Gavin Giovannoni

Cladribine Retreatment

What do you do when you get recurrent disease activity on cladribine?

I am repeatedly being asked what to do about disease activity in patients treated with cladribine. The following is my suggestions on how to approach this thorny issue.

As you know disease activity on immune reconstitution therapies (IRTs) don’t necessarily mean you failed or are failing the therapy. Disease activity could be an indication to retreat with an additional course. Interpreting when and what to do depends on when the disease activity emerges and how severe it is.

Post-course 1

If you have a relapse after the first course (cycles 1 & 2) of cladribine I would hold fast and have the second course. There is no reason why someone who has disease activity in year 1 post-cladribine won’t necessarily respond to the second course. There is, however, one proviso here. With alemtuzumab, another IRT, rare patients get rebound activity, over and above baseline activity, around months 7-9 post the first course of alemtuzumab infusions. Why this happens we don’t know. We have not observed this with cladribine yet, but it could theoretically happen. In this situation, the disease activity is so severe that most of these patients are offered alternative treatments, in particular, anti-CD20 therapies (rituximab or ocrelizumab), mitoxantrone, cyclophosphamide or HSCT.

When we see recurrent disease activity in year 1 post-alemtuzumab we have often brought forward the second course of alemtuzumab. I see no reason why we wouldn’t consider this with cladribine as well, provided the total lymphocyte counts have recovered to above 800/mm3.

Post-course 2 – year 2

If disease activity occurs in year 2 this is not good news. This would indicate that the patient has not responded to cladribine and would be an indication to switch therapeutic strategies.

Post-course 2 – year 3 & 4

If you have disease activity in years 3 & 4 the timeframe covered by the current cladribine label you are not meant to retreat with cladribine. However, this makes no sense to me. IRT works by depletion and reconstitution. In some people, the two cycles of depletion with cladribine may not be sufficient to deplete the autoreactive pool and hence MS disease activity resurfaces. I personally think there is no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is exactly how we use alemtuzumab in this situation; the difference being alemtuzumab is now licensed to be used in this way. Clearly there is an evidence gap around cladribine and hopefully, this will be filled as real-life data sets emerge in the future.

Post-course 2 – after 4 years

Similar to the above I see no reason why a further course of cladribine should not be offered alongside other DMTs in this situation. This is how we use alemtuzumab and other IRTs. I am aware of one patient in the US has had 7 courses of intravenous cladribine over a period of 21 years.

The future

Cladribine has a variable treatment effect on the total lymphocyte counts. There are biochemical reasons why this may occur. I see in the future adapting the dose of cladribine we use to achieve an optimal level of lymphocyte depletion. This makes sense.

I also see cladribine being used as induction therapy, i.e. after an initial course of cladribine, we will be following it with maintenance therapy. Based on the memory B-cell hypothesis BTKi (Bruton’s Tyrosine Kinase inhibitor) or teriflunomide (antiproliferative/antiviral) makes the most sense at present.

I would love to do a trial of an IRT followed by maintenance therapy. Any takers? Any funders? In terms of safety and cost, I would go off-label and test rituximab followed by leflunomide vs. rituximab as an IRT.

The following is a visual summary of some of the information above.

CoI: multiple

Heat

My thoughts are for our readers with MS who are having to live through and cope with the latest heatwave. The BBC has just reported that this is the hottest late August bank holiday on record; “Temperatures had reached 33.2C (91.8F) at Heathrow by 14:16 BST, the Met Office said, beating the previous record of 28.2C set two years ago. On Sunday, the record for the hottest late August Bank Holiday weekend was broken, with a high of 33.3C”.

How are you tolerating the heat? I suspect many of you with heat sensitivity will be experiencing worsening fatigue, pseudo-relapses (heat-induced intermittent symptoms) and difficulty sleeping. Are you coping? Do you have any advice for your fellow MSers?

Please note that the main consequences of a raised body temperature in demyelinated, or remyelinated, pathways is slowed conduction. The commonest example is exercise-induced fatigue, but this summer’s heatwave will be causing symptoms without the need for exercise. Some of you will find difficulty walking difficult; your legs will begin to drag minutes into walking rather than after 20-30 minutes. Others will notice blurring of vision mid-morning when in the past this would only happen in the late afternoon. The reason for this is that the demyelinated segments in the nerve stop conducting due to conduction block induced by a slight rise in temperature affecting the functioning of the sodium channels. The latter are the molecules in the membranes of nerve cells that transmit the electrical signal down a nerve fibre, which require energy to work. These sodium channels are ion pumps, which are optimised to function at a certain temperature and explains why MSers are heat sensitive.

Most of you will have heard of Uhthoff’s phenomenon. Wilhelm Uhthoff (1853-1927) was a famous German Professor of ophthalmology who described temporary visual loss associated with optic neuritis linked to physical exercise. This was later found to be caused by a rise in body temperature. This phenomenon is now known to affect other neurological systems as well; for example, the motor system when walking, balance and sensory pathways and even the cognitive centres.

Apart from cooling, we do not had a treatment for Uhthoff’s phenomenon. The drug Fampridine has been licensed to improve walking speed in MSers. Interestingly, several MSers have said to me in the past that their heat sensitivity has improved since taking Fampridine.

CoI: Multiple

#ThinkSocial – work, work, work

The following is an excerpt from the executive summary of ‘Health and Work Champions: a Pilot Training Programme’, (Martin et al. Feb 2018). I am highlighting it because it has relevance to MSers and MS-related HCPs. HCPs are being fingered as part of the unemployment problem; “healthcare practitioners, who may consider that giving advice to refrain from work is part of their duty of care“.

Is it inevitable that MS will lead to early unemployment or medical retirement? What has been your experience with your MS team? Have they helped try and keep you employed? Any suggestions to help?

Shift.ms have put together material to help HCPs. Please check-it out.

“Ill-health among working-age people costs the UK economy £100bn a year in sickness absence (DWP and DH, 2016). Unemployment is not only costly for society but also bad for health because of its association with greater physical and mental health morbidity and mortality (Janlert, 1997; Martikainen and Valkonen, 1996; Waddell and Burton 2006).

The Royal College of Occupational Therapists (RCOT) and Public Health England (PHE) share a common aim to close the disability employment gap and support people who wish to remain in work or return to work after illness, injury or disability. Hence, they have jointly set up the Health and Work Champions Project, which features peer-to-peer education to shift healthcare culture in relation to work and health. This project features as an example of good practice in both the original Government Green paper about employment and disability (DWP and DH 2016) and the follow-up command paper Improving Lives: the Future of Work, Health and Disability (DWP and DH 2017).

Research suggests that unhelpful misconceptions around work and health can sometimes be reinforced by healthcare practitioners, who may consider that giving advice to refrain from work is part of their duty of care (Wade and Halligan, 2004; Mowlam and Lewis, 2005; Pires et al, 2006). Healthcare professionals’ attitudes and beliefs in this area may influence the outcome of rehabilitation (Bishop, 2008) and it is reported that they do not routinely address work issues (Moore, 2011).

A shift is therefore required that would see it become routine practice across healthcare to use employment as a useful functional outcome of healthcare interventions and a clinical tool for assessing a patient’s/service user’s recovery/or adaptation to illness or injury. Asking questions about staying in or return to employment will become standard practice for all healthcare professionals. The project aimed to use Health and Work Champions to facilitate the shift while also providing the Champions with leadership roles in their employing organisations to raise their profile and utilise their expertise in occupation, health and wellbeing.

Evidence suggests that most health care professionals tend to base practice decisions on entry-level education and personal experience (Schreiber et al, 2005). They typically solve clinical problems through consulting with their peers and opinion leaders before examining empirical evidence, which supports the choice of a Champion’s model with opportunities for interpersonal interaction, when promoting quality improvements in routine clinical practice (White, 2011). “

MSology Masterclass

We still have places left for this year’s MSology MasterClass from the 6th-8th November. The Multiple Sclerosis Academy aims to train healthcare professionals with a specialist interest in multiple sclerosis. If you are interested in joining the Academy and attending the MasterClass please register your interest via this LINK. This course is not only for HCPs from the UK we welcome international delegates on the programme as well.

Do you want a cure?

MSers want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. How can this be?

Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; I call this delayed neurodegeneration.

The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, etc.

Clearly, anti-inflammatory drugs that prevent new lesions formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that have damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why did the PROXIMUS trial and are promoting the OXO trial; add-on neuroprotective drug to try and modify the delayed die-off of neurons and axons.

What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that MSers, who have been treated with highly-effective DMTs and have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off in the future. In other words, they were treated with DMTs too late to prevent SPMS. This is why we keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.

There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system.

The ageing hypothesis of progressive MS is a major factor that underpins our Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.).

So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived plasma cells that continue to make intrathecal (within the CNS) antibodies that my drive progressive MS. The exception may be natalizumab. There are several reports of MSers on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.

To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial to test a therapy for myeloma (malignant plasma cells) in MS. Can we scrub the MS brain free of plasma cells?

CoI: multiple

#ThinkSocial

At Barts-MS we #ThinkSocial. We hypothesise that MS is like other chronic diseases and is affected by social capital and the social determinants of disease (SDOD). In short, if you have high social capital you will have a better outcome and if you have a favourable social profile you will also do better regardless of the type of MS you have. We are now actively researching these issues and have posted about them in the past and review them in this short video.

We hypothesise that you can increase your social capital by adopting practices to maintain and develop new relationships. These reciprocal relationships help you develop resilience to cope with chronic diseases such as MS. To this end, we are pleased to be involved with Oceans of Hope; a sailing charity that will ‘change the perceptions of multiple sclerosis by showing what is possible when people with a chronic disease are empowered to conquer their individual challenges, by engaging people whose lives are touched by MS and developing networks as a foundation for life-changing behaviours’.

Saúl Reyes, our Social Capital ECTRIMS fellow, Sue Radford (MS Brain Health) and I are in Edinburgh today to support Oceans of Hope and to celebrate what they are doing for people with MS. Sailing in the open ocean may seem quite extreme, but you could launch and run your own initiatives locally.

A lot of you were quite upset by my post of a patient of mine who is socially isolated and living on a diet of tea & toast. As a medical practitioner working in the NHS as it is currently configured I am relatively powerless to change this lady’s trajectory. This is why we need social prescribing and initiatives like Oceans of Hope, which promise to change things.

I envisage a future when social prescribing will be part and parcel of the holistic MS service we provide and we will have much less social isolation and more importantly better MS outcomes and happier MSers. Or am I wrong?

Envy – will we ever be in a position to prevent MS?

On the 5th August, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to teplizumab (anti-CD3) for the prevention or delay of clinical type 1 diabetes (T1D) in individuals at risk of developing the disease. This is quite amazing and has implications way beyond T1D.

The question in relation to anti-CD3 treatment is this ‘true prevention’ or simply a disease-modifying effect, i.e. a treatment that prevents the end-organ damage that eventually leads to clinical T1D? These were all antibody-positive subjects at very high risk of developing T1DM; i.e. they had a ~85% chance of developing T1DM and arguably had subclinical inflammation or autoimmune attack ongoing in their pancreas when they were treated with anti-CD3.

In the MS space, this study would analogous to treating radiologically-isolated syndrome and delaying RIS patients from having their first clinical attack.

The question for MSers is that if we could identify who of your children or siblings are at very high risk of getting MS – for argument’s sake let’s say they had a >50% risk of getting MS – would you volunteer them to participate in an anti-CD3 MS prevention trial?

The difference between T1D and MS is that endocrinologists have insulin; i.e. when the end-organ fails you simply replace insulin. In MS when the end-organ fails you become disabled with all its socio-economic consequences. Type 1 diabetics do so much better than MSers; in short, the stakes are so much higher for MSers.

I wonder how the EMA will respond to teplizumab? Breakthrough Therapy Designation (BTD) is an FDA program designed to expedite the development and review of therapeutic candidates intended to treat serious or life-threatening diseases. I predict that the European regulators arguing that in the modern era T1D is not a serious or life-threatening disease. We need to push back against such criticisms as they may use similar arguments if we ever get to this position in relation to MS.

I am so envious of the T1 diabetologists. I have a dream of being in a position one day of either offering people at high risk of developing MS, or members of the general public, an intervention to either reduce their risk or prevent them from developing MS. The question I have is society, the MS community and the regulators ready for MS prevention studies?

Herold et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613.

BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.

RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization – 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed.

CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

Building a Rocket

As I write this I am on the way back from an ‘atypical’ summer holiday with my family. We spent a week in the ‘Oude Land’, South Africa, celebrating my mother in law’s 80th Birthday and then a week in the subtropics for some warm sunshine. The internet access was dismal, which was a good thing that allowed me to switch-off, sleep, eat, exercise, think, relax and recharge my batteries.

The insights learned, or relearned, is that my family are my priority and for quality reading and thinking time you need to take yourself offline for long as possible. One consequence of the latter is that I now have two inboxes with over 3,000 unread emails (panic).

As I lay next to the pool I had ample time to contemplate life, the universe and all things MS. I came to the conclusion that the biggest threat to our field, at least in the short term, is dogma and groupthink. We are so entrenched in the MS autoimmune hypothesis that it is becoming increasingly difficult to see the light, and blue sky, because of the sheer depth of the autoimmune trench we have dug ourselves into.

In ‘Range: How Generalists Triumph in a Specialized World’, by David Epstein, one of my holiday reads, I learnt that Arturo Casadevall believes that specialisation has created a ‘system of parallel trenches‘; everyone is digging deeper into their own trench and rarely standing up to look in the next trench over, even if the solution to their problem happens to reside therein.

Using the trench analogy we are going to have to build a human scaffold several generations deep to get out of the trench the MS community has dug, or we could build a rocket. I can’t resist the rocket analogy. Whilst away I also read ‘Loonshots: How to Nurture the Crazy Ideas That Win Wars, Cure Diseases, and Transform Industries’ by Safi Bahcall, which describes how out-of-the-box thinking has the ability to transform a field.

It is clear that the autoimmunity model has many flaws or as Safi Bahcall would say warts. As a result, it is becoming increasingly difficult to support the autoimmune hypothesis intellectually. Some of the holes in the autoimmune hypothesis have been rehearsed many times before on this blog.

Dear MSologist, why am I progressing despite being NEDA?
What is causing my accelerated brain volume loss when my disease is in remission?
You say I am in long term remission, and possibly cured, from MS, but my last CSF analysis shows that I am still oligoclonal band positive? Why?
My head is full of slowly expanding blackholes. Can you please stop them expanding?
There is an epidemic (increasing incidence) of MS in Scotland and almost every geographical area studied. Why? Is the increasing incidence explicable by the autoimmune hypothesis?
If MS is an autoimmune disease please tell me why your immunotherapies are only partially effective at preventing disease activity and worsening disability?
How do you explain the early Prineas MS lesion; massive oligodendrocyte apoptosis without T- and B-cell infiltration?
Why does rebound happen post natalizumab and fingolimod? And why are anti-CD20 therapies so effective in preventing rebound? How do these observations fit into the autoimmune hypothesis?
What about the evidence that EBV plays such a pivotal role in MS? How does this fit in with MS being an autoimmune disease?
Is the human endogenous retroviral or HERV activation within the peripheral and CNS compartments of MSers simply a bystander phenomenon or part of the disease? Are HERVs a non-specific trigger of autoimmune disease?
Does the memory B-cell data and hypothesis sit comfortably with MS being an autoimmune disease? Could this be explained by EBV alone?
Does the strong MHC association with MS have to be due to autoimmunity? Could the MHC link be explained by an infection or dual-infection hypothesis?
How does the epidemiological data on vitamin D, childhood/adolescent obesity, smoking, solvent exposure, HIV and MS, explain autoimmunity?

It seems to me that most people in the field of MS are content with fitting a square peg into a round hole. I am not. So what am I going to do about all my angst and increasing doubts? We have been trying to do something about it with our Charcot Project and our Preventive Neurology Unit, but things are happening too slowly. What we need is a turbocharge – a rocket – to accelerate our programme of work. In short, we need people, resources and money. Therefore, the 2019/2020 academic year will be a year of grant writing focusing on MS prevention and loonshots.

Measles a known unknown

I was called to casualty to assess one of my patients with MS who was on natalizumab. She had been admitted with a temperature, confusion, seizures and a generalised skin rash. Within thirty minutes of seeing her, she went into status epilepticus and had to be sedated, intubated and admitted to ITU. Within 72 hours she was dead. At post-mortem, she had a measles pan-encephalitis. Four days before presentation she had unknowingly come into contact with a friend’s child who had measles. The friend was a staunch anti-vaxxer who believed that the measles vaccine caused autism and would corrupt her child’s immune system.

The above scenario is fictitious, but could happen, or more likely will happen sometime in the near future. This is a ‘known unknown’.

Things have a tendency to happen in threes; I experienced two today let’s hope the third remains science fiction.

(1) As I left home this morning on my daily commute to Whitechapel I finished listening to an Audm podcast “FEAR, MISINFORMATION, AND MEASLES SPREAD IN BROOKLYN” by Amanda Schaffer (Wired, 24-06-2019); scary stuff about the real impact of the anti-VAXX campaign on residents in Brooklyn, New York.

(2) I followed this by reading a review about measles in the latest NEJM (Strebel & Orenstein. Measles. N Engl J Med. 2019 Jul 25;381(4):349-357), which reminded me of medical school and my time on the medical wards in South Africa.

I then had flashbacks to my days as a neurology registrar in South Africa seeing and managing many patients with SSPE (subacute sclerosing panencephalitis) a relatively rare, but fatal, complication of measles infection.

More recently there was a fatal case of measles inclusion body encephalitis presented at our Association of British Neurologists meeting; tragically this young woman had not been vaccinated against measles.

Why is this important? We are living through a measles epidemic. The anti-VAXX campaigners have convinced enough parents over the last two decades to not vaccinate their children against measles, mumps and rubella (MMR). Once a certain proportion of the population is not immune to measles, so-called herd immunity becomes ineffective; i.e. the shield offered by a population of people immune to measles is too porous to isolate susceptible people from wild-type infection in the community. In fact, vaccination works because of herd immunity.

Another factor to consider is that unvaccinated people also get MS. If you are unvaccinated and have not been exposed to the wild virus you are now at relatively high-risk of acquiring measles as an adult. If you then decide to go onto longterm immunosuppression to treat your MS you are putting yourself at risk of serious complications from these infections, in particular measles. In addition, once you are on a longterm immunosuppressive therapy you can’t be vaccinated with the MMR vaccine as it is a live attenuated vaccine.

Measles is also a neurotropic virus and hence seeds to the brain. If you are on natalizumab and contract measles you will be in serious trouble. Natalizumab works by blocking trafficking of lymphocytes to the CNS and hence will stop your lymphocytes detecting, attacking and clearing the virus from the brain. The consequences of an unimpeded measles virus infection of the brain will be in all likelihood be lethal. This is a similar scenario to what happens with PML. Although natalizumab is being fingered here there is a risk will all of our immunosuppressive DMTs.

Because of this known unknown, I am proposing that all MSers are screened at baseline, i.e. before initiating a maintenance immunosuppressive therapy, to make sure they have immunity to MMR. If they are antibody negative they should be offered the option of receiving the MMR vaccine, or at least the individual components of the vaccine if they are still available in your country, to make sure they are immune to these viruses before they start treatment with the DMT concerned.

I sincerely hope my case scenario remains fiction and things don’t have to happen in threes.

OXO Study

We want to build a sandwich to tackle the many facets of multiple sclerosis that result in neuroaxonal loss. At the base of treatment pyramid, we need an anti-inflammatory onto which we want to add a neuroprotectant, i.e. the combination therapy strategy.

You need to protect damaged and vulnerable axons so that you can then remyelinate them or restore their function. We assume this makes sense, but still, we get push back from many in the field who are determined to still do monotherapy neuroprotective trials.

What is the point of protecting an axon, allowing it to be remyelinated and to recover function for it to be damaged again in the next round of inflammatory attack?

Barts-MS Dictum: It makes no biological sense to do monotherapy MS neuroprotective trials in the modern era.

With this in mind, we had a ‘brainstorming’ session last week and came up with a new neuroprotective trial design in primary progressive MS; it is called the OXO PPMS trial or ‘Add-on OXcarbazepine to Ocrelizumab in PPMS Study’.

Why PPMS? We feel that PPMS has a massive unmet need and that as ocrelizumab is now licensed as the only DMT in PPMS it makes an ideal platform therapy. We have chosen oxcarbazepine, a sodium channel blocker, as our add-on agent because we have pilot data (animal and clinical) showing it may work and it seems to be better tolerated than other sodium channel blockers. In an ideal world, we would want this study to be done with a new agent that has a long patent life, which would allow Pharma to invest in the necessary studies to get the drug licensed. But alas we can’t find a Pharma company with a new sodium channel blockers who would be interested in MS.

Raj Kapoor, David Baker and I have spent an extraordinary amount of time trying to get Big Pharma to buy into the add-on sodium channel blocker neuroprotection paradigm. Sadly none of the decision-makers has bought into the paradigm, yet. Just maybe with new data and the fact that all the low-hanging fruit on the MS tree has been picked they may change their minds.

Please note that neuroprotection is only a small part of the solution to worsening or progressive MS. To tackle this problem we need a lot more than neuroprotection, which is why we need to manage MS holistically.

To reiterate the philosophy of marginal gains “if you break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together. This also means avoiding things that make MS worse”. This is why anti-ageing strategies, in particular, lifestyle factors, need to be included in the longterm treatment strategy to manage MS.

What do you think of the OXO PPMS study? If you have PPMS would you volunteer for this study?

CoI: multiple