Tag: WHO Essential Medicine List

Damp Squib

The Editors’ of The Lancet Neurology weigh-in with a commentary on the decision of the WHO committee not to recommend glatiramer acetate, fingolimod and ocrelizumab for the WHO EML (Essential Medicine List). 

The Editors’ reiterate the usual recommendations to address the challenge of treating MS in resource-poor countries. 

  1. They acknowledge that adequate funding is needed for national health-care systems in low-income settings. 
  2. They suggest treatment guidelines that consider the different resource levels available in each setting, are also essential.
  3. They make the point that easily accessible training and peer-support for neurological specialisation would enhance multiple sclerosis care worldwide. 
  4. They highlight that the cost of treatment could be tackled either through 
    1. negotiations with the pharmaceutical industry 
    2. differential pricing (ie, the drug price varies according to several parameters such as affordability)
    3. voluntary licensing through organisations such as the Medicines Patent Pool
    4. or by looking at the potential of repurposing medicines already available in low-income settings for other diseases

They conclude with the comment that “it is essential to ensure that people with multiple sclerosis have timely access to safe and effective treatments. Repeated strong global advocacy efforts through organisations such as the WHO are needed to reduce the global burden of multiple sclerosis”. 

Why didn’t the Editors call for a political campaign to challenge the WHO? In my opinion, their editorial is a damp squib; it is far too passive, it lacks energy and direction. I suspect it will not make an iota of difference for people living with MS in low- and middle-income countries. Do they really care?

What we need is for the MS community to learn from HIV-activists and Amnesty International. We need a start a letter-writing campaign targeting all WHO country representatives to move multiple sclerosis up the WHO agenda. The letters need to be country- and region-specific with hard data and emotional stories. For example, personal narratives of how hard it is to live with MS on the streets of Kibera in Nairobi or in Diepsloot on the outskirts of Johannesburg. The targets need to be wider than the WHO and include health ministries, politicians and other people of influence. 

Diepsloot, Johannesburg, South Africa; image from Wikipedia

The access campaign needs to be managed and run like a political campaign. It needs a public relations and multi-media plan. The question I am asking is why is this not happening already?  Who is responsible for making it happen? One of the problems is that organisations who are meant to be representing pwMS are conflicted and essentially in the pockets of big pharma. Their committees are stuffed full of representatives who are conflicted and will not rock the boat. If you are interested in how far the tentacles of Big Pharma extend you need to read Ben Goldacre’s book ‘Bad Pharma’ or the House of Commons Health Committee report on ‘The Influence of the Pharmaceutical Industry’. 

To the get to the bottom of this, I have briefed a journalist to investigate these conflicts to see if they may explain the apathy of the MS community to address access to DMTs in resource-poor environments. 

The plan that I am currently formulating is to come at this via a grass-roots movement. I suggest starting small and local:

  1. Identifying local MS champions and creating an international database.
  2. Creating and disseminating an essential off-label DMT list with detailed protocols on how to use each agent.
  3. Modified diagnostic criteria for use in resource-poor environments; these will need to country-specific.
  4. Protocols for derisking and monitoring DMTs in these environments.
  5. Creating a platform and network to allow neurologists and other HCPs from these countries to share their experience.
  6. Identifying countries with suitable infrastructure to collect real-world data to assess the effectiveness of off-label DMTs in these environments.

Barts-MS Essential Affordable DMT List

  1. Azathioprine*
  2. Cladribine
  3. Cyclophosphamide*
  4. Fludarabine*
  5. Leflunomide
  6. Methotrexate*
  7. Mitoxantrone
  8. Rituximab*
  9. Generic dimethyl fumarate (Skilarence)
  10. Compounded dimethyl fumarate
  11. HSCT

*on the 19th WHO Model List of Essential Medicines (April 2015)

If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments please sign-up to our Grass Roots Affordable DMT Initiative (GRAD Initiative)

The Lancet Neurology. Essential medicines for patients with multiple sclerosis. EDITORIAL| VOLUME 18, ISSUE 12, P1067, DECEMBER 01, 2019.

Why is everyone drinking anti-CD20 kool-aid?

Prof G will ocrelizumab and rituximab prevent SPMS?

Just back from the COMBAT-MS stakeholders meeting in Pasadena with the Kaiser (Kaiser Foundation Research Institute) and Swedish (Karolinska Institute) trial teams, PCORI (Patient-Centered Outcomes Research Institute) and many brave an wonderful people with MS and their families.

The COMBAT-MS study (NCT03193866) is recruiting well and is on schedule to deliver very important comparative data on the effectiveness of rituximab in real-life. The full title of the study is ‘COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient’s Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis’. In short, COMBAT-MS will be comparing Rituximab with Natalizumab, Fingolimod, Alemtuzumab, Interferon-beta, Glatiramer acetate and Dimethyl Fumarate. Because the use of alemtuzumab seems to be quite limited in Sweden, with the majority of patients going onto rituximab, the study will not have enough power to compare rituximab with alemtuzumab. This a great pity because the real question I have is how does anti-CD20 therapy compare to our top-guns, i.e. alemtuzumab and HSCT. This question is becoming a priority for me.

We had a comprehensive safety update from the COMBAT-MS trial team, which will be presented later this year. However, the safety profile of rituximab is broadly in keeping with what is seen in rheumatology, with a few interesting exceptions. However, the overall safety profile will help with the adoption of rituximab as a treatment of MS in resource-poor environments.

I included in my presentation on why I think anti-CD20 is not good enough to treat MS in the long term and why we need to think beyond NEDA. I presented data, mainly from ocrelizumab, that shows MS continues to smoulder away on ocrelizumab despite patients being NEDA. The response to the data was what we are seeing was simply secondary progressive MS. Yes and no. It may be a secondary progressive disease, but the pathology driving smouldering MS (microglial activation, slowly expanding lesions, subpial cortical lesions, intrathecal immunoglobulin production, demyelination, mitochondrial toxicity and energy failure, oxidative damage, delayed axonal loss, synaptic pruning, premature ageing, etc.) are all present at the very earliest stages of the disease, even the asymptomatic stage of the disease, i.e. radiologically isolated syndromes. This is why I don’t think SPMS really exists and why MS is one and not two or three diseases.

The construct that MS has distinct phases, an early inflammatory and a delayed degenerative phase, is artificial and comes from the Pharma industry’s need to get interferon-beta licensed under the orphan drug act, i.e. MS had to have a prevalence of fewer than 200,000 affected people for the orphan drug act to apply. The only way to get the numbers down to less than 200,000 was to salami-slice up MS into three diseases, i.e. RRMS, SPMS and PPMS. Later on, a fourth category, CIS (clinically isolated syndrome) was added. However, CIS has largely disappeared as a category because of diagnostic creep and the earlier diagnosis of MS with the evolving definition of MS based on the newer versions of the McDonald criteria. Having looked hard I can find no scientific justification for making SPMS a different disease.

In my opinion, smouldering MS and the pathologies driving it do not seem to be anti-CD20 responsive. If they were then we would see a much better impact of anti-CD20 on brain volume loss, disease improvement and the slowly expanding lesion. What does this mean for people with MS? It means that anti-CD20 therapies may be a good platform to start on but you will require additional add-on therapies to stop smouldering MS. Can I please urge you to re-read Stephen Hauser’s case report below. You may argue that one swallow doesn’t make a summer, but Stephen Hauser implied two year’s ago in a response to a question at ECTRIMS that anti-CD20 was not the panacea everyone wants it to be and that a lot of his long-term rituximab-treated patients were now secondary progressive, i.e. they had smouldering MS.  

The concept of smouldering MS is a difficult one for people in the field to grasp. Why? It is because NEDA-3 has become de-facto what defines MS. We need to move beyond what we can see and measure and focus on end-organ markers of disease activity, i.e. whole brain and regional or grey matter volumes, the expanding MS lesions, neurofilament levels and more sensitive clinical outcomes. An EDSS view of the world is simply too narrow. We need to look at cognition, visual function and more sensitive functional tests of different neuronal systems. One of the attendees was horrified when I said that the best thing that could happen to the field is if we could automate the neurological examination using a validated technology platform. The idea of using a neurologist to assess eye movements and balance, when it can be done so much better with eye tracking systems and balance sensors, shocked this individual. Bring on the robots and maybe our worldview of MS, in particular, smouldering MS, would change.

I was also able to deliver good news about our WHO Essential Medicine List (EML) application that includes ocrelizumab as one of the three drugs and rituximab as a suitable replacement for ocrelizumab if access to ocrelizumab is a problem. If our EML application is successful this will allow us to pressurise governments to prioritise the treatment of MS in low prevalence countries. I explained to the group that what had started out for me as an ‘Essential Off-label DMT list’ in 2014, may become an official WHO-backed Essential DMT list in 2019. I am holding thumbs we get MS onto the EML, it needs to be there for many reasons.

I also covered in my talk alternative hypotheses, i.e. that MS may be due to a virus and that our current world-view of MS being an autoimmune disease driven by T and B-cells may be wrong. I briefly presented the B-cell-EBV hypothesis and our proposed EBV vaccination trial. I stressed that we need to use anti-CD20 as a tool to explore the EBV hypothesis and the good news is that Fredrik Piehl is going to explore EBV biomarkers as part of the COMBAT-MS study.

I used my lecture to represent my ‘marginal gains’ philosophy as it applies to treating MS and how we need to manage MS holistically and focus on the small things that may make a big difference to MS outcomes in the future. This is only the second time that I have presented this concept to my peer group, but it is something that still needs work to make it sticky.

The following are my slides from the meeting, which you can download from my slide sharing site.

I would like to thank PCORI and the Kaiser team for including me in this study and for your wonderful hospitality. I have little doubt that the COMBAT-MS study is going to help change the way the MS community treats MS globally. I would also like to thank the MSers who attended and spoke at the meeting; you are are the reason why we are doing what we do.

von Büdingen et al. Onset of secondary progressive MS after long-term rituximab therapy – a case report. Ann Clin Transl Neurol. 2016 Dec 20;4(1):46-52.

A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS.

CoI: multiple

Playing second fiddle to the Swedes

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.

Supporting the NHS & social medicine

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.