Saturday, 22 April 2017

#ThinkSpeak: blinkered

What do you do when your neurologist knows best and says no? #ThinkSpeak #MSBlog

The other day an esteemed colleague, who is based in the US, contacted me as a co-author on the ocrelizumab in PPMS (Oratorio) study, to ask me 'how could I support the study's claim that ocrelizumab was effective in PPMS?'. He said the study was only positive because it was loaded with relapsing patients. The latter is based on the observation that approximately a quarter of subjects had Gd-enhancing lesions on their baseline scan.

I informed him that he was wrong for several reasons:

1. Firstly, the subjects in this study had PPMS. Anyone with a history of relapses was excluded.

2. It is not uncommon for pwPPMS to have Gd-enhancing lesions on MRI, particularly early in the course of their disease. I pointed out that the reason why a quarter of subjects had active baseline scans was that this was an early, and relatively young, population of PPMSers. The latter didn't occur by chance but by design. The study design was informed by the rituximab in PPMS trial, which showed that younger people with active MRIs were more likely to respond to treatment in a short period of time. To ignore this insight would have been folly.

3. I mentioned to him that the study was also positive across numerous secondary and tertiary endpoints, including objective MRI outcomes. Surely this meant the drug was working?

4. I explained to him my length-dependent axonopathy hypothesis and sent him our recent publication, which goes a long way to explaining the ORATORIO results. He said very interesting, but this didn't change his position.

5. I pointed out to him that although the treatment effect on EDSS and timed-25ft walk was relatively modest (~25% slowing of progression), the impact on upper limb function (9-HPT) was almost double (~45%). Wasn't ocrelizumab indicated on this observation alone? This particular individual is fully aware about how important hand function is for pwMS.

6. I also said that ocrelizumab worked in both cohorts of subjects, those with and without Gd-enhancing lesions at baseline. Although the results in these two subgroups were not statistically significant, the positive trends were obvious. It is important to realise the study was not powered to test a treatment effect in these two cohorts therefore we have to accept the overall results at face value. 

Despite my protestations he informed me that although all my points were interesting and valid he was not convinced by the science and therefore would not be offering ocrelizumab to his patients with PPMS. How do I respond to this? As I said last weekend neurologists are never wrong they can always justify their position from their own perspective. All I that I can hope is that pwPPMS under his care are informed and active. They need to arm themselves with knowledge and ask the right questions. If you aren't satisfied with the answers challenge them and ask some more questions. If you are still not satisfied you can always vote with your feet. 

This episode is deja vu. Almost the exact scenario played out in the UK when the interferons were launched for treating RRMS. Many neurologists would not accept that this class of drug was effective and hence were not offering them to their patients. Gradually things changed and most neurologists now accept that DMTs do modify the course of RRMS. I can only expect the same thing to happen with the treatment of more advanced MS (formerly know as progressive MS). Let's hope so for the sake of the thousands of PPMSers out there. 

Montalban et al. Ocrelizumab versus Placebo in Primary Progressive Multiple SclerosisN Engl J Med. 2017 Jan 19;376(3):209-220.

Background: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primaryprogressive form of the disease. 

Methods: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. 

Results: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. 

Conclusions: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO number, NCT01194570 .).

CoI: multiple


  1. Are disagreeing with your colleague, or not? Is he wrong?

  2. Let's say we are agreeing to disagree. As I have said both of us are right, but from our own perspectives. I am convinced that the data in the ORATORIO trial is robust, he isn't convinced. Interestingly, his is position is at odds with the FDA decision to license the ocrelizmuab for PPMS.

    What people don't understand is that medicine is not black-and-white but gray.

  3. Dr. G, I'm interested in your feelings regarding ocrelizumab versus Rituxamab. My own neurologist, whom I believe you are acquainted with, is refusing to prescribe Ocrevus, primarily on the basis of the perceived cancer risk. He will continue to prescribe Rituxan, though, as he's had much success using this drug in his relapsing patients, and some success with his progressive patients.

    I must say that I am bothered by the Ocrevus progressive MS trial design. Yes, of course, it was based on the previous Rituxan PPMS trial results. But by overloading the trial with patients who had enhancing lesions, Genentech basically guaranteed a positive signal for this trial.

    Furthermore, the trial population does not represent properly the PPMS population at large. The trial population included roughly double the amount of patients with enhancing lesions than would be seen in the real-life PPMS population. And was it by sheer accident that the trial was "underpowered" to provide data on a subset basis? Wouldn't it have been prudent to design a trial that would properly discern which patients derived the most benefit from the drug?

    Can't help but think that Genentech designed the trial this way precisely to avoid having to publish such details, as this would have inhibited their getting a blanket FDA approval for progressive MS.

    I also fear that he "success" of this trial will only further take the attentions of researchers off of looking for the underlying root causes of the neurodegenerative process seen in progressive MS, and send them yet again looking for newer and better ways to suppress the immune system.

    Seems to me that MS research has fallen into a vicious cycle, whereby the success of the immunosuppressive drugs has diminished the search for the actual root cause of the disease. Clearly, the aberrant immune response seen in multiple sclerosis and other autoimmune diseases is more a symptom than a cause, as some much deeper ill must be causing the immune system to go awry. And fewer and fewer researchers seem to be searching for this deeper ill. After all, shouldn't the goal be to cure, rather than to treat?

    I truly do appreciate your hard work on this topic, and the sweat equity you put into the ocrelizumab research and trials. I hope the drug eventually proves even more successful (and safer) than the trials indicate. However, given the failed Lupus and RA trials (halted due to patient deaths), the quite high cancer rate seen in the PPMS trials (more than one in 50 patients developed neoplasms), and the remaining questions over efficacy, I'm left to wonder whether my neuro is right in sticking with Rituxamab (with its long history of relative safety and efficacy) and shying away from Ocrevus, at least until real-life clinical data can be accumulated.

    Would love to know your thoughts on these matters…

    1. WK - thanks for the comment. I am going to have to take time to answer all your questions and will need to do a separate post on the trial design of the ORATORIO study.

      However, I have already made the case for the use of ocrelizumab, over that if rituximab, based on NABs.

      Regarding cancer risk this is difficult, but I have heard from an unofficial source that there is also a Ca signal for rituximab in RA. The latter is likely to complicated by other exposures. So I don't think rituximab is necessarily safer than ocrelizumab.

      At present the cancer risk on ocrelizumab needs more data; it was only seen in 1 out of 3 studies and at present the confidence intervals are still within the ‘standardise incidence rates’ from the general population. We will only answer the question regarding cancer risk from post-marketing surveillance studies. In other words we need the drug to be used to collect the data.

      What will drive prescribing is economics. This won't be an issue in the UK. The NHS will not allow us to use rituximab. However, in resource poor settings I am sure patients, neurologists and payers will push for the use of the cheaper option.

      The deaths in the SLE/RA trials are complicated by possible genetics factors; almost all the deaths were in people in with Asian ancestry and were likely to be due to rare genetic variants that predisposed carriers to infections. In addition, SLE and RA patients who were exposed to ocrelizumab were generally 'not systemically healthy', i.e. they had been exposed to a large number of other immunosuppressive drugs prior to receiving ocrelizumab. Going back to the data from the three phase 3 studies ocrelizumab looks very clean; in fact it was safer than interferon beta. The latter, however, does not refer to long-term safety.

    2. Regarding the trial design of the Oratorio study and PPMSers with enhancing lesions, would not most if not all progressive patients have enhancing lesions? They have active, inflammatory lesions that lead to increased EDSS without remission. I would expect that SPMS patients may not have active inflammation but long term axonal loss and neurodegeneration.

    3. As a follow up to my initial comment, if progressive patients (SPMS and PPMS) do not have BBB permeability as described in previous papers then why would they respond to ocrelizumab iv? As noted, PPMSers with enhancing lesions were in the ORATORIO trial. Is there still a debate whether progressive MS has a peripheral immune component?

    4. Dr. G, thanks so much for your answer. Looking forward to reading your take on the ORATORIO trial design.

      In regards to the Ocrevus cancer risk, the thought that we'll only be able to ascertain the actual level of risk by using the drug in a clinical setting over time is discomforting. Of course, there's no way to do it otherwise, but I fear that the MS population is already being treated as guinea pigs in a mass experiment on long-term profound and targeted immunosuppression, so throwing in the added risk of cancer only compounds the issue.

      Thanks for the info on the SLE/RA patient deaths, I hadn't realized there was a ethnic component involved. Wonder why that hasn't been publicized, political correctness?

      As far as NAB's go, have we seen a problem with NAB's in relation to Rituxamab? As you noted, the drug has been used rather extensively in RA, and in some places to treat MS, and I've not read of any problems caused by neutralizing antibodies. The Swedish retrospective study didn't mention this, nor anything about a cancer signal.

      Just FYI, here is the statement put out by my neuro's clinic regarding Ocrevus and the cancer risk. They mentioned nine cancers in patients from the RRMS trial, developed within three years after the trial ended. This is in addition to the cancers seen in the progressive MS trial:

      Any comments on this that you would care to share would be much appreciated. Again, thanks for your comments, and I hope you don't mind my lengthy inquisitions.

      Steve S-most progressive MS patients do NOT have enhancing lesions. In fact, one of the hallmarks of progressive disease is the lack of enhancing lesions. It's estimated that somewhere between 10%-15% of PPMS patients have enhancing lesions, and these are mostly patients very early in their disease course (younger, less disabled). It would appear that there is some other neurodegenerative process going on in progressive MS, which probably has little to do with the peripheral immune system. Very well could be linked to immune activity sequestered entirely within the CNS, via tertiary lymphoid tissues producing B cells and other immune components. Not sure this would explain the continuous neurodegeneration seen in many patients, though, as B cells are not always detected in the CSF of such patients.

      SPMS patients later in their disease course also do not commonly display enhancing lesions, though those in transition from RRMS or early in the SPMS process sometimes do.

    5. Thank you WKamikaze. It's good to read something down-to-earth and honest.

    6. "In regards to the Ocrevus cancer risk, the thought that we'll only be able to ascertain the actual level of risk by using the drug in a clinical setting over time is discomforting."

      This will be true of all drugs and cladribine, this is because a two year study is simply not long enough to capture relatively infrequent events. We have to remember that cancer is part of life, but immunology tells us that anything that removes large chunks of the immune system, will put the person at increase risk of cancer, as the immune system can keep them in check.

      10-15% have gadolinium lesion. A lesion lasting a month at a point in time,

  4. Wow. You deserve a decent answer. I hope Gavin will respond.


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