Just arrived back from the AAN 2019 in Philadelphia. Jetlagged, which is why I am writing this at 2 am in the morning.
As always the AAN is more a meeting of meetings or networking in academic lingo. These meetings have allowed us to progress several of our ideas including (1) DrK’s #MSAttack study with natalizumab, (2) to think more deeply about our proposed ADIOS Trial (adaptive dosing ocrelizumab study), (3) support for our plasma cell and (4) social capital hypotheses and to (5) to gain a deeper understanding of the emerging new ’safety’ issues surrounding alemtuzumab.
Alemtuzumab is getting an unnecessarily rough ride. I had an opportunity to review all of the vascular events and AEs that led to the EMA triggering article 20. These are all rare events. The intracranial haemorrhages appear to be related to transient hypertension and may relate to the amount of hydration the US infusion centres use when administering alemtuzumab. It is clear that MSers develop a transient rise in blood pressure when receiving alemtuzumab, which means this rare complication can be derisked with anti-hypertensives.
When it comes to the cases of arterial dissections and arterial thromboses on alemtuzumab I was not convinced alemtuzumab is to blame. The majority of the cases had comorbidities or had had procedures that are a more likely explanation for the ischaemic events. In many of the cases, the events were poorly characterised and it was not clear if they had occurred at all; this is particularly in relation to the so-called myocardial infarctions.
It is clear that most if not all of the ‘vascular cases’ have arisen in the USA. Why? I suspect it is because alemtuzumab is being used in a much riskier and older population compared to the other parts of the world. Herein lies the problem. The fact that the EMA has now copied the FDA and made alemtuzumab a 3rd-line DMT will shift the use of alemtuzumab into a riskier older population and thereby increase the likelihood of us seeing these vascular AEs in Europe.
To be honest I am not convinced that the risk-benefit profile of alemtuzumab has changed at all. I would, therefore, appeal to the EMA to include the new AEs in the SmPC, but not to change alemtuzumab’s label. We need to be able to offer alemtuzumab to MSer with early MS when they have the most to gain from the treatment. I am sure MSers are in the best position to weigh up the risks and benefits of alemtuzumab. My big fear is that restricting access to alemtuzumab will simply increase HSCT tourism abroad.
If I needed proof that our blog is read it was in abundance at the AAN. Several people were interested in our ADIOS trial and were thinking of doing versions of their own. The one caveat was new data that Stephen Hauser presented showing that the efficacy of ocrelizumab may be linked to the level of B-cell depletion, i.e. the greater the peripheral B-cell depletion the greater the treatment effect of ocrelizumab on disability progression. There was no dose-related signal on MRI or relapses because these have a floor effect, i.e. virtually all patients are NEDA 1&2 and hence it is impossible to use these outcomes to assess a dose-effect. The one caveat is the dose effect on disability was confounded by body weight; i.e. the larger the patients the less B-cell depletion. As you know MSers with an increased BMI (body mass index) are at increased risk of comorbidities, which may explain why they do less well on ocrelizumab and the observation has nothing to do with the level of peripheral blood B-cell depletion.
The peripheral B-cell depletion data, however, needs to be taken further and tissue and CNS B-cell depletion kinetics need to be studied further. I am convinced the ADIOS trial will be a good place to start with some of these studies. Clearly, it is time to get our grant writing hats on. We need to do this study in the UK.
DrK and I had several meetings with key stakeholders in Biogen about our #MSAttack study. There is little doubt about the efficacy of natalizumab in MS, its safety even in JCV-positive MSers when used for short periods, its rapid onset of action (weeks) and it reversibility (washout) that make it the only suitable DMT for this study. We have changed our trial design slightly, but hopefully, we will be able to get this study funded in the near future. If the #MSAttack study is successful it will change the way we treat and think about active MS and may help natalizumab obtain a first-line indication, which many MSers and CISers deserve; particularly if you want to save brain and spinal cord.
NeuroDoc Gnanapavan got very excited when she saw some posters supporting the use of proteasome inhibitors as a treatment for autoimmune disease. This supports our new SIZOMUS trial (Safety of IxaZOmib targeting plasma cells in Multiple Sclerosis) to try and scrub the brain clean of plasma cells. We will be letting you know much more about this trial in the next few weeks now that we have ethics and MHRA approvals. We will be needing volunteers for this study.
Saul, or Dr Reyes to some, is now one of the pioneers in studying social capital and MS outcomes. His poster on the topic was well received. It is clear that the social determinants of health outcome are very important and have not been systematically studied in MS. Dr Reyes will be changing all that and has many activities planned as part of his ECTRIMS fellowship The poster he presented at the AAN is self-explanatory, but if you have any queries please don’t hesitate to ask.
I have a new hero or heroine; Dr Riley Bove, from UCSF. Riley has developed a telemedicine service to help people with neurological problems in resource-poor areas. The service is provided for free by the USCF residents and staff and is linked to an educational course to train the staff in these countries. The whole service is run using Zoom an online teleconferencing service. Well done Riley; if you lived in the UK I would be putting your name forward for an honours award from our Queen. And if I had more bandwidth I would join and contribute to your service; maybe something for my retirement? Could this platform be expanded to help diagnose and manage MS in resource-poor settings?
It is now 4:10 am and I am beginning to feel a bit groggy. So I will signoff now but will come back with some more AAN highlights in the week.