Thursday, 28 June 2018

Off-label disease modification for people with multiple sclerosis in resource poor settings.

Drugs are rationed on the basic of cost-effectiveness. This is all well and dandy if you live in a place where you can get access to treatment x or y because you have socialized medicine or access to a health insurance scheme. 

However, live outside these regions and your annual income may be less than the cost of all current MS drugs.

If you live as a pwMS or work as a Neurologist in a resource poor country you need to read this paper. This was written by one of our Non-UK based Neurologists. It is open access and can be read by anyone.


Zhifeng Mao, César Álvarez-Gonzalez, Christo Albor, Gabriel Doctor, Derek Soon, George Pepper, Benjamin P Turner, Monica Marta, Joela Mathews, Gavin Giovannoni, David Baker, Klaus Schmierer. Cladribine: off-label disease modification for people with multiple sclerosis in resource poor settings. Multiple Sclerosis Journal – Experimental, Translational and Clinical.Volume: 4 issue: 2. https://doi.org/10.1177/2055217318783767



Abstract
A considerable number of people with multiple sclerosis (pwMS) live in low- and middle-income countries (LMIC), where lack of resource adversely affects access to effective disease-modifying treatment.

The objective of this commentary is to propose a useful cost-effective disease-modifying treatment option for pwMS in LMIC with potential high efficacy and high convenience to the pwMS and treating physician.
Viewpoint: We propose using generic 2-chloro-2’-deoxyadenosine (cladribine), a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II and III trials to be a highly effective disease-modifying treatment for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high-income economies where an oral preparation has recently been licensed by the European Medicines Agency.

Our viewpoint takes into account experience we have gathered over the past three years in the use of generic cladribine to treat pwMS. Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.

Two years ago we tried to get a clinical trial underway in Mexico to get more supportive class I data and had a large team of neurologists talking together and willing to do a study to compare cladribine to the available treatment. But neither funders in the US nor UK wanted to support it. The Mexican Neurology team would have put resource into the project and this was a real opportunity wasted. For the price of a few mouse projects on microbiome etc. You could have had real data. I am sure it would not have failed to impress over the "CRAB" alternatives.


If you look at how much people earn, compared to the average cost of a (FDA/EMA) licensed MS drug, you will see that getting treatment is not compatible, especially for drugs that have recurrent costs.

The average salary in many places is lower than the cheapest of the cheap, yes I know there is no such thing, drug. You can see, this is especially so, where the drug costs in the US are massively higher than the UK price.

Likewise, the same issues are faced by people without health insurance or social medicine and insufficient income who live in the Western World. Drugs are simply outside their budget.

Even within the NHS in the UK access to treatment is restricted by prescribing guidelines.

So people may buy a few weeks worth of an interferon and hope that it will do the trick.

You would think the MS Societies would embrace off-label use of cost-effective alternatives, but it appears that a common view is that sub-standard treatments, or treatments without evidence, should not be used in resource Poor Countries, if they are not good enough for the Western World.

This means do nothing. 

Importantly Do not Rock the Pharma Boat.

You could go for a very cheap immune modulator like azathioprine, which costs peanuts by Western standards. However, why go substandard as we know that azathioprine has efficacy in the range of a beta interferon:

Massacesi L, Tramacere I, Amoroso S, Battaglia MA, Benedetti MD, Filippini G, La Mantia L, Repice A, Solari A, Tedeschi G, Milanese C. Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial. PLoS One. 2014;9(11):e113371.

However, generic cladribine is unlikely in that medium efficacy league, as oral cladribine is in the highly active treatment bracket based on studies with the oral preparation.

The data indicate that all of the generic cladribine that is injected gets into the blood, compared to the oral route where about 40% gets into the blood. Therefore to achieve similar blood levels you simply need 60% less of the injected variant.

The MS International Federation who represent the World view of MS have actually done very little to support equitable access. Yep, I will get into trouble for voicing this opinion, but let the facts prove me wrong.
 


"Our vision is a world without MS
Our mission is to inspire, mobilise and bring the world together to improve the quality of life of everybody affected by MS and to end MS forever.and support international research into better treatments and ways to manage the disease".
Let's hope the The 2017 strategy has some meaning

  • Improved access to effective treatments and health care
"Repurpose & translate materials for adaption and use around the world."

This seems to mean "repurpose" where there is no pharma activity, However repurposing generic cladribine surely cannot fail to have benefit and would be a low hanging fruit for success.

Cladribine will be out of patent by about 2024 unless they have something up their sleeve. Fingolimod will have gone by 2019 and the MS treatment landscape will change.

Maybe then the World of MS will indeed become more equitable

However, why not surf the treatment wave rather than wait for it to break?

Summary points
  • A considerable number of people with multiple sclerosis (pwMS) live in low and middle income countries (LMIC), where lack of resource adversely affects access to effective disease modifying treatment (DMT).
  • We propose using generic cladribine, a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II & III trials to be a highly effective DMT for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high income economies, where an oral preparation has recently been licensed by the European Medicines Agency.
  • Our viewpoint takes into account experience we gathered over the past three years in the use of generic cladribine to treat pwMS.
  • Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.

Obviously, you can wheel out the "innovation costs" argument about why we should not tread on pharma profits, but then you should also bring out the moral argument. "Is it right to do nothing in LMIC's whilst we wait for patent lives to expire?"  

If companies wish to talk about social responsibility, they could provide an access scheme, where different countries are being charged different prices. 

We know the manufacturing costs are not related to the physical purchase cost and 10mg can be bought for $35.

Likewise, companies do charge different amounts in different countries, USA, vs, Europe vs UK.

Read the paper you can see that if you are living in the US, you are paying the price.

If there is a will there is a way.

COI: Members of the Team have helped Merck develop the oral preparation of cladribine (Mavenclad) for people with relapsing MS.  Members of the team have also helped other MS DMTs to the market, including fingolimod, natalizumab, ocrelizumab, and alemtuzumab. BartsMS have been using generic cladribine in pwMS off-label for nearly 4 years.

6 comments:

  1. Wish I knew this 4 years back than, when I spent a cost of apartments in cash for the dose of alemtazumab

    ReplyDelete
  2. I had not previously considered the UK as a low- and middle-income country - RETHINK! Considering the long-standing financial pressures of the NHS, the financial basis for NICE medical approvals (e.g. recent ocrelizumab decision), and the way that most pwMS are reliant on the NHS treatments, conclude that we are. This article and the use of cladribine makes a lot of sense and gives great hope for a fundamental change in attitude. Bring it on!

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  3. From formal studies and from off-label use, how effective is cladribine in non-relapsing MS?

    You had that one paper about 2 patients

    How many others have you treated?

    ReplyDelete
    Replies
    1. We've submitted a paper on 71 patients, some of which were non-relapsing. We're close to 200 having had a first course; we'll present an update at ECTRIMS. And we're hopeful #ChariotMS will be funded so we'll whether there is measurable benefit for people with an EDSS of 6.5 or more.

      Delete
  4. MSIF agrees access to treatments in low and middle income countries is an urgent issue. We have currently two projects for that objective, one exploring access with the World Health Organisation (WHO), the other specifically looking at issues in Latin America.

    ReplyDelete
  5. Is MS too small an issue for the WHO to make any form of priority?

    ReplyDelete

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