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…

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…

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…

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…

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…

---------------------------------------------------------------------------------------------------------------

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!

Healthline

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…

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.

----------------------------------------------------------------------------------------------------------------------------------------------------------------------

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.

--------------------------------------------------------------------------------------------------------------------------------------------------------------------

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…