Thursday, 18 June 2015

OffLabel: should we be using more off-label rituximab in the UK

Will a biosimilar rituximab solve the MS DMT pricing crisis before generic fingolimod does? #ClinicSpeak #MSBlog #MSResearch #OffLabel

"The case report below reminds me of the era prior to NHS England setting new prescribing guidelines. I have treated several patients with malignant MS with rituximab via the so called IFR (individual funding request) route with similar success to the case below. As these cases are not unique, and there are more than 5 of them in England and Wales, we have to put in a business case for using Rituximab off-label. As there are now other treatment options and the data regarding Rituximab is currently limited to only one positive class 1 evidence trial, supported by several small case series, I have been told the business case will fail. Therefore we are in a Catch-22 situation at present with regard to the use of off-label rituximab for treating MS in the NHS. This is  great pity as it is a really effective treatment and it is actually reasonably cheap relative to natalizumab and alemtuzumab. As a result of this I have had two MSers pay, and receive, rituximab privately. The latter is particularly galling as it challenges everything the NHS stands for; equity and free care at point of access. All of a sudden we have new NHS playing field dictated by money."

"Interestingly, MSologists in Sweden are using a lot of rituximab off-label to treat MS, in particular high-risk MSers who are JCV-positive coming off natalizumab. As rituximab only depletes B cells and leaves the T-cell compartment relatively intact this strategy makes sense. I suspect it will put MSers making the switch at much lower risk of developing carry-over PML compared to other options that are immunosuppressive. Protection from and recovery from PML is linked to intact T cell function, in particular the CD8+ T cells (cytotoxic T lymphocytes)."

"It will be interesting to see how Sweden deals with the wide use of off-label rituximab, if and when ocrelizumab is launched. I suspect ocrelizumab will be much more expensive than rituximab and there will be pressure on payers to save money by allowing the use of the cheaper alternative. This may trigger some of the same shenanigans that has happened around the use of bevacizumab (Avastin) instead of ranibizumab (Lucentis) to treat wet age-related macular degeneration in the UK and other countries."

"The issue of rituximab vs. ocrelizumab is not a trivial one. Rituximab comes off patent later this year and there are several rituximab biosimilars due out. There is already one available in India. This should lower the price of anti-CD20 treatment and may disrupt the MS market outside of Europe. Please remember we can't prescribe an off-label, or unlicensed, drug for MS if there are licensed alternatives. EU law was created to protect Pharma innovation and Pharma are not scared of using the law to protect their investments and assets; for example, Novartis successfully challenged the NHS over the off-label use of bevacizumab, instead of ranibizumab the licensed product."


Parfenov et al. Management of Fulminant Multiple Sclerosis With Rituximab: A Case Report. Neurologist. 2015 Jun;19(6):155-7.

INTRODUCTION: Malignant variant is a rare subtype of multiple sclerosis (MS) that is rapidly progressive and may lead to significant disability or even death. No consensus exists on best management of this disorder, although corticosteroids and plasmapheresis are commonly used in the acute phase, followed either by MS-specific disease-modifying therapy or an immunosuppressant.

CASE REPORT: The patient is a 30-year-old man with relapsing-remitting MS previously well controlled with natalizumab, who has developed fulminant disease activity upon natalizumab cessation. In the acute phase, patient had a suboptimal response to multiple corticosteroid treatments but responded very well to plasmapheresis. Patient continued to have worsening disease activity despite fingolimod treatment. Disease control has been eventually achieved by switching to rituximab.

CONCLUSION: Rituximab treatment should be considered for a patient with fulminant MS who responded well to plasmapheresis.

CoI: multiple

18 comments:

  1. We need anti-CD19 therapies in MS if we want an actually efficacious treatments. All the rest are hogwash.

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    1. Then you are going to have to wait, anti-CD20 is on the cards

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  2. Yes.

    This is my first post.

    I have lived in New York for years and have seen the differences between the US and UK health care models. I think that the NHS is wonderful, but it is not perfect. I am on Natalizumab and am JC virus negative but will probably switch to Rituximab as it performs better, is a 6 monthly infusion and my doctor recommends it. Rituximab is a bridge to Ocrelizumab which will probably be FDA approved mid 2017. My view is that money is a form of rationing of resources just as post code is a form of rationing in the NHS; therefore, I don't understand why money as a rationing factor is any different from post code. What is wrong with giving a patient the option to pay for Rituximab? We should only need this drug in MS for a few more years.

    Aidan

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    1. Hi Aidan, I feel the unrest in the NHS is going to soon change some the way in which treatments are provided. Hospitals may find themselves footing a chunk of the bill for patients they treat, which will pave the way for off label, cheaper alternatives. That is a sound business model. Should we expect our patients to foot the bill? - I hope not, this goes against the ethos of the NHS. Personally, I'm more inclined to may more taxes if it means propping up the NHS; because in a free health care system there is no preconceived bias, not your wealth or origin.

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    2. When I was working full time, I could afford to pay for private Physiotherapy, cleaners, gardeners, etc. I saved money for when I developed SPMS. As my MS onset was in my early 20s, private health insurance wasn't an option. Now I can only work a few hours a week when well enough, I am using my savings that do not accrue interest due to the banking crisis. My MS took away my ability to earn enough to pay for treatment, that's what is wrong with healthcare based on ability to pay.

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    3. As an old-school lefty, I entirely agree with you. The NHS is one, if not the UK's greatest achievements. Also the founding father Aneurin Bevan was Welsh which is also a source of great pride to me.

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    4. Is there clinical evidence that Rituximab performs better than Natalizumab?

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    5. There is no head to head study so it is unknown but i guess they are of similar efficacy.

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    6. http://www.sciencedirect.com/science/article/pii/S089543561500058X
      Regarding important head-to-head comparisons, I think it is important to note that many are not conducted by non-profits and that "favorable" results may be influenced by the company performing the study.

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  3. How positive is ocrelizumab looking? Is rituxima not used in alot of the pre conditioning regimens for hsct?

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    1. There are rumours...anyone from Roche passing through? I wish I knew, we're all interested in the preliminary results from ORATORIO (ocrelizumab in PPMS). I also want more on the safety data, look for ocrelizumab in rheumatoid arthritis.

      Your right about rituximab in hsct, relatively safe also. Alemtuzumab is also used for T cell depletion in hsct.

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  4. ocrelizumab in PPMS - They are in Phase 111 at present. Does that mean than Phase 1 and Phase 11 looked positive. Is this currently the main hope for PPMS at the moment ? If so Roll on 2017 and lets hope we have not deteriorated too much on the waiting. In this meantime I would like to try the alternative of rituximab. I would be prepared to pay as opposed to the alternative which is do nothing and deteriorate. I would take a life raft with holes as opposed to none at all.

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    1. The fact it is in phase III (large scale trial) indicates that Phase I & II have been passed.
      Phase I - Aims to test the safety of a new treatment/ medicine and see how well it is tolerated. Often, Phase I studies are carried out on a small number of volunteers (usually healthy).
      Phase II - Tests on a larger number of patients to monitor how well a treatment/ medicine performs.
      Phase III - Involves a larger number of patients and follows the same process as Phase II. The aim is to gain a more in-depth understanding of how effective and beneficial the treatment/ drug is.

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  5. If ocrelizumab works would that suggest that rituximab works in PPMS too and support the theory regarding inflamation being a driver in Ppms

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    1. Rituximab has been tried in PPMS and I believe the results show that it inhibits relapsing progression in gadolinium enhancing PPMS. This may argue against a generalised effect of ocreluzimab. They are also looking at delivering rituximab directly into the brain in case not enough of the rituximab crosses the blood brain barrier

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  6. Dear Dr Gnanapavan,

    Just to clarify, did not say and never would say that access to health care would be based on a person's origin. Glad I posted anonymously.

    I believe that Perfection is the enemy of the good.

    Of course Rituximab should be offered to a patients even if they have to do it privately. This is not a left/right political issue, we need to get as many people as possible, through the next few years, with as little damage as possible by any means. The current pipeline will most probably provide a 'hold' drug in the next three to four years.

    NHS coverage differs across post codes and post code is a derivative of wealth, so why the consternation about paying? I have lost two immediate family members to MS and I believe that they would have received better care if we had lived in a different part of the country.

    Aidan

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    1. Hi Aidan, having the option to pay for care in the NHS is the slippery slope to privatisation, we do not want to hand this to the government on a plate when we have been battling this for so long. Have a look at this post on the BBC a while back which debates these exact questions: http://www.bbc.co.uk/guides/zqvhpv4.

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  7. Agree with the Neuro doc Gnanapavan totally :) well said

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