#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 ClinicalTrials.gov number, NCT01194570 .).

CoI: multiple

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