Playing second fiddle to the Swedes

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Why can’t we use anti-CD20 therapies as immune constitution therapies?

For some years we have been promoting our Barts-MS Essential DMT list to treat people with MS (pwMS) in resource-poor environments. One of the big guns on our list has been rituximab (anti-CD20).  One of the problems is that rituximab at a dose of 1g every 6 months is still too expensive to accessible for the vast majority of MSers living in these environments. The good news is that several developments have brought the price of rituximab down.

  1. The Swedes, who are treating more than half their MS population, have data showing that 500mg every 6 months is as good as 1g every 6 months in terms of NEDA, i.e. preventing new relapses and new MR lesions from forming.
  2. Rituximab has come off patent and several cheap biosimilars are now entering the market.
  3. The Swedes are also testing adaptive dosing, i.e. after 2 years of 6 monthly infusions, they are extending the interval between doses to 12 months or more and/or are even beginning to redose rituximab based on peripheral memory B-cell reconstitution.  At a recent meeting, I was at one Swedish neurologist is beginning to use rituximab as an IRT (immune reconstitution therapy), i.e. only redosing with rituximab if and when disease activity re-emerges.

I classify anti-CD20 therapies as both a maintenance therapy and an IRT. At the last AAN in Los Angeles, I attended a meeting of like-minded clinical scientists to set-up a trial to test anti-CD20 as a maintenance therapy vs. an IRT. The retreatment arms of the trial were to test redosing based on the reemergence of disease activity or the repopulation of memory B cells. Using anti-CD20 therapies as an IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and ability to respond to vaccines.

I am therefore very interested in seeing the results of the Swedish experiment of testing rituximab as a maintenance therapy vs. rituximab as an IRT. Just maybe we can get the price of treating MS with rituximab down to affordable levels for low-income countries.

The following is a back of envelope calculations based on the current BNF prices:

Mabthera (Roche) 500mg = £873.15 per 500mg vial
Rixathon (Sandoz) = £785.84 per 500mg vial
Truxima (Napp) = £785.84 per 500mg vial

  1. Standard dose (1g) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £8731.50 for the first 2 years and then £3492.60 annually.

  2. Standard dose (1g) biosimilar maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £785.84 x 5 = £7858.40 for the first 2 years and then £3143.36 annually.

  3. Reduced dose (500mg) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £4365.75 for the first 2 years and then £1746.30 annually.

  4. Reduced dose (500mg) biosimilar maintenance regimen: 1g Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.

  5. Reduced dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.

  6. Adaptive dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly for 2year and then 500mg approximately every 12 months = £785.84 x 5 = £3929.20 for the first 2 years and then £785.84 annually (the latter may be lower if redosing is done using peripheral B cell reconstitution).

Please note these figures are the list price and don’t include discounts, VAT nor the infusion costs. In reality, these costs could come down with central, say NHS, purchasing power. Unfortunately, they are still too high to help pwMS in low-income countries. Just maybe getting MS and anti-CD20 therapies onto the WHO Essential Medicines List may bring down the costs by creating political pressure on the Pharma industry or innovations in making cheap biosimilars may also help.

The Caveat

There is one major caveat I have about putting up anti-CD20 as the solution for MS is that we may be getting it wrong. I personally don’t think relapses and focal MRI activity are the disease we call MS; these markers are an inflammatory response to what is causing the disease. Therefore I suspect we may be lulling ourselves into a false sense of security with anti-CD20 therapies and ignoring what is really driving the disease, i.e. what is causing the end-organ damage in MS.  

Do we know what is driving the slowly expanding lesion? What is causing the extensive cortical lesions in MS, which we can’t see on conventional MRI? What is driving the progressive brain volume and grey matter loss in MS? Don’t we need to go beyond NEDA as a treatment target? I know some would argue we have done this already, which is why so many MSers want HSCT as a first-line treatment option.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

12 comments

    • They are doing the COMBAT-MS trial of rituximab vs. DMF. I think this is being done as part of routine clinical care, but as all data is being collected as part of their register it will emerge as real-life data.

  • Nice and very relevant discussion. So, how do you know that HSCT and alemtuzumab are better than RTX? Are there any data? My impression is that they also affect primarily the adaptive immune activity and don’t have any effect on slowly expanding lesions etc. or are there any data to prove otherwise? Treat with RTX as IRT, achieve NEDA with minimal side effects, and do trials with other new medications for ongoing inflammation and neurodegeneration in the brain. There are no data showing that the latter is stopped by HSCT or alemtuzumab. Also diagnose, not only treat, early is the way to go to prevent further end organ damage, since progression despite NEDA strongly correlates with lesion volume. These are my thoughts and would love to hear Prof G opinion.

  • Is chronic eliminination of a specific compartment of the immune system considered reconstitution? Tecfidera can lead to chronic elimination too but it’s not an IRT…

    • Depletion then wait for reconsituion and disease does not reactivate for some time. This is distinct from stop treatment and disease returns.
      The studies of treat stop and wait are not done…except perhaps the phase II extension studies. I would have to go back and look for BG12 (Tecfidera data) data. However if is not a good enough to classed as a high efficacy DMT.

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