off-label – Page 2 – Prof G's MS Blog Archive

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.

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.
Rituximab has come off patent and several cheap biosimilars are now entering the market.
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

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.
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.
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.
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.
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.
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.

Why don’t you support private prescribing and HSCT abroad?

The social media response to yesterday’s Barts-MS Hangout on HSCT has been rather mixed. A lot of commentators are being critical of us for creating too many hurdles regarding the access to HSCT and that we shouldn’t stop our patients going abroad for treatment. From my perspective, going abroad or to private units in the UK for HSCT is private healthcare at its worst. The countries who offer private HSCT, on a fee-for-service basis, are some of the countries with the largest health inequities in the world. These private HSCT units are in it for the money and hence are not that selective in whom they will treat. Can you pay? If you say yes, then you can be treated next week, but only after you put down a large deposit.

The founding principles of the NHS and other socialist healthcare systems are that healthcare is a basic human right, therefore it should be free at the point of access and it must be equitable. Private HSCT, private prescribing and even off-label prescribing undermine these principles and this worries me a lot. This is why I can’t and won’t openly support my patients travelling abroad for HSCT; you need to understand that when it comes to access to healthcare I am card-carrying socialist.

We at Barts-MS have been pushing our Essential Off-Label list to improve access to treatments in resource-poor environments. The problem with this is that adoption of off-label prescribing is patchy at best and creates pockets of prescribing in a desert of limited access. The latter creates massive variances in prescribing and inequity. This is why we decided a few years ago to hand the baton of promoting an Essential DMT List, including HSCT, which is on our list, to the MSIF (Multiple Sclerosis International Federation).

The MSIF is an umbrella organisation representing all of the MS Charities from across the world and is therefore in the best position to endorse and promote an Essential DMT list. The MSIF made the strategic decision to go via the WHO Essential Medicines List (WHO-EML). Over the last 2 years, we have actively been working on this and I have had the privilege of co-chairing the MSIF WHO-EML Taskforce with Professor Brenda Banwell. We managed to get an international consensus on three DMTs (glatiramer acetate, fingolimod and ocrelizumab) to be considered for the WHO-EML. Please note HSCT did not make the shortlist mainly because we are trying to address the unmet need in resource-poor countries. Our application is now online and we hope the wider MS community get behind our application. Our application is more than about these three DMTs, it is a political campaign to get the WHO and the world to realise that MS is a problem across the globe; MS is not just a rich world disease. For example, did you know that there are more people with MS in India than there are in the UK?

So to our critics out there, we at Barts-MS have a wider responsibility to the MS community and to support the NHS and the pwMS living in the UK by trying as best we can to uphold the founding principles of the NHS.

Tag: off-label

Playing second fiddle to the Swedes