Monday, 24 October 2016

#ClinicSpeak & #OffLabel: rituximab in sweden

The MS off-label vs. licensed-innovator drug wars are about to get nasty. #ClinicSpeak #MSBlog #OffLabel

The study below summarises the off-label experience of using rituximab to treat both relapsing and progressive forms of MS in Sweden. An updated data set was presented at ECTRIMS to gasps from the audience. It is clear that anti-CD20 therapies are very effective DMTs, in both relapsing and progressive MS. These results are no surprise and back-up an enlarging data set on the efficacy of anti-CD20 therapies in MS. 

Rituximab is about to come off-patent and there are several rituximab biosimilars waiting in the wings , with one already available in India. Off-label rituximab may therefore disrupt the MS market, particularly markets that are price sensitive. We tried to get NHS England to let us use rituximab in the NHS and they said no. The reason was that rituximab was not licensed for treating MS. It is clear that the NHS don't mind promoting and supporting the use of off-label drugs provided they are low cost and don't involve specialist commissioning, i.e. payment from central, rather than local, budgets. This is the NHS version of Catch-22! With the NHS on its knees you would expect them to embrace off-label drugs. I suspect they want to avoid any more high profile legal disputes with Pharma. 


As you are aware we have included rituximab on our essential off-label DMT list and we continue to encourage neurologists in resource-poor settings to consider using rituximab in patients with highly-active MS. In wealthier, developed markets, the debate about high-cost innovator drugs is getting very heated. We are fortunate in the NHS to have NICE that assesses the cost-effectiveness of drugs and negotiates a very good deal of the NHS. In other countries, particularly the USA, this does not occur and drug price inflation has become a political issue. The USA is now subsidising international drug development and this position is unsustainable in the long-term.

For people with MS the good news is that the ocrelizumab, a follow-on from rituximab, should be licensed in the major markets within the next 12-24 months. Ocrelizumab has several advantages over rituximab, the main one being that it is less immunogenic than rituximab with a very low anti-drug antibody rate. An interesting question will arise is whether or not these advantages will change prescribing habits in countries such as Sweden and the USA. 

Salzer et al. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology. 2016 Oct 19. pii: 10.1212/WNL.0000000000003331.

OBJECTIVE:  To investigate the safety and efficacy of rituximab in multiple sclerosis (MS).



METHODS: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded.

RESULTS: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected.

CONCLUSIONS: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS.

CoI: multiple

11 comments:

  1. "Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months"

    - How long can/should patients continue with this routine of infusions every 6-12 months?

    - Patients must have got 3 or 4 infusions on an average. What happened after that?

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    1. I was speaking to someone in the USA a copuple of weeks ago and they were saying it may have induction therapy properties.

      Anyone know of references e.g. extension data of trial.

      When paper is submitted and published I will let you hae my thoughts...back in a year :-(

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    2. Too slow...but why do we have to trawl the AAN and ECTRIMS abstracts for all that data that never gets published?

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  2. Ritux is recommended after HSCT from Mexico. If ritux is not allowed and Ocrelizumab is not available yet what would be the alternative.

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    1. Using Rituximab post-HSCT makes the procedure and follow-on treatment very expensive.

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    2. Joanna you may want to look into Dr Burt's recommendations for those who relapse post HSCT - I think you'll find the answer to the question you're actually asking.

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  3. Sweden is not a resource-poor country, why is it then used so extensively there? Also, isn't the Swedish health system afraid of legal disputes with pharmas?

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    1. In the North of Sweden the use was about 80-90% but in the South of Sweden use was 5-20% if I remember the ECTRIMS presentation and yes I believe that pharma was complaining (Suing) to the Swedish Government. It was discussed in Parliment and they they said to carry on using the off-label drug.

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    2. The Swedes started using Rituximab about a decade ago when there was an unmet need and fewer options available for pwMS. The economic motivation to use it came later.

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    3. Please note that Rituximab is not a cheap drug; it still costs over £8,000 per year. However, this is much cheaper than MS DMTs.

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  4. Rituximab £8000 per year?

    Prices stated in BNF

    Concentrate for intravenous infusion, rituximab 10 mg/mL, net price 50-mL vial = £873.15
    If you use 1000mg (2X50mL) twice a year = 4X £873.15 + 2 half days of infusion day unit...

    Solution for subcutaneous injection, rituximab 120 mg/mL, net price 11.7-mL vial = £1344.65 (size not adapted for neurology use, I guess) - to avoid infusion day unit

    Even with 20% VAT on price, my stingy person has a hard time to see how much you would charge me!

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