Tisch Center MS Stem Cell Trial: Interview with Dr. Saud Sadiq, Director and Lead Research Scientist (Part Two)

Dr. Sadiq and research staff at the Tisch Center

The Tisch MS Research Center of New York (click here) will soon begin its first-ever FDA approved Phase 2 regenerative stem cell study for multiple sclerosis. Last week, I published the first part of my interview with Dr. Saud Sadiq, the Director and Lead Research Scientist of The Center, which discussed  the Phase 1 study and its results (click here). As promised, here is the second part of our discussion, which focuses on the upcoming Phase 2 study, the Tisch Center's new stem cell laboratories, how stem cells might help repair damaged nervous system tissues, and some of the other multiple sclerosis research projects being conducted by Tisch Center researchers and scientists.
This interview has been lightly edited for readability, and I’ve added some “WK Notes,” which attempt to translate overly complicated medical jargon into plain English.

WK: The Tisch center is now preparing to embark on Phase 2 of your MS stem cell trial. When do you expect this next phase of the study to get started?

Dr. Sadiq: After the  Phase 1 study ended, we made a commitment at The Tisch Center that we needed to make our stem cell laboratories absolutely state-of-the-art. We’ve invested heavily in building a new stem cell lab, which is being completed now. Everything’s automated, it’s a next generation stem cell facility that will be functional and certified in about a month and a half. Then we will be prepared to start the Phase 2 study. We do still need some additional funding for Phase 2. We are applying to the National Multiple Sclerosis Society for a grant. Though they didn’t support Phase 1, given the impressive results of that trial we are hopeful that they will support us as we go forward. We also expect private contributions to help fund Phase 2, as these have always been the lifeblood of the foundation.

WK: How many patients will be involved in the Phase 2 study?

Dr. Sadiq: There will be 50 patients involved. It will be a double-blinded crossover study specifically designed to establish the effectiveness of the neural progenitor stem cells we've developed in our laboratories. So it has an entirely different aim than the Phase 1 sstudy, which was intended primarily to determine the safety and tolerability of our stem cell procedures. We are going to give Phase 2 study participants six treatments, one every two months. Therefore there will be more treatments given in greater frequency than in the Phase 1 study.

WK: So, with 50 patients, 25 will be getting actual stem cells, and 25 will be getting placebo treatments?

Dr. Sadiq: Yes, in the first year 25 subjects will get treatment and 25 will get placebo, and in the second year the ones who got placebo will get treatment and vice versa.

WK: What will the patient population look like for this Phase 2 trial?

Dr. Sadiq: The patients for this trial will have to meet much tighter inclusion criteria then the patients in Phase 1. They all must be diagnosed with SPMS or PPMS. They have to be ambulatory, so they’ll all have EDSS scores between 3 and 6.5. The FDA is requiring that we have an equal distribution of the EDSS scores. So there will be equal numbers of patients distributed between all the points along the EDSS scale. The other limitation is that all patients will need to have had the disease for 15 years or less.

WK: Will the study participants continue with their disease modifying drugs?

Dr. Sadiq: Yes, but they can’t have switched medications within six months from the start of the trial.

WK: Once they are in the trial they’ll have to remain on the same DMD for the duration of the study?

Dr. Sadiq: Yes.

WK: What will be the total duration of this trial?

Dr. Sadiq: There will be two years of study and placebo, and one year of follow-up. So a total of three years.

WK: Just to be clear, in the third year none of the patients will be receiving stem cells?

Dr. Sadiq: That’s correct, in the third year there will be no stem cells and no placebos. After the second year, all patients will have received six treatments. The patients who received stem cells in the first year will have placebo in the second year, and the patients who received placebo in the first year will receive stem cells in the second. The third year will be for observation of all patients.

WK: For all the folks out there with RRMS, if the Phase 2 trial proves successful then the stem cell protocol developed at Tisch could be applied to them as well, correct?

Dr. Sadiq: For patients with relapsing-remitting disease who experience a relapse that results in damage from which they don’t recover, stem cells could be introduced in an attempt to repair that damage. That would be the dream scenario, and it could render disability resulting from MS a thing of the past. But at this point were getting ahead of ourselves…

WK: As we move forward into a world in which stem cell treatments for MS become a standard of care, would you anticipate that patients will need continued and repeated stem cell treatments to maintain or advance whatever benefits they realize until a cure is finally found for multiple sclerosis?

Dr. Sadiq: Yes, that’s likely. I think the Phase 2 trial will really go a long way towards answering that question. It will be important to ascertain what happens to patients in the years after they receive their stem cells. Do they maintain their benefits, do they return to baseline, or do they fall somewhere in the middle? These will be significant findings. The design of this crossover trial will allow us to figure that out. My feeling going in is that patients will need stem cell treatments over the long-term, maybe not six a year after the initial treatment., but perhaps less frequently to maintain whatever improvement is seen.

WK: The neural progenitor cells developed by the Tisch Center – or any regenerative stem cells, for that matter – don’t directly address the disease process, correct? If so, does the disease remain active despite the use of these stem cells?

Dr. Sadiq: Yes, that’s right, the cells are not a cure for the disease. They hopefully secrete trophic factors that would stimulate the body’s own progenitor cells to activate and induce repair at sites of injury. (WK Note: trophic factors are elements which cause the body to maintain or start some action, in this case repairing damaged nerve cells and possibly affording some protection against attack from immune cells.)

WK: So, the stem cells may not necessarily repair injury all by themselves, but they may jumpstart natural repair mechanisms within the bodies of the patients in which they are implanted?

Dr. Sadiq: I think that’s the most likely mechanism. Whether they play some direct role is something we have to figure out, but I think it’s more likely that they’ll turn on a patient’s own progenitors and also create a trophic environment that acts as a shield from the immune system and allows the body to make repairs.

WK: I know that stem cells aren't the only focus of the Tisch Center's researchers and scientists. I’d like to touch on The Tisch Multiple Sclerosis Research Center of New York itself, and some of the other areas of research that are currently ongoing in The Center’s labs. Could you give us a peek inside and tell us about some of the other projects Tisch researchers are working on?

Dr. Sadiq: Well, at the Tisch Center our original goal was to identify the root cause of the disease. It may be some type of immune cell, or some unidentified infectious agent, or maybe some other environmental element. Once we can identify the cause of multiple sclerosis, we can then methodically work towards a cure. And finding a cure is our ultimate goal.

WK: So, the Tisch Center currently has researchers who spend their days searching for the root cause of multiple sclerosis?

Dr. Sadiq: Yes, absolutely. I try to focus on the real challenges that I see as a clinician treating patients every day. My focus is on trying to understand primary progressive MS, which is perhaps the most challenging form of MS as far as treatment is concerned. There are very few treatments that can alter the course of progressive MS. We’ve created an animal model in our lab to try to understand the mechanisms of progression and why remyelination does not take place at all in this form of the disease. In relapsing-remitting MS we see damage occur and then some repairs get made by the body, especially in early disease. This is something not seen in progressive MS. We need to understand the mechanisms of progression better. We are also focused on cognition dysfunction because that can really dehumanize the patients who suffer from severe cognitive deficits.

We are also hard at work identifying biomarkers that can indicate the activity and severity of the disease. We’ve published a lot of papers in this area. We are doing a lot of work on metabolic dysfunction in the central nervous system in MS, and hopefully, that will lead us to readily identify markers that can pinpoint progression and disease activity, which will, in turn, allow us to assess the effectiveness of treatments in individual patients. In conjunction to the Phase 2 stem cell study itself, one of our aims is to analyze the spinal fluid of all of the study participants for markers that may predict which patients are going to get better by Identifying which patients experience actual repair and remyelination. The goal of identifying biomarkers is to be able to tailor treatments to each individual patient, specific to them and the intricacies of their disease. MS is a very heterogeneous illness, meaning that it affects each patient differently. Through the use of biomarkers, we hope to be able to address these differences on a patient by patient basis.

WK: The Tisch Center is not affiliated with any hospital or academic institution, correct, so it’s an entirely independent research entity?

Dr. Sadiq: Yes we are completely independent. We run Tisch like an academic center in every regard. We have guest speakers and all of the activities that would be associated with typical University research centers, but we are not affiliated with any academic centers. We retain absolute independence in choosing our areas of research.

WK: If you don’t have any of these affiliations, how is all of the research we’ve discussed funded?

Dr. Sadiq: We rely entirely on grants and donations. We use almost all the funds raised directly for research. Fully 90% of all monies raised goes directly into research, which is really an extraordinarily high number compared to other organizations. We keep expenses very low, so only a small percentage of funds raised go towards administrative costs and other such overhead. All of our tax forms and documentation in this regard are available online.

WK: My understanding is that you are not currently receiving any funding at all from the National Multiple Sclerosis Society. Is this correct?

Dr. Sadiq: Yes, that's right, we’ve had some bad luck with the MS Society, but they promised to look into our Phase 2 study, and I’m putting in a grant application. Hopefully, this time they’ll get involved.

WK: Obviously, the Tisch family (click here) is involved, but where does the rest of the Center’s funding generally come from?

Dr. Sadiq: The Tisch family is a very big supporter, but so are our patients and their loved ones. We have a very loyal following of patients and their families and other supporters that really enable this to happen. They’ve been supporting us for close to two decades, even before we were formed as an independent center.

WK: How much is this Phase 2 trial going to cost?

Dr. Sadiq: The build-out of the laboratory cost $5 million, and that’s a done deal. The trial itself calls for another $4 million, and we are currently raising funds for the study itself.

WK: So funding is still needed for the Phase 2 trial?

Dr. Sadiq: Yes.

WK: Well, speaking strictly for myself as a patient who has been ravaged by this disease, I can’t think of any cause more important and worthy of donations.

Dr. Sadiq: That’s very kind. Maybe I should hire you as a fundraiser…

WK: You can pay me in stem cells… Even though I know I don’t qualify for the trial because of my  level of disability…

Dr. Sadiq: That’s true, but don’t ever lose hope. Every day researchers here at Tisch and others around the world are working hard towards solving the puzzle of MS. I’m personally obsessed with curing multiple sclerosis.



As a patient of Dr. Sadiq’s, I can attest to his obsession with curing the disease. The man works at least six out of every seven days and even has a bedroom behind his office at the clinic affiliated with the Tisch Center. The clinic is called The International Multiple Sclerosis Management Practice (click here).  I’m also acquainted with some of the researchers at the Tisch Center, who are so dedicated that they'll even put up with my incessant questions when I manage to corner one of them with my wheelchair.

For those interested in donating to the Tisch Center, you can learn about the various ways to contribute by (clicking here). If you’d like to encourage the National Multiple Sclerosis Society to get behind the first ever FDA approved Phase 2 MS stem cell trial with a nice big grant, here’s a webpage with contact info for all of the Society’s senior leadership (click here). Please be polite If you do reach out to the NMSS. As my grandmother always told me, you can catch more flies with honey than you can with vinegar…

Tisch Center MS Stem Cell Study: Interview with Dr. Saud Sadiq, Director and Lead Research Scientist (Part One)

The Tisch Multiple Sclerosis Research Center of New York (click here) recently published the Phase 1 results of the first-ever FDA approved multiple sclerosis regenerative stem cell study (click here). The results created quite a buzz in the MS community, as the headline results stated that 70% of trial participants experienced increased muscle strength, and 50% saw improved bladder function. As the study included only patients with progressive MS, many of them with advanced disability, these results seem especially impressive.

Given the level of interest in this trial and stem cells in general, I thought it important to interview the man behind the study, Dr. Saud Sadiq, the Director and Lead Research Scientist of the Tisch MS Research Center. Luckily, Dr. Sadiq has been my MS neuro for the last 14 years, so a simple phone call was all that was needed to set things up. Dr. Sadiq and his researchers had been working towards this Phase 1 study for over a decade. Since the Tisch Center is not affiliated with any academic or healthcare institution, all monies for the trial were raised privately through a certified nonprofit foundation.

My interview with Dr. Sadiq is quite long but full of important information, so I’ll publish it in two parts. This installment will explore the recently released Phase 1 trial results and their potential implications. The next installment will include an overview of the upcoming FDA approved Phase 2 trial, as well as a discussion of how regenerative stem cells might work and their possible impact on the treatment landscape of multiple sclerosis. It also covers some of the many different areas of groundbreaking research currently underway at the Tisch Center's laboratories. I’ll publish the second installment next week.

This interview was lightly edited for readability. I’ve included some “WK Notes”, which explain in layman’s terms some of the more complicated medical jargon used in the discussion.

WK: Dr. Sadiq, you recently published the results of your Phase I MS stem cell trial, and they look quite strong. To start, can you tell me about the patient population of the study?

Dr. Sadiq: The patient population consisted of patients with clinically definite multiple sclerosis who had either secondary progressive or primary progressive MS. They had relatively stable disability scores – we use the EDSS scale to assess disability scores – in the years preceding inclusion into the study. Their EDSS needed to have not changed in the six months proceeded the study. Of the 20 people in the study, 10 of the patients we included used wheelchairs or had EDSS of 7.0 or above, and another 10 patients had an EDSS of between 3.5 and 6.5. The majority of patients were in the more disabled category and were using aids such as canes or wheelchairs.

WK: Why didn’t the study include any relapsing-remitting patients?

Dr. Sadiq: Well, remember, this was a Phase 1 trial that was designed primarily to assess safety. Relapsing-remitting patients tend to do well with disease modifying treatments, so evaluating recovery would have been much more difficult, even though this wasn’t a primary focus of this trial.

WK: You mentioned disease modifying drugs. Were the patients chosen for the study on disease modifying drugs, and if so, did they continue them throughout the study?

Dr. Sadiq: Yes, most of the trial subjects were on the drugs we commonly use to treat MS, including Tysabri, Rituxan, and intrathecal methotrexate (WK note: intrathecal (spinal) injections of methotrexate is one of Dr. Sadiq’s preferred treatments for patients with progressive MS. He also treats many of his progressive MS patients with Rituxan).

WK: What was the age range of the patients?

Dr. Sadiq: The youngest patient was in his 20s, and the oldest were in their 60s.

WK: Let’s talk about the type of cells that were used. These were not raw mesenchymal stem cells, which are the most common type of cells used in other stem cell trials and in for-profit clinics, correct?

Dr. Sadiq: That’s right. Basically, in our laboratory, we take a patient’s bone marrow and separate out the mesenchymal stem cells. We then purify and clone them, and then freeze them for use in subsequent treatments. The cells harvested from one bone marrow extraction – we harvest from the breastbone – can be used for multiple procedures. Before the actual treatment, the cells are then grown to about 100 million mesenchymal stem cells which we then convert into neural progenitor cells, cells which are committed to a neural lineage (WK note: neural progenitor cells are stem cells specific to the central nervous system). We usually get between 5 million and 10 million neural progenitors, and that’s what we inject into the spinal fluid of the patients.

WK: What exactly are neural progenitor cells as compared to raw mesenchymal stem cells?

Dr. Sadiq: Mesenchymal stem cells have the ability to differentiate into several different types of tissues. They can turn into fat cells or cartilage cells, but they can also differentiate into heart cells and liver cells, among others. Because we were injecting cells directly into the spinal fluid, we wanted to commit them to neural lineage so they would not differentiate into other kinds of tissues once inside the patient.

WK: I understand that the transformation process that turns mesenchymal stem cells into neural progenitors is something that was developed exclusively in the Tisch Center’s laboratories?

Dr. Sadiq: Yes, we published the process in a number of papers. The details of the differentiation process were detailed in these reports.

WK: So, the details of this process aren’t a secret, they can be replicated in any stem cell laboratory?

Dr. Sadiq: Yes, between this paper and previously published papers all of the details are available.

WK: To your knowledge, though, the Tisch laboratories are the only ones using this process?

Dr. Sadiq: Yes.

WK: Let’s talk about the treatment protocol that was used in this Phase 1 trial. How many stem cell treatments did the trial subjects get, and at what time intervals?

Dr. Sadiq: In this Phase 1 trial, we used three treatments on each patient, and the treatments were given every three months. We used between five and 10 million cells for each treatment. So, in this trial of 20 patients, we did a total of 60 stem cell treatments, and roughly 80% of those involved the injection of 10 million neural progenitor cells.

WK: How long did the study last? And was there a placebo control group?

Dr. Sadiq: The trial lasted two years, and there was no placebo control group. The capacity of our laboratories at the time was a limiting factor, so we had to stagger the treatment of patients.

WK: Even though the trial lasted two years, none of the patients received more than three treatments, and they all received them at three-month intervals, correct?

Dr. Sadiq: That’s right, nobody got more than three treatments.

WK: Okay, let’s move on to the topic that’s probably of most interest to patients, the actual results that you saw from the trial. The headlines were that 70% of the patients are an increase in muscle strength and that 50% saw improvement in bladder function. Could you give us some details on those numbers?

Dr. Sadiq: I think the main thing that has to be stressed is that the study was designed to look at safety and tolerability because nobody in a trial setting had previously injected stem cells multiple times at regular intervals into patients. We really had to establish safety and tolerability. We did this successfully, as all patients received all of their treatments and tolerated them well. There were no adverse effects except for very mild headaches and fever, which were transient and generally didn’t last more than 24 hours. There were no hospitalizations and no deaths, and this safety profile was really the primary purpose of this Phase 1 study.

As to the question of efficacy, we have to be very careful because this was not a placebo-controlled or blinded study, and most of the patients expected that they would get better. What we did see when assessed by muscle exam using the standard assessment tools – which were performed by a neurologist who wasn’t involved in the administration of the cells – was that 70% of the treated patients did see an increase in muscle strength in at least one muscle group. In addition, 50% of patients had significant bladder function improvement.

WK: Did some patient groups appear to respond better than others?

Dr. Sadiq: Yes, although patients did tend to improve across the board. Not unexpectedly, the less disabled they were, the more likely they were to improve. Overall, the less disabled did better than those with higher degrees of disability. Also, the secondary progressive patients tended to do better than the primary progressive patients. But remember, these were very small numbers, only a total of 20 patients of which only four had PPMS. But generally, we saw a drop off in response rates in patients with EDSS 6.5 and above.

WK: Why do you think there was this drop-off in efficacy seen in patients with EDSS 6.5 and above?

Dr. Sadiq: I think the integrity of axons is probably a key factor in whether they will rehabilitate or not. If you still have an electrical connection, it’s easier to repair, and scar formation from lesions probably also impedes repair. The less structural damage there is, the easier it is to repair the problem.

WK: What are your thoughts on repairing the damage of patients with higher levels of disability, who currently must rely on wheelchairs?

Dr. Sadiq: I think these are our hardest challenges. Once we can figure out how to eliminate scar tissue in the central nervous system, that will really open the door (WK note: scar tissue is created by the damage done by long-standing MS lesions). At one point we were using enzymes to try to eliminate scars. Once we can understand not just remyelination but also the regeneration of axons, I think that will be the way to achieve the goal of restoring function in more disabled patients (WK Note: axons are the long threadlike part of a nerve cell along which impulses are conducted from the cell body to other cells). That’s why we are so focused in our lab in trying to figure out primary progressive multiple sclerosis.

WK: Were any of the patients complete nonresponders?

Dr. Sadiq: Yes, there were. Some of the PPMS patients as well as some of the more disabled SPMS patients.

WK: You mentioned the lack of a placebo-controlled group. I’d like for a minute to discuss the placebo effect because many patients don’t, I think, have a very good understanding of what the placebo effect actually entails. Many believe that when improvements are attributed to the placebo effect that these benefits are being disparaged as imaginary or “made up” by the patient. Could you comment on the science behind the placebo effect?

Dr. Sadiq: The placebo effect is real. It’s scientifically shown to be real. Even in cancer trials, whatever the mechanism, it’s real. It’s not simply psychological. It’s a conviction where the patient thinks they are going to get better and somehow that has a physical impact. Now whether the brain produces certain well-being cytokines or humoral factors or if you get an endocrine surge, somehow that has a positive effect that we still don’t fully understand. Since the late 1950s, the placebo effect has been recognized as a genuine phenomenon. In fact, there is a case of a cancer patient who got cured even though they had been given a placebo and not the drug being tested. So it’s not just some insignificant, mild effect. Generally, it’s considered that in any study without a placebo arm there’s about a 30% effect that can be attributed to placebo. This is real, when the patient is hopeful, the patient often feels better.

The thing about our study which is encouraging and leads me to believe the improvements we saw are not all attributable to the placebo effect is that we saw the most improvements in the patients that were the least disabled. This is something you would expect to see in a double-blind trial. In our trial, we probably chose the worst patients to study in that they had the disease for many years and most of the patients had significant disability. Our mean EDSS was 6.8 at baseline. Our average disease duration was about 18 years. These are never the patients who are chosen for pharmaceutical company studies, who are generally much less disabled and have shorter disease duration. The patients we used actually stacked the study’s chances against getting any positive effect.

WK: Just to be clear about EDSS, what’s the difference between 6.0, 6.5, and 7.0?

Dr. Sadiq: 6.0 is somebody who needs a cane to walk, 6.5 is somebody who needs bilateral assistance like a walker or bilateral crutches, and a 7.0 is a somebody who requires a wheelchair.

WK: In the trial, what kind of results did you see in patients who were EDSS 7 or above?

Dr. Sadiq: We saw two patients who had not been able to take more than a step or two who after treatment were able to walk with a walker for 25 feet. Whether that was placebo or not, I don’t know because this level of effect hard to explain. This was out of 10 patients who needed wheelchairs. It’s certainly intriguing.

WK: So two out of ten patients who hadn’t been able to ambulate at all and were entirely reliant on wheelchairs before the trial were able to walk with the aid of a walker for 25 feet after the study, correct?

Dr. Sadiq: Yes.

WK: Well, placebo or not, that seems like a remarkable result.

Dr. Sadiq: Yes, but we need to see if similar results are seen when we do the Phase 2 trial, which will be specifically designed to assess efficacy.

I hope readers have found Part One of my interview with Dr. Sadiq useful and informative. Look for Part Two next week, in which the Phase 2 study and just how the stem cells might work are explored. We’ll also talk about some of the other research currently being conducted in the Tisch Center’s laboratories.

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 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!

Healthline

Ocrelizumab PPMS Trial Data Released, Offers Reasons for Hope and Concern

Last month, at the annual ACTRIMS (American Committee for Treatment and Research in Multiple Sclerosis) conference, the full trial results for the Ocrelizumab PPMS drug trial were finally revealed. These results had been much anticipated by the MS community, as there are currently no proven effective treatments for Primary Progressive Multiple Sclerosis, and many previous PPMS drug trials have ended in failure.

Coincidentally, a few days before the conference, Ocrelizumab received “fast-track status” by the FDA (click here). The “Fast-Track” designation is given to drugs which promise to fill a prior unmet need, and generally shortens the approval process from 10 to 6 months. Since PPMS has no approved treatments, Ocrelizumab fits the requirements for the designation. Though fast-track designation means that Ocrelizumab will have an expedited approval process, it does not guarantee that the drug will ultimately be approved.

The anticipation over Ocrelizumab, which was developed by Roche Pharmaceuticals subsidiary Genentech, stems from the fact that trial results appear to demonstrate the drug to be effective in slowing down progression of disability in PPMS patients. In results presented at ACTRIMS, Ocrelizumab showed itself to be very potent in treating RRMS (click here), and in PPMS the drug slowed down disability progression by 24% (click here), making it the first major pharmaceutical product to demonstrate effectiveness in treating Primary Progressive Multiple Sclerosis in a scientifically rigorous placebo-controlled trial.

The data set presented at ACTRIMS confirmed info originally released last year, but the numbers revealed at the recent conference provided more details on the patient population included in the study (click here). Specifically, results were provided for two different subsets of patients – those with enhancing lesions (which signify acute immune activity within the central nervous system) and those without enhancing lesions. Only about 15% of patients with PPMS display enhancing lesions on their MRIs, and it was widely assumed that Ocrelizumab would likely only be effective in treating those patients. The results provided by Genentech at ACTRIMS , however, demonstrated that the drug appears to be just as effective in patients whose MRIs did not show any signs of enhancing lesions.

Great news, right? Well, if the numbers hold up it is great news, but there are certain aspects of the Ocrelizumab PPMS trials that raise some red flags. Ocrelizumab is a close cousin of the decades old drug Rituxan, which is also manufactured by Genentech. Both drugs work in almost the exact same fashion, by targeting and destroying immune system B cells, effectively ridding the body of the cells for periods of at least six or seven months. Ocrelizumab, like Rituxan, is administered approximately every six months, in two intravenous doses given one or two weeks apart.

Rituxan was originally intended for use against blood cancers, but was later found to be effective in treating a variety of autoimmune diseases, including Lupus, Rheumatoid Arthritis, and Relapsing Remitting Multiple Sclerosis. The human immune system consists of a wide variety of cells, but is primarily made up of B cells and T cells. Therefore, Ocrelizumab and Rituxan both eliminate a major component of the very complex immune system, which, it’s assumed, is why they are effective in treating so-called autoimmune diseases. Though Rituxan was never officially approved for use in MS, many MS neurologists prescribe the drug “off label” for their RRMS patients, in whom it has proven to be very effective in reducing relapses and the occurrence of MS lesions.

Back in 2008, trials of Rituxan on PPMS patients were deemed a failure, much to the intense disappointment of many patients, myself included. Subsequent analysis of the data generated by that failed trial, however, revealed that a subset of patients did seem to have a somewhat positive response to Rituxan – namely younger patients who displayed enhancing lesions, had been more recently diagnosed, and were less disabled than other trial participants (click here). Instead of pursuing more targeted trials with Rituxan, though, the drug’s manufacturer, Genentech, decided to develop a newer version of the compound, and thus Ocrelizumab was born.

Why invent a new version of an older, proven drug that uses the exact same mechanism of action as that older drug? Well, Genentech says it was done to develop a safer, more effective product, but a cynical person might point out that Rituxan had already proven itself to be relatively safe and quite effective but was due to come off patent in 2015, meaning that its window for generating tremendous profits was rapidly closing. By the time new trials were completed, Rituxan would no longer have patent protection. A new version of the drug, on the other hand, could be a golden egg laying goose. But, of course, only a very cynical person would point that out, not someone is bright eyed and bushy tailed as me.

Anyway, back to the current Ocrelizumab PPMS trials. Based on the lessons learned from the failed Rituxan trials, it looks like Genentech populated the Ocrelizumab PPMS trials with patients who were selected specifically because they were more likely to respond to treatment (click here). Whereas only about 15% of PPMS patients display enhancing lesions on their MRIs, the Ocrelizumab trial included about 27% of such patients. When compared to the trial’s placebo group, the patients that received the actual drug had twice as many enhancing lesions, meaning their disease was much more immunologically active. In addition, compared to other PPMS trials (all failed), patients in the Ocrelizumab trial were generally more recently diagnosed, and were much less likely to have been on any prior disease modifying medications (in the parlance of the medical research community, most of the patients were “treatment naïve”).

Still, when the numbers were broken down at ACTRIMS, they showed that the drug decreased the rate of disability progression by about 24% in both patients with enhancing lesions and without enhancing lesions. However, each subset of patients was too small to make these results statistically significant, meaning that the trial was, in the parlance of the medical research community, “underpowered”. Knowing that this was sure to be a very important issue, why would Genentech go ahead with a trial that was underpowered in this regard? Wouldn’t logic dictate that they design the trial to settle this vital issue in a statistically definitive manner? Seems kind of strange, no?

What may ultimately turn out to be the most troubling aspect of the Ocrelizumab PPMS trial, however, is that 11 cancers were detected in patients taking Ocrelizumab, versus only two in the placebo group. Eight of the cancers in the Ocrelizumab patients were breast cancers, versus zero in the placebo group. This is especially concerning because back in 2010, when Ocrelizumab was first developed, trials were started not only in MS but also on lupus and rheumatoid arthritis patients. Both the lupus and rheumatoid arthritis trials were halted because of patient deaths (due mostly to opportunistic infections), but the MS trials were allowed to continue because it was thought that MS patients would have a higher tolerance for risk (click here). Interestingly, in the Ocrelizumab RRMS trials, which actually included more patients than the PPMS trials, “only” four cancers were detected in the drug group, versus two in the placebo group.

Incidentally, in its over two decades of service, Rituxan has not been associated with the development of cancers or an alarming number of opportunistic infections, although rare instances of PML (the brain infection that is so concerning in patients taking Tysabri) have been seen in patients taking the drug.

If anything derails an FDA approval for Ocrelizumab in treating PPMS it may very well turn out to be the cancer issue. Even though the positive effect on PPMS generated by Ocrelizumab isn’t overwhelming (a 24% decrease in progression rates is nothing to sneeze at, but then again it’s hardly the dramatic effect PPMS patients are desperately seeking), on its own it would seem encouraging enough to garner an approval. However, given some of the questions regarding trial design and safety issues, it will be very interesting to see what the FDA decides. Another one time promising MS drug, Cladribine, was rejected by the FDA primarily because of cancers detected during drug trials (click here).

For some expert opinions on Ocrelizumab, here are two videos. The first is a video of Ottawa MS neurologist Dr. Mark Freedman discussing progressive MS in general, and then commenting specifically on the Ocrelizumab PPMS trial results. For those of you with short attention spans, he starts talking about Ocrelizumab at the 3:50 mark of the video. Dr. Freedman has some very interesting comments regarding the drug and its effectiveness, and B cell therapy in general. The video is well worth watching.





Here’s another MS neurologist, Dr. Clyde Markowitz, Director of the MS Center at the University of Pennsylvania, who seems much more enthusiastic about Ocrelizumab and its prospects for treating PPMS:





Being the always curious person that I am, and also hyperaware that drug companies often funnel money to doctors who prescribe their products, I did some quick checking and found that Dr. Markowitz received $64,461 from various pharmaceutical companies between August 2013 to December 2014, mostly for “consulting” and “honoraria” fees (click here). At least $6000 of this rather large sum came from Genentech, which, it turns out, was the number one drug company in handing out payments to doctors during that period (click here). And this was before the Ocrelizumab trials were completed.

One can only imagine that Genentech is now going all out to, um, “influence” key doctors in its efforts to get the drug approved, much like politicians target key precincts and states in their quest to get elected. I’ve done plenty of ranting on the subject of drug companies making direct payments to the doctors who prescribe their products in previous blog posts, so I’ll refrain from launching into yet another insane tirade here, but suffice it to say I’ve yet to find any logical argument as to why this practice is tolerated, much less legal.

In all fairness, since Dr. Freedman practices in Canada, I was not able to find any info on payments he might’ve taken from drug companies. The truth is that very few MS neurologists are not on the pharmaceutical company dole. I’d encourage you to enter your doctor’s name in the “Dollars for Docs” database (click here), and see if your neuro has his hand in the cookie jar. Again, this doesn’t mean that the doctors named in the database allow pharmaceutical company money to affect their decision making process, but then again, the pharmaceutical companies wouldn’t be doling out millions and millions of dollars if they weren’t getting an appreciable return on investment.

Okay, sorry, I got a little sidetracked there. I certainly hope that all of my concerns about Ocrelizumab turn out to be completely unfounded, as having even a modestly effective treatment readily available for PPMS would be a major step forward in fighting the disease. However, it seems clear (to me, at least) that going after the immune system isn’t going to be the magic bullet that solves the Progressive Multiple Sclerosis problem, or the broader overall Multiple Sclerosis riddle.. Researchers urgently need to step outside the box and start coming at the issue from new angles if any truly dramatic progress is ever going to be made. In the meantime, here’s to hoping that Ocrelizumab proves itself to be a safe and reliable option for Primary Progressive patients, whose desperation for proven treatment options is beyond words.