Hi Sharmilee thank you for chatting to us. There's been a slight change in focus when it comes to DMDs from the ‘wait and see’ attitude to people now being told to look into treatments earlier on. Can you tell us about this shift?
It's all a matter of neuronal reserve. We know that brain atrophy is a progressive thing and even as we age, it progresses quite rapidly. With conditions like MS which affect the brain, neuronal content and neuronal reserve, this is going to be occurring at a much faster pace than with normal aging so you need to get in there early with the treatments.
In terms of clinical efficacy, if you go in early with DMDs you're going to have a better impact in terms of disability progression. If you wait, you have less of a neuronal reserve on which you can impact. With the availability of all these options it makes sense to start treating now.
If you were told a few years ago to ‘wait and see’ and you have not been in touch with your MS team since then, should you ask to be seen again and start talking about DMDs?
As I said, times have changed and things need to be current in terms of managing your MS. If you're not certain that the disease is well controlled then I don't think there's any harm in making an appointment and finding out for yourself.
We sometimes hear from people who've been told by their neurologist or their MS team that they're too well to go on disease modifying treatments. Should these people open up the conversation or should they accept what they've been told?
That’s an interesting question because what is too well? If you have a neurological condition, in my opinion, there's no such thing as being too well.
There are always subclinical symptoms, good days, very bad days and so on. If you really look at a person with MS under a microscope over the course of a year, you find that they do have subclinical disease activity which they've learned to ignore or are not picking up as they should be. With the development of new treatments there are now new ways of looking at someone with MS through MRI lesions, brain atrophy and also the introduction of CSF neurofilaments into clinical practice.
The idea of simply being ‘well’ is now made more granular so you need to be more personalised in figuring out what the underlying pathophysiology is, and by looking at the biology of the disease in yourself. You may find you that you are doing well compared to others or you may not be. I think as science has moved on, so have the clinicians managing it.
There are currently 14 different DMD options available for people with RRMS with more making their way to the market. What are the options in terms of escalation versus induction? For example, starting with a less effective DMD and then switching when your MS becomes more active. Or should you start with a more effective one from the outset?
This is based on personal preference and picking the correct individual for the correct treatment. In terms of the two types of treatment, induction therapies are generally high efficacy drugs. They are higher efficacy at the start and the risk then lessens because you're giving just one year's worth of treatment. Then you monitor with maintenance strategies or escalate maintenance.
With escalation strategies you are increasing the risk by swapping higher and higher. You also have to think about what has preceded it and the cumulative risk. If you were treated for your MS almost 10 years ago and received Mitoxantrone, which is now very rarely used, you may not want to follow it up with Natalizumab because it compounds the PML risk.
In many ways lifestyle also matters. If you are young and in employment then you want a medication which is going to have the least impact on you. For example, with an induction strategy you could have four years disease free. That's four years of your life where you can go around doing whatever you want to do.
There are lots of things which go into deciding which approach you go for. The caveat to all of this is that the more you swap treatments, the least effective they become. You need to find the correct one which is going to work for your MS right at the beginning.
Another option is to not go on disease modifying drugs at all. What advice have you got for people who have made this choice?
It's important to re-evaluate your disease on a regular basis, maybe every year. When you choose not to go on treatment it's not necessarily going to remain that way. There are lots of ways to monitor your disease, including various apps which will do it for you.
If you find that there is a problem you may want to make an appointment and re-evaluate the entire disease course again.
There has been a lot of talk about HSCT recently. Should this be considered as an option when it comes to choosing treatment?
HSCT is probably the closest to a cure you're going to get with MS disease modifying treatments. I think it is probably the ceiling of what is available for MS and for those with highly active MS.
There is something called the Pan London HSCT Group which reviews all referrals on a case-by-case basis but I've also had patients who have it done privately too.
Do you think that there will be a move to treat progressive MS with HSCT as well?
The current data suggests that HSCT is not effective in progressive MS. The MIST study which everybody seems to quote shows that when used in RRMS, compared to standard treatment, HSCT reduces the risk of progression by 20% as opposed to 80% with a standard treatment.
However, in progressive MS it hasn't been found to be as effective. What studies have found is that disease duration, the EDS score, the disability level at entry and whether you have active disease all matters.
The way to think of HSCT is as a very highly active anti-inflammatory treatment option. You have to demonstrate some form of inflammatory activity to really benefit from it. There are also risks associated with HSCT, many of which are long-term and need to be factored in.
If you have been told that your MS is progressing and DMDs are no longer helping, what should you expect next?
I would clarify what it means when a DMD is not helping. You need to look to see if it's a demonstration of inflammatory activity, if there isn't any then we need to consider other forms of treatment. At the moment there's multiple clinical trials which are available for progressive MS, some of them quite innovative and I would say that if your doctor hasn't thought about it you should be asking whether you can be referred to these studies. Some of them have come back positive on phase two studies and are going into phase three, so it's definitely no longer where things don't work. It's at the more interesting stage, to see where these will evolve in in the phase three analysis so something to look out for I would say.
Are there more treatment options coming for progressive MS?
Most definitely. If you look at the licensed disease modifying drugs, there’s one for PPMS which is ocrelizumab. Recently Siponimod has been licensed for active SPMS as well so I think these are turning points in the management of progressive MS.
Now I think the unmet need is what we call the non-active progressive MS for those without demonstration of inflammatory activity. The investigator-led studies which have been performed around the world are really filling that gap. One of the ones which looks positive is the Ibudilast which is an anti-inflammatory treatment. It showed a reduction in confirmed disability progression of just under 50% in the secondary progressive MS group.
Recently, the Bruton tyrosine kinase (BTK) inhibitors are being trialled in secondary progressive as well as primary progressive MS. These target B cells in terms of their activation but they may also target microglial and astrocytes which are what we think causes slow burn neurodegeneration in MS and leads to disease progression. It will be interesting to see what we get from those studies as well.
We ourselves are doing a treatment trial looking at an antiplasma cell drug, which is the first of its kind. The hypothesis being that oligoclonal bands form once you develop MS and these are antibodies which are constantly turned into your brain and spinal cord in the spinal fluid. If we can target the plasma cells which are producing the bulk of these then, that may be another potential mechanism, which can work at relapsing remitting as well as progressive.
Any final advice for people who might want to open up the conversation about DMDs with their MS team?
Approach your neurologist or your MS nurse and say, “I want to re-evaluate my disease, I want to learn more about what the disease is doing to my body and I want to see if I'm at the correct trajectory.”
It's not all about disease modifying treatments either, there are a lot of lifestyle changes such as exercise that can really modify disability progression. It's best to just make an appointment and have that discussion.