Wednesday, March 2, 2016

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.

23 comments:

  1. Thanks Marc for this! Talking about B cells and breast cancer...I was on a trial for a drug called Atacicept and it too was targeting B cells. It was halted because it was shown to cause more relapses rather then less. I was informed that I had been receiving the drug and not placebo and interestingly within 3 years I developed a breast lump that grew very rapidly and fortunately was removed ASAP and I am now fine. I wondered sometimes if it wasn't due to the drug. Now I wonder even more. I am remaining drug free for the moment!

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    1. Beverly, I guess it's impossible to know whether your lump was caused by the drug or not. I would say, though, that all of these drugs that suppress the immune system are really a big unknown, as we've never before had large patient populations having their immune systems suppressed for years on end. This is one of the points brought up by Dr. Freedman in the video above. I do worry about the as yet unknown consequences of keeping people rather severely immunosuppressed for years and years and years. I guess only time will tell, but let's hope that there aren't any nasty surprises lurking somewhere down the line…

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    2. My partner has a history of breast cancer prior to MS and chose HSCT rather than prolonged immunosuppression. Neuros tried to talk her out of it talking about the risk of breast cancer post HSCT, haemo and her oncologists told her they would be no more worried about HSCT in context of breast cancer then they would be if she was immunosuppresed over a long period. The neuros downplayed the cancer risk in the context of prolonged immunosuppression. She went with the oncologists' advice lol

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  2. Oh dear Marc, you've ruined it all.

    Besides your clear thinking and excellent expository skills, my image of you as a dashing, fashionably dressed, sophisticate New Yorker lent authority to your posts.

    But now, the only image is of those large rodent teeth, big eyes and the large bushy tail of a tree rat or best case, Bullwinkle's friend, Rocky. :>)

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    1. Edward, I guess I let my secret accidentally slip out… Not only has my MS (or whatever the hell it is) put an end to my days as a sophisticated, erudite New Yorker, but it's also transformed me into one of New York City's other native populations, namely squirrels. Trying to dictate these posts with my cheeks filled with nuts is really difficult…

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  3. Thank you Marc. I am a 58(soon to be 59) year old diagnosed with PPMS in Sept of 2014. Two lesions, one on my brain stem. Never enhanced, never had an attack, limping for about 15 yrs. The main lesion was found May 2014 and it took 4 months for my diagnosis. I have passed on your blog to many of the medical providers that have crossed my path. My neurologist is very excited for the Ocrelizumab to be approved. In the meantime, I was taking ibudilast (or placebo) from May until January. No new lesions but "evidence" of progression. February 11 I had adult stem cell treatment with Stemgenex. An amazing journey with amazing Doctors. I am now down to supplements (albeit not your normal ones!) and I have been fortunate to not have any reactions as of yet to Betaseron (18 months so far). I am leery of taking a new drug and like most with
    PPMS, I await the review comments from FDA. One of my fellow patients in February is severely disabled in a wheelchair.............I am so anxious to keep track of his progress. The FDA in April is on the path to shut down stem cell clinics saying that our stemcells are investigational new drugs............UGH. I seem to be rambling on but I just wanted you to know that your blog strikes a chord with me and is so greatly appreciated.

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    1. Joan, sorry to hear about your diagnosis and subsequent illness, but happy to hear that you had some success with stem cells. Would love to know exactly what kind of improvements you experienced.

      I think the FDA is really only targeting those clinics that are offering "same-day" stem cell infusions using adipose derived materials, which are most likely nothing more than a scam. These clinics don't separate and expand the mesenchymal stem cells they harvest, and the doses they administer very likely have no effect at all.

      If you are really anxious to give Ocrelizumab a try, I would suggest talking to your doctor about Rituxamab, which is currently available and uses the same mechanism of action as the newer drug. It also appears to be a lot safer, as it's been in use for decades with a pretty good safety record.

      Wishing you the best, and gratified to know that my blog has helped you, if even in just a small way.

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  4. Marc, your blog post came at an opportune time – I had just received an alert that the drug Ocrelizumab had been given Breakthrough Therapy status by the FDA. After having PPMS for over 10 years and being severely disabled, I jumped on the chance to get any drug that would affect my condition. After reading your well researched and objective blog post, I have been able to form an educated opinion about this drug. Thank you so much.

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    1. Melinda, it will be very interesting to see how things go with the FDA. The more I read about the Ocrelizumab trial results, the less impressed I am. Although "any port in a storm" certainly applies to those of us suffering from this horrible disease, I have a feeling the relatively nominal benefit provided by the drug might not warrant an approval given the cancer risks and the underpowered trial design. Then again, the drug companies are holding more and more sway with the FDA, so an approval wouldn't be a surprise at all. Stay tuned…

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  5. As my husband says about those running for public office up to and including commander in chief, everyone should have to dress like NASCAR drivers and wear sponsor/large donor/lobbyist logos on their apparel!

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    1. I've heard this proposal before, and I wholeheartedly endorse it. Really, the fact that drug companies are allowed to pay the doctors who prescribe their products is a travesty. Just goes to show that the golden rule is still in effect, those with the gold get to make the rules…

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  6. Thanks for another great post, Marc. I saw my neuro right after Ocrelizumab got its breakthrough designation and asked about it. He's still pushing Lemtrada, even though Lemtrada is approved for RRMS and I'm PPMS with a disease process supposedly not driven by inflammation. He thinks the theory that PPMS isn't inflammation-based could be wrong since old lesions had to be active once and there could be active spinal lesions that are hard to see on MRI due to resolution issues in the narrow spinal cord and (of course) impossible to see on brain MRIs.

    He thinks I should do Lemtrada because (1) it uses a similar chemotherapy-based immune system reboot strategy to Ocrelizumab, but it targets both T-cells and B-cells vs. Ocrelizumab which targets only B-cells, and (2) Ocrelizumab won't be FDA approved for at least six months, if at all.

    That's what I'm thinking of doing. What are your thoughts on Lemtrada vs Ocrelizumab? Thanks again for all you do for the MS community.

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    1. Neil, I'm not a medical professional, so please take whatever I say with several grains of salt.

      That said, Lemtrada and Ocrelizumab aren't really in the same class of drugs. Lemtrada is an induction therapy, meaning that it is given in one course, I believe in two or three doses given a year apart, and after that most patients don't require any further treatment for quite a few years. Lemtrada basically wipes out the existing immune system and allows it to repopulate with a brand-new set of cells. It's kind of like HSCT in a bottle.

      On the other hand, Ocrelizumab and its close cousin Rituxamab are drugs that are intended to be given to the patient indefinitely (like Tysabri and all of the other current crop of disease modifying drugs). Ocrelizumab and Rituxamab both destroy most of the bodies B cells, and keeps them suppressed for about six or seven months, at which point the drug must be given again, and this process will be needed to be repeated ad infinitum.

      If I might make a suggestion, you could ask your doctor about giving Rituxamab a try now, since it is currently available, and seeing if it has any beneficial effect on you. If it fails, you can then go for Lemtrada, which is more of a nuclear option.

      Wishing you the best, and always remember to keep on being your own best advocate.

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  7. Orphan drugs for orphan PPMS'ers. Anything isn't always better then nothing if it's an awful drug. Based on your research, it doesn't sound awful. I SO agree that the focus has to shift off of the immune system in treatment research.

    Great post and very timely!

    Marc, check out the research and feedback about high-dose Biotin.

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    1. No, I don't think that Ocrelizumab is an awful drug, I just don't believe it's going to live up to the hype that has surrounded its development. The patient that did benefit from it so that disease progression slowed, but Ocrelizumab certainly didn't put the kabosh on their disease. Still, I suppose it may be a start.

      I have written a few blog posts on Biotin, if you use the search box in the upper left-hand corner of the blog page you'll be able to find them. I'm encouraged by the Biotin trial results, although, in this case as well, the results aren't as robust as we keep hoping for. I believe Biotin should be up for FDA review sometime soon, but I haven't heard anything lately…

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  8. Marc, another well researched and eloquently expressed blog post! My neurologist shares your skepticism about the overall effectiveness and safety of this drug. As a severely disabled person with PPMS, I've set the bar pretty low for both safety and efficacy, so I may yet give Ocrelizumab a try. But I'll do so with eyes wide open. Thanks for doing what you do.

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    1. Hey Mitch, glad you found this post to be of value. I hear you loud and clear on being willing to try just about anything to put the brakes on this beast, and I know that like me, you've tried a litany of potential treatments. Sure would be nice if one of them actually worked, wouldn't it?

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  9. Reading about Lemtrada and ocrelizumab and thier suppression of the immune system makes me feel all the more interested in pursuing HSCT (the myleo version). Why not knock the immune system out, then build it back up instead of repeatedly knocking it down. I can't be constantly immune compromised with my young children. Which is what my doctor has to offer. I was so pleased when she assisted me in getting tests and filling out forms to submit for my application. And she's willing to follow along and assist in any way she can. And afterwards I'm keen to see what Dr. Sadiq's work will have to offer in the way of reparative therapy.

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    1. Doctors are reluctant to recommend a procedure that is not fda approved. Unfortunately this means HSCT is on hold. Also, I doubt insurance will cover the cost.

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    2. I was on Rebif for 13 years and my kids went from Kindergarten to Highschool. I was still the healthiest person in the house. Enough immune system may not be a worry.

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  10. Great essay,

    I think your right in that rolling out immune suppressing therapies over and over is not going to get at the root of the problem, it is just a bandaid but pharma has found this to be a cash cow so why should they stop?

    Personally I believe the issue lies in a problem between the communication of the nervous system and immune system. The notion that the immune system functions autonomously as is the current thinking goes against all logic when every other system is governed by the nervous system.

    Some researchers are starting to unravel this interaction but they are few and far between.

    Keep up the good work as I enjoy reading your blog.

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  11. Great article Mark, always appreciate the unbiased approach, pointing out the good, the bad and the ugly!

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  12. This is excellent and confirms some of my suspicions about how great this product may be in PPMS. I am sure that it is one of the better products for RRMS - again.

    Genetech has also opened up an Expanded Access Program (EAP) so you can go to a study center and enroll and you can take the drug until it becomes commercially available. However, it has the same age limit as the studies (55 years). I called and asked about this and they said the wanted to keep the entry criteria the same as the clinical trial. There are only 60,000 people supposedly with PPMS, so I do not understand why if you are older than 55, you cannot give it a try for free by being in this EAP study.

    If you do have PPMS, you should look into signing up. Go to clinicaltrials.gov and search for this study to see if there are any study sites near you.

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