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…

19 comments:

  1. In the 2-years of the OPERA and ORATORIO studies IgA and IgM levels dropped, but not IgG. Only IgM levels went below normal. Please note that plasma cells have a long half-life so the fact that IgG levels are preserved is not surprising. However, with long-term use these levels will drop. Hypogammaglobulinaemia, with infections, is a well described complication of long-term Rituximab use and will almost certainly occur with ocrelizumab. The safety profile of the anti-CD20 agents will get worse with time, not better.

    Maintenance immunosuppressants accumulate risks over time. In comparison PIRTs (pulsed immune reconstitution therapies), for example alemtuzumab, cladribine and HSCT, front-load risk. The latter is one of the reasons why some pwMS choose a PIRT.

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    1. Thank you for that explanation, Dr. Giovanonni. Of course, it makes sense that the prolonged absence of CD20 B cells would ultimately result in a marked reduction in antibody levels. I certainly hope all prescribing neurologists maintain vigilance in this regard.

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    2. https://www.facebook.com/CCSVI.IVCC/posts/1465385820192129?comment_id=1465507950179916&comment_tracking=%7B%22tn%22%3A%22R%22%7D

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  2. I am one of the neurologist who earns money from the Pharmacovigilance industry. We have a lot to learn from how disease modifying therapies work. Each DMT is an experiment. So working on the mode of action of DMTs allows you to obtain insights you wouldn't have otherwise. In addition, the definitive experiments that will prove EBV is the cause of MS will require Pharma investment.

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  3. Dr. G, I understand completely that, given the realities of today's medical research model, partnering with pharmaceutical companies is the only way to advance research. As you note in your own blog, this does pose conflict of interest problems, as the for-profit pharmaceutical entities only funnel money towards research with high profit potential. Your own Big Pharma Alternative endeavor is an attempt to address this very paradox.

    As for your earning money from the Pharma industry, it seems that most of the money you earn comes from conducting legitimate scientific research. My big problem is with physicians of all types who take money in the form of "consulting fees"," honoraria" and other such vehicles that oftentimes amount to nothing more than discussing a pharmaceutical product with other doctors over expensive dinners in five-star restaurants.

    Here in the states we have a website called "Dollars for Docs" which allows patients to search a database of pharmaceutical company payments to doctors, excluding monies received for legitimate research purposes. Just a quick search for some of my local New York City based MS Neuros reveals that some of them raked in figures in excess of $500,000 over an 18 month period. These very same doctors turn up time and time again in newspaper articles and TV interviews talking up the drugs produced by their pharmaceutical company benefactors. These "thought leaders" have in fact become paid spokespeople. I've yet to find any palatable explanation for these practices.

    The fact that most Big Pharma companies spend more on marketing than research is simply obscene. I believe the problem is much worse in the US than elsewhere in the world.

    I deeply appreciate the work you have put in searching for ways to conduct research outside of the currently accepted medical research model, The Charcot Project and the Big Pharma Alternative being two such examples. The fact that you are doggedly pursuing EBV as the cause of MS, as well as your investigations into the role of HERVs and other "outside the box" lines of thought are both heartening and inspiring on both emotional and intellectual levels, and has helped to lift my spirits and keep me in the fight more times than I can count. For that I give you a heartfelt "thanks"…

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  4. Once again Marc, you have hit one out of the park. Excellent science review of the trial and the drug, followed by a PERFECT rant.

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  5. Attaboy Marc, and also, thank you Dr Giovanonni, for hosting such an open and frank blog yourself.

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  6. Go Marc go. Hurra för your posts that keep me a well-informed patient.

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  7. Sandra SchneiderMay 15, 2017 at 3:45 PM

    Amen. You're preaching to the choir. But keep on preaching. We'll fill the pews. After 32 years of this ghoulish disease, I would donate blood or risk taking part in any clinical trial addressing EBV or HERV. If only we COULD fund the research.

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    1. Yes, if only we could fund the research! Unfortunately, the reality of the situation is that only the pharmaceutical companies have the financial might necessary to run late stage clinical trials. I was heartened to see that simvastatin is being put into phase 3 trials for MS, in a trial not funded by the pharmaceutical companies. Hopefully we will see more of this in the future, as the conflicts of interest are rampant when you hand almost all major late stage medical research to private, for-profit companies.

      But there I go again, preaching to the choir…

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  8. A few things to consider. What triggers a disease is EXTREMELY difficult to figure out. And cures basically unattainable given how complex the human body is and since pathways do not operate independently of one another. Most people don't have one autoimmune disease, which further complicates matters. Also these break throughs are highly unlikely to come from clinical teams, but rather pure scientists in the lab. And as we know, 99.9% of "discoveries" never make it out of the lab, which is why I completely ignore research in mice at this point.

    Also, to address your comment about the purity of clinical trials in humans. They rarely match the general population. They're extremely restrictive. Often times do not allow co-morbidities in order to keep the data pure. Which is why we don't know how most drugs really work until they've been out in the general population for several years. Then you have the full picture of co-morbidities, how people are really taking the medicine vs how it's indicated, etc.

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  9. Hi, thanks for your comments.

    Yes, cures are extremely difficult to come by, for all of the reasons you mentioned. But they are impossible to come by if nobody is looking for them, which is largely the case for MS and other autoimmune diseases.

    The tremendous financial success of the immunosuppressant disease modifying drugs has led to a research mindset that often neglects to search for the root causes of autoimmunity, without an understanding of which there will never be a cure.

    We are getting more and more indications that EBV in combination with genetic susceptibility may be the genesis of many AI diseases, and if as much intellectual and financial equity was put into research investigating these interactions rather than developing newer generations of immunosuppressant agents we might very well come up with something approaching a cure, or at least therapies with far less toxicity than those currently offered.

    The recent study by Bender et al shows the potential of just such an approach. A small trial, yes, but a journey of 1000 miles…

    As for the purity of clinical trials, again, everything you state is absolutely correct. However, trials which are specifically set up to succeed (as was the Ocrevus trial) can produce misleading results when applied to a patient population that bears little resemblance to the trial population. And the fact that we can only fully assess the real impact of a drug (both negative and positive) after several years of it being on the market means that we have turned patients into guinea pigs. What will be the long-term effects of profound manipulation of the immune system? The highly effective generation of MS drugs hasn't been on the market long enough to fully assess their long-term effects, and one can only hope that we aren't suddenly confronted with waves of cancers or other unexpected negative outcomes. Of course, there's no way around this, as drug trials can't last 10 years or more. We'll just have to hope for the best…

    Not to say that these drugs haven't been of tremendous benefit to many MS patients. At the very least they've dramatically improved the quality of life for many of those taking them. The question remains, though, at what ultimate price? We've never before had large populations spend years on drugs that effectively knock out large portions of the immune system. On the flipside, we know for sure that doing nothing to treat MS can lead to horrific results. So, in this case the potential evil unknown is likely better than the evil known…

    Oh, yes, the studies done on mice are very much ignorable…

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  10. Google Italian-English Translator

    How many Balleeeeee ... on thyroid dysfunction! ! (AND ON ALL PATHOLOGY-DISTURBI-SNC, "SMSP or SMPP" Multiple Sclerosis Secondary and / or Primary Progressive with New Drug-Poison, approved by the American FDA "OCREVUS"!!) ALL DIPENDS FROM MASSAGE-BALANCE-ABSORPTION -ACCUMULATION-PRESENCE, AT LEVEL OF IONS, OF MINERAL-OLIGOELEMENTS DETERMINED THAT DO NOT ACTIVATE ENZYMEN DETERMINED IN OUR MICRO-CELL-MITOCONDRIES-DNA-RNA! ! And with the presence of accumulation of heavy metals, due to CHELATION deficiency! Which reacts with the equilibrium-presence of all Minerals-Observations !! And therefore also general reactivation of the Lymphatic System and, at the SNC level, also of the Glinfatic System, as well as arterial-venous circulation! .
    In summary, after a minimum of one month, a general improvement of the body is felt.
    All these minerals-traces are present, at no cost and with no side-effect, in "My Alkaline Cuttlefish" drink, and / or other marine products, even "scraped" from the fish markets on Google! ! And also containing the Marine Plankton and all Amino Acids-Vitamins-Hormones !! And if used, post-reduction in micro-powder, in yellow-gold lemon juice, it also improves the Krebs cycle! .
    The upstream and downstream control of the restoration of mineral-trace elements, at the tissue level, results from Nuca's hair analysis, called MINERALOGRAMMA! , TESTED BY THE OFFICIAL MEDICINE, AND INSURANCE AND / OR SUB-VERIFICATION, OF MANY-MORE-MANY MEDICINES !!

    In the Patient SMSP or SMPP, Multiple Sclerosis SP or PP, suffering from constipation-constipation-chronic constipation, for at least six months, I would recommend to use, to disinfect the entire Digestive System, to drink during the day 200-250ml of oil Of dense yellow gold olive oil at the crushed oil, extracted from black mature emesocarp-pulp purple color dense vivid to the kernel and Giammai VERDE !, with the addition of ripe lemon juice, yellow to the tree, drank heated in bain-marie, with effect, Even body weight normalization over time. To improve-regenerate the endothelial cells inside the veins, I would always recommend using salad, to use before the main meals, pieces of Cladodi cactus opuntia, 100 g of sprouted Lettuce seeds, Portulaca and Fumaria, seasoned with golden yellow olive oil 4-6 g of Ginkgo Biloba powder from yellow gold and yellow green leaves as they are on the market! .
    ;

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  11. Yes Marc - I had to grapple with the $(latest item) thing too!
    Use the squiggly brackets (just above the return key) and it'll be fixed
    Dave

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  12. maegan@healthline.comMay 18, 2017 at 5:36 PM

    Hi Marc,

    Healthline would like to congratulate you on making our list of the Best Multiple Sclerosis Blogs of 2017!

    Our editors carefully selected the most up-to-date, informative, and inspiring blogs that aim to uplift their readers through education and personal stories. We’re glad to have you on the list!

    We’ve created a badge that you can embed on your site to let your readers know about your win. The embed code is at the link below.

    Winners list: http://www.healthline.com/health/multiple-sclerosis/best-blogs-of-the-year
    Badge to embed: http://www.healthline.com/health/multiple-sclerosis/best-blogs-badge-2015

    If you have any questions or need help embedding the badge, feel free to be in touch. Congratulations and keep up the great blogging!

    Warmly,
    Maegan

    --
    Maegan Jones | Content Coordinator
    Healthline
    Your most trusted ally in pursuit of health and well-being

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