Tuesday, 5 April 2016

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%); Umeå 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

26 comments:

  1. "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?"

    Close to zero I'd say as this would be BartsMS Blog going one better than the CRG, and we shouldn't get carried away. Big Money will keep driving the agenda as long as it can with lobbying (politicians, health care [NHS and others] managers, doctors, pharmacists, MS nurses...), perks (invitations to conferences/educational activities/advisory boards) and sticks (none of the above) skilfully applied.

    It is almost impossible to make 'independent' decisions based on medical need only - if that were the case, why does Gothenburg prescribe four times as much fingolimod as Umeå does? Did most of these neurologists not train in essentially the same health care environment?

    Apart from the impressive primary result, this study is a welcome reminder how budget allocation influences decision making, in this case leading to an excellent outcome in favour of an off-label treatment. Particularly health care environments with limited budgets (but perhaps less of the type of regulation that serves Big Money at least as much as the safety of pwMS) should take note and perhaps produce better outcomes!

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    1. When ocreluzimab comes along will they switch to ocrelizumab which is going to be more expensive or stay with something they have experience on?

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    2. They might be in a reasonable position to negotiate a rebate (or some bearers with Mossack Fonseca - just joking!).

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    3. FYI Mossack Fonseca is a law firm in panama who have apparently helped clients launder money, dodge sanctions and avoid tax...wonder if phamra are clients:-)

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    4. The leak of Mossack Fonseca data been doing a real mess around here in Brazil ...

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  2. ProfG is this your real life experiemence of about 20% of people relapsing. You say you are switching to fingolimod as NHS England won't pay for rituximab and you have said in the past your are doing yearly scans. Confirmatory evidence would be good and it should be simple to check your records?

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    1. Not ProfG, but we've presented some evidence at the European Academy of Neurology last year.

      pwMS were divided into short interval (n= 15; mean 30 days delay) and long interval (n=10; mean 179 days delay) groups. Mean follow-up was 6.5 months.

      No relapses occurred within one year in the short, however 3 in the long interval group (which we don't do anymore, unless there's a specific reason, which is often not driven by the medical team).

      Am aware this doesn’t fully answer your question; a re-audit of our (now significantly larger) fingolimod population is under way.

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  3. Since all pharma is doing is tweaking existing immunosuppressants for patentabillity there is no real innovation going on. You might as well prescribe Rituximab off label because pharma has not lived up to their side of "The Grand Bargain".

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    1. Too right. It's like going to the cinema and getting remakes over original ideas. There is no more risk or vision. They play it too safe. There is too much fear of failure.

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    2. Re: "There is too much fear of failure."

      I am not sure sure about that; Teva is doubling-down with their Laquinimod development programme and Biogen is full-steam ahead with their anti-Lingo-1 antibody. These both represent real innovative products (1st-in-class). Not to mention Mouse Doctor's VSN16 programme. It is all very exciting and it is what gets me up in the morning!

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    3. First in class ProfG isn't laquinimod just a bit of pharma repurposing
      from the arthritis drug linomide.So adding chloride and a wad of cash is innovative? Shame they didn't remove the cardiac signal whilst innovating.

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    4. Ouch...however even adding that chloride is innovation, someone thought it up put in the work to make a drug for you.

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    5. The laquinimod development programme is not repurposing; linomide never made it to market.

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    6. Bringing a brand new drug to market takes at least a decade after its design. It makes sense to me to tweak existing drugs for other illnesses. We would not be left with a lot of options if all drugs had to be designed from scratch!

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    7. OK, if that's your position (as well as Pharma's), why has the cost of MS drugs continued to skyrocket since the introduction of the first line injectables? If the goal is to introduce a drug that is easier to get to market by tweaking a version of an existing drug it should not demand a premium price.

      In the case of Rituximab it is essentially the same as Ocrelizumab and has years of safety data. Pharma is cutting the innovation too close in this case and is just going for a money grab. There should be an understanding that if you bring out a new drug that is a carbon copy of an existing drug, you (pharma) will not be protected from off label prescribing.

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    8. The costs sky rocket because they work in a cartel to maximize price. Companies own slices of other companies assets too. Also if their price was lower it would be seen as inferior so not a good marketing approach.

      I like you view but unfortunately this is not the way the world works

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  4. I know this is a sensitive question, since aggressive off-label prescribing is a no-no for all the political reasons listed above, but if one were at a good MS center in the UK, would they prescribe rituximab off label after natalizumab? What does Barts do?
    I think the government's argument earlier was that "we're not preventing off label prescriptions, which NHS doctors are free to do, we're just not going to do anything to help make off label prescriptions easier so pharma gets their $$$ (or, in your case, £££)."

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    1. Though Rituximab is significantly cheaper than the licensed options, it's not cheap enough for Barts Health NHS Trust to pick up the bill. Licensed drugs are funded (in England) via a separate, central pot meaning these drugs don’t cost the local Trust anything - at least theoretically. There are, of course, administration costs, and dealing with adverse effects, etc., and there is also a maximum n pwMS that each Trust is allowed to treat per year (else the Trust gets penalised), but in principle it is a pass through cost. The only effective drug where price doesn’t matter is Cladribine, which costs £165/10mg vial.

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    2. What fo you mean by there is a max number of pwMS that a trust can treat before being penalised? How does this work at Barts which surely has a large number of out of area patients because of its reputation?

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    3. I'll check with our pharmacist what our current limit is.

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  5. Brain volume loss seems to be the most important treatment effect. Fingolimod has a remarkable effect to prevent end-organ damage. (Reduces neurofilament levels in the CNS) But what about, Anti-CD20 family?
    Fingolimod not only a 'trapping lymph' drug, but also promotes the increase of the regulatory B cells rate in the 'B cells family' into the blood, and - which is more important - into the CNS too. The increased Reg B cells has increase IL-10 prod. which inversely correlates the EDSS counts.

    So fingolimod (Gilenya) not only reduces ARR, but also the end-organ damage too, which is may connected a subclinical inflammation.

    Has Anti CD20s family simillar effect (remarkable effect on the end-organ damage)?

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    1. What about anti-CD20 data..we have to wait until it is published. ProfG may know as a an anti-CD20 investigator, but he will be gagged until it is published/presented

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    2. Have they said when they'll be publishing the data? It has to be published before the drug is put up for sale in the UK or US markets, right? Or am I terribly naive?

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  6. does it make sense to make this switch for a patient doing great on Fingo ? (assuming he can)

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