Politics, campaigns and information – Page 5

Air pollution and MS

We know that smoking, passive smoking and solvent exposure increase your risk of getting MS. The hypothesis, supported by animal work, suggests these risk factors alter antigens or proteins in the lung that then trigger autoimmunity. In other words, the altered proteins are interpreted as being foreign by the immune system.

Particulate air pollution is another respiratory toxin that has been studied in Iran and is associated with an increased prevalence of MS. I suspect that particulate matter air pollution also increases your risk of getting MS based on similar mechanisms to smoking and solvent exposure.

Another aspect of particulate matter air pollution exposure is that it drives comorbidities and is therefore likely to make MS progress more quickly. The second paper (below) in this week’s BMJ is quite shocking in that it shows you how high the health burden is for particulate air pollution, at a general population level. Is there anything we can do about this? Yes, there is. We need to nudge our politicians whenever we can to enact legislation to clean up the air that we have to breathe. I am aware that there are retrograde steps in the US to reverse some of the clean air legislation; this should be resisted. My heart goes out to people living in low- and middle-income countries who will have to wait for a generation or two to get to the point when air pollution drops to safer levels.

Why should people with MS be exposed to unnecessarily high levels of air pollution that are likely to make their MS worse?

Why should people at high risk of getting MS, be exposed to environmental pollutants that may push them over the “autoimmune tipping point” resulting in them developing MS?

Part of our lifestyle and wellness campaign is focusing on environmental health; air pollution is one of the things that impact wellness. Our marginal gains management philosophy has just acquired another component; environmental pollution. Do you agree?

Heydarpour et al. Potential impact of air pollution on multiple sclerosis in Tehran, Iran. Neuroepidemiology. 2014;43(3-4):233-8.

BACKGROUND: Multiple sclerosis (MS) incidence has dramatically increased in Tehran, Iran. The health impact of air pollution in Tehran underscores the attention to a possible association to this environmental risk factor. In this study, the authors aimed to analyze the spatial distribution of prevalent MS cases and their association with the spatial patterns of air pollution.

METHODS: Patient records meeting McDonald’s criteria for definite MS diagnosis with disease onset during 2003-2013 were obtained. Next, the location of 2,188 patients was successfully geo-referenced within Tehran metropolis by geographic information system (GIS) bureau of Iran’s post office based on their phone numbers. A cluster analysis was performed using the average nearest neighbor index (ANNI) and quadrat analysis. The long-term exposures of MS patients to particulate matter (PM10), sulfur dioxide (SO2), nitrogen oxide (NO), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated using the previously developed land use regression models.

RESULTS: Prevalent MS cases had a clustered pattern in Tehran. A significant difference in exposure to PM10, SO2, NO2, and NOx (p < 0.001) was observed in MS cases compared with controls.

CONCLUSION: This study revealed the potential role of long-term exposure to air pollutants as an environmental risk factor in MS.

Wei et al. Short term exposure to fine particulate matter and hospital admission risks and costs in the Medicare population: time stratified, case-crossover study. BMJ. 2019 Nov 27;367:l6258. doi: 10.1136/bmj.l6258.

OBJECTIVE: To assess risks and costs of hospital admission associated with short term exposure to fine particulate matter with diameter less than 2.5 µm (PM2.5) for 214 mutually exclusive disease groups.

DESIGN: Time stratified, case-crossover analyses with conditional logistic regressions adjusted for non-linear confounding effects of meteorological variables.

SETTING: Medicare inpatient hospital claims in the United States, 2000-12 (n=95 277 169).

PARTICIPANTS: All Medicare fee-for-service beneficiaries aged 65 or older admitted to hospital.

MAIN OUTCOME MEASURES: Risk of hospital admission, number of admissions, days in hospital, inpatient and post-acute care costs, and value of statistical life (that is, the economic value used to measure the cost of avoiding a death) due to the lives lost at discharge for 214 disease groups.

RESULTS: Positive associations between short term exposure to PM2.5 and risk of hospital admission were found for several prevalent but rarely studied diseases, such as septicemia, fluid and electrolyte disorders, and acute and unspecified renal failure. Positive associations were also found between risk of hospital admission and cardiovascular and respiratory diseases, Parkinson’s disease, diabetes, phlebitis, thrombophlebitis, and thromboembolism, confirming previously published results. These associations remained consistent when restricted to days with a daily PM2.5 concentration below the WHO air quality guideline for the 24 hour average exposure to PM2.5. For the rarely studied diseases, each 1 µg/m3 increase in short term PM2.5 was associated with an annual increase of 2050 hospital admissions (95% confidence interval 1914 to 2187 admissions), 12 216 days in hospital (11 358 to 13 075), US$31m (£24m, €28m; $29m to $34m) in inpatient and post-acute care costs, and $2.5bn ($2.0bn to $2.9bn) in value of statistical life. For diseases with a previously known association, each 1 µg/m3 increase in short term exposure to PM2.5 was associated with an annual increase of 3642 hospital admissions (3434 to 3851), 20 098 days in hospital (18 950 to 21 247), $69m ($65m to $73m) in inpatient and post-acute care costs, and $4.1bn ($3.5bn to $4.7bn) in value of statistical life.

CONCLUSIONS: New causes and previously identified causes of hospital admission associated with short term exposure to PM2.5 were found. These associations remained even at a daily PM2.5 concentration below the WHO 24 hour guideline. Substantial economic costs were linked to a small increase in short term PM2.5.

What’s in a name?

The Barts-MS team are in the final stages of preparing a UK MS Society grant application to tackle the ‘real MS’ that lives inside you. Our focus is on studying or defining what is smouldering MS. This is a massive unmet need and refers to what we currently call inactive SPMS and PPMS. This is likely to affect a lot of you; at present, you remain in the so-called untreated MS camp. Ocrelizumab and siponimod are only licensed or reimbursed for patients with active PPMS and active SPMS, respectively. We are hoping our grant will be able to identify and/or repurpose drugs to modify this stage of MS or using current terminology inactive worsening SP/PP MS.

Our campaigns of treat-early-and-effectively, treat-2-target, zero-tolerance, NEDA (no evident disease activity) have exposed the real MS, i.e. smouldering disease. Many pwMS who are NEDA on DMTS and ‘doing well’ are not necessarily doing well. When we interrogate these sorts of patients they almost all have subtle symptoms and signs of disease worsening; worsening fatigue, cognitive slowing, reduced walking distance, dropped feet on exertion, nocturia, sexual dysfunction, numbness and clumsiness of the hand, subtle unsteadiness of gait, poor balance in the dark and when tired, increased leg spasms at night, reduced auditory discrimination, problems with night vision, etc. Do you recognise yourself?

The new norm is smouldering MS or more likely the realisation that the ‘real MS’ is smouldering MS. Our anti-inflammatory DMTs are doing what we say they should do, i.e. they are stopping focal inflammatory lesions and relapses, but are they getting to the core of the disease? I suspect not, or at least not in the majority of pwMS.

We have argued several times before on this blog that focal inflammation is not MS and that the real disease is what is driving the immune system to produce the focal inflammatory events. I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS, by exposing smouldering MS. The one hypothesis that is being explored at present is that if you treat MS early and effectively you may prevent the damage, innate immune activation and B-cell follicle formation that is thought to drive smouldering MS.

If you have MS this post will be very depressing, but as soon as the MS community faces up to the above the better. We could then start directing our limited resources to tackle smouldering MS. This is the purpose of our grant application.

We are proposing to do deep phenotyping and biomarker studies and try and discover new treatments directed at CNS B-cells and plasma cells, microglia inhibitors or activators (both need to be tested), drugs that target astrocyte and oligodendrocyte biology, antiviral trials and in the future drugs targeting ageing mechanisms.

I would like to thank you all for helping out with our grant naming survey. It is clear that from a scientific perspective PIRA (progression independent of relapses) only just won out. However, as PIRA only refers to relapse-onset MS we prefer the name smouldering MS. We will keep you posted on how things turn out. We are interested to know what the reviewers will say about the terminology and the concept of smouldering MS?

Time is Brain

So what has the UK’s poor performance in relation to cancer survival has to do with MS? A lot. These cancer statistics are collected as part of a national audit and are a bellwether for NHS services in general. If we had national MS statistics they would indicate similar problems, i.e. delays, delays, more delays and poorer outcomes. This is why we wrote a policy document ‘MS Brain Health: Time Matters’ to try and get the MS community to treat MS more urgently and effectively. This is also behind the motivation of our ‘MS Service Provision – Raising the Bar’ initiative to improve MS services and outcomes across the country.

I would be interested to know if the same issues exist with MS as the do with cancer diagnosis and treatment?

How long did it take to see your GP?

Did you feel you were wasting your GP’s time?

Did your GP interpret your initial symptoms correctly?

Were you promptly referred to see a neurologist?

How many GP visits did it take to get a neurology referral?

Were you forced to go via accident and emergency to see a neurologist?

How long did you wait to see a neurologist?

How long did it take to get a diagnosis of MS?

How long did it take to be started on treatment?

Are you being monitored for subclinical MRI activity with annual MRI scans?

Have you been offered escalation therapy or an immune reconstitution therapy?

Were you involved in the decision making around your treatment?

Etc.

These are the kinds of data we need via a national MS audit to benchmark MS services. The idea is to use the data to get rid of unnecessary variation in the provision of MS services.

Ruth Thorlby. UK’s poor performance on cancer survival. BMJ 2019;367:l6122

Excerpts:

…. the UK had the lowest five-year survival rates for four out of seven cancers….

…. If international variations in cancer survival are real and represent important differences in healthcare systems, what have ICBP studies revealed about their causes? A 2015 survey of around 19 000 people aged ≥50 found that public knowledge of possible cancer symptoms was not substantially worse in the UK than in other countries, but people in the UK were more likely to worry about wasting their general practitioner’s time (34% agreed with this in the UK compared with 9% in Sweden)…..

….. A parallel study of GP referral practices across countries found an association between higher survival rates and GPs’ willingness to investigate or refer quickly, which led some to argue that health systems where GPs have a gatekeeping role were more likely to have poorer cancer outcomes….

…… Although differences between countries existed in the time it took for patients to see their GP for the first time and in time to onward referral, diagnostic tests, initial diagnosis, and start of treatment, these were not obviously associated with survival differences. Each country had a long “tail” of patients waiting many months to start treatment…..

….. Closing the gap between the UK and other countries will require further progress in all four devolved countries. In England, the NHS Long Term Plan, published in early 2019, contains a comprehensive plan for improving cancer services, including multiple strategies for earlier diagnosis with the aim that by 2028, 75% of cancers will be diagnosed at stage 1 or 2. This is ambitious in the current climate…..

…… Interviewees for our 2018 report Unfinished Business were clear that the 2012 Health and Social Care Act brought unwanted organisational upheaval—for example, to cancer networks. A period of relative austerity in the English health service since 2012 has magnified other problems too. These include worsening workforce shortages in essential professions (such as general practice, diagnostics, and specialist nursing), the diversion of capital funding into everyday expenditure at the expense of maintenance and investment in new equipment, and, more broadly, a short term approach to planning services. Without tackling these fundamental problems, England will struggle to make its contribution to closing the survival gap between the UK and other countries…

CoI: multiple

Participating in Oratorio-Hand?

At the recent ORATORIO-HAND investigators’ meetings in Barcelona and Athens, several investigators’ made the point that it may be hard to retain people with PPMS in this trial because ocrelizumab has already been licensed to treat MS. I said YES and NO.

For one a lot of neurologists, HCPs and payers don’t think the original ORATORIO trial was positive. They think the trial was driven by the 25% or so of the subjects with PPMS who had active disease, i.e. those with Gad-enhancing lesions at baseline. I have even heard some people claim that this trial was positive because it was contaminated by relapsing patients. This was not the case, all subjects had to have PPMS to get into this study. Any history of previous relapse excluded them from the trial. As a result of this doubt, many countries and insurance companies have not agreed to license or reimburse ocrelizumab for PPMS. To convince the naysayers, laggards and sceptics we need another PPMS trial to confirm the original results and extend the findings into pwPPSM with more advanced disease to show that ocrelizumab has a treatment effect in older and more disabled pwPPMS. This is why our age cutoff for the ORATORIO-HAND study is 65 and EDSS cut-off is 8.0 (wheelchair users). In the original ORATORIO study, these cutoffs were 55 years and EDSS of 6.5 (bilateral support, but still mobile).

Statisticians will tell you that when you only do one trial, which is positive, there is about a 1 in 20 to 40 (2.5% to 5%) chance that result could be positive by chance. In statistical jargon, this is referred to as a false-positive result or type 1 error. This is why the regulators usually require two positive trials to license a product; the first trial to test the hypothesis and the second to confirm the results of the first trial. If one trial is positive and the second trial is negative, or vice versa, this usually results in a third trial being required. This is what happened with laquinimod in RRMS; you may recall the third trial (CONCERTO) turning out to be negative so the laquinimod MS development programme was halted. Herein lies a hidden danger. If ORATORIO-HAND is negative and does not confirm a significant treatment effect in PPMS it could be used by regulatory authorities to question the result of the ORATORIO trial and potentially withdraw the license. A negative result will justify payers refusal to reimburse the costs of ocrelizumab to treat PPMS. I am confident this is not going to happen, but we need your help to makes sure this does not happen.

The ORATORIO-HAND is a very well-designed study and is adequately powered to give a positive result. The scientific principles underpinning this study are sound. However, if too many subjects drop-out to accept being treated with ocrelizumab when it is reimbursed in their countries or game the trial, i.e. find a way to unbind themselves, and drop-out this could potentially result in the study being underpowered, i.e. there are too few subjects to show a significant result when comparing placebo and active treatment groups. If this happens it could not only jeopardise treatment for themselves but the whole PPMS community. This is why I am appealing to all potential ORATORIO-HAND trial subjects if you are not sure about your longterm commitment to the trial you should not volunteer.

We are very aware that half the trial subjects will be allocated to placebo. Someone investigators asked why didn’t we make the randomisation 2:1, i.e. for every one person on placebo two people would be allocated ocrelizumab. The logic is that by having a 2-out-of-3 chance of being on active treatment the more likely pwPPMS are likely to volunteer for the study and to stay the distance. There are two reasons for the one-to-one randomisation ratio; time and possibly cost. Increasing the time it takes to recruit study participants is important. We estimate to recruit another 500 subjects, to allow a 2:1 ratio, would take another 12-15 months, which means we would be exposing a third of the subjects to placebo for an additional 12-15 months and potentially denying many pwPPMS across the world earlier access to the ocrelizumab. A 12-15 month extension to the recruitment phase means 12-15 month delay for drug getting to wider PPMS population. These are the factors that convinced the steering committee to choose the 1:1 randomisation ratio. Although cost is an obvious potential consideration we didn’t even ask senior management at Roche the question.

At the end of the day, we are asking pwPPMS to be altruistic. We are asking you to volunteer for a study and have a 50% chance of being randomised to a placebo knowing that ocrelizumab may be available to you as part of routine clinical practice or could become available to you during the trial. I know some people will ask does it have to be a randomised double-blind controlled trial? Could we generate the evidence in another way? The answer is no; the regulators will only change the label of ocrelizumab if the study is done to their standards. As you are aware it is virtually impossible to get a healthcare system-wide adoption of an MS treatment without a marketing authorisation from the appropriate regulatory body.

There are also other advantages to being in a trial. We don’t know why but trial participants tend to do better than non-trial participants even if you are randomised to placebo. This may relate to better care offered in a trial or participating in a trial has psychological benefits that can’t be quantified. I favour the latter explanation. There is evidence that people who have a purpose, a sense of belonging and are valued have better health outcomes than people without. Being a trial participant gives you a sense of purpose and being valued in that they are contributing the greater good. I have also noticed over the years that trial participation expands social capital; trial participants get to know the trial staff and other trial participants. I even know of two study subjects from one of the early trials who ended up marrying each other. Others have become friends and see each other outside the trial unit; I have bumped into two of trials participants in a local east curry house together. These intangibles can’t be quantified, but they definitely exist.

In countries in which ocrelizumab is not licensed or reimbursed for treating PPMS the advantages of participating in the ORATORIO-HAND study are obvious. But even in countries where ocrelizumab is reimbursed receiving it as part of a trial may help as well. Although we can’t pay for you to participate in the trial all of your out-of-pocket expenses related to travel will be covered.

I want to emphasise the positive of ORATORIO-HAND. For decades pwPPMS have felt neglected, ignored and left to smoulder away. Not anymore. The fact that the first ORATORIO trial was positive has shifted the goalposts and there will now be a flurry of PPMS trials. If ORATORIO-HAND fully recruits and is completed without too many dropouts the study will change the playing field for good. It will mean that PPMS is truly modifiable regardless of disease activity and potentially even people in wheelchairs will benefit. Getting a license for ocrelizumab in wheelchair users will affect the DMT stopping criteria, in other words even if you have to start using a wheelchair the treatment will have to be continued to preserve your arm and hand function. More importantly, it will get the whole MS community to say ‘Yes, we now agree that ocrelizumab works in PPMS’ and will allow pwPPMS across the world to access treatment.

We acknowledge that there are many legitimate reasons for why study subjects dropouts in clinical trials. We have factored this into the power calculations. What I am focusing on here is excess drop-outs over and above what we expect to occur from experience of other ocrelizumab trials.

This post is simply rehearsing some of the reasons for pwPPMS who volunteer for the ORATORIO-HAND study to stay the distance and complete the study. Please let me know if you agree, or disagree, with these points. I am also keen to find other reasons to help the many participating centres retain their patients in this trial.

CoI: multiple; importantly, I am the principal investigator on the ORATORIO-HAND study and I want to give this trial the maximum chance of being successful. Our #ThinkHand campaign will only be judged a success if and when we get a DMT licensed to protect upper limb and hand function in pwMS.

Unaccountable

The European Union and its Institutions have been heavily criticised as part of the Brexit debate as been undemocratic and unaccountable to the man or woman on the street. However, it is only when their decisions impact on you, or your patients, that you realise that these critics have a valid point.

Last week the European Medicine Agency’s safety committee (PRAC or Pharmacovigilance Risk Assessment Committee) did something that makes me despair. They railroaded through changes to alemtuzumab’s SmPC (summary of product characteristics) against the advice of experts and without data to support their position. Their advice is therefore not evidence-based and as a result, it is likely to deny many pwMS access to one of our most effective DMTs.

The PRAC states “Alemtuzumab should no longer be used in patients …. who have autoimmune disorders other than multiple sclerosis”. There is no evidence to support this statement. PwMS who have a pre-existing autoimmune disease are not at an increased risk of developing complications from alemtuzumab or secondary autoimmune disease when compared to pwMS who don’t have a pre-existing autoimmune disease.

The problem I have is that the PRAC made this decision despite robust evidence to the contrary being presented by Genzyme and advice from experts in the field. I even co-signed a letter that Prof. Alasdair Coles penned to the PRAC, CHMP and MHRA, which clearly fell on deaf ears.

The behaviour of the PRAC reminds me of the Michael Gove interview with Faisal Islam on Sky News that took place on the 3rd June 2016 in the run-up to the Leave-Remain EU referendum:

Gove: I think the people in this country have had enough of experts, with organizations from acronyms, saying—

Faisal Islam: They’ve had enough of experts? The people have had enough of experts? What do you mean by that?

Gove: People from organizations with acronyms saying that they know what is best and getting it consistently wrong.

Faisal Islam: The people of this country have had enough of experts?

Gove: Because these people are the same ones who got consistently wrong what was happening.

Faisal Islam: This is proper Trump politics this, isn’t it?

Gove: No it’s actually a faith in the —

Faisal Islam: It’s Oxbridge Trump.

Gove: It’s a faith, Faisal, in the British people to make the right decision.

Does the EMA expect us to have faith in their decision-making?

As an MSologist looking after pwMS this upsets me and worries me immensely. The implications of ignoring experts is one thing, but what are the implications for my patients? What impact will this PRAC decision have in practice?

I estimate that about a third of pwMS will have a comorbid autoimmune disease and may even be more than a third. The latter depends on how you define autoimmunity. This means many people with MS will be denied access to alemtuzumab because of EU officials who ignored the evidence presented to them and without any transparency around their thought processes and why they made this decision. This is no way for EU officials to be acting when we are trying to argue the case for Britain staying in the EU.

Lack of transparency with the EMA is not new. I have been involved with many EMA-CHMP decisions and it really depends on the whim of rapporteur or co-rapporteur. Unlike the FDA which holds its meetings in the open, with the EMA and its various sub-committees you have no idea of the decision-making processes that go on behind closed doors. I am often asked why the British voted to leave the EU. The elephant in the room is the EU itself and how it functions; its decisions impact the lives of its citizens and this is another example of very, very, poor decision making with many downstream ramifications.

CoI: multiple

Rituximab combination therapy

A dark age is when society regresses; it goes backwards in time. The shocking revelations in last week’s New England of Journal of Medicine on the dire situation of some type 1 diabetics upset me and indicates we may be entering a dark age. An age when we are forcing our patients to turn their backs on innovation because they, or society, can’t afford to purchase the necessary medications to allow them to treat their disease.

“The price of insulin has risen to a level where some patients have reported rationing their medication, which has resulted in worsening glycemic control and, in some cases, diabetic ketoacidosis and death. Approximately 90% of insulin sold in the U.S. is manufactured by one of three companies (Eli Lilly, Novo Nordisk, and Sanofi). The rising cost of insulin in the United States can be attributed primarily to two phenomena. First, U.S. law allows pharmaceutical manufacturers to price their products at whatever level they believe the market will bear and to raise prices over time without limit. Second, direct competition in the insulin market is lacking.”

Excerpt from Michael Fralick & Kesselheim. The U.S. Insulin Crisis — Rationing a Lifesaving Medication Discovered in the 1920s. N Engl J Med 2019; 381:1793-1795.

I can only conclude that the politicians, with their neoliberal agenda, are failing these patients and society in general. The plight of type 1 diabetics is just the tip of the iceberg in a healthcare system that is being ripped apart by raw and unbridled capitalism. This is why the Labour party in Britain are warning us about the potential consequences for the NHS when we lose the protection of the EU post-Brexit.

Is the rationing of DMTs happening to people with MS? Several pwMS have commented on this blog how unaffordable DMTs are in the U.S. if you don’t have medical insurance and/or are covered by one of the socialist healthcare systems you are being forced to forego treatment. For me, as an academic working in MS, this is worrying because as we move into an era of combination therapies we are going to have to make combinations of treatments affordable. If one company controls all the components of the combination they can then price the therapy at an affordable price. However, if the components of the combination are controlled via different companies then the price of the individual components may make combination therapies too expensive.

We have been making the case of building a sandwich with a potent anti-inflammatory at the base and superimposing on top centrally acting anti-inflammatories, neuroprotective and remyelination therapies, neurorestorative treatments and anti-ageing agents. In addition to this, we may need a cocktail of drugs targeting comorbidities, either treating them or preventing them. As you can see the cost of treating MS will rapidly become prohibitively expensive.

In HIV Gilead tackled this problem by in-licensing different drugs from other companies to create their polypills. I envisage this happening in MS. If it doesn’t happen then the price of treating MS will beyond most people.

At the moment anti-CD20 therapies are rapidly becoming the base of the treatment pyramid, but the innovator anti-CD20 compounds are simply too expensive at present for competitors to use them as part of a combination therapy strategy. Even when ofatumumab and ublituximab get licensed for treating MS the cost of anti-CD20 therapies, in general, is unlikely to fall significantly. Maybe as part of our #AffordableDMT initiative, we can get wide adoption of rituximab biosimilars and use these more affordable anti-CD20 biosimilars at the base of the pyramid?

The problem we have is that rituximab is not licensed to treat MS. Outside of Sweden and the Kaiser Permanente in the U.S. systematic rituximab prescribing is patchy. Most HCPs are not confident enough to take on the risks of prescribing rituximab off-label. Even in Sweden the medical insurance company that covers Swedish neurologists in relation to their practice has said they won’t be able to cover their rituximab prescribing because of the extent of its use in Sweden. I am told that the Swedish government is having to create a bespoke medical insurance policy to cover system-wide off-label prescribing. Surely a better solution would be for the Swedish government to license rituximab as a treatment for relapsing MS and then this issue will go away?

If rituximab is licensed as a treatment for MS in Sweden then under reciprocal recognition rules in Europe we may be able to start using rituximab in the UK and other EU countries. This is assuming it happens before Brexit-related divorce laws disconnect us from Sweden and the EU. Another option would be for the NHS to license rituximab in the UK. I am not sure of the NHS has the will and/or the mechanisms for licensing a therapy for a specific disease, but it is something worth exploring. This would be a real game-changer both in the UK and internationally. This will allow us academics to at least build a combination therapy strategy with an affordable anti-CD20 at the base of the pyramid. This will allow us to test our induction-maintenance therapy hypothesis using generic drugs; for example, induction with rituximab followed by leflunomide as maintenance therapy.

Getting rituximab licensed to treat MS could be another strategic objective of our GRAD Initiative (Grass-Roots Affordable DMT Initiative). What do you think? This may appeal to low- and middle-income countries, particularly a country such as India that has a large and burgeoning biosimilars industry.

Please don’t be shy we need #AffordableDMT champions and wider engagement from the MS community. If you would like to get involved please get involved and register your interest. I would also like ideas from the wider community about how we get rituximab licensed as a treatment for MS. If you can’t beat Pharma you might as well join them 😉

CoI: multiple

Affordable DMTs

My post on the ‘Damp Squib’ has upset several close colleagues. I need to explain my reasons for doing it; the main one being is that I am very frustrated that change happens so slowly, whereas shit happens so quickly.

The catalyst for our Barts-MS off-label initiative was my sabbatical 5 years ago and kicked-off with a blog post I did on the 3rd October 2014. I am ashamed that it is now 5 years since our first activities in this space and nothing has really changed for people with MS living in resource-poor environments. I can count the number of centres on one hand (excluding rituximab users, which is really a high-cost DMT) that are using off-label DMTs and they are all in high-income countries. As a proponent of ‘Time is Brain’ in MS, and that includes the brains of pwMS living in resource-poor countries, I have to ask myself how many brains have been shredded whilst we procrastinate. We want this campaign to become urgent.

A good analogy would be the anti-retroviral access campaign that was run to get people with HIV living in low- and middle-income countries onto treatment. Why can’t we do something similar for people with MS?

When I criticise my colleagues I want to make it clear that there is likely to be an unconscious bias against off-label prescribing of generics and biosimilars despite a robust evidence base. This is the invisible elephant in the room. Whenever I have attempted to shift this issue to the top of the agenda it gets watered down and put at the bottom of the list of solutions for treating people with MS in low- and middle-income countries. In addition, the term off-label tends to be avoided and replaced by euphemisms, for example, repurposed.

I suggest we avoid off-label and use a neutral term that will be all-encompassing and acceptable to all parties. I, therefore, suggest referring to these treatments as “affordable DMTs”, which is counterbalanced by the term “high-cost DMTs”. Affordable captures everything we are trying to do without stating the obvious. The term ‘affordable DMT’ solves the issue as it not only refers to off-label DMTs, but includes generic, biosimilar, and bioequivalent DMTs, and unlicensed and compounded DMTs and any other variation that emerges. In addition, what is affordable may vary from one country to the next.

It is clear that a lot of people in the MS community don’t want to rock the boat when what we really need to do is capsize the boat. Many of my colleagues, including me, are so conflicted that we tend to toe the Pharma-line because we have been indoctrinated by the system, i.e. the only solution to treat and manage MS is with high-cost innovative DMTs. This is clearly not the case and we need to collect and summarise the evidence to make the MS community realise that there are other ways to manage this disease.

So I want to rebrand this the GRAD Initiative (Grass-Roots Affordable DMT Initiative), which may be more acceptable to the wider community and potentially neutralise our cognitive biases. The plan that I am currently formulating is based on a simple grass-roots movement, starting small and local:

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

We are hoping to try to do something small and local in Africa, India and Pakistan. We plan to visit all these countries/regions in 2020.

Please don’t be shy we need champions and wider engagement from the MS community to make this happen. Please get involved and register your interest.

CoI: multiple

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.

They acknowledge that adequate funding is needed for national health-care systems in low-income settings.
They suggest treatment guidelines that consider the different resource levels available in each setting, are also essential.
They make the point that easily accessible training and peer-support for neurological specialisation would enhance multiple sclerosis care worldwide.
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:

Identifying local MS champions and creating an international database.
Creating and disseminating an essential off-label DMT list with detailed protocols on how to use each agent.
Modified diagnostic criteria for use in resource-poor environments; these will need to country-specific.
Protocols for derisking and monitoring DMTs in these environments.
Creating a platform and network to allow neurologists and other HCPs from these countries to share their experience.
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

*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.

Compounding Pharmacies

“It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us, we were all going direct to Heaven, we were all going direct the other way – in short, the period was so far like the present period, that some of its noisiest authorities insisted on its being received, for good or for evil, in the superlative degree of comparison only.”

A Tale of Two Cities (1859) is a historical novel by Charles Dickens.

Although global inequality seems to be receding since its peak in 2016 we still live in a world of ‘the haves’ and ‘the have nots’. A stark reminder of this is for people living with MS and having to experience global inequality in access to effective MS therapies.

My memory of a relatively wealthy young woman with MS in Banglore, India, who I met back in 2014 when on sabbatical, reminds me that we have so much still to do. This woman was having to raise money from her extended family, and her social network, to purchase her weekly Avonex injection one syringe at a time. If she couldn’t raise the necessary money she would simply miss that week’s injection. Her neurologist informed me that since developing MS her family was facing financial ruin. The question I asked myself later was ‘Why wasn’t her neurologist treating her with an alternative DMT that she could afford?”. Therein lies the problem, i.e. how do we get the neurology community and wider MS community to accept that there are cheaper, effective, alternatives for managing MS in resource-poor environments.

Please note that I prefer using the term resource-poor environments and try to avoid using the term resource-poor country. This is deliberate because even in rich countries there are pockets of disenfranchised people without access to healthcare, for example, refugees, immigrants and the medically uninsured. Britain may soon be included. In the event of a no-deal Brexit, a large number of foreign EU nationals with MS living in this country may have their free-access to the NHS withdrawn. At present, there is no clarity on how the EU and the UK will deal with healthcare coverage in the event of a no-deal Brexit.

As an MSologist with a large number of EU nationals under my care, the prospect of a no-deal Brexit gives me sleepless nights. How will we respond to a scenario of a home office and/or NHS official demanding that we stop prescribing high-cost DMTs to some of our patients? Rebound MS disease activity on withdrawing natalizumab or fingolimod is potentially life-threatening.

It is essential that the MS community seek solutions for treating people with MS in resource-poor environments. This is why we are exploring different solutions including prescribing low-cost off-label DMTs, developing compassionate access schemes, creating low-cost generics and buyers clubs. Another grass-roots solution is to use compounding pharmacies.

In short, compounding refers to the process of creating a pharmaceutical preparation or drug by a licensed pharmacist to meet the needs of a community when a commercially available drug does not meet those needs or is too expensive. When you look at our list of essential off-label DMTs we could add dimethyl fumarate to that list. There will criticism from Pharma that compounded, or home-brew, DMF formulations are inferior. But when it comes down to a choice of either bankrupting your family due to the high-costs of innovative treatments or taking a chance on a compounded formulation of the drug I know which one I would choose.

We have previously covered the topic of a DIY DMF formulation on this blog and you can read how to make your own DMF tablets via this website. I am not advocating that individual pwMS do their own compounding, but this could be done centrally via a licensed compounding pharmacy. The quality of the compounded formulations could then be tested using an international quality control laboratory. The latter could be funded by the global MS community (MSIF) or charities with a vested interest in finding solutions to this problem, for example, the Melinda and Bill Gates Foundation or the Wellcome Trust.

How to make a DIY version of Tecfidera or DMF

Obviously, Pharma will object and produce papers such as the one below claiming their product is superior and that compounded formulations are inferior, but maybe this will nudge them to do something about the hundreds of thousands of untreated people living with MS in resource-poor environments. To be fair to Biogen they were the only Pharma company who responded to my call-to-arms a few years ago about trying to find a solution to treating MS in resource-poor environments and I note that one of their senior executives has already signed up to our Grass Roots Off-Label DMT Initiative (GROLDI). To do this is bold and I suspect brave, but their action shows you that even Pharma executives are prepared to acknowledge that access to DMTs is a global problem.

Please note our Barts-MS Essential Off-label DMT list has just been expanded to include compounded DMF and the generic version of DMF that is used to treat psoriasis.

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

Compounding pharmacies could be one way of improving access to DMTs in low-income countries. Do you think compounding pharmacies will address the problem of access to DMTs in resource-poor environments? Let us know your thoughts.

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

Thank you.

Boulas P (Biogen, Cambridge, MA, USA). Compounded Formulations of Dimethyl Fumarate Show Significant Variability in Product Characteristics. Drug Res (Stuttg). 2016 May;66(5):275-8.

BACKGROUND: Pharmacy compounded products are not regulated to the same standards as commercially available, approved products, increasing potential safety and efficacy risks to patients. This report describes an in vitro study examining consistency of content and release profile of compounded dimethyl fumarates.

METHODS: Samples of compounded dimethyl fumarate (cDMF-A, cDMF-B, cFumaderm) from separate Austrian compounding pharmacies were analyzed for drug content, uniformity of dosage, impurity, and in vitro release.

RESULTS: The average dimethyl fumarate (DMF) content ranged from 102.5 to 96.7% of the 120 mg content listed on the product labels. While the DMF capsule-to-capsule content of cDMF-A was somewhat uniform (~20% difference), there was greater variability amongst cDMF-B and cFumaderm capsules (> 30% difference). Impurity testing revealed 2 and 4 unknown components within cDMF-A and cDMF-B, respectively, with levels ranging from 0.05 to 0.81% of total drug content. In in vitro testing of cDMF-A,>10% (12 mg) of DMF was released after 120 min in simulated gastric fluid and 17% (20 mg) released in simulated intestinal fluid after 60 min. While minimal amount of DMF was released from cDMF-B in simulated gastric fluid, 50% (60 mg) of DMF was released after 60 min in simulated intestinal fluid. Similarly for cFumaderm, a fraction (< 20 mg) of the 120 mg target dose was released after several hours in simulated intestinal fluid. The uniformity of release rates across capsules varied significantly.

CONCLUSION: These results demonstrate that compounded fumarates are not equivalent to licensed products and may present unknown safety, efficacy, or quality risks.

CoI: multiple

Buyers Club

Have you seen the film Dallas Buyers Club? It is one of the movies that haunt me and keeps coming back to me in my thoughts and dreams. I now know why.

Dallas Buyers Club is a 2013 American biographical drama about a patient diagnosed with AIDS in the mid-1980s when there were no licensed treatments for HIV. It was in an era when HIV infection was highly stigmatizing. Out of desperation, the main character Ron Woodroof, brilliantly played by an anorexic-looking Matthew McConaughey, establishes the Dallas Buyers Club, to smuggle unapproved pharmaceutical drugs into Texas for treating his symptoms and starts distributing them to fellow people with AIDS. As a result, he faces massive opposition from the Food and Drug Administration (FDA) and most sectors of the medical establishment. The movie is a monument to the human spirit and our desire to live and be treated as equals.

McConaughey and Jared Leto, who played Rayon a transgender AIDS patient, received the Academy awards for Best Actor and for Best Supporting Actor, respectively in the film. The film also won the Academy Award for Best Makeup and Hairstyling and was nominated for Best Picture, Best Original Screenplay, and Best Editing.

If you haven’t seen the film it is a must, but be warned you won’t finish seeing the movie without shedding a tear.

So what has it got to do with MS? In the latest BMJ, there is an article on Buyers Clubs in general. They are now quite common in the UK and have evolved out of the desperation of patients and their families to access treatments for many conditions where there is a current lack of access to specific medications under the NHS. Interestingly, the London gay community have set-up a buyers club to purchase pre-exposure prophylaxis or PREP to prevent themselves from becoming infected with HIV. There is nothing like the gay community to show us how health activism should be done.

Matthew McConaughey and Jared Leto in Dallas Buyers Club.

Could buyers clubs be the solution for people with MS to access high-cost DMTs in resource-poor countries? Are there any local MS Champions in Kenya, Tanzania, Uganda, Zambia, etc. who are interested in setting-up a buyers club? We could explore the logistics and cost of purchasing generic equivalents of high-cost DMTs and biosimilars and shipping them into areas of greatest need. I am sure we could find some philanthropic neurologists in these areas who we be able to screen, monitor and look after these people with MS who need treatment? One successful buyer’s club could become a template on how to clone and reproduce them across the world.

Buyers clubs could even become a way of improving access to DMTs in middle-income countries with inadequate socialist healthcare systems; for example, many people with MS in Eastern Europe can’t access DMTs or have limited access to newer generation high-efficacy DMTs.

Do you think buyers clubs will address the problem of access to DMTs in resource-poor environments? Let us know your thoughts.

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

Thank you.

CoI: multiple