GROLDI – Prof G's MS Blog Archive

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.

Azathioprine revisited

Has azathioprine been given a fair chance as a treatment for MS?

I have noticed over the years that most neurologists, including myself, don’t always use azathioprine correctly. In general, we under-dose azathioprine. Why?

As an example, one of my patients with myasthenia gravis, an autoimmune disease of the nerve-muscle junction, came in this week with a relapse. He weighs 107kg and was on 200mg of azathioprine per day, which is less than 2mg/kg. He had a normal lymphocyte count. Therein lies the problem; his dose of azathioprine was too low, which is one of the reasons his myasthenia had broken through.

Azathioprine is a drug that is broken down by an enzyme called TPMT (thiopurine methyltransferase). There are genetic variants in TPMT which means you can be a slow, intermediate or rapid metaboliser of the drug. Before we start someone on azathioprine we test the activity of TPMT in their red blood cells and then adjust the target dose according to the enzyme activity. In general, we avoid using azathioprine in slow metabolizers as they can develop a low white cell count on very low doses. Intermediate metabolizers need a dose of 2-3mg/kg and rapid metabolizers a dose of 4-5mg/kg. This is a general guide and in practice, I titrate the dose upwards until I cause a mild lymphopaenia of between 0.8 and 1.2, whilst maintaining a normal neutrophil count.

As all the MS trials of azathioprine were done in the pre-TPMT enzyme activity monitoring era I looked up the azathioprine MS trials to see what doses were used. I was horrified to find out that except for one study all the other studies used a sub-therapeutic dose of azathioprine. In the Ellison 1989 trial, azathioprine was started at a daily dose of 2.2 mg/kg body weight, with the dose being increased by 25 mg each month until the white blood cell count was maintained between 3,000 to 4,000 or adverse effects were encountered. In this study, the daily dose was even increased above 4.4 mg/kg when appropriate. All the other studies used fixed-dose protocols with daily doses of azathioprine between 2mg/kg and 3mg/kg (2 mg/kg, Milanese 1993; 2.5 mg/kg, British & Dutch 1988, Ghezzi 1989; 3 mg/kg, Goodkin 1991).

What this is telling me that azathioprine has never really been trialled properly in MS and the fact that subtherapeutic doses seem to work is MS is quite remarkable (see Cochrane review below). This supports many old school neurologists anecdotal evidence that pwMS do better on azathioprine compared to patients, not on treatment. Maybe the WHO committee, who decide on the WHO Essential Medicines List, was right in telling us to reconsider our decision not to revisit azathioprine as a potential DMT for resource-poor countries.

One could argue in an era of treat-2-target and adaptive azathioprine dosing that we should relook at azathioprine as a cost-effective treatment for MS in resource-poor environments. We could start azathioprine at a low dose and titrate it slowly upwards to target a “therapeutic-dose” based on lymphocyte counts. We could then rebaseline and the monitor patients on a 6 or 12 monthly basis and only escalate therapy in patients who had breakthrough activity. I would not be surprised if azathioprine, under these circumstances, worked as well as our other platform therapies.

What do you think?

Barts-MS Essential Off-Label 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 Off-Label DMT Initiative (GROLDI)

Casetta et al. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003982.

BACKGROUND: Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis (MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in multiple sclerosis.

OBJECTIVES: To compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with multiple sclerosis.

SEARCH STRATEGY: The Multiple Sclerosis Group’s Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2006), Cochrane Database of Systematic Reviews (CDSR – Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE – searched 28.12.06) MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006). Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects.

SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with multiple sclerosis. Cohorts, case controls, case series and case reports were also used to assess adverse effects.

DATA COLLECTION AND ANALYSIS: Potentially relevant references were evaluated and all data extracted by two independent authors.

MAIN RESULTS: The five trials that met our criteria included 698 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients at one year’s, from 488 (70%) at two years’ and from 415 (59.5%) at three years’ follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years’ (RRR =23%; 95% CI = 12% to 33%) and three years’ (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies. Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years’ follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials. Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%). Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g.

AUTHORS’ CONCLUSIONS: Azathioprine is an appropriate maintenance treatment for patients with multiple sclerosis who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating multiple sclerosis. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in multiple sclerosis has not been made.

CoI: multiple

GROLDI hits a wall

To help with our #OffLabel campaign to help HCPs treat pwMS in resource-poor environments I asked Gisela Kobelt, a health economist, who I have worked with for many years for help. What she said to me made me realise that the hurdles we face are much higher than I expected.

These are her relevant comments:

“The economic case for any treatment in resource-poor countries is difficult, simply because not treating is cheaper than treating, and as no one seems to take care of disabled people in these countries they are left in the charge of their families. Therefore, the usual health economic arguments do not apply. As the economic arguments have been wasted in Europe and the USA, how could we expect them to work in these countries?”

“You need something bigger, in fact, something at the strategy level where the main message is that any health care system, even in poor countries, has been designed to help people with the means available. You need to make humanitarian arguments more than economic ones. Politicians that actually have a heart and a brain (rare birds these days!!) can promote the right arguments. Maybe an economic component would be that currently, even the things that are being done are pretty useless, hence resources are being wasted, and some could be switched to interventions that have some utility.”

The bottom line is that we need to shift the emphasis away from the economic arguments to the humanitarian ones. So if you have any stories to highlight the plight of people with MS living in resource-poor countries to share with us please come forward; you can use the Barts-MS blog as a soap-box. We need to make politicians in these countries and the WHO sit-up and listen.

*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 Off-Label DMT Initiative (GROLDI).

CoI: multiple

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

Off-label methotrexate

Prior to interferon-beta being licensed, I used to manage several patients under Prof. W. Ian McDonald who were insistent on being on treated with some form of DMT. The rationale was better to be on something rather than nothing. At the time there was some evidence that methotrexate was effective in MS and as it was relatively safe, so Prof. McDonald acquiesced. In retrospect, I have no idea if these patients responded or not as we didn’t monitor them clinically nor with MRI. How things have changed since then.

As you may be aware there is class 1 evidence that methotrexate works in RA and some evidence that it works in MS as well (see below). I suspect it works rather well and in an era of treat-2-target of NEDA (no evident disease activity) it would seem reasonable in resource-poor settings to try oral methotrexate and if there was breakthrough disease to switch to another agent.

T2T-NEDA changes the dynamic of how we use DMTs; instead of leaving someone on a suboptimal or ineffective therapy we move onto something else. However, T2T-NEDA does mean that resources need to be found to do annual MRI studies or potentially peripheral blood neurofilament levels to monitor for treatment response. This I suspect will be a problem in resource-poor countries, but even then clinicians could fall back onto clinical monitoring, which is better than nothing.

What I am saying is yes, if I was working in a healthcare system with limited access to licensed high-cost therapies I would consider low dose oral methotrexate appropriate as one of the off-label first-line DMTs in active relapsing MS. This is why low dose oral methotrexate is on the Barts-MS essential off-label DMT list for treating MS.

Interestingly, several US neurologists are still using low-dose oral methotrexate for patients in their care who don’t have medical insurance coverage. It is quite interesting to note that we all want to do the best for our patients and adapt our prescribing behaviour to achieve this aim.

This is why when a neurologist in Venezuela recently asked me for advice about how to manage one of her patients with active MS we settled on low-dose methotrexate; in reality, it was the only immunosuppressive or immunomodulator available to her. There was no supply of azathioprine, leflunomide or parenteral cladribine the other 1st-line DMTs on our essential off-label DMT list.

I don’t expect methotrexate to be highly effective, but probably it will fit in the moderate efficacy zone. The important thing is that works in some patients without causing catastrophic health expenditure or ruinous poverty.

Please note the low-dose methotrexate trial in chronic progressive MS (SPMS & PPMS) is the one study that we use as an example to support our length-dependent axonopathy study. Approximately two-thirds of the subjects in this trial had already lost most of their lower limb function (EDSS 6.0 or 6.5), which is why the trial was positive in the upper limbs, but not the lower limbs.

What is needed is for an MS champion to do a trial of low-dose methotrexate vs. an active comparator or to simply collect real-world data on the number of subjects rendered NEDA on the drug. The investigators should also include regular blood sampling to measure peripheral blood neurofilament levels. In fact, we may be able to use an area-under-the-curve analysis of peripheral blood NFL levels to see how effective methotrexate and other off-label DMTs are in the real world.

If you are interested in using methotrexate or other off-label DMTs in resource-poor settings please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI).

Goodkin et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995 Jan;37(1):30-40.

Objectives: A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic.

Methods: Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients’ Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure.

Results: Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity.

Conclusion: We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

Goodkin et al. Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology. 1996 Nov;47(5):1153-7.

Background: Methotrexate is a platform therapy for managing patients with rheumatoid arthritis. There is anecdotal evidence that it may work in MS.

Methods: We monitored 56 patients with chronic progressive multiple sclerosis (MS) who participated in a clinical trial of weekly, low-dose oral methotrexate with annual gadolinium-enhanced MRIs of the brain (Gd + MRI). Not of these patients had clinical exacerbations during the 8 months preceding study entry. We also monitored 35 of the patients with serial Gd + MRIs every 6 weeks for 6 months.

Results: We observed a treatment effect, measured by absolute change in T2-weighted total lesion area (T2W-TLA), in the cohort that completed 6-week scans. We found change in T2W-TLA in this cohort to be significantly related to sustained change in performance on the nine-hold peg test but not to sustained change on the Expanded Disability Status Scale. Gadolinium enhancement of lesions on 6-week and annual scans was uncommon. Prestudy exacerbation frequency appears to be an important consideration in designing future clinical trials in patients with secondary and primary progressive MS.

Currier et al. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry. 1993 Nov;56(11):1217-8.

An 18-month double-blind treatment of multiple sclerosis with low dose oral methotrexate showed it to be well tolerated and suggested effectiveness in exacerbating-remitting MS but not in the exacerbating progressive and chronic progressive stages.

CoI: multiple

Politician G

If I was a politician I would change the way drug regulation works to stimulate repurposing of off-label and unlicensed drugs.

The wider MS community thinks off-label prescribing is accepting second-best. This is not the case. The fact that a drug has a license or a label for a certain indication is because a pharmaceutical company has submitted an application to one of the regulatory authorities and has been given a marketing authorisation. The marketing authorisation allows the pharmaceutical company to advertise and promote the drug in question for a particular indication.

Getting a marketing authorisation is not a simple task; it requires a substantial investment in generating the necessary data, analysing it and submitting it in a form the regulatory authorities require. In fact, regulatory submissions are now so complex that a third-party consulting industry has emerged to help the pharmaceutical industry to do their submissions.

Once a marketing authorisation has been granted it often comes with several post-marketing commitments, in particular, a requirement to collect data on safety in the so-called post-marketing environment. There is no way a pharmaceutical company is going to take on a new drug application and the post-marketing obligations unless the financial incentives are there to do it. I was once told by a senior pharmaceutical representative to cover the regulatory costs and post-marketing commitments for an MS-related DMT, global sales would have to be greater than $150M just to break even. Therein lies the problem!

The upshot of this is that for drugs that are off-patent, have a patent life that is too short for a return on investment or are unlicensed (never been submitted for a license before) there are simply no incentives to license them. These drugs could theoretically be more effective than licensed drugs for a particular disease indication, but without head-2-head studies we can’t tell. A good example of this is the off-label use of rituximab in neuromyelitis optica; it may be good as, or better than, the three new players in the field (eculizumab, satralizumab or inebilizumab) but we may never know.

Another issue is that the regulatory authorities be it the MHRA in the UK, EMA in Europe or the FDA in the US, rely on the pharmaceutical companies for their funding; i.e. by pharma submitting licensing applications or requesting advice (consulting activities) they pay fees, which are used to run the show. This creates a perverse symbiotic relationship between the pharmaceutical industry and the regulatory authorities and explains why these parties work together to actively discourage off-label prescribing.

Off-label prescribing undermines both the activities and survival of the regulatory agencies (turkeys’ don’t vote for Christmas) and challenges the current and very lucrative pharmaceutical business model.

In an ideal world, the regulatory authorities should be funded by the government and be independent of pharmaceutical funding. Regulatory authorities could then be tasked with policing and regulating off-label prescribing; i.e. they could be asked to review the evidence in favour of these drugs and grant these drugs the equivalent of marketing authorisation to support their wider use.

For example, I would envisage the MS community submitting a request to the EMA to review the evidence that rituximab a potential DMT for treating relapsing forms of MS. The EMA would then review the evidence and make a decision whether or not to extend the license of rituximab to cover MS. This would be independent of any pharmaceutical company. I would even envisage the regulators having the power to give a provisional approval with guidance on what data gaps need to be filled for full approval. This would then allow funding agencies and/or healthcare organisations to put out specific calls to the MS community to do the necessary trials to address the regulatory requirements. This would stimulate a robust development path for ‘neglected’ or ‘forgotten’ drugs independent of the pharmaceutical industry.

Even more radical idea would be to create a division within the regulatory authorities to actually review and address unmet medical problems, which off-patent and unlicensed drugs may address, i.e. for the regulators to actually administer grant funds to do drug-repurposing trials. The latter may even be linked to new legislation to tempt pharmaceutical companies to apply for these funds.

Governments could enact legislation to grant unique marketing authorisations for repurposed drugs, similar to the orphan drug act. In a modern economy, it would be relatively easy to police a system where two products of the same drug could be marketed to make sure that a specific product is being prescribed and used for the repurposed indication, but at different prices. In fact, this happened with pregabalin in the UK. The anticonvulsant patent for pregabalin expired earlier than its patent for pain. Pfizer made sure that the NHS prescriptions for pain were of the more expensive branded formulation Lyrica, and not the cheaper generic formulations. The motivation for policing indication-based pricing would be to incentivise the pharmaceutical industry to repurpose off-patent drugs. In other words, they would get their return on investment.

I think the economists, and possibly the pharmaceutical industry, would like the latter solution to the drug repurposing conundrum because it involves a market solution. Repurposing legislation of this type would open up the possibility of doing innovative combination therapy studies using off-patent medication. The latter is urgently needed in the MS space to address add-on neuroprotection trials.

With Brexit looming and the UK about to leave the EMA, I don’t envisage this sort of solution happening anytime soon. Like the orphan drug act, drug repurposing legislation would need to be done at scale, i.e. at an EU level and not a UK level. At the end of the day, the UK market is simply too small with not enough profit margins to make it worthwhile for Pharma to invest the required amount of money to ensure an adequate return on their investment for repurposing a off-patent drug.

We can daydream and come up with many potential political solutions for the off-label repurposing issue, but this is not going to help MSers living in resource-poor settings access DMTs anytime soon. So I would please urge you to act local and to help us start our Grass Roots Off-Label DMT Initiative (GROLDI, please sign-up to help) and to remind you of our subcutaneous cladribine protocol, which you can download. There is no reason why we can’t treat MS early and effectively in resource-poor environments.

Barts-MS Essential Off-Label DMT List

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

CoI: multiple

Catastrophe

Have you heard the term catastrophic health expenditure or CHE before? You should have as many MSers and their families are exposed to catastrophic health expenditure.

CHE occurs when the spending on health exceeds a pre-defined percentage of a person’s or household’s capacity to pay. CHE has a massive impact on MSers’ lives and usually discourages them from using healthcare services and often leads to a reduction in the use of other essential goods and services. In summary, CHE exposes families of MSers to poverty and economic ruin.

In 2014 when I was visiting India on my sabbatical I remember meeting a relatively well-off woman with MS who was having to buy her weekly Avonex (interferon-beta-1a) injection one syringe at a time. She told me that if she couldn’t raise the money from family and friends she would simply miss that week’s injections. Her neurologist told me that she was from quite a wealthy middle-class family and that her MS had devastated their finances. Does this story sound familiar?

If you live in the UK or another country with a socialist healthcare system you are generally protected from CHE by having free access to healthcare and social safety net in the form of unemployment and/or disability benefits. However, if you live in a country with a healthcare system that is based on a fee-for-service private model with substantial out-of-pocket payments it is easy to see how MS can cause CHE.

Iran is a country with substantial out-of-pocket payments for health system financing. The study below shows that about 1 in 25 families with someone with MS encounter catastrophic healthcare costs. Importantly, the brand of DMT, housing, income and health insurance were significantly correlated with catastrophic expenditure. This is one of our motivations for forming a Grass Roots Off-Label DMT Initiative (GROLDI), which promises to lower the costs of treating MS in countries such as Iran by addressing the unacceptable costs of innovator DMTs in countries such as Iran. Iran is not even a good example as the government has at least allowed biosimilars and generics to emerge to try and lower prices of the so-called ‘innovator DMTs’.

Not surprisingly there is a literature of CHE in many low- and middle-income countries, for example, Brazil. Kenya, China, Nepal, Korea and India. But it is also a growing problem in countries such as the USA in the medically uninsured. Over 60% of personal bankruptcies in the USA are triggered by health crises. I sincerely hope you will agree that CHE is another reason why we need to move off-label DMTs up the political agenda and to push-back on Pharma’s influence to prevent off-label prescribing.

I am prepared to bet that if we studied the economic impact of MS worldwide we would find that MS is a common cause of CHE. Is anyone prepared to take on this challenge? How common is CHE in your country and how often is it triggered by someone in the family being diagnosed with MS?

Juyani et al. Multiple Sclerosis and Catastrophic Health Expenditure in Iran. Glob J Health Sci. 2016 Sep 1;8(9):53778.

BACKGROUND: There are many disabling medical conditions which can result in catastrophic health expenditure. Multiple Sclerosis is one of the most costly medical conditions through the world which encounter families to the catastrophic health expenditures. This study aims to investigate on what extent Multiple sclerosis patients face catastrophic costs.

METHOD: This study was carried out in Ahvaz, Iran (2014). The study population included households that at least one of their members suffers from MS. To analyze data, Logit regression model was employed by using the default software STATA12.

RESULTS: 3.37% of families were encountered with catastrophic costs. Important variables including brand of drug, housing, income and health insurance were significantly correlated with catastrophic expenditure.

CONCLUSIONS: This study suggests that although a small proportion of MS patients met the catastrophic health expenditure, mechanisms that pool risk and cost (e.g. health insurance) are required to protect them and improve financial and access equity in health care.

CoI: multiple