Wednesday, May 24, 2017

The Starvation Chronicles: That's A Wrap!

Yippee, I’ve reached the end of the road of my Fasting Mimicking Diet (FMD). I’ve successfully made it through five days of dramatically reduced caloric intake, and I’m no worse for the wear. In fact, I feel pretty darn good! Of course, it’s still way too early to judge whether the FMD will be successful in positively bending the arc of my Creeping Paralysis. I can at least report that I’ve lost 5 pounds since I started the diet last Friday.

I’d say the FMD regimen was much easier to get through than I anticipated. Day one, during which I consumed 1100 calories, was no problem at all. My caloric intake was reduced to 800 calories on day two, a level that was maintained throughout the duration of the diet. I faced the most difficulty on day three, but even that wasn’t all that terrible, just some pangs of hunger. At no point did I experienced excessive weakness or dizziness, but then again, it’s not as if I’m a whirling dervish of physical activity. I’m sure the diet would be harder on somebody who was more mobile and engaged in a physically active life.

That said, kudos to the company that markets the diet, Prolon. Although the prepackaged foods aren’t cheap (I paid $220 for my five-day kit), and I’m sure the company makes a nifty profit on the deal, the supplied meals did a good job of keeping me from being famished despite the severely reduced daily calorie load. The soups, nutritional bars, crackers, and olives provided in the kit have certainly done a good job of keeping me well-nourished even as they slashed my caloric intake dramatically.

I’m scheduled to have a phone consult with my naturopath tomorrow, and I expect that I will repeat this exercise in dining austerity again next month, and probably the month after that. As I’ve mentioned before in these Chronicles, my naturopath – who works in my MS clinic and specializes in treating MS with natural remedies – has reported very good results in one of the first few patients who tried this diet. Of course, MS is a tricky beast and it’s nearly impossible to pin down just why any individual patient experiences upswings are downswings in their disease state, but sound scientific research does suggest that a starvation diet can trigger beneficial changes in body chemistry and kickstart cell regeneration.

At the very least, committing to the diet and seeing it through has provided me with a perceived mechanism to strike back at the disease, and that alone has given me an emotional lift. I find my mood darkens when I’m stuck in the doldrums between treatment options, and especially when it seems that those options may be running out. By hook or by crook, and with the help of a neurologist who is open-minded and not afraid to experiment, I’ve managed to occupy most of the 14 years I’ve spent dealing with this crap with active efforts to fight back. Unfortunately, none of these attempts to thwart the disease have proven to be of any lasting value, but maybe, just maybe, one of these days my efforts will strike paydirt.

A huge thanks to all the good folks who’ve left comments and sent notes of encouragement and advice these past five days. Despite my propensity for verbosity, I really don’t have the words to express my appreciation to each and every one of the readers who have been my virtual copilots during this flight of fancy starvation.

Finally, since I’m supposed to ease back into a regular diet starting tomorrow by sticking with fruits, vegetables, breads, and pasta, I’m thinking that a simple omelette, some fruit salad, and a bialy with a touch of cream cheese will make for a nice digestible lunch. Later, perhaps some linguine with white clam sauce for dinner. Yum!

Okay, signing off – 5 pounds lighter, with an empty stomach and a heart full of hope…

Tuesday, May 23, 2017

The Starvation Chronicles: Day Four

A Basket of Bialys
Well, that’s four down, one to go.

I’ve finished the fourth day of my five day Fasting Mimicking Diet, and I’m happy to report that today was relatively easy. Much better than yesterday, when hunger pangs and a lack of olives on the menu had me out of sorts. Today I’m in sorts. And shorts; it’s hot in my apartment.

According to the company that markets this diet, Prolon, the body adjusts to the program’s reduced caloric intake after a few days. As is evidenced by how I feel today, I suppose they know what they’re talking about – despite their sadistically depriving me of olives on day three.

Speaking of olives, today was chock full of them. I got to scarf down a whopping 10 olives today. For those who are undoubtedly wondering, the olives supplied in this diet are of the green variety. I typically favor black olives, Kalamata olives to be exact. But the greenies will do in a pinch, and in a martini. Which I can no longer drink because of my MS, as alcohol consumption makes my nervous system go kablooey. Cruel, dastardly disease. If I were to wake up magically cured tomorrow, I’d go on a bender that would put even Hemingway to shame.

After yesterday’s Starvation Chronicles diatribe about olives, I received some very interesting comments and emails. Much to my surprise, it seems that some people hate olives. I can’t even imagine. Have the olive haters ever had really good salty briny delectable fresh olives, not the horrible rubbery bland things that come out of a can? And do olive haters also hate capers, which are kind of like tiny olives supersaturated with flavor? I would think it would be impossible to hate olives and like capers, or vice versa. Please, report back, inquiring minds want to know.

Okay, now that I’m sitting here writing about olives and capers, I’m getting hungry. Suddenly visions of a toasted garlic and onion bagel with cream cheese, smoked salmon, and capers is crowding out all other thoughts from my mind. Must. Stay. Focused.

One of the things I missed most about New York when I lived in Florida was the bagels. Well, that’s not exactly true, there were a whole lot of things I found sorely lacking in Florida, including brain cells, but I won’t go into details for fear of insulting any Floridians reading these pages. But back to the bagels. They do have bagel shops in Florida, but whatever the things are that those shops sell, they’re not bagels. Good God, they put things like strawberries and cinnamon and raisins and cheddar cheese in their “bagels”! Ugh! Blasphemy!

I’ve got news for you, just because a bread product is round with a hole in the middle does not make it a bagel. If it contains any sorts of fruits, berries, cinnamon, peppers, or cheese within the dough itself it’s a Danish or some other sort of pastry. No self-respecting bagel would put up with such adornments; an honest to goodness bagel is topped strictly with the following, either individually or in combination: chopped onion, garlic, salt, sesame seeds, or poppy seeds. I usually go for an “everything” bagel, which includes all of the above. Also, pumpernickel bagels are allowed, and even preferred by some native New Yorkers.

Now, what really sends me into writhing wriggling culinary ecstasy is a good bialy (click here). For those sadly unaware that such things exist, bialys are a close cousin to the bagel and are a foodstuff I’ve never encountered outside of New York City. Whereas a bagel is boiled and then baked, a bialy is just baked. In place of the bagel’s hole there is a deep depression in the center of a bialy, a vessel filled with bits of garlic and onion, which are mixed in with the dough as well. The damned things are indescribably delicious, positively bursting with flavor, especially when toasted and adorned with just a schmear of cream cheese. There is no more perfect combination in the culinary universe. None.

When I was a kid you could get a bialy on practically every street in New York City, but these days, as the city has changed and mutated into something I sometimes barely recognize, the bialy is becoming an endangered species. My heart bleeds for those untold millions who have never savored the pleasures of the bialy, and tragically, most likely never will.

All right, now that I’ve got myself all worked up, I’d better proceed with just a quick rundown of my food intake for today. Lunch was a nutrition bar, vegetable soup, and olives. Dinner was quinoa minestrone soup, olives, and a Choco crisp nutrition bar for dessert. The Choco crisp bar is just a little thing, and for whatever reason tonight’s was much more chocolatey than the two I’ve previously eaten during this diet. Perhaps the Prolon people were trying to make up for yesterday’s lack of olives.

Unfortunately, tomorrow, the last day of the diet, also includes no olives. I can now see the light at the end of the tunnel, though, so I’ll soldier on, despite the dearth of those luscious green orbs.

As for Wednesday, well, I’m supposed to transition slowly back to a regular diet, but something tells me there just might be a bialy in the offing…

Geez, when wheeled up to the computer I wondered what the hell I was going to write about. I sure can write a lot about nothing. Sorry about that…

Monday, May 22, 2017

The Starvation Chronicles: Day Three

I’ve now finished day three of my five day Fasting Mimicking Diet (FMD), during which my caloric intake has been drastically reduced. The how's and why's of the diet are explained in full in my first Starvation Chronicles post (click here).

Today turned out to be a “no olives for me” day. Suffice it to say I was heartbroken, as the heretofore steady supply of olives on the menu has been my favorite part of the diet. On the spectrum of heartbreaks I have experienced in my lifetime, I will admit that this one lands near the bottom of the heap. Still, right about now I would kill for an olive.

I found day three of the FMD to be the most difficult day yet. I was dealing with pangs of hunger most of the day, but nothing I couldn’t handle. Yes, I am a manly man. Of course, some olives would have been nice. Do the originators of this damned diet have even one iota of understanding about just how important olives can be to a person, just what a lifeline they can represent to the desperate? Apparently not. I feel for them; those sad, misguided beings.

Instead of olives, I was treated to some kale crackers, which, though not bad, are NO SUBSTITUTE FOR OLIVES! Would it have been so hard for the diabolical diet designing geniuses who concocted this plan to have included even one measly olive to help get me over this hump day? Thoughtless, heartless, olive depriving bastards. A pox on them and all their ancestors. I don't feel for them, I don't! There, I said it.

In addition to the kale crackers and lack of olives, today I consumed tomato soup (IMO, the best of the soups contained in the kit) along with the aforementioned crackers for lunch, and minestrone soup (not bad, but tastes more like a barley) and a nutritional bar for dinner. All through the day I drank a proprietary glycerol based energy drink, which, sadly, contained no olives. I also had the prescribed 2 cups of herbal tea. Again, no olives. If there is one hard fact this diet has driven home, it’s that olives should be a staple of every meal, snack, and drink. And, yes, I’m talking martinis. Very dirty martinis.

Tonight, instead of sugar plums I’m sure I will have visions of olives dancing in my head. Might I be getting a bit olive obsessed? But who among you can blame me, are not olives the very stuff of life itself? Water, air, soil, sunshine and olives, the scientifically acknowledged prerequisites for the development of life, on this world or any other. Why do you think, eons ago, the first crude single celled organisms started to divide and become ever more complex creatures? Surely, only in the hope that one day they might consume an olive.

Checking tomorrow’s menu, I’m over the moon to discover it includes two servings of olives. I tremble in anticipation…

Sunday, May 21, 2017

The Starvation Chronicles: Day Two

Okay, it’s about time to cross day two off of my five day Fasting Mimicking Diet (FMD) calendar. Today my caloric intake was reduced from 1100 calories on day one to 800 calories, the level which will be maintained for the remainder of the diet.

For those joining this party late, you can read more details about the diet and my reasons for doing it in my introductory Starvation Chronicles post (click here). Here’s a quick Cliff Notes version (do they still make Cliff Notes?): I’m engaged in a five-day restricted calorie diet that is supposed to mimic starvation, in order to change body chemistry and kickstart my body’s natural stem cells to help regenerate damaged tissues. The diet uses products designed and marketed by a company called Prolon (click here) which has published studies (click here) that show the Fasting Mimicking Diet reduces autoimmunity and encourages cell regeneration. The diet is also used for help cancer patients protect against the side effects of chemotherapy, and many people use it in the hopes of increasing longevity.

Quite a few folks have asked if this is a ketosis diet, and after doing some investigation I can tell you that it is not. Without getting too deep in the weeds, a ketosis diet is very high in fats, and includes lots of meats and dairy products, with the intent of inducing the body into a ketogenic state in which body fats are broken down to fuel metabolic functions. The FMD I am doing uses only plant-based foods, is limited to five days, and does not induce ketosis.

My second day on the diet was a little bit more difficult than the first, which I suppose is only to be expected since my caloric intake was slashed by nearly 30% from yesterday’s already reduced intake. I was quite peckish between meals, but I’m feeling pretty good now. Since it’s good practice to live in the moment, I guess everything is just hunky-dory.

Really whets the appetite, no?
As I mentioned in yesterday’s post, I typically eat two meals a day because of my naturally nocturnal predilections, which generally preclude breakfast. Today’s first meal consisted of mushroom soup, a nut based nourishment bar, and six olives. This was accompanied by spearmint lemon tea. In addition, on day two the diet adds an energy drink, mixed at home, made of water, plant derived glycerol, and some hibiscus tea for flavor. This energy drink will be a staple for the rest of the diet. At the left is a photo of meal one in the packaging provided by Prolon (excluding the tea and energy drink). The mushroom soup was quite good, the nourishment bar palatable, and olives are a favorite of mine, so no complaints there.

I can't believe I ate the whole thing…
My second meal, pictured in all its glory at the right, consisted of a minestrone and quinoa blend soup, some more olives, and a small “choco crisp” nourishment bar, washed down with spearmint tea and more of the energy drink. As you can see by the photo, it was a sumptuous seven course meal, if you count each olive as a course. As I mentioned above, I was feeling hungry before eating meal two, but, surprisingly, it proved to be a satisfying nose bag (a little equine reference in honor of today’s Preakness Stakes). Maybe the people who designed this diet know something.

That’s it for now, but watch this space for another scintillating report on day three of The Starvation Chronicles. This is your intrepid Fasting Kamikaze, signing off…

Saturday, May 20, 2017

The Starvation Chronicles: Day One

As I wrote yesterday (click here), from now through Tuesday I’ll be subjecting myself to a Fasting Mimicking Diet (FMD), in the hopes that severely reducing my caloric intake for five days will force changes in my body chemistry and cellular activity, with the goal of reducing autoimmunity and jumpstarting my natural stem cells to regenerate damaged tissues. The diet is also used by some in the hopes of increasing longevity, but that’s not my immediate goal. As far as I’m concerned, life is all about quality, not quantity.

I’m happy to report that day one is in the book. Or, in this case, on the blog. And so far so good, I must say that today’s 1100 calorie intake was easy peasy lemon squeezy (a term that is used all too rarely in medical literature). As I write this, I’m not feeling hungry at all.

I’m using prepackaged foods provided by a company called Prolon (click here). Though the company recommends a daily menu of suggested meals using the items provided for each day, they do state that meals can be combined any which way a person chooses. Which is great, as I am an avowed night owl – I’m writing this at 2:30 AM – and due to of my odd schedule I typically only eat two meals a day, skipping breakfast because I don’t do mornings. As an old jazz man once said, I’d prefer not to know that there are two 10 o’clocks in one day.

So, I combined the suggested breakfast and lunch items into one “big” midday meal. It consisted of a tomato soup that was shockingly yummy, a nutritional bar made up of a variety of nuts, coconut, and honey that was not half bad, some crackers made of kale, seeds, and cumin that had a nice little kick to them, and five green olives. I love olives. My lunchtime beverage was spearmint-lemon herbal tea, and some water. The diet allows you to drink as much water as you want.

Tonight’s dinner was minestrone soup, which actually tasted more like a barley soup. Since I was expecting minestrone, at first the taste was a little offputting, but once I decided I was actually eating barley soup it was much more palatable. We do indeed create our own realities. Along with the soup I had another one of those nutritional bars, and for dessert a different, smaller nutritional bar that contained some cocoa. Spearmint tea was the beverage of choice.

All in all, a very pleasant start to this starvation diet journey. Tomorrow I drop down to the 800 calorie mark, which will be maintained for the remaining four days. According to Prolon, the second day is usually the hardest, as the body then adjusts to the new diet regimen. Call me crazy, or maybe even a nut job, but I feel like today’s easy start has removed some of the pressure I was feeling about the diet. Who knows what the next few days will bring?

Oh, a tremendous thank you to everybody who responded to yesterday’s announcement of my impending diet with comments (both here and on Facebook) and notes of encouragement and advice. I wish I had the time and energy to answer each individually, but please know that they have all been read and greatly appreciated.

Watch this space for tomorrow’s 800 calorie update…

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I'm happy to announce that Healthline.com has named Wheelchair Kamikaze one of 2017's best MS blogs. A big thank you to Meagan Jones and the rest of the Healthline team. I urge all WK readers to head on over to Healthline's 2017 list (click here) and check out the other chosen blogs. There's a lot of really good stuff there!

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Friday, May 19, 2017

The Starvation Chronicles: Prologue

Starting Friday, May 19, I’ll be subjecting myself to a five day starvation diet, in an attempt to beat back the disease that is slowly but surely consuming me. In effect, I’ll be reducing my consumption of food to near starvation levels in order to stop my illness’s consumption of my bodily functions. Yes, I’ll be crossing the junction of function consumption.

As I’ve talked about before on these pages, I work closely with a naturopathic doctor who is employed at my MS clinic. She's is one of the sharpest people I’ve ever met, and is a heckuva nice person to boot.

She recently approached me with a rather radical idea, but one based on sound scientific research and her own clinical experiences – asking if I would be willing to try a Fasting Mimicking Diet (FMD), in which caloric intake is dramatically reduced for five days. I was already acquainted with research which demonstrated that such a diet had increased the lifespans of laboratory animals as much as 25%, and that it had the potential to positively impact chronic illnesses and even cancers as well. When my naturopath told me that she had seen some rather startling results in one of the first few MS patients she had convinced to try this diet, I was all in.

The diet is designed and marketed by a company called Prolon (click here), which supplies five days’ worth of plant-based foods that provide nourishment while tricking the body into thinking that no food is being consumed. Thus, the name Fasting Mimicking Diet. During the diet, food consumption is limited to specially formulated vegetable broths, nutritional bars, herbal teas, and snacks (such as a few olives). Each day’s “meals” come in their own individual box, filled with packets of that day's allotted foodstuffs.

The first day of the diet caloric intake is reduced to 1100 calories, and during the remaining four days this is further reduced to 800 calories per day. On day six regular foods are gradually reintroduced, starting with fruits, rice, pasta and other easy to digest items. For the rest of the month a regular diet can be resumed. Dr. Bates (my naturopath) would prefer me to try to stick as much as possible to a Mediterranean diet (low-fat, with lots of fish and veggies).

In scientific studies, the FMD diet has been shown to promote and maintain healthy levels of a variety of inflammatory and regenerative markers. In an animal model of MS, FMD reduced inflammation, suppressed autoimmunity, and promoted the regeneration of damaged nervous system tissues (click here). The diet appears to stimulate the body’s own stem cells. While all this sounds terrific, what really sold me was Dr. Bates telling me that she had seen verifiable improvements in the mobility of one of the first patients who had agreed to give the diet a go.

I figure that if worst comes to worst and I don’t get any disease benefit from this experiment, I'll lose a few pounds (I’m developing the physique of an elephant seal) and the diet will allow my body to detox. In addition, it’ll be kind of fun to take on the challenge (he says with a full belly). Besides, this will give me the perfect excuse to lay around and binge watch some cheesy 60s and 70s horror flicks (queue up “Gore Gore Girls”). For the sake of my wife, I think I’ll steer clear of any films having to do with cannibalism. I'd hate to have Karen wake up to find that she's missing a finger or two. I wonder how many calories there are in a finger? Gives a whole new meaning to the phrase "finger food".

So, I expect that over the next five days I just might experience a few pangs of hunger here and there. I might even get Jewish VD (Veak and Dizzy, said with a Yiddish accent). I’ll report back at the end of every day to tell you guys how it’s going, as long as I have the strength to guide my wheelchair to the computer and put on my voice recognition headset. Of course, if I do experience any benefit, it won’t be for several months, but I’ll keep y’all apprised of all such developments (hey, I managed to affect Yiddish and southern accents all in the space of four sentences!). I plan on doing the diet for at least two or three consecutive months.

Wish me luck…

Monday, May 15, 2017

Ocrevus: Dialogue Between Two Neurologists

Yes, folks, another post on Ocrevus. Hope I’m not beating a dead horse here, but I feel this is a very important subject given the amount of hyperbolic press coverage this newly FDA approved drug has received. The Ocrevus picture is a complicated one, especially for patients with progressive MS. It’s now the only approved drug for this form of the disease, which is a good thing. Unfortunately, there are still questions regarding the efficacy and risk associated with Ocrevus when used on the progressive MS population. Much of these questions can be accounted for by the drugs newness to the market because its risk/reward profile in a real-world setting has not yet been established. While this is true of all new drugs, the fact that the progressive MS population is clamoring for treatment options puts these uncertainties under a bright spotlight.

I first read the below email exchange between two MS neurologists about a week ago on the invaluable MS Research Blog (click here), which is written by the MS neurologists and researchers at the Barts and London School of Medicine in Great Britain. The neurologist who posted this exchange is Dr. Giovanni Giovanonni, who was one of the co-authors of the Ocrevus progressive MS trial research paper. The other neuro involved in the exchange preferred to keep their anonymity. I posted a comment to Dr. Giovanni asking if I could repost this in Wheelchair Kamikaze to give it further exposure, and he agreed. A big thank you to him.

Here then, is the dialogue on the use of Ocrevus in PPMS between Dr. Giovanonni and his anonymous colleague. Just to be clear, in all the verbiage between the linebreaks "I" refers to Dr. Giovanonni, and "his/her" refers to the other neurologist. NEJM is the New England Journal Of Medicine, in which the Ocrevus PPMS trial results were published. I’ll add my two cents at the end of this post.

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I have started-up another email exchange with a colleague about the ORATORIO (ocrelizumab in PPMS) study. I have asked him/her if we could have this debate in the open on the blog, but he/she has asked to remain anonymous.

When I respond to MS-related questions that may be of interest to the broader community I prefer to answer them in the open, which is why I have redacted the discussion and posted it below:

The following are his/her primary questions:

'You were a co-author on the ocrelizumab in PPMS NEJM manuscript, which didn’t really address the issue of age/inflammatory activity as markers for treatment response. Both the rituximab data in OLYMPUS and the Gadolinium data in the supplement of the NEJM article indicate that the population that benefits is the young patient with inflammatory activity. B cell depletion is not benign, especially in the older population, and the ocrelizumab manuscript infers that all PPMS patients should be treated with ocrelizumab. Are you really treating all of your PPMS patients with B cell depletion, and, if not, why didn’t you push for more discussion about this issue in the NEJM paper?'

My response:

We tried to restrict the trial population as much as possible to mirror that of the responder subgroup in OLYMPUS (rituximab in PPMS) study. Please note the following specific inclusion criteria for the trial:

Age cut-off of 55 years of age

Disease duration of symptoms of less than 15 years in patients with an EDSS score of more than 5.0 at screening or less than 10 years in patients with an EDSS score of 5.0 or less at screening

Documented history or the presence at screening of an elevated IgG index or at least one IgG oligoclonal band detected in the cerebrospinal fluid

​The presence of absence of Gd-enhancing lesions was not part of the inclusion criteria and hence should not be used to select patients for ocrelizumab treatment in the real-life situation. The detection of Gd-enhancing lesions also depends on the frequency of imaging. If you are going to select patients for treatment I suggest you use the the three inclusion criteria above as your guide. I predict that these will probably exclude 70% of a typical PPMS clinic population.

Please note that the trial population in the ORATORIO study was not typical of other PPMS trials; the population was younger, less disabled, had higher proportion with Gd-enhancing lesions at baseline and higher on study number of relapse​s. As I have said before there were strong trends in both the Gd+ve and Gd-ve cohorts, therefore, we shouldn't limit treatment to patients with Gd-enhancing lesions only. If we did this we would be denying many patients access to an effective treatment.

I personally don't buy into MS being 2 or 3 diseases. MS is one disease and PPMS is simply more advanced MS; if patients are active they should be offered treatment regardless of their presenting clinical phenotype.


Regarding my own practice. We can't use rituximab in the UK; the NHS won't pay for it and are unlikely to pay for ocrelizumab either. NICE will assess the cost-effectiveness of ocrelizumab based on its price for relapsing-forms of MS and in PPMS ocrelizumab will be compared to best-supportive care. The latter means ocrelizumab is unlikely to pass the NICE cost-effectiveness threshold. I am hoping that Roche, who will be marketing ocrelizumab in Europe, approach NICE and the NHS to discuss differential pricing and to offer ocrelizumab at a cheaper price for patients with PPMS. Differential pricing is a 'hot potatoe' and I am not sure the NHS is ready for it; but I live in hope for my patients.

Please note ocrelizumab has yet to be licensed in Europe and we can't assume its license will be the same as the US.

At present we offer our patients with active PPMS off-label cladribine, a relatively cheap B-cell depleting agent. Like all DMTs it is a choice and not all patients take-up the offer. I am also aware that in the US a large number of neurologists are still using low-dose methotrexate in PPMS.

I am not sure we have enough data on B-cell depletion in PPMS to make a call on whether it is benign or non-benign. Hopefully, good quality safety data will emerge from post-marketing surveillance studies. I suspect as with all immunosuppressive therapies it won't be benign. I would recommend telling all your patients about infusion reactions, the herpetic infection risk, the possible malignancy risk and the likelihood that in time they may develop hypogammaglobulinaemia and need Ig-replacement therapy. Please note we have a large amount of clinical experience in children with agammaglobulineamia and these kids do well long-term, as long as we keep the Ig levels normal.

I am not sure you are correct in suggesting that we are recommending ocrelizumab for all-comers. The trial population defines the group we are advocating its use in. I am surprised the FDA did not include the CSF findings in the label. If I was a regulator I would state that CSF-ve PPMS should not be treated with ocrelizumab.


Regarding discussion in the NEJM paper; the editors of the NEJM essentially cull all speculative discussion and limit the discussion to issues in the trial. NEJM editors are renowned for rewriting submitted papers to keep them consistent for style. The NEJM article is not the forum for the kind of discussion you want to have. I suggest we have this discussion on the blog.

His/her response:

'Thanks for your prompt and thoughtful response. It was very helpful. When do you think we’ll be able to see the age cutoffs for the study? Given that the average age for the study was 45 (and for OLYMPUS it was much higher—about 50), there should be enough patients who entered the study between 50 and 55, to know whether the relatively small treatment effect in the whole group was made up primarily of those under 50. I would certainly like for my older PPMS patients to avoid the potential adverse effects of this drug if there is no clear benefit for this group.

I agree with you about MS being one disease( except possibly for unusual outliers, like the NMO story). So, wouldn’t you expect B cell depletion to work for the younger, more active SPMS patients, too?'

My second response:


There are numerous post-hoc subgroup analyses that are ongoing. I will ask the trial team to include your question about age on the list.


Regarding SPMS; yes, I would expect B cell depletion to work for SPMS as well. I wouldn't limit it to young, or early, SPMS either. Based on our length-dependent axonopathy hypothesis I would even expect patients in wheelchairs to benefit, however, the benefit will be limited to arm and bulbar function. The latter is why we are lobbying Roche to do a trial of ocrelizumab in more advanced MS, with the primary outcome being upper limb function.

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Just a few points that grabbed my attention when I first read this exchange: first, I was surprised to read that the Ocrevus PPMS trial was specifically designed to test the drug on patients identified as likely responders, based on the “failed” rituximab PPMS trials, which were held about 10 years ago. Even though that trial had been officially deemed unsuccessful, a subset of patients were identified who did respond well to the drug (younger, less disabled, shorter disease duration). Although I highly suspected that the Ocrevus trial was intentionally frontloaded with likely responders, I’d never before come cross info confirming my suspicions. I’m not aware of any other study that has been designed in such a fashion. I believe most drug trials try to mirror the general demographic makeup of the patient population in question, although almost all MS trials exclude patients with higher degrees of disability. Due to this trial design, Dr. Giovanonni  states that he’s surprised the FDA didn’t put some sort of prescribing restrictions on the Ocrevus label.

I also found it quite interesting that Dr. Giovanonni states that the prescribing guidelines for the drug, if based on the Ocrevus trial design, would generally exclude 70% of the PPMS population. This in the face of the FDA giving a blanket approval for Ocrevus to treat PPMS with no restrictions whatsoever. While I fully understand why many PPMS patients are anxiously awaiting being offered the drug, I fear that many may have unreasonably high expectations based on the breathless press coverage that greeted the Ocrevus FDA approval. Of course, there is the “any port in a storm” factor. With the dearth of other available treatment options, why not give the drug a shot, especially if a patient finds themselves being ravaged by the disease? It is, of course, up to each patient to decide how aggressively they want to treat their illness, and their tolerance for risk.

Dr. Giovanonni also makes mention of hypogammaglobulinaemia, a general term for a patient having an insufficient number of antibodies in their bloodstream to fend off infections. While it makes sense that Ocrevus could cause this condition, since the drug wipes out a patient’s B cell population and B cells produce antibodies, I hadn’t heard of this being of much concern. Rituxan (rituximab) also obliterates most B cells, and that drug has been used off label to treat MS and other autoimmune diseases for years, to the best of my knowledge without necessitating supplementation of patients’ antibodies via the use of IVIG infusions. PLEASE NOTE: Dr. G has explained, in the comments section below, that long term Rituximab therapy does indeed cause this antibody deficiency. I stand corrected. Thank you, Dr. Giovannoni. 

Lastly, I found it intriguing that this drug might not be made available to PPMS patients in Great Britain, based on its cost-effectiveness versus supportive care. This means that in the eyes of the NHS, Great Britain’s national healthcare system, the relative effectiveness (or lack thereof) of Ocrevus in treating PPMS may not warrant its approval for use, simply because supportive care is less expensive and the impact of Ocrevus on the disease is minimal enough to disqualify it based on the drug’s high price tag.

Having said that, let's not forget that slowing the progression of disease, even if only for a portion of the PPMS population, is no small feat. In addition, the beneficial effects of Ocrevus may accumulate over time, a data point that wouldn't have been caught during the short two-year clinical trial window. Any slowdown in the progression of disability provides patients valuable time during which more effective treatments work their way through the pipeline. While I have concerns about the drug itself, my primary beef is with the way the drug has been portrayed in the media, with eye-popping headlines and hyperbolic coverage by reporters without the depth or breath of experience to look much past the pharmaceutical company press releases. Let's hope that all MS neuros do their due diligence regarding Ocrevus, and keep their patients well-informed about reasonable expectations of benefit and also the downside potential of the drug. It's always important to keep in mind that doing nothing has tremendous proven downside potential, as well.

In short, while Ocrevus does appear to be quite potent in treating relapsing MS, those with progressive MS should likely keep their expectations in line with what was seen in the PPMS trial results. The drug displayed a 25% slowdown in the rate of disease progression, which although not insignificant is certainly not the miracle that the media has made it out to be. Patients shouldn’t expect Ocrevus to reverse their symptoms, or even stop the progression of their disease. Make no mistake, slowing down progression is a very good thing, but according to the above dialogue many PPMS patients may not even see that by way of benefit. Of course, there is always the possibility that the drug proves to be more effective in clinical use than was seen in the phase 3 trials, which is something we have seen with several other drugs.

All that being said, please allow me this one brief little editorial interlude:

HEY, ALL YOU MS NEUROLOGISTS  OUT THERE! STOP STUFFING YOUR POCKETS WITH PHARMACEUTICAL COMPANY MONEY AND START LOOKING FOR THE ACTUAL CAUSE OF THIS DAMNED DISEASE! ENOUGH WITH THE “TREATMENTS” WITH POTENTIALLY HORRIFIC SIDE EFFECTS! WE WANT CURES, DAMMIT! AND UNLESS YOU FOLKS STOP LOOKING FOR NEWER AND FANCIER WAYS OF TINKERING WITH THE HUMAN IMMUNE SYSTEM AND START LOOKING FOR THE ACTUAL REASON WHY THE MULTIPLE SCLEROSIS IMMUNE SYSTEM GOES BONKERS, WE WILL NEVER, EVER, GET A CURE! AN IMMUNE SYSTEM ATTACKING ITS OWN BODY IS A SYMPTOM, NOT A CAUSE! WE PATIENTS ARE SICK AND TIRED OF BEING SICK AND TIRED, AND IF WE WEREN’T SO SICK AND TIRED WE MIGHT AT THIS VERY MOMENT BE FORMING LYNCH MOBS! SO GET WITH IT, OR ELSE!!! WHEELCHAIRS CAN BE USED AS DEADLY WEAPONS!!! AND DON'T EVEN THINK OF ASKING ME HOW I KNOW THAT!!!

Okay, feeling a bit calmer now… And, yes, I realize there are MS researchers and neuros who aren’t inflating their incomes with legal pharmaceutical company bribery while their patients clamor for truly momentous breakthroughs. Those folks should be applauded, along with those pursuing creative approaches for tackling multiple sclerosis. As for the others, well, I still want/need their help, so I better keep my mouth shut…

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.