sandwich when the addition of a few slices of banana can make all the difference between banal and splendiferous. So, bananas it is!

I suppose the roots of my appeal to those who are somewhat off kilter may lie in the fact that my family is chock full of endearing kooks of all varieties, from the full on nutso to those with quieter quirks. In my formative years I spent much of my time with an aunt who was practically a shut in, a woman who had retreated from the world at large and instead, with her vivid imagination, created one of her own; a realm full of magic incantations and mystical powers in which, it seemed to my young mind, absolutely anything was possible. In fact, I'm still half expecting the massive and all-powerful robot that she promised was going to be delivered decades ago to arrive at my door any day now. As my aunt would almost certainly say, "Malika Malika Woo, Make It Come True!".

My paternal grandfather was a gangster during prohibition, and my paternal grandmother a larger-than-life figure whose presence filled any room to bursting. She had a massive personality and could be wildly generous, wickedly narcissistic, wonderfully charming, and willfully infuriating all in the space of a single sentence. I adored her, though at times I wanted to run her over with my car. And this is just a tiny taste of the family milieu in which I grew up, a roiling jumble of the wacky, goofy, and kooky, an environment that left me with a high tolerance for eccentricity and quite comfortable with those who trickle just a bit wide – perhaps even more so than with those whose existence stays well within the lines.

With that bit of explanation out of the way, please allow me to introduce to you the woman who cuts my hair, Muntha, who is quite unique among New York City hairdressers. Back when I was healthy and working in the music industry, it was practically de rigueur for me to get my hair cut in one of the many trendy New York City hair salons, which all seemed staffed from stem to stern with the fashionable and fabulous. The women who styled my hair almost always had exotic Eastern European accents and legs that were longer than some of the compound sentences I’ve used in this essay.

I never felt comfortable surrounded by the fashionista hair styling brigades, and back then, when haircut time rolled around I’d often find myself filled with a combination of panic and dread. These feelings were only compounded when I got sick and started getting visibly disabled, as I could imagine myself limping through the salon door and setting off “imperfection” alarms, instantaneously followed by my getting zapped and vaporized by laser beams, just like those unfortunates who reached their 30th birthday in the movie Logan’s Run. The chic would then let out a little “huzzah”, congratulate each other on their wonderfulness, and soon get back to their snipping, teasing, and rinsing.

I found Muntha soon after I became wheelchair bound (I know, not a politically correct term, but I really don’t care). She works in a dowdy little beauty parlor in my neighborhood, which caters mostly to the elderly inhabitants of a 45-year-old condominium complex that is located across the street. Muntha is a Thai woman around 60 years old, a bit pear-shaped, maybe an inch or two over five feet tall, and she usually sports bright red or fuchsia hair. Around her neck she wears a half dozen or so gold plated pendants, all depicting the Buddha in various poses. She always has a huge smile on her face, and we’ve grown to share a genuine affection for each other.

Muntha practices her own peculiar form of evangelical Buddhism. The words “evangelical” and “Buddhism” are not usually used in combination, as practicing Buddhists are almost always profoundly serene souls, more inclined to inspire by example than by word. Not Muntha, though. During my haircuts she chatters endlessly about the Buddha, his teachings, and her fairly simple and slightly skewed take on the tenets of the religion.

She often tells me of her bus trips down to Atlantic City, where she plays the slots and feeds the feral cats that live underneath the boardwalk. I’ve seen her walking around the neighborhood spreading breadcrumbs and birdseed for the city's pigeons and squirrels. A belief in reincarnation is at the core of most forms of Buddhism, and Muntha is intent on insuring that her next life will be much more comfortable than the one she’s now living. Apparently, feeding critters and building up the good karma this engenders is key to her mission.

During Muntha’s haircut soliloquies she sometimes reveals insights she’s gained while meditating. Soon after Michael Jackson died, she quelled my anxieties and fears about how The King of Pop might be faring in the afterlife by spontaneously telling me that Jacko had found a spot in one of the higher levels of Buddhist heaven and was very comfortable indeed, resplendent in golden pajamas and eating all sorts of heavenly biscuits that were free for the taking. What a relief! I thought of querying her on whether the whole pedophilia thing might negatively impact his lot in life next time around, but then thought better of it. Muntha brings simplicity to the complexities of life, why throw a sticky wicket into the works?

And now, dear readers, I will finally reveal to you the how's and why's and where's of my illness, the metaphysical circumstances which not only led to my getting sick, but also to my wife being tasked with being my caregiver. During a recent meditation, Muntha was struck with the revelation that my current unfortunate circumstances were brought about because – brace yourself – in my most recent past life I was a raging alcoholic who was cruel to animals, and my wife Karen was the person who plied me with booze. Thus, our plight in this life is directly attributable to the misdeeds we committed in our previous incarnation, mine for hitting the sauce and then doing the same to our furry friends, and Karen for encouraging the thirst that made me misbehave so horribly. Makes perfect sense, no?

I’m planning on writing Muntha’s revelations up into a scholarly paper and submitting it to one of the prestigious medical journals, as this explanation for my illness makes at least as much sense as anything the neurologists have told me. My only quandary is whether I should share my Nobel Prize with Muntha. I suppose it’s only right that I do. Besides, if I don’t, in the next life I might be a leper.

At the end of every haircut, Muntha gives me a ritualistic Buddhist blessing of her own design, and I give her a tip for herself and also some money for the Buddha, which she donates at the Buddhist temple she attends. We always part by giving each other a sweet little peck on the cheek. Muntha assures me that in my next life I will be rich and strong as an ox, and that Karen will be there once again at my side, this time around living the good life. At least we have something to look forward to.

I hope this meandering tale has been of great value to my Wheelchair Kamikaze brethren. If any of you are right now guzzling malt liquor and getting ready to drop kick the family Pomeranian, for the sake of all that is holy –  stop and take heed ! The life you save may be your next one.

I’d just like to add that I am, in fact, a student of many Eastern philosophical/religious beliefs, and I don’t mean to denigrate in any way the tenets of Buddhist thought and practice. It’s just that Muntha and her antics tickle me to no end, and often provide comic relief just when it’s needed most. Thank heavens for people like Muntha, without whom this earth would be a very dreary place indeed.

Tuesday, April 4, 2017

Ocrevus: Former Genentech Researcher Speaks Out

First, let me preface this by saying that I am not anti-Ocrevus. As I’ve stated on these pages any number of times, it is my firmly held belief that MS patient advocates who are fervently “pro” or “anti“ any MS treatment, especially to the extent that they will disparage other treatment options, are doing a disservice to themselves and anybody who listens to them. The simple fact of the matter is that there is no perfect MS treatment; each and every one has its upsides and downsides and even these are mutable depending on the particulars of any individual patient. I’m all for any treatment that offers MS patients a chance to beat back their illness relatively safely and against supposed treatments that are either completely ineffective, dangerous, or blatant rip-offs.

It's my sincere hope that Ocrevus proves to be safe and even more effective than was shown in its clinical trials. Discretion is the better part of valor, though, and it's prudent to be wary of any drug new to the market. We've seen many drugs pulled after FDA approval because of unforeseen side effects, and have also seen other drugs that in time proved more successful than was initially expected. I've written extensively on the complicated history as well as the promise of Ocrevus, which you can read by (clicking here).

During my 14 years as an MS patient, I’ve learned to be highly critical of any medical news that I read or see in nonmedical newspapers or TV shows. These outlets generally overhype any treatment or medical discovery being discussed, and are often reported by journalists who don’t have the depth of background necessary to fully question the PR put out by the drug and medical device manufacturers. I’ve oftentimes wanted to throw things at my TV set when so-called experts state “facts” that are inaccurate, deceptive, and sometimes just flat out wrong.

The mainstream press has been heralding Ocrevus as a tremendous breakthrough, practically falling all over themselves with hyperbole in describing the revolutionary nature of this drug. The truth of the matter is that the real breakthrough came about a decade ago, when the much older drug Rituxan was first trialed on MS patients. The success of the Rituxan trials on relapsing MS shook the foundations of how multiple sclerosis was viewed by most researchers. Rituxan and Ocrevus both target immune system B cells; previous to the successful Rituxan trials, MS was generally thought to be mediated strictly by immune system T cells.

Ocrevus and Rituxan are made by the same drug company, Genentech. Even though the early-stage Rituxan relapsing MS trials were successful, Genentech chose to develop a newer molecule, now called Ocrevus, and abandon further research on Rituxan for MS. This despite the fact that Rituxan had a long record of relative safety in its original use treating non-Hodgkin’s lymphoma, and trials on Ocrevus would have to start from square one. The reasons behind this decision remain cloudy to this day, and include many that rely on absolutely legitimate scientific rationale. But, prominent among the reasons that must be considered is that Rituxan was due to come off patent in 2015, seriously limiting the profit potential of the drug.

On that note, today I came across a terrific article on the website Health News Review (click here). The piece discusses the pros and cons of the media’s coverage of Ocrevus, exploring issues such as the pharmaceutical company’s PR spin, the drug’s pricing, and the complexities surrounding its similarity to Rituxan. The article features MS neurologist and research scientist Dr. Annette M. Langer-Gould, a former employee of Genentech who worked on the development of Rituxan and Ocrevus. Her perspectives on these two drugs and on the introduction of Ocrevus are quite enlightening. Here’s an excerpt from the article, the whole of which you can and should read by (clicking here):

The Times and STAT’s piece on Ocrevus included statements from sources who hailed the drug approval, calling it a “big deal,” a “significant improvement,” “quite stunning,” and a “major therapeutic advance,” among other accolades.

But those compliments also could be applied to Rituxan, said Langer-Gould, who added that these “major therapeutic advances” actually happened more than a decade ago. But few benefited because Roche delayed Rituxan’s development and then eventually stopped it altogether. It’s misleading to paint Roche and its scientists as heroic now, she said.

“When they stopped Rituxan’s development, it was the main reason I left Genentech,” she said. “I told them ‘you’re just withholding a highly effective treatment for MS patients for another decade’–and that is exactly what happened.”

This article is so good that it speaks for itself, but I would like to add a few thoughts on a factor which hasn’t been much discussed in regards to the launch of Ocrevus. As we all should be aware by now, it’s common practice for drug companies to funnel payments directly to doctors who prescribe their drugs through the use of “consulting fees”, “honoraria, and other vehicles. According to the website Dollars For Docs (click here), Genentech, the maker of Ocrevus, leads the list of companies that engage in these practices, having doled out to doctors an eye-popping $727 million between August 2013 and December 2015. To put this in perspective, the next company on the list is on the hook for $167 million during the same period.

I’ve heard from several of my neurologist contacts that Genentech has been quite copious with its payments to MS doctors in advance of the Ocrevus launch. There is absolutely nothing illegal about this, and there is no saying how much such payments influence any individual doctor, but drug companies wouldn’t engage in these practices if they weren’t seeing a healthy return on investment. MS Neuros are among the largest recipients of pharmaceutical company monies, a fact that must be kept in mind by well-informed patients when discussing potential therapies. The Dollars for Docs website (click here) allows patients to search for any individual physician and see how much that doctor received from pharmaceutical companies during the time period mentioned above. I’d encourage all patients to take advantage of this resource by looking up their own physician to better inform themselves of what could be a motivating factor in their doctor’s decision-making practice.

If your doctor seems to have taken an inordinate amount of money from Big Pharma, don’t be shy about asking them the how’s and why’s of what you’ve learned. It’s your health that’s at stake here, and you have every right to ask as many questions as needed to make informed decisions on your course of treatment. If your doctor refuses to give you those answers, or answers in ways that leave you uncomfortable, I’d say it’s time to find a new doctor. Remember, your doctor works for you, you don’t work for your doctor.

Gee, I may just have lost a few of my neurologist friends…

Thursday, March 30, 2017

Ocrevus: Prominent MS Clinic Issues Cautionary Statement

 

On March 28, 2017, the new MS drug Ocrevus was approved for both relapsing MS and progressive MS, becoming the first drug to achieve FDA approval for the progressive form of the disease.


One of the nation's leading multiple sclerosis clinics, the International Multiple Sclerosis Management Practice (IMSMP), today published a statement on their website regarding Ocrevus and its possible link to cancer and opportunistic infections (click here). Here is the clinic's statement in full:


Ocrelizumab (OCREVUS™), an anti-B cell therapy has been approved by the FDA as of March 28th 2017, for the treatment of Relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). This treatment is highly effective for RRMS, based on the data from the Phase III clinical studies. It is also the first drug approved for use in PPMS. At IMSMP/TISCH we have used Rituximab, a similar anti-B cell treatment, for the past 16 years with great success. It is because of the effectiveness of this therapy (Rituximab) we were able to persuade Medicare to cover the costs of this therapy in New York.

Rituximab, however, is NOT approved by the FDA for use in MS. At our center we use it as an off-label drug. This unfortunately can require several weeks to obtain approval from insurance carriers and often approval may be denied.

Therefore, the approval by the FDA of Ocrelizumab, which should have almost identical anti-B cell activity to Rituximab, appears to be good news for MS patients. However, there are some serious concerns with Ocrelizumab that patients need to be made aware before they consider this therapy. First, in the RRMS trial, there were 9 patients who developed various malignancies within three years of taking Ocrelizumab (4 patients within the first 2 years and 5 patients in the following year). This is alarmingly high considering that these patients were mostly in their third decade of life and had no previous history of cancer. In the trial for PPMS patients, 13 patients developed cancer within the three years of taking Ocrelizumab (11 in the first two years and 2 additional cases in the following year). This means that more than 1 in 50 patients developed cancer within three years of taking Ocrelizumab among the PPMS patients. These risks of malignancy associated with Ocrelizumab are not seen with Rituximab (more than a thousand patients just at our center since 2001 and several hundred thousand worldwide). This risk of cancer with Ocrelizumab is not explained at present and the magnitude of the problem cannot be defined, as the medication has not been given for a period longer than 3 years.

There are also additional concerns with Ocrelizumab, such as the risk of life threatening infections which caused the trials in patients with Rheumatoid arthritis and SLE to be halted in 2010.

Although, it is indeed progress that the first medication for PPMS has been approved, the patients should be fully informed of its’ potential risks. For patients who can obtain Rituximab, it would be safer to continue with this therapy, until with time, we are better able to advise patients about the risks associated with Ocrelizumab.

The IMSMP is the clinic at which I receive my MS care, and I am personally acquainted with all of the medical professionals who work there. I know firsthand that the staff is wholly dedicated to the well-being of MS patients and that they wouldn't issue such a statement without diligent consideration.

Having said that, in the interest of fairness, I reached out to Genentech, the makers of Ocrevus, for a statement on the IMSMPs comments on their drug.  I received the following response from Genentech spokesperson Kimberly Muscara:

The FDA approved Ocrevus as an important new medicine for people with relapsing forms of MS and the first and only treatment for people with primary progressive MS. Genentech encourages healthcare providers to prescribe medicines as per their label and indication, and as a company we cannot comment on off-label usage. As you know, Rituxan is not an FDA approved medicine for multiple sclerosis and has not been rigorously investigated in Phase III clinical trials.  

Additionally, Rituxan and Ocrevus are different molecules in structure and how they interact with the immune system. 

In controlled clinical trials, there was an imbalance in malignancy. An increased risk may exist. The incidence of malignancy was within background rates, and to date continued follow-up in the open-label extension study has not shown increased risk of malignancy with longer time on Ocrevus. Patient safety is very important to us at Genentech and we are committed to conducting long-term post-approval safety studies on Ocrevus.

Muscara also noted that some patients have been on Ocrevus longer than three years, as enrollment in the phase III trial started in 2011 and a number of patients have remained on the drug in extension studies. It should also be noted that Ocrevus is the first anti-B cell therapy approved for use in MS, and that the research that led to the drug has profoundly shifted the thinking of many MS researchers.


In the days since Ocrevus received FDA approval, I've seen and read countless articles and reports in the mainstream media heralding the drug as the latest medical miracle. While Ocrevus may indeed prove to be a major step forward in the treatment of MS, there are legitimate reasons to exercise discretion when considering this new drug. I'd urge all patients to have well-informed conversations with their neurologists before embarking on any new MS treatment. Each MS patient has their own set of priorities and tolerance for risk. What is completely unacceptable for one patient may be well within another's comfort zone.


I wrote a thorough review of the complicated history of Ocrevus (click here), and also conducted a lengthy interview with one of the drug's researchers, Dr. Peter Chin (click here). I hope that patients can glean valuable information from both of these articles.


Remember, the patient-doctor relationship MUST be a partnership, not a dictatorship, especially when it involves a chronic progressive illness such as multiple sclerosis. Arriving at any treatment decision is a multifactorial process, and as patients suffering from a potentially devastating disease we owe it to ourselves to fully participate in all decisions related to our ultimate well-being. Knowledge is power, my friends, use it wisely.

Tuesday, March 28, 2017

Ocrevus Approved by FDA for Relapsing MS and Progressive MS

The new MS drug Ocrevus (generic name ocrelizumab) was approved today for use in patients with both relapsing multiple sclerosis AND progressive multiple sclerosis (click here). Ocrevus is the first drug to receive FDA approval for the treatment of progressive multiple sclerosis, thus representing a milestone in the history of MS treatments.

While this is exciting news for people with progressive MS, it's important that patients keep their expectations reasonable and in line with what was shown in the Ocrevus clinical trials. Ocrevus could very well prove to be the most effective relapsing MS drug available when it hits the market (which should be in about 2 weeks); it will be the only FDA approved MS drug for progressive MS when it hits the shelves. Based on the Ocrevus progressive MS trial results, some patients may expect to see a slowing of their disease progression by about 25%. There is some reason to believe that the drug will work best on patients with enhancing lesions on their MRIs. While this is not nearly the kind of momentous intervention all patients with progressive MS crave, it is a start, and one would expect to see an increase in research for this type of MS as other pharmaceutical companies race to get competing drugs on the market.

I've reposted a commentary on Ocrevus I wrote back in January, after interviewing one of the lead researchers on the drug, Dr. Peter Chin. I would encourage all readers with an interest in Ocrevus to read my commentary (click here) and the interview with Dr. Chin (click here). Both include important info for patients considering taking this drug.

As long-time readers of Wheelchair Kamikaze are undoubtedly aware, I've often been skeptical when it comes to MS drugs. However, I owe it to myself and my readers to go where the science takes me, and there is an ever increasing body of evidence that the newer generation of immunosuppressive MS drugs do positively impact the course of the disease, sometimes dramatically. Many of them do carry with them a list of serious and sometimes fatal potential side effects, and as always a frank discussion with your neurologist is mandatory when considering the risk/reward ratio before beginning any drug treatment. Let's hope that with time Ocrevus shows itself to be even more effective than was demonstrated in its clinical trials, and that its safety profile proves robust.

Wishing all WK readers and those who love them the realization of their fondest dreams…


Ocrevus 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 new MS drug Ocrevus (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)


Ocrevus, a new MS drug which was approved 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 Ocrevus 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. Ocrevus, which will be marketed under the brand name Ocrevus, is a close sibling of the much older drug Rituxan (rituximab), whose mechanism of action Ocrevus closely mirrors. Rituximab, which is manufactured by the same company that makes Ocrevus, 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 Ocrevus rather than rituximab was advanced in studies as an MS therapy are somewhat controversial; complicating matters further are Ocrevus’s failure in trials for use in treating other autoimmune diseases (lupus and rheumatoid arthritis). Therefore, when attempting to make a sober assessment of Ocrevus, 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 Ocrevus 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.

Ocrevus 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 Ocrevus – 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, Ocrevus, 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 Ocrevus 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 Ocrevus and another taking the interferon drug Rebif, and comparisons were made as to the overall effectiveness of Ocrevus versus the interferon drug. The results were very impressive. Compared to the Rebif treated patients, the Ocrevus 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 Ocrevus and Rebif treated patient populations in the relapsing multiple sclerosis trials.

The Ocrevus 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 Ocrevus or a placebo. In other words, twice as many trial subjects received Ocrevus than received placebo. The highlight of this study was that the Ocrevus treated patients experienced a 25% reduction in time to progression when compared to their placebo-controlled counterparts. Specifically, 29.6% of Ocrevus 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. Ocrevus 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 Ocrevus 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 Ocrevus, 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 Ocrevus trials, the PPMS trial did reveal some potentially troubling adverse events. Opportunistic infections (mostly respiratory infections and oral herpes) were more common in Ocrevus than placebo, and the rate of cancer in Ocrevus 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 Ocrevus 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 Ocrevus 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 Ocrevus, since the drug acts in much the same way as rituximab. The Ocrevus 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 Ocrevus 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 Ocrevus, 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 Ocrevus 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 Ocrevus, 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 Ocrevus rather than rituximab as a potential treatment for MS.

The scientific rationale for choosing to proceed with Ocrevus 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 Ocrevus 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 Ocrevus 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 Ocrevus 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 Ocrevus would be split 70–30 in Genentech's favor, accounting for Genentech’s enthusiasm to move ahead with the development of Ocrevus 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 Ocrevus 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 Ocrevus to treat MS were initiated. In addition to the MS trials, Ocrevus 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 Ocrevus 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 Ocrevus 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.

Ocrevus studies in MS were continued because these disastrous infections and patient deaths were not seen in early Ocrevus 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 Ocrevus 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. Ocrevus 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 Ocrevus for relapsing multiple sclerosis and primary progressive multiple sclerosis is certainly warranted, expectations, especially for those with PPMS, should be kept realistic. Ocrevus 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 Ocrevus 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 Ocrevus trials in RA and lupus, and the increased cancer rates seen in the Ocrevus PPMS trials (again, these rates could be aberrations). These factors need not make patients shy away from Ocrevus, 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 Ocrevus 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.

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 hearty looking cancer patients staring joyfully up at claims of the drug’s effectiveness projected on the buildings of a big 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

Ocrevus 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 (tradename Ocrevus) 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.

Ocrevus, 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, which will be called Ocrevus if it gets FDA approval, 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. Ocrevus 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 Ocrevus 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 Ocrevus 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 Ocrevus 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…

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