ResearchSpeak: rituxumab vs. fingolimod post-natalizumab

When is real-life evidence good enough to change clinical practice? #ResearchSpeak #MSBlog #MSResearch

"When head-2-head trials are difficult to do, i.e. they are too expensive and/or involve off-label prescribing, you have to rely on real-life data. In Sweden, due to local economic factors, neurologists have been using off-label rituximab post-natalizumab in MSers at high-risk of PML. The practice has been variable with some centres using fingolimod in this situation; fingolimod is what we tend to use at Barts-MS. When the Swedes compared the results of the rituximabers vs. the fingolimoders it was quite clear that rituximab was superior to fingolimod in preventing rebound post-natalizumab. Am I surprised? No, based on the phase 2 rituximab, ocrelizumab and ofatumumab trials and the phase 3 ocrelizumab results you would expect anti-CD20 as a class to be superior to fingolimod. The more important question is will rituximab be safer? I am aware of at least 15 cases of carry-over PML in patients transitioning from natalizumab to fingolimod and fingolimod is itself associated with a PML risk (5 cases reported to date in MSers not previously not exposed to natalizumab). Although rituximab has been associated with PML in the setting of RA and SLE, all the cases of PML, except for may be one, were complicated by prior treatment with multiple immunosuppressive agents. Therefore, rituximab, and anti-CD20 therapies in general, will probably have a low risk of PML when used as monotherapy. Why? Anti-CD20 treatments are selective B-cell depleters and leave the T-cell compartment intact. T-cells, in particular CD8+ cytotoxic T cells, are what you need to fight and keep the JC virus at bay. Therefore I suspect the PML risk post-natalizumab in anti-CD20 treated MSers will be low."

"When the data below was presented at ECTRIMS last year we applied to NHS England to get rituximab into our guidelines to be used post-natalizumab in place of fingolimod. We were told that the neurology clinical reference group (CRG) will review the evidence and come back to us with a decision of either yes or no. Well it is now 6 months later and we haven't heard anything. Not only is rituximab more effective than fingolimod, and possibly safer, it is also cheaper than fingolimod. So a switch in prescribing from fingolimod to rituximab would actually save NHS England money. However, I suspect the decision not to allow us to use rituximab is more nuanced and relates to the fact that we would be using it off-label. In comparison, fingolimod is a licensed drug for treating RRMS. The political shenanigans of payers goes way beyond common sense and I suspect they have to protect the innovations of big pharma from predatory off-label prescribing. Once you allow off-label prescribing for a narrow indication, prescribing will spread to other areas. Pharma tell us if we don't protect their IP it will remove their incentive to innovate and we will all be the poorer for it in the long-term. Unlike the Swedes we will almost certainly have to wait for a licensed anti-CD20 therapy to come along. If all goes well we should be able to start prescribing ocrelizumab to MSers in about 18-24 months time. The problem with having to wait 24 months is that we are disadvantaging a relative large group of pwMS. Who knows may be NHS England, after reading this post, will surprise us and allow us to prescribe rituximab to pwMS off-label. What do you think the chances are, of this happening?"

"Please note rituximab is one of our essential off-label DMTs to be used to treat MS in resource poor settings. In addition, there are rituximab biosimilars out there that look as good as the innovator compound." 

Alping et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016 Mar 31. doi: 10.1002/ana.24651.

OBJECTIVE: Many JC-virus antibody positive relapsing-remitting multiple sclerosis (RRMS) patients stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy (PML).

METHODS: We compared outcomes for all RRMS patients switching from natalizumab due to JC-virus antibody positivity at three Swedish MS centres with different preferential use of rituximab and fingolimod, respectively; Stockholm n=156 (fingolimod 51%); Gothenburg n=64 (fingolimod 88%); UmeĆ„ n=36 (fingolimod 19%); yielding a total cohort of n=256 (fingolimod 55%).

RESULTS: Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab 0.10 (95% CI: 0.02-0.43)). The hazard ratio (favouring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI: 0.10-0.59) and 0.07 (95% CI: 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) vs 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio 0.05 (95% CI: 0.00-0.22)). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study centre).

INTERPRETATION: Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC-virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in two of the centres mitigates these concerns. This article is protected by copyright. All rights reserved.

CoI: multiple

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