Monday, May 15, 2017
Ocrevus: Dialogue Between Two Neurologists
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.
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?'
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 relapses. 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.
'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.
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…