Are you eligible for an MS disease-modifying therapy?
Who should decide on eligibility criteria for MS therapies; the regulators, the payers, professional societies, healthcare professionals or patients?
Are you eligible for being treated with disease-modifying therapies or a DMT? This is another question that needs to be answered before you commit yourself to a specific treatment strategy or DMT.
Am I eligible for treatment with a DMT?
What are the attributes of the specific DMTs?
How can I derisk or reduce my chances of getting certain adverse events on specific DMTs?
Disease-modifying refers to treatments that change the natural history of the disease. When I say natural history I mean the long-term trajectory of MS. DMTs are treatments that reduce the rate of disability worsening, i.e. protect the end-organ. This concept is often quite difficult to explain. Let’s say it takes pwMS on no treatment an average of 18 years to start using a walking stick (EDSS = 6.0), whereas it takes those on a treatment 24 years, i.e. a 6-year delay, then the treatment can be called disease-modifying. Please note the treatment effect or 6-year delay in getting to EDSS 6.0 is an average effect and some pwMS will do better than others. The downside is that some will also do worse than average.
There have been endless debates in the early days of interferon therapy about whether or not simply reducing the relapse rate, relative to placebo treatment, by 30% but without slowing down the worsening of the disease over 2-years was disease-modification or not. However, subsequent trials and follow-up of pwMS treated with interferon-beta showed an impact on the real MS with slowing down of disease worsening, delays in becoming secondary progressive and finally on mortality.
In comparison to DMTs, symptomatic treatments improve the symptoms associated with MS, without affecting the natural history. Although treatments are classified as symptomatic in relation to their mode of action some classes of treatment may yet prove to be disease-modifying. For example, we often use sodium channel blocking agents, such as phenytoin, carbamazepine, oxcarbazepine and lamotrigine, for MS-related neuralgia and other pain syndromes. However, there is evidence that this class of therapy may be neuroprotective and hence disease-modifying.
Eligibility for treatment with a DMT depends principally on:
The licence the drug receives from the regulators in your country, e.g. European Medicine Agency (EMA), the Federal Drug Administration (FDA) and the MHRA now that the UK has left the EU.
The payers or the organisation who pay for DMTs, e.g. NHS or your medical insurance company.
National, regional or local guidelines, e.g. NICE (National Institute for Health and Care Excellence) MS management guidelines, the Association of British Neurologists guidelines and the NHS England’s treatment algorithm.
In summary, regulators decide in which group of pwMS the DMT can be used and the payers, who hold the purse strings, make cost-effective assessments to try and optimise the use of the drug in clinical practice. Guidelines are typically pragmatic and usually based on consensus to try and bridge the gap between the regulators and payers. Guidelines are formulated to help HCPs use the DMTs in the most appropriate way within a particular healthcare system. Guidelines often go much further than the regulators and payers in that they try to address potential ambiguities in the prescribing of DMTs.
In the NHS in England, we have to abide by NHS England's algorithm that is predominantly based on NICE technology appraisals, NICE standards of care and the Association of British Neurologists guidelines. To navigate the specifics of the eligibility criteria is quite complex. However, a simpler way of looking at this is to start by defining how active your MS is.
There are four levels of disease activity:
Inactive MS - not eligible for DMTs
Active MS - eligible for so-called platform therapies (interferon-beta, glatiramer acetate, teriflunomide and dimethyl fumarate) and ocrelizumab or ofatumumab.
Highly active MS - eligible for all therapies except natalizumab. Please note in England fingolimod can only be used second-line.
Rapidly-evolving severe MS - eligible for all DMTs
The NHS allows MSers to be treated with haematopoietic stem cell transplantation or HSCT. At present, there are no official NHS or national guidelines covering HSCT. Therefore, you need to ask about local eligibility guidelines, for example, London’s AHSCT network (please see ‘AHSCT: who should have access’; 20-Sept-2021). I describe disease activity in more detail in my MS-Selfie Newsletter ‘Do I have active MS? (3-Jul-2021)’.
Advanced or progressive MS
As you are aware NICE has approved ocrelizumab and siponimod for the treatment of active PPMS and active SPMS. To be classified as having active PPMS you will need to have evidence of recent MRI activity on your MRI, i.e. the formation of new T2 lesions and/or the presence of gadolinium-enhancing MRI activity in the last 3 years. In the case of active SPMS, it is the presence of superimposed relapses and/or the formation of new T2 lesions and/or the presence of gadolinium-enhancing MRI activity in the last 2 years.
The problem with the MRI criteria for activity not being quite the same for active PPMS and active SPMS is NHSE recognises that people with PPMS are less likely to be having regular monitoring MRI scans. There is an ongoing initiative to try and standardise definitions on what constitutes active MS by NICE.
Based on these very narrow definitions of active PPMS and active SPMS the majority of patients with PPMS and SPMS will not be eligible for ocrelizumab or siponimod respectively.
Please note that NHS England has a disability cut-off in that pwMS who are wheelchair users are not eligible for DMTs. The reason for this is that pwMS with more advanced MS have generally been excluded from phase 3 clinical trials and hence there is no data to support the notion that licensed DMTs work in this group of patients. This is why we have been running a #ThinkHand campaign to raise awareness of the importance of hand and arm function in pwMS and the need to do clinical trials in this population. At present we are doing the CHARIOT-MS (oral cladribine) and ORATORIO-HAND/O’HAND (ocrelizumab) studies in people with progressive MS.
The medical dogma that more advanced MS has reduced inflammation, or is non-inflammatory, needs debunking. There are clinical, imaging and pathological data that show inflammation still plays a large, and possibly a major, role in advanced MS. Therefore not targeting more advanced MS with an anti-inflammatory is counterintuitive, and may explain why so few monotherapy neuroprotective trials have been successful. Now that ocrelizumab and siponimod have been licensed for active primary and secondary progressive MS, respectively, these DMTs may form the platform for future add-on trials.
It is important to acknowledge that reserve capacity (in particular neuronal systems) plays an important part in how MS worsens. Neuronal systems with reserve capacity are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; I refer to this as therapeutic lag. These observations could be explained by the length-dependent axonopathy hypothesis of worsening MS, i.e. progressive MS manifests initially in pathways that have the longest axons (bladder and lower limb motor function). This is why we are focusing more on the arm-and-hand function as a primary outcome in pwMS who have already lost too much neurological function in their lower limbs (EDSS>=6.0).
Once someone with MS has lost lower limb function and becomes a wheelchair user, they still have neuronal systems that are potentially modifiable, for example, upper limb, bulbar (speech and swallowing), cognition and visual function. In fact, there is an extensive evidence base showing that several licensed DMTs can slow the worsening of upper limb function despite subjects having advanced MS. I feel very strongly about this point and I am keen to argue for future trials in advanced MS to include wheelchair users with a focus on upper limb function as the primary outcome measure. What keeps pwMS independent and functioning in society is arm and hand function and cognition.
I am aware that many of you with more advanced MS will find this Newsletter disquieting. Please don’t shoot the messenger. I have been trying to make the point that MS is one disease, not two, three or four diseases for some time and that MS is modifiable regardless of whether you have early or advanced disease or active or inactive MS. Do you agree?
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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 generic advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.