Sunday, October 4, 2015

Experimental MS Drug Ocrelizumab Deemed A Success In Progressive MS Trial, But Questions Remain

Last week, the drug company Genentech (a subsidiary of Swiss drugmaker Roche Pharmaceuticals) announced that its Phase III trials for treating Primary Progressive Multiple Sclerosis with the experimental MS drug Ocrelizumab had met with success. According to a press release titled “Roche’s Ocrelizumab First Investigational Medicine to Show Efficacy in People with Primary Progressive Multiple Sclerosis in Large Phase III Study”, the drug met the trial’s primary endpoint, “showing treatment with Ocrelizumab significantly reduced the progression of clinical disability sustained for at least 12 weeks compared with placebo, as measured by the Expanded Disability Status Scale” (click here). Earlier this summer two previous trials had shown Ocrelizumab to be more effective than the beta interferon drug Rebif for treating RRMS, resulting in reduced relapse rates, number of MS lesions, and a reduction in progression of disability (click here). Ocrelizumab is an intravenous drug that is administered twice over a two-week period, and then not again for six months.

While this would all appear to be great news, especially for people with PPMS who currently have no approved treatment options, just how great this news actually is remains to be seen as the press release provided absolutely no details on the study results, which will only be revealed on October 9 and 10th at the annual European MS conference ECTRIMS, being held in Barcelona, Spain. Understandably, news of Ocrelizumab’s success in treating PPMS has created quite a buzz in the MS community as well as in the financial pages of publications around the world, as the drug stands a good chance of becoming the latest multibillion-dollar blockbuster MS treatment (click here).

There is reason to believe, however, that Ocrelizumab may only be effective in treating a subset of patients suffering from Primary Progressive MS, specifically those who are less disabled (still walking), younger, and who display enhancing lesions on their MRIs. And though the press release states that the side effects experienced by study subjects taking Ocrelizumab were not much different than those who were given a placebo, back in 2010 trials testing Ocrelizumab for the treatment of Lupus and Rheumatoid Arthritis had to be abandoned because of an unacceptable number of serious and sometimes fatal opportunistic infections seen in trial subjects (click here).

How can I make any assumptions on Ocrelizumab’s efficacy at all based on the scant details divulged in Roche’s press release, you may ask? Well, it turns out that Ocrelizumab’s mechanism of action is nearly identical to that of a much older drug also manufactured by Roche, called Rituxan (Rituximab), which has been used for decades to treat cancers of the blood and for the last seven or eight years, on an off label basis, to successfully treat Relapsing Remitting Multiple Sclerosis.

In fact, back in 2008 Rituxan completed early stage trials (phase I and phase II) investigating its use in treating both RRMS and PPMS. In these earlier trials, Rituxan was deemed successful in treating RRMS (click here), but the drug failed in its much-anticipated trial for PPMS (click here). Subsequent to the PPMS trial’s completion, however, researchers combing through the data discovered that Rituxan did appear to have a beneficial effect on a subset PPMS patients, specifically those who were less disabled, were 50 years old or younger, and who had enhancing lesions, (click here). Ocrelizumab’s mechanism of action is so nearly identical to Rituxan’s that within the industry the drug has been nicknamed “brother of Rituxan”.

Why then was Rituxan not further investigated for the treatment of RRMS and PPMS, Roche and Genentech instead shifting their all of their attentions to costly process of developing a brand new drug that works in a very similar fashion, Ocrelizumab? Well, this is where things get interesting and more than a little bit curious. If I were a cynical man I might conclude that purely financial considerations were involved, but far be it for me to be so cynical. Instead, I’ll present you with the evidence as I know it, from which you may draw whatever conclusions you wish.

As I mentioned earlier, Rituxan is an older drug, and it is scheduled to lose its patent protection this year. Once the Rituxan comes off patent, Roche will lose its exclusive rights to the drug and thus the ability to generate tremendous profits from marketing it (click here). This fact made the return on investment of proceeding with very costly late stage MS trials in 2008 decidedly negative even if they proved wildly successful, because after 2015 another company could step in and market a generic version of Rituxan, thereby killing the drug’s profit making potential for Roche.

Both Rituxan and Ocrelizumab are in a class of drug called monoclonal antibodies, which are manufactured antibody cells that work by targeting specific cells in the human body. Rituxan and Ocrelizumab work by attacking B cells, one of the two primary types of cells that comprise the human immune system (these two types of cells are called T cells and B cells). They both seek out the same protein expressed on the cell walls of B cells, CD 20, and both drugs ultimately destroy almost all of the B cells in the human body using nearly identical mechanisms.

This anti-B cell approach is not taken by any other current MS drug, as until very recently it was believed that the MS disease process was driven primarily by T cells, which are the focus of drugs such as Tysabri and Gilenya (the latter of which recently failed in a recent PPMS trial). The fact that Rituxan and Ocrelizumab – which exclusively target B cells – are proving to be so effective in battling MS is forcing researchers to completely rethink much of what has been assumed in the understanding of the disease. Roche’s recent Ocrelizumab press release also contains hints that the drug’s action on B cells may have some neuroprotective properties, which if true would be truly remarkable. Of course, since Rituxan has already been used successfully to treat RRMS for quite a few years, the knowledge that a B cell immunosuppressant was capable of dramatically impacting the Multiple Sclerosis disease state was readily available, but also easy to ignore given the somewhat rogue nature of treating MS with Rituxan.

The difference between Ocrelizumab and Rituxan is the fashion in which they are manufactured. All monoclonal antibodies are “biologic” drugs, meaning they are derived from living animal cells, usually from a combination of mouse and human tissues. Most older monoclonal antibody drugs, such as Rituxan, are what is known as “chimeric monoclonal antibodies” (click here), meaning they contain both mouse and human DNA. Newer drugs such as Ocrelizumab are “humanized monoclonal antibodies” (click here), and have their DNA structure manipulated to more fully resemble completely human cells.

Although one might assume that humanized monoclonal antibodies would always be preferable to those that contain non-human DNA, Rituxan has been used for decades and has shown itself to be a very safe and effective drug. Although some cases of opportunistic infections, including PML, have been associated with Rituxan, they’ve appeared far less frequently than those seen with Tysabri (click here). Rituxan has proven itself successful in treating RRMS both in trials and in real life practice (the drug is FDA approved for the treatment of Rheumatoid Arthritis, and is used off label to treat a variety of other autoimmune diseases).

The Rituxan PPMS trials, though at first deemed a failure, did reveal a subset of PPMS patients on whom there was evidence of efficacy, and it appears that the Ocrelizumab PPMS trial was designed to capture as many of this type of patient as possible (click here). Had Roche pushed ahead with its Rituxan MS trials even in the face of a looming patent expiration we might have had another very effective treatment for RRMS, and perhaps even PPMS, for at least the last five years. Alas, ‘twas not to be, quite likely because Rituxan was scheduled to soon lose its patent protection.

I truly hope that when the full details of the Ocrelizumab trials are revealed at the upcoming European MS conference they exceed all expectations and make Rituxan look like a rusty old Model T compared to Ocrelizumab’s shiny brand new Maserati. If the new drug is in fact capable of stabilizing the disease progression of the majority of PPMS patients we will have a true game changer on our hands. Even if, as I suspect, the drug is shown to be effective on just a subset of PPMS patients – those who are younger, less disabled, and have enhancing lesions – it will represent a tremendous leap forward in the treatment of what has up until now been an untreatable disease. The fact that the drug exclusively targets B cells and benefits both the relapsing remitting and progressive forms of Multiple Sclerosis should send researchers scrambling to develop an entirely new model of the MS disease process, and, who knows, may lead to an eventual understanding of the ever elusive underlying cause of Multiple Sclerosis.

Here’s to hoping that the new drug proves to be as safe and reliable as the old one, Rituxan, and Ocrelizumab will become not only a powerful new weapon in the fight against MS, but also a catalyst for an entirely new way of thinking about the disease. For people with PPMS, this successful drug trial, even if limited, finally opens a door to treatment options and allows rays of hope to filter in through the clouds. We’ll begin to get our answers in just about a week, and I for one can’t wait for the data to be released.

Geez, that last line may be just about the wonkiest sentence I’ve ever written. I guess I just have to own up to the fact that I’m now a full-fledged MS research nerd…

40 comments:

  1. I will hope for the best. Of course I have reservations as well as others do. But I must keep hope in my heart because progressive MS has been ignored over the years by the pharmaceutical companies who seek profit=making medications (did I just say that?) I pray this new drug, and many others to come, will be able to provide a better quality of life for the more difficult forms of MS.

    Excellent, excellent post, Marc. Well done.

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    1. Thank you, Cathy. Unfortunately, if my presumptions about the trial outcomes are correct – that the new drug is effective in progressive patients with enhancing lesions – then a majority of people with PPMS will still be left without treatment. This will, of course, put the emphasis on the vital necessity of identifying the disease sooner rather than later, as enhancing lesions will show up early in the disease, if at all.

      Since the market for RRMS drugs has become "saturated" (their word, not mine) researchers are finally turning their attentions to progressive MS. This shift in focus may finally lead us to understand the root cause of the disease, as there is a growing amount of evidence that the aberrant immune response seen in MS patients is secondary to some other, yet mysterious underlying disease cause…

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    2. Will the drug manufacturers come to the conclusion that most ms patients end up progressing to ppms after a course of rrms whether it takes a year or 30 years to get there? Just make a drug for all occasions!?!?
      So they'll make their money off of us sooner or later (or all the way thru the unpredictable course of this damn disease) A win for them no matter what.
      Just a thought to ponder.
      Dee/OH

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    3. Editing my above post:
      I don't use the spms, ppms, prms, rrms terms correctly.
      But my point was _ I think most of us progress eventually.
      Dee/OH

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    4. Hey Anonymous, IN REPLY TO YOUR..."I think most of us progress eventually." My experience confirmed by what I was told by my neuro, is that most people that are unfortunate enough to develop/contract or otherwise catch MS start out with Relapsing Remitting MS then a percentage develop into Secondary Progressive MS, which mine did within a year of my RRMS whereas others, I'm thinking the Kamikazi developed from RRMS into Primary Progressive MS sometime after having already experiencing RRMS. As with all of our (MS sufferers) symptoms each person is unique and has their own experience with regards to disease development and progression.

      I have a question for the Kamikazi, I am on the cusp of beginning a prescription for medical marajuana and I have been doing my dutiful research investigating what my options are since it has been quite a few years since I have smoked or been involved with the culture/world of stoners in my youth. My question is, do you have any experience and would you mind sharing? I have given up on disease modifying pharma as I've found them of no use (Copaxone for 5 years). I also went to Poland for Zamboni's procedure that only alleviated my symptoms for 2 or 3 days...that was an expensive trip though Warsaw was a great trip. I live in Canada so I can actually access med mara legally and very inexpensively. Your thoughts would be appreciated.

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    5. Hi, just to be clear, patients with PPMS never go through a relapsing remitting phase, their disease just starts out in the progressive form. Anybody who turns progressive after having RRMS has SPMS. By definition, PPMS (primary progressive MS) means that the disease starts out as a progressive condition. SPMS (secondary progressive MS) is named "secondary" because it comes after the initial RRMS phase.

      I tried using marijuana a couple of years ago, but didn't really have much success with it. I do know a lot of patients who use it for their spasticity issues, and say it works well.

      I wasn't using medical marijuana, though, and there are certain strains of MJ that are bred to be high in the chemicals that would help alleviate spasticity. So, medical marijuana could very well work whereas the stuff that I was getting "off the street" just wasn't doing the trick.

      Another problem for me is that I never really enjoyed the marijuana high, even when I was a kid. And these days, the stuff is SO MUCH stronger than when I was a teenager (the 70s) that it's like a totally different drug. I used to be able to share a joint with a friend and go to algebra class and be mildly amused. Now, I take one or two tokes and I am completely ossified…

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  2. The other 'late breaking news' presentation at #ECTRIMS2015 is the work of the French group studying Biotin. It appears there is a race on for the market shares. Like you, I am awaiting the news on Saturday and what the true numbers might show.

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    1. Hi Laura, actually, I don't think Ocrelizumab and biotin would be in competition, rather their use may complement one another. Biotin MAY be neuroprotective, or it might just help damaged nerves conduct signal. Ocrelizumab is a sophisticated immune suppressant, so the action of the two drugs should be compatible. Maybe even synergistic. One can only hope…

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  3. Very interesting article... Especially since I'll be at ECTRIMS to cover the release of OPERA and ORATORIO...

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    1. Waiting with bated breath on the release of the study data. Lucky you, going to Barcelona. Should be a fascinating conference, lots of other very interesting presentations being given alongside the Ocrelizumab unveiling…

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  4. Thank you for your insight. I was waiting to hear your response about Ocelizumab! Everything you wrote was "spot on"!

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    1. Thanks Emma, and thanks for commenting. Hopefully this will be just the first in a growing number of ever more effective drugs for treating progressive MS…

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  5. Great post! I can't imagine what I'd do without your insights and research.

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    1. Shucks, Melinda, I'm unworthy of such praise. Why bother soaking up all of this MS research if I can't share it and make myself useful? As my mom used to say, share share, that's fair…

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  6. Just today I was met my new neurologist (last one closed shop). The discussion di touch on the available drugs existing today are for RR however what about the rest of us!
    Thank you the insight, ALWAYS appreciated.

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    1. You're very welcome. Hope things go well with your new neuro, and remember, if things don't go well don't hesitate to find yet another new neuro. Unfortunately, we're in long-term relationships with our treating physicians, so it's very important to find one that you can work with.

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  7. I understand, sort of, but, I can also afford to be less hopeful as MS is still an unknown. One drug for both RR and PP, alter the immune system, and life changing negative risks? I hope answers are offered to knock off my socks, as well as yours, Marc.

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    1. I'm not expecting any numbers that will knock my socks off, though I usually don't wear socks these days because it's so damned difficult getting them on. I am in complete agreement, all of the drugs currently available leave much to be desired, and the fact that so little research has been directed at finding the cause of MS borders on the criminal. But we are in a "pay to play" system, and curing people would put a big crimp in the bottom line of the big pharmaceutical companies. There is some reason for hope, though, as some of the upstart biotech companies are actually coming up with cures (hepatitis C was cured within the last couple of years, for instance), although the prices of the curative drugs are pretty much obscene. I'm a staunch capitalist, but as I've written many times on this blog, the marriage between unfettered capitalism and medicine is an unholy one.

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  8. I understand, sort of, but, I can also afford to be less hopeful as MS is still an unknown. One drug for both RR and PP, alter the immune system, and life changing negative risks? I hope answers are offered to knock off my socks, as well as yours, Marc.

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  9. Is it possible that this PP subset is actually more of an SP incarnation of MS? And if not, where do you think Secondary Progressive fits in all of this?

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    1. I think will be the same story with SPMS is with PPMS. If the SPMS patient in question still shows signs of active inflammatory disease (in the form of enhancing lesions) then Ocrelizumab will likely be effective. So, too, may be some of the currently available targeted immunosuppressants (Tysabri, Gilenya, etc.). The fact that you Ocrelizumab targets B cells does make it unique among the other drugs, though…

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  10. This was such a great post--thank you! I fit two of the criteria: I am young (39) and still walking relatively well, but I do not have enhancing lesions and I am actually SPMS, not PPMS. So curious to know whether the drug could possibly hold any hope for people like me. Fingers crossed...

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    1. We should know within the next few days what the study results holds. Are you currently on any disease modifying drugs? If so, that could be the reason you don't have enhancing lesions, as these drugs would suppress the immune system enough to curtail the formation of enhancing lesions. There is a trial investigating the use of Tysabri in SPMS, and the results should be coming out sometime this fall. So, yet another hook to hang some hope on. Unfortunately, even if successful, none of these drugs does a whit to cure the disease, but that's an old refrain by now…

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    2. Thank you SO much for this reply. Yes, I am on Tecfidera and I had never had it explained to me that that alone could be a reason I don't have enhancing lesions. So that is fascinating! (Although, to be totally honest, in my pre-Tecfidera MRI, I didn't have enhancing lesions either...) I am actually going to be starting intrathecal methotrexate next month, so right now, I'm holding out hope for that! thank you again for responding.

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  12. Thank you. �� Your writing is easy to follow and understand. I have HOPE.

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    1. Very happy to have given you some hope. Without hope, we are lost…

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  13. "..specifically those who were less disabled, were 50 years old or younger, and who had enhancing lesions."

    If these patients had enhancing lesions, shouldn't they be claissified as Primary Relapsing MS (PRMS) instead of PPMS? I think many of the DMD's do show efficacy in PRMS also.

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    1. Not necessarily. People with PPMS don't ever have relapses, but people with PRMS suffer relapses along with ongoing progression of disability. The presence of relapses is a likely indicator of enhancing lesions, so I would suspect that a higher proportion of people with PRMS then PPMS would have these inflammatory markers. But, still, it's important to differentiate between these two flavors of the disease.

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    2. It seems enhancing lesions may be more prevalent in the early stage of PPMS, so possibly this is why this was chosen as an inclusion criteria:

      http://www.ncbi.nlm.nih.gov/pubmed/20203148

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  14. I am also very curious for the results as I am in taking ocrelizumab already. I participeted in the OPERA study.

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    1. Has the drug been effective for you? Do you fit my supposed criteria – under 50, still walking, with enhancing lesions? Inquiring minds want to know… Thanks, too, for taking part in the study.

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  15. http://www.medpagetoday.com/clinical-context/MultipleSclerosis/54037
    You were completely right though, to tell the truth, I wouldn't have minded if you were wrong (no offense but im holding onto my last sliver of hope)
    Monica

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  16. Marc, I appreciate your comments here a great deal. I woke up with PPMS 10 years ago, and have been taking a yearly course of Rituxan for the last 5 (off-label of course, and getting it paid for is a story for another post since it is quite expensive) to "keep me stable" as my doctor sez. I take it on faith, since I have had no dramatic results but also don't appear to be developing lesions or declining much. On the other hand, I am over 60 and in a wheelchair, so I am not a “prime” subject for this to be a miracle drug for me.

    I read about the ocrelizumab trials a couple years ago, along with the Rituxan patent expiration and projected financial windfall if the new version could be marketed with FDA approval, so I am also quite skeptical. At this point, I’m not ready to chase ocrelizumab but would like to see what my doc thinks, he seems pretty good at trying to find functional, affordable approaches to those of us with PPMS. I tolerate the Rituxan well with virtually no adverse side effects, so I would love to see the price come down. Otherwise, I’ll probably stick to it as long as it seems to work for me.

    PS Last week I was shocked to see ads for Tecfidera on television! There must be a critical mass of MS patients to make it worth the investment … or mebbe they want to get a jump on the clamor for ocrelizumab soon to come?

    Nan in New Mexico

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  17. Sorry, forgot to publish the source for the above negative information:

    Source
    http://multiple-sclerosis-research.blogspot.com/2015/10/clinicspeak-highlights-and-hot-topics.html

    Regards
    Olof

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  19. Is there a way to become a test patient for new drugs if one can´t afford them when they come out?

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    1. Your best bet is probably to look at the ClinicalTrials.gov website to look for appropriate trials in your area. I believe you can search by disease and location…

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  20. Mark, with the deluge of articles about the new Roche drug, have you been able to decipher whether or not it's considered to be enough different from Rituxan to make it preferable? I share your concerns that this is a financially driven event because of the fact that Rtiuxan's patent is about to run out.

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    1. Well, given the fact that Rituxan has been used quite successfully and with relative safety for quite a few years now, it would be hard for Ocrelizumab to beat it in any objective terms. The mechanism of action between the two drugs is not quite identical, but very close. Rituxan is still being used to treat rheumatoid arthritis and lupus, and, as I've written, the Ocrelizumab trials for those two indications had to be halted due to patient deaths. So…

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