Off-label DMTs
A call for help from a young woman with active MS living in a country without a national programme to treat multiple sclerosis. Can we help her?
Case study
I have just received the following message on Twitter:
“I urgently need medication to be able to move around and do at least a quarter of my vital activities I am incapable of treatment. It is not available in my country and in other countries, but I do not have the money to buy it. Please help me.”
Prof G’s advice
Similarly, a few years ago, I received a tragic email from a young woman from Los Angeles who had been recently diagnosed with MS. Unfortunately, she couldn’t access DMTs due to being uninsured. She described having active MS, and unless she was treated early and effectively would almost certainly be unable to continue working. She was desperate enough to ask what would be required for her to move to the UK to live, work and have her MS treated on the NHS. Although moving to the UK is possible, she would need a work permit and a job. I put her in contact with a very compassionate neurologist in LA who helped this young lady get onto a DMT via one of the compassionate free access programmes that the pharmaceutical companies run in the US.
What about low or middle-income countries, which I assume this young woman lives in? For example, just before the COVID-19 pandemic, a neurologist in Venezuela emailed me asking for advice about managing one of her patients with active MS when there were almost no available DMTs in her country. After email ping-pong, we settled on low-dose methotrexate as the only accessible immunosuppressive or immunomodulator available to her. At that time, there was no supply of azathioprine, leflunomide or parenteral cladribine. In other words, Venezuelan neurologists and doctors had to make do with what was available. I hope things have changed in Venezuela.
I have always made the point that treating MS with an off-label medication is better than no treatment. Do you agree?
Another case is the Syrian refugee with MS living in a refugee camp in Lebanon. The email I received from her sister brought tears to my eyes. I have lost contact with them, but after speaking to a friend and colleague in Beirut, I believed that the Lebanese government and healthcare system would help them. However, the subsequent email exchange I had with this poor patient’s sister implied that they would have to pay for the DMT privately. I, therefore, recommended off-label parenteral cladribine or leflunomide (pro-drug for teriflunomide). I am not sure if this was ever taken up.
I could go on with case histories of this kind that I have been asked advice on over the years. The initial contact comes from the patients themselves, their families and friends, or their neurologists and the list of countries these requests come from is quite long. Over the last eight years, since I launched my essential DMT list, many middle-income countries have implemented state-funded MS treatment programmes. So change do change it just takes time.
The other issue in low- and medium-income countries is access to high-quality MS services, and affordable DMTs are highly variable. This is a problem that is not going to be solved easily. One solution we explored, unsuccessfully, was the WHO essential medicines list or EML. The MSIF coordinated a multi-stakeholder application, which I co-chaired with Brenda Banwell, to get glatiramer acetate, fingolimod and ocrelizumab onto the WHO Essential Medicined List. The WHO acknowledged our approach but noted that some relevant therapeutic options for MS were not included in the application (azathioprine and natalizumab) or were not given full consideration (rituximab). The committee recommended we relook at azathioprine, despite them having rejected azathioprine in 2015. This recommendation was odd because, to my knowledge, no new data has emerged since 2015 to change Azathioprine's position as an off-label treatment for MS.
As for natalizumab, we did not add it to the EML application because it is still on patent, i.e. expensive, it needs to be given as a monthly infusion, which adds to its expense, and is associated with a high monitoring burden for PML. The latter would be very difficult in resource-poor environments. At the moment, the PML JCV serology assay is controlled by Biogen, so when natalizumab comes off-patent and natalizumab biosimilars emerge, what will happen to the international JCV serology monitoring system that currently exists? Would the WHO take it over from Biogen? Would it be distributed to national labs? Can resource-poor countries incorporate this assay and pharmacovigilance programmes into their already overstretched laboratory systems? Not to mention frequent MRI monitoring.
We went through all these factors in our deliberations and concluded that 6-monthly ocrelizumab and rituximab if ocrelizumab is not available, would be a better alternative than natalizumab. Another factor was that ocrelizumab is now licensed to treat PPMS. If we excluded ocrelizumab from the list, what message would this send to people with PPMS? Another factor in favour of having anti-CD20 therapies on the EML is that the monitoring requirements for anti-CD20 therapies are much less burdensome than natalizumab. However, this may change as the long-term safety profile of anti-CD20 therapies changes with time.
The MSIF is still working on getting licensed DMTs onto the WHO EML. However, this is no guarantee that resource-poor countries can afford high-cost drugs for their citizens. Surely we, as an MS community, need to do something else?
I have often asked myself, “do we expect the young lady above with active MS to wait for the WHO to deliberate and for her country’s healthcare system to enact the changes before her MS is treated?” If the drugs are high-cost and likely to remain high-cost, then poorer countries, including her own country, may just ignore the WHO EML. This doesn’t help people like her living with active disabling MS now.
Neurologists in resource-poor environments must act locally and start grass-roots movements in their own countries to get MS diagnosed, managed and cared for properly, including off-label prescribing.
If you are from a resource-poor country, the following are the nine options I have argued for in the past. Not all of these options will be available or appropriate for your county. For example, rituximab biosimilars are still relatively expensive and require quite a sophisticated infrastructure to deliver them, but this is not insurmountable as many countries, even high-income countries, have adopted off-label rituximab treatment for MS with gusto. In comparison, in very low-income countries, drugs such as leflunomide (class 1 evidence), subcutaneous cladribine (class 1/2 evidence) and possibly azathioprine and methotrexate may be more appropriate.
Azathioprine*
Cladribine
Cyclophosphamide*
Fludarabine*
Leflunomide
Methotrexate*
Mitoxantrone
Rituximab*
AHSCT
* on the 19th WHO Model List of Essential Medicines
I also suggest this patient contacts her local MS patient organisation for help. Many of these patient organisations are against off-label prescribing as a solution to the management of MS, but at the same time receive funding from the MS Pharmaceutical companies, which creates a conflict of interest. This is why patient organisations tend to prefer and support compassionate access schemes. However, we explored the compassionate access route a few years ago with Biogen to implement and test such a scheme in Zambia, but we failed to get it off the ground. There were too many hurdles, politically and logistically, and then there was a question mark about its long-term sustainability. It would have been unethical to provide a free DMT to a patient with MS for three or four years for the scheme to be discontinued because the local healthcare system couldn’t take over the prescribing and monitoring the drug in the future.
Another solution is a market solution, which the Medicines Patent Pool (MPP), a United Nations-backed public health organisation, is exploring. The MPP licenses patents of high-cost drugs from Pharma and then sublicenses them to generic companies to produce a generic equivalent for low- and middle-income countries. This model has worked very well for HIV and hepatitis C. Before the COVID-19 pandemic, I was working with the MPP on MS. Although the MPP does great work, it takes time for things to happen and does not address this patient’s unmet need in the present.
My recommendation for this lady would be to see if she can be treated with subcutaneous generic cladribine or rituximab. Both of these are high-efficacy DMTs. If this is not possible, maybe oral generic leflunomide, a prodrug converted to teriflunomide, would be another option. Other oral options included fludarabine, azathioprine or methotrexate. Cyclophosphamide, mitoxantrone and AHSCT should be reserved if all else fails.
If you were in this young lady’s position, what would you do?
The following is a paper from our group on how to use off-label subcutaneous cladribine.
BACKGROUND: 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.
OBJECTIVE: 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.
CONCLUSION: 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.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
Good news. Just received the following response from Merck MENA (middle East and North Africa):
Availability: Palestinian MOH has received Rebif 44 mcg supply in 2022 to cover their estimated demand for West Bank and Gaza Strip for the year.
Process: The Palestinian MOH has an official process for dispensing medications, where patients must be enrolled in the MOH list of patients to receive their respective medication. To be enrolled, all patients must complete and submit an application to the MOH, and accordingly, the MOH can dispense the medication to them on monthly basis, free of charge.
Support: Due to the security situation in Gaza Strip, Merck does not have a PSP/PAP there, however, we do have in West Bank. Merck’s PSP nurse in West Bank would gladly support this patient in completing the application and guiding here through the above mentioned process (Merck PSP/mobile number ***).
To be blunt with what seems to be some sort of postcode lottery regarding MS treatment in the UK its not so different here I’m afraid. My wife two years after initial diagnosis- no neurologist follow up, no determination of type of MS, no ‘frequent’ scans (had to ask for one after two tears of in action - still waiting 8 weeks later to even get an appointment letter let alone an appointment). So no determination of type of MS and if appropriate DMT/antiviral treatment.
Meanwhile her disability is getting worse.
Tbat doesn’t mean I haven’t got huge compassion for people in a similar situation in lower income countries and they deserve treatment and answer just as much but things need to change here too. The feeling of despair of disability increasing in the face of inaction knows no borders.