Is it right to go off-label? the rituximab story continues to run....

CD20 depletion seems an obvious choice when you look at the real-life data.

The Swedish neurologists are walking-the-talk. It looks as if the majority of people with MS are being treated with rituximab off-label? How come? I was under the impression that this was illegal under EU law. EU law is meant to protect Pharma's interests, i.e. healthcare systems are meant to support licensed drugs. This issue is a hot potato in England. Bayer has brought a legal case against NHS England about the off-label use of bevacizumab (Avastin, Roche) to treat wet macular degeneration instead of the licensed products aflibercept (Eyelea, Bayer) and ranibizumab (Lucentis, Novartis). Maybe Britain's gift to the EU as it exits the EU is the halting of off-label rituximab use for MS across Europe. If Bayer wins their case in Britain, a legal precedent will be set and the ruling will ripple across Europe. 

My personal opinion on off-label use is well known. I actively promote it in resource-poor environments where patients simply can't afford the high-cost licensed innovator treatments. As a neurologist treating patients in these circumstances you have to make do with what is available, and affordable, and in the best interests of your patients. However, in rich countries, we have a collective responsibility to reward innovation and protect the incentives that drive investment in drug development, not only for MS but other diseases. This does not only apply to Pharma but also for University-based drug discovery. The wide off-label use of rituximab in Europe to treat MS is challenging these guiding principles. It is clear that EU politicians are going to have actively engage with this issue. Or not? 

One way to get around this issue is for the wider MS community to generate data of sufficient quality to get rituximab licensed to treat MS. The COMBAT-MS study that is currently being performed in Sweden and the US may provide such evidence.  The question I have is will anyone have the resources and motivation to file a submission to the EMA to get rituximab licensed?
NHS England will not reimburse the use of rituximab to treat MS on the NHS. This means it is not possible for English people with MS to benefit from rituximab in the same way as hundreds if not thousands of Swedish MSers do. It is clear from the Swedish data below that Rituximab is a very high efficacy therapy in the same bracket as Natalizumab. Real-life data also demonstrates that rituximab use in real-life is relatively safe. 

At Barts-MS we are particularly interested in what anti-CD20 therapy is telling us about MS. Its effectiveness is telling us something fundamental about the pathogenesis of MS. We have hypothesized that all DMTs work via depleting memory B-cells, or by preventing the trafficking of memory B-cells into the CNS. The only way to test this hypothesis is it to develop a specific therapy that selectively depletes, or inhibits, the memory B cell population. 

Testing such strategies will be difficult because we now have such effective anti-inflammatory DMTs, which makes the ethics of comparing new, or emerging DMTs, against placebo or less effective platform therapies questionable. Any ideas of how to solve this problem would be welcome? 

Granqvist et al. Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis. JAMA Neurol. 2018 Jan 8. doi: 10.1001/jamaneurol.2017.4011.

IMPORTANCE: Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.

OBJECTIVE: To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab.

MAIN OUTCOMES AND MEASURES: All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed.

RESULTS: Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Västerbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Västerbotten compared with Stockholm (0.09 and 0.37, respectively).

CONCLUSIONS AND RELEVANCE: Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.

Memon et al. Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases. PLoS One. 2018 Jan 8;13(1):e0190425. doi: 10.1371/journal.pone.0190425. eCollection 2018

BACKGROUND: B-cells play a pivotal role in several autoimmune diseases, including patients with immune-mediated neurological disorders (PIMND), such as neuromyelitis optica (NMO), multiple sclerosis (MS), and myasthenia gravis (MG). Targeting B-cells has been an effective approach in ameliorating both central and peripheral autoimmune diseases. However, there is a paucity of literature on the safety of continuous B-cell depletion over a long period of time.

OBJECTIVE: The aim of this study was to examine the long-term safety, incidence of infections, and malignancies in subjects receiving continuous therapy with a B-cell depleting agent rituximab over at least 3 years or longer.

METHODS: This was a retrospective study involving PIMND who received continuous cycles of rituximab infusions every 6 to 9 months for up to 7 years. The incidence of infection-related adverse events (AE), serious adverse events (SAE), and malignancies were observed.

RESULTS: There were a total of 32 AE and 4 SAE with rituximab treatment. The 3 SAE were noted after 9 cycles (48 months) and 1 SAE was observed after 11 cycles (60 months) of rituximab. There were no cases of Progressive multifocal leukoencephalopathy (PML) and malignancies observed throughout the treatment period. Rituximab was well tolerated without any serious infusion reactions. Also, rituximab was found to be beneficial in treating PIMND over a 7-year period.

CONCLUSIONS: This study demonstrates that long-term depletion of peripheral B-cells appears safe and efficacious in treating PIMND. Longer and larger prospective studies with rituximab are needed to carefully ascertain risks associated with chronic B-cell depletion, including malignancies. Recognizing that this is a small, retrospective study, such data nonetheless complement the growing literature documenting the safety and tolerability of B-cell depleting agents in neurological diseases.

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