click here), Ocrelizumab was touted as the first MS drug shown capable of putting the brakes on Primary Progressive Multiple Sclerosis (PPMS) – a subtype of the disease which until now has been largely untreatable – as well as it being highly effective in treating the more common Relapsing Remitting Multiple Sclerosis (RRMS). These results were even more noteworthy because Ocrelizumab is the first MS drug to specifically target immune system B cells, while other currently available MS drugs (Tysabri, Gilenya) were developed to target T cells, which until now were believed by many to be the primary culprits driving the MS disease process.
Though the initial Ocrelizumab press releases were scant on details, the news certainly appeared promising, though reservations were expressed by many MS researchers based on Ocrelizumab’s development history and its close similarity with another Roche product, Rituxan, a much older drug that had gone through early trials in RRMS (very successful) and PPMS (largely a failure, but with some hints of success) back in 2005-2008. Rituxan’s development as an MS treatment was halted by Roche because of what many believe to be strictly financial concerns. Reading my previous essay (click here) will provide much background on Ocrelizumab’s development and the issues surrounding the drug.
Roche presented the details of the Ocrelizumab RRMS and PPMS trials this past weekend at the ECTRIMS conference in Barcelona, Spain. The RRMS trials were named OPERA I and OPERA II, and the PPMS trial was named ORATORIO. The results of the OPERA I and OPERA II RRMS studies were indeed impressive. These studies compared Ocrelizumab to Rebif, an interferon drug long used to treat RRMS, and found that treatment with Ocrelizumab resulted in a 50% reduction of annualized relapse rates, a 40% reduction in progression, and an 80% reduction in enhancing lesions as shown on MRI when compared to patients taking Rebif (click here – login required, but sign-up process is easy and well worth it). Adverse events were found to be similar in both groups, which is encouraging as Rebif is considered one of the safer MS medications currently available.
It should be noted, however, that the two-year length of these trials may be insufficient to detect longer-term problems that may develop as a result of the intense B cell suppression that is Ocrelizumab’s primary mechanism of action. Nevertheless, it does appear that Ocrelizumab will become a very valuable weapon in the growing arsenal of drugs used to combat RRMS, though, like all current MS drugs, it doesn’t do a thing towards actually curing the disease. But I’ll save that rant for another day…
(Please note, the following information and accompanying commentary were largely gleaned from materials contained in articles and interviews that can be accessed by clicking here, here, here, and here. I would urge all to read them for greater context and background)
Results of the ORATORIO PPMS study, while initially impressive, still remain riddled with questions. Despite the screaming headlines hailing Ocrelizumab as a “revolutionary new MS drug” by the – as usual – hyperbolic mainstream medical media (click here), the actual picture remains far more nuanced. The ORATORIO trial design was heavily influenced by the results of the failed Rituxan PPMS trial back in 2008. Though that trial was officially deemed unsuccessful, subsequent examination of the data revealed that a subset of PPMS patients in the study were seemingly helped by the drug. These patients were generally younger, had shorter disease duration, were less disabled, and had enhancing lesions on their MRIs. It’s thought that patients who fall within these parameters make up about 15% of the overall PPMS population.
It appears that in designing the ORATORIO study, Roche chose trial subjects who were most likely to benefit from Ocrelizumab treatment, specifically those who fit the demographic and disease parameters outlined above. As presented at ECTRIMS, the results of the ORATORIO study are indeed impressive, demonstrating a marked slowing of disease progression, a reduction in MS enhancing lesions, a reduction in brain volume loss, and a stable time to walk 25 feet when compared to trial subjects given a placebo. Of course, these results also mean that many of the ORATORIO trial subjects were patients with enhancing lesions (only a fraction of PPMSer’s have such lesions) and who were relatively less disabled (as evidenced by the fact that they could still walk). The majority of trial subjects also appear to have been relatively recently diagnosed, with a disease duration of approximately 3-5 years, and were under 50 years old.
Unfortunately, when Roche presented the ORATORIO results at ECTRIMS, they declined to detail the breakdown of results by patient subgroups, claiming that such subgroup analysis had not yet been satisfactorily completed. This beggars belief, as one would think that examining the data in such a way as to determine which patient groups benefited the most from treatment would be among the highest research priorities, especially given the mixed results of the previous Rituxan PPMS trials. Instead, Roche chose to give a broad overview of favorable trial results without answering some of the most important questions about those results, primary among them whether or not the patients who most benefited were those with enhancing lesions. Indeed, in the Q&A period following Roche’s presentation, presenters were questioned on just this issue by conference attendees, who were given no suitable answers other than promises that the data would be forthcoming. Roche's presentation led several experts to say the primary progressive data were less impressive than those seen with Ocrelizumab in relapsing remitting disease.
Although Roche portrayed the safety profile of Ocrelizumab in the ORATORIO trial to be excellent, they did note that there were 11 cancers detected during the ORATORIO trial on patients taking Ocrelizumab, versus only two in the placebo group.
The results of the Ocrelizumab RRMS and PPMS studies have not yet been published in any scientific journals, and it is expected that much additional data will need to be provided to publishers before the trial results will be deemed fit for publication. Getting the drug through the regulatory approval process required by government agencies such as the FDA will also necessitate a much greater detailing of trial results, including subgroup analysis which will shed light on just which patient groups were treatment responders. While it seems that the RRMS results will likely stand up to more intense scrutiny, the PPMS results may prove to be less dramatic than originally portrayed when subjected to the spotlight of journal publication and regulatory approval.
That said, even in a worst-case scenario in which only a small subgroup of PPMS patients, those with enhancing lesions, prove to benefit from Ocrelizumab treatment, the fact that any headway at all has been made in treating PPMS is a significant step forward. If in fact the drug’s efficacy is limited to patients with enhancing lesions, and such lesions are most likely to be found in patients in the earliest stages of the disease, the importance of early diagnosis will be brought to the forefront. Given current diagnostic tools and techniques, many patients with PPMS aren’t correctly diagnosed until the disease has long since taken hold, beyond the period when enhancing lesions are likely to be present. Additionally, the fact that Ocrelizumab targets B cells should open up new avenues of investigation for MS researchers worldwide, as this potential mechanism of MS disease action has until now been largely discounted by most mainstream researchers. Perhaps these investigations might finally unravel some of the deepest mysteries of the disease, and (crossing the fingers I can still cross) eventually lead to a cure for all forms of the disease.
At this point, only time will provide us with the answers we seek. The next chapters of the Ocrelizumab saga will be getting these studies peer-reviewed and published in medical journals, a process which will shed much light on issues still in need of clarification. Roche is targeting the first quarter of 2016 for regulatory approval in both RRMS and PPMS. It will be very interesting to see whether or not Ocrelizumab is approved for the PPMS population as a whole, or, as many researchers suspect, for only a subgroup of progressive MS patients. Again, even if the latter case holds true, we will have at least made some headway in the fight against an insidious form of Multiple Sclerosis that until now has defied efforts to combat it.
At long last, it appears that the attentions of Multiple Sclerosis researchers are finally focusing on progressive MS, an area of investigation which until very recently had largely been neglected. The confounding problems represented by progressive MS will never be solved until well-funded trials are directed specifically at this disease subtype, a circumstance that finally seems to be coming to fruition. And that’s no small thing…
Excellent summary. Thank you very muchReplyDelete
You're very welcome…Delete
Marc, thank you so much for your analysis. As someone with PPMS who is older, has had MS for 15 years, has no and enhancing lesions, and is more severely disabled, you are helping me keep this in perspective. By the way, I was part of the earlier Rituxan trial for PPMS to which you refer. I found that Rituxan stopped my disease progression for the first year, but the progression returned in the second year.ReplyDelete
Hey Mitch, thanks for commenting. I actually think it's fairly egregious how Roche and the medical press have overhyped Ocrelizumab as a treatment for PPMS. They've gotten lots of people's hopes up, and unfortunately I'm afraid many folks are going to be very disappointed. I also tried Rituxan years ago, but it didn't do anything for me. I suppose the fact that he gave your one-year reprieve is a good thing, and certainly worth the effort, I would think. Hope you're doing well, or at least as well as well can be…Delete
Thank goodness you are tracking this stuff, Marc; thank you!ReplyDelete
Would you do an update on the CCSVI thing one of these days?
Hey Daphne, I would do an update on CCSVI if there was anything to update. There are a few research efforts ongoing, but for the most part things on that front of really quieted down. Very few doctors are doing the venoplasty procedure, and patient interest is dropped off dramatically. The majority of patients who did undergo the procedure found that the benefits they attained, if they attained any at all, wound up to be relatively short-lived. There are still does, however, who did see dramatic improvement that prove to have durability. Lots left to learn, I think, so hopefully the ongoing research will bear fruit.Delete
The other big question that is still to be answered given that Ocrelizumab will likely be priced in the stratosphere is how this compared with the earlier studies of Rituxan.ReplyDelete
Well, let's put it this way. Rituxan is still being used to treat lupus and rheumatoid arthritis, where is the Ocrelizumab trials for those diseases were halted because of patient deaths. Rituxan has proven to be an effective and relatively safe drug when used to treat RRMS, and the 11 cancers seen in the Ocrelizumab RRMS trials are worrying, to say the least. Despite the protestations of the drug company, it's hard to draw any conclusion other than the primary factor driving Ocrelizumab's development was the fact that Rituxan is due to come off patent this year. And, yes, I'm sure the drug will be priced in the same $50,000-$60,000 range of all of the other MS drugs… Free-market capitalism when it comes to the pharmaceutical companies? Ha! Seems like collusion at it's very worst… Then again, as a society we have allowed to go into affect the rules and regulations that make for this kind of an environment. So maybe the shame is on us…Delete
Marc, thanks so much for your diligence on this matter. Your accounts are SO much more readable and understandable than the more "scientific" reports put out by clinics and drug companies. I've had two courses of Rituxan for PPMS and, to be honest, can't determine either a positive or negative outcome at this point. But isn't that the way with almost all drugs? It's difficult to know how you'd be doing had you taken nothing. Have you found anything put out by Roche that even mentions Rituxan? Or any data that would indicate it being worthwhile trying to change from Rituxan to Ocrelizumab?ReplyDelete
Seems like Roche would rather people forget about Rituxan, although they do continue to market the drug for other indications. I wouldn't think there would be any benefit of switching from Rituxan to Ocrelizumab, since they use an almost identical mechanism of action.Delete
It is very difficult to judge the efficacy of drugs in progressive MS trials, because in general progression of disability proceeds at a much slower pace than is usually expected, even by the patients themselves. Therefore, either drug trials need to be of longer duration, or other markers, perhaps something like brain volume loss, need to be implemented.
Thanks for your kind words, and for your comment…
Doesn't Alemtuzumab (Campath) also target b cells?ReplyDelete
Alemtuzumab targets just about the entire human immune system. It basically takes down a patient's existing immune system and then re-populates it with new cells. Much like HSCT, the stem cell therapy in which strong chemotherapy drugs are used to ablate the immune system, which is then rebooted using a patient's own bone marrow derived stem cells. In many respects, alemtuzumab is HSCT in a bottle.Delete
Also, in theory, at least, the vast majority of patients correctly chosen to do alemtuzumab would most likely not need further treatment for many years after going through the initial one-year regimen. Ocrelizumab will require intravenous infusions every six months, and likely won't have the efficacy rates seen with alemtuzumab. Unfortunately, alemtuzumab also comes with some troublesome side effects, including a potentially deadly blood disorder. Seems like there's always a catch…
BTW, alemtuzumab will not be of any use in patients without enhancing lesions, which includes the vast majority of patients with progressive MS…
Thank you. I have PPMS and I feel it progressing. I am fearful.ReplyDelete
You have every right to feel fearful, but don't give up hope. Researchers are finally starting to focus on progressive MS, and though progress won't be as fast as we like, there should be some breakthroughs on the horizon… Wishing you the best…Delete
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I'm going to translate in Italian, your post. thank you!ReplyDelete
Thank you Marc for an excellent analysis and report. I always read your artcles with great interest. Thank you again. JohanReplyDelete
You're very welcome, Johan. It pleases me to be of service…Delete
That was an outstanding report. Well done.ReplyDelete
Have you reviewed March 2016 update? Thanks for your service! http://www.nationalmssociety.org/About-the-Society/News/More-Results-Released-from-Positive-Phase-III-ClinReplyDelete
Thank you for the much needed reportReplyDelete
Excellent practical & succinct overview of a subject with much misinformation & conflicts of interest! Great blog. Keep smiling. ;-) RossReplyDelete