If you have been on ocrelizumab for two years would you be prepared to participate in the ADIOS (adaptive dosing ocrelizumab study)? One of the study arms would mean that you would not receive any ocrelizumab until you had a relapse or new MRI activity. In other words, we would be using ocrelizumab like we use alemtuzumab or cladribine, i.e. as an immune reconstitution therapy (IRT).
Some of our colleagues doubt whether people with MS would volunteer for such a study. I personally think they being affected by their own preconceived biases. We don’t know if we can use ocrelizumab or other anti-CD20 therapies as an IRT, which means we have equipoise. It is clear that using anti-CD20 therapy in this way will be safer, i.e. you would be less likely to develop hypogammaglobulinaemia and infections as a complication of continuous therapy. Similarly, the risk of secondary malignancies should be lower and you will be vaccine ready. The latest paper below shows that the time from the last dose of an anti-CD20 therapy predicts seroconversion after a COVID-19 vaccination; i.e. the longer you wait after a dose of rituximab, and probably ocrelizumab, the more likely you are to seroconvert after having the COVID-19 vaccine. I suspect going forward people on anti-CDC20 therapy may have to take drug holidays anyway to make sure they respond to vaccines. In fact, I was on a Medscape recording yesterday with a colleague from UCSF and a vaccinologist and they both said that most MSologists and rheumatologists in North America are already doing this. At the moment I have been saying get #GetVaccinatedASAP and cross the vaccine-readiness bridge when the boosters arrive. We will also have evidence, such as below, to guide us in the future.
The following data from Anat Achiron will hopefully be out as a pre-publication this week.
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Disclaimer: Please note that the opinions expressed in this blog post are those of Professor Giovannoni and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Surely, the DODO and ADIOS studies are incompatible with each other scientifically? How can I, on the one hand, support a higher dose of ocrelizumab and on the other hand suggest reducing the dose in the longterm. The hypothesis is all about timing and how you use anti–CD20 therapies.
You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously. Time is short so we need to run trials in parallel.
However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to use ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study.
In reality, if we could convince a national funding agency, a pharma company or a wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 (vidofludimus) or ASLAN003 (selective second-generation DHODH inhibitors), HAART (highly active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of an anti-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will also be derisking the long-term immunosuppression associated with anti-CD20 therapies and prevent the development of hypogammaglobulinaemia. In addition, you will be allowing patients to respond to vaccines.
The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I am exploring as a proof-of-concept trial.
The good news is that Roche-Genentech is testing the principles of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.
You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions. If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years. But don’t we have a hint of this already? Ofatumumab was not better than teriflunomide at slowing down brain volume loss in year two of the ASCLEPIOS I and II clinical trials (NCT02792218 and NCT02792231) despite being superior to teriflunomide on relapses and MRI activity. The latter is more proof that focal inflammatory disease (relapses and MRI activity) is not MS but in response to what is causing the disease. The real MS is what causes smouldering pathology and end-organ damage.
DODO vs. ADIOS vs. iTeri: which one would I prioritise? Almost certainly iTeri; the iTeri trial makes the most sense in terms of our current understanding of the pathogenesis of MS, mode of action of anti-CD20 therapies and the long-term risks of chronic B-cell depletion.
Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.
Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.
Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.
Conclusions: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).
I have recently been criticised by a colleague for supporting the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies. How you can I on the one hand support more ocrelizumab and on the other hand suggest reducing the dose in the longterm. I responded that it is all about timing and how you use anti–CD20 therapies.
You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which I hypothesise house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously.
However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to test using ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study.
In reality, if I could convince a national funding agency, a pharma company or wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 or vidofludimus (selective second-generation DHODH inhibitor,) HAART (highly-active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of ant-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will be derisking the long-term immunosuppression associated with anti-CD20 therapies and you should prevent the development of hypogammaglobulinaemia.
The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I need to explore (another task for my expanding ToDo list).
The good news is that Roche has bought into, and run, with the principle of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.
You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions. If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years.
Roche is the first company to publish their data on how patients with MS are doing with COVID-19 who are being treated with ocrelizumab. Please note the data is on the first 100 cases that have been reported to Roche via their adverse event (AE) reporting mechanisms. Twenty-six of the cases have been reported as being severe with 5 being critical (see table below). These figures are pretty much in line with what happens in the general population in relation to COVID-19 outcomes with a similar proportion of severe and critical cases. The one caveat is that ocrelizumab-treated patients may be younger and have fewer comorbidities than the general population.
Some of my colleagues have accused Roche of hiding data and selective reporting. Why would they do that? Pharma’s pharmacovigilance systems are transparent and open to audit by the regulators. It is not in Roche’s interests to not be open and frank about their data. At the end of the day, the data is what it is and we need to use it to help us make decisions about treatment.
I agree the data is full of warts and open to interpretation. It is likely to be biased in that clinicians are more likely to report hospitalised and severe cases as AEs and miss the milder cases. For example, I have collected 9 patients who have likely had COVID-19 over the last 8-10 weeks. Only one of these nine patients was admitted to a hospital with moderate COVID-19. In this case, the COVID-19 syndrome was confirmed on chest x-ray and other clinical features and her nasopharyngeal swab was positive for SARS-CoV-2. She was fortunately discharged after 4 days well and didn’t need any ventilatory support. The other 8 patients with MS all self-isolated and recovered at home and had no swabs taken. Only the admitted patient is part of the UK’s official figures the other 8 cases are not. Patients with COVID-19 who have mild disease, who don’t come to the hospital to get swabbed don’t get counted in the official figures. The same phenomenon is almost certainly happening with ocrelizumab and our other DMTs. Mild cases are not getting swabbed, diagnosed and reported. I, therefore, suspect that the Roche data represents the worse end of the spectrum.
Overall the Roche data is in keeping with the Italian, French and other registry data that people with MS on ocrelizumab don’t appear to be at higher risk of getting severe COVID-19. This also needs to be interpreted in the context of the immunology of COVID-19 and SARS-CoV-2. It looks as if innate immunity (monocytes and macrophages) and T-cells, in particular CD8+ T-cells, are the most important lines of defence against SARS-CoV-2. The fact that two patients with X-linked agammaglobulinaemia recovered from COVID-19 and that anti-CD20 treated patients with no B-cells in the peripheral blood are recovering from COVID-19 tells you that B-cells are not essential for the antiviral response. The latter is also in keeping with the trial data that patients on B-cell depleting therapies don’t seem to have a problem dealing with viral infections.
Could there be an upside to B-cell depletion? Yes, I suspect there may be. As the humoral or antibody response emerges antibody-mediated damage to lung with complement activation may be responsible for some of the delayed tissue damage that occurs in COVID-19. This is why it will be important to get more data and better-defined comparator groups to see if anti-CD20 therapy treated patients may be doing better than expected. The recently presented Swedish data suggests not. However, the Swedish data is on rituximab, and not ocrelizumab, and the rituximab doses used in Sweden may not be high enough to block antibody responses to SARS-CoV-2 and hence the data can’t simply be extrapolated to ocrelizumab or vice versa. For those of you who don’t know ocrelizumab is a much more potent B-cell depleter than rituximab.
Now, what about vaccine readiness? Are people on ocrelizumab less likely to develop an antibody response after COVID-19 and if they do is the antibody response good quality, i.e. capable of neutralizing the virus and preventing reinfection? We are in the process of validating an ultrasensitive assay and doing an antibody study to answer this question. So watch this space.
Even if antibody responses to SARS-CoV-2 are blunted in ocrelizumabers, who have had COVID-19, this doesn’t mean they are not immune to reinfection. Cellular responses are likely to be sufficient to prevent reinfection. The latter has been shown to occur with the measles virus.
Vaccine readiness may become a real issue if a vaccine for SARS-CoV-2 emerges. However, I suggest crossing that bridge when we get there. With anti-CD20 therapies, all you will have to do is miss a dose or two, wait for naive B-cell reconstitution and then have the vaccine. We have very good data that after 3 or 4 courses of ocrelizumab missing infusions for the next 12-18 months is unlikely to affect MS disease activity. The latter observation is why we are still planning to do an adaptive-dosing study in the UK (ADIOS Study).
I personally want to congratulate and thank Roche for putting their data into the public domain so rapidly. I have asked other Pharmaceutical companies to do the same. Having access to this data alongside other real-life data sets is what we and others are using to adjust treatment guidelines and is why we as an MS treatment centre are starting and redosing patients with MS with ocrelizumab. At last, we can say our practice is evidence-based rather than opinion-based.
CoI: Multiple. Importantly I am a steering committee member on the ocrelizumab phase 3 development programme and I am PI on the ORATORIO-HAND study of ocrelizumab in PPMS.
When I highlighted the risk of hypogammaglobulinaemia and infection in MSers receiving anti-CD20 therapy after ECTRIMS I go a very long email from someone from Roche playing down the risks. The following study is therefore very timely and shows that when comparing interferon-beta, glatiramer acetate, natalizumab, fingolimod and rituximab with each other it is rituximab that comes out worst in relation to infectious complications.
You also need to remember that not all anti-CD20 therapies are made equal and that ocrelizumab is a more potent B-cell depleter than rituximab. We know this based on the infectious complications seen in study subjects with rheumatoid arthritis and lupus and the observation that there is a clear varicella-zoster signal in the ocrelizumab phase 3 programme. In this context, an interesting observation was that there was a lower rate of anti-herpes/anti-virals in the rituximab-treated MSers compared to the other DMTs. This is interesting and raises questions of why this should be? Could it be because rituximab only reduces the CD8+ T-cell counts by about 15% after the first infusion and his little impact thereafter?
So don’t let anyone pull the wool over your eyes that anti-CD20 therapies are not immunosuppressive and are not associated with an infection signal. It is becoming clear to me that continuous dosing with anti-CD20 therapy will result in a cumulative increase in infections and at some stage we are as an MS community are going to have to derisk this problem by using (1) anti-CD20 therapy as an immune-reconstitution therapy (IRT) or as (2) an induction agent or (3) by correcting the immune deficiency by giving immunoglobulin replacement therapy when our patients develop hypogammaglobulinaemia.
I think we need to do the ADIOS study sooner than later. Don’t you?
Question: What is the risk of infections in association with different disease-modifying treatments for multiple sclerosis?
Findings: This nationwide cohort study found that patients with multiple sclerosis are at a generally increased risk of infections, and this risk is partly dependent on the choice of treatment. The rate of infections was lowest with injectable therapies; among newer treatments, use of rituximab was associated with the highest rate of serious infections but less use of herpes antiviral medications compared with fingolimod and natalizumab.
Meaning: Per the results of this study, physicians and patients should be aware of infection risks associated with newer multiple sclerosis treatments and perhaps particularly anti-CD20 therapies.
Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.
Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.
Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.
Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon-beta and GA.
Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.
Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).
Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
POST-SCRIPT
In response to a comment, the following figures put the serious infection (requiring hospitalisation) risk on ocrelizumab in context; i.e. how common is this complication. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months 1 patient will be admitted to hospital with a serious infection.
However, if you develop low IgG levels (hypogammaglobulinaemia) the risk rises to 5.48 serious infections per 100 patient-years or for every 18 patients on ocrelizumab for 12 months 1 patient will be admitted with a serious infection. This is why we are now monitoring peripheral blood immunoglobulin levels on an annual basis in all our patients on anti-CD20 therapy.
BACKGROUND:Anti-CD20 monoclonal antibodies such as ocrelizumab, rituximab, and ofatumumab target B-cell lineage. Clinical trials have demonstrated their effect on reducing both magnetic resonance imaging (MRI) active lesion burden as well as clinical activity. Zytux™ (Rituximab, AryoGen Pharmed) used in the present study for multiple sclerosis (MS) patients is basically a biosimilar rituximab. In this observational study, a total of 100 patients receiving Zytux™ were collected to see its effect on the clinical course of the disease.
RESULT: A total of 100 MS patients including 36 males and 64 females participated in the present study. The patients included 20 relapsing remitting MS (RRMS), 20 primary progressive MS (PPMS), and 60 secondary progressive MS (SPMS) patients. Totally, the mean of EDSS score before and after the administration of drug was 5.50 ± 1.04 (ranging from 1 to 7) and 5.11 ± 1.59 (ranging from 0 to 7), respectively, with the difference between them being very significant (p-value: 0.000). Also, the mean of ARR before and after the initiation of the medication was 0.47 and 0.10, respectively, whose difference was also significant (p-value: 0.000). In our study, the greatest effect of Zytux™ was observed in RRMS patients. At the time of injection, 70 patients indicated some reactions including limb pain, skin sensitivity, and throat irritation. One month after the injection, one of the patients suffered from pneumonia and two patients had a urinary tract infection.
CONCLUSION:The observed results revealed that the Zytux™ could have a positive and significant effect on all types of MS
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?
Dr Riley Bove, UCSF, AAN 2019
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.
Yes, why can’t we use anti-CD20 therapies as an immune constitution therapy (IRT) or at least adapt the dose based on B-cell reconstitution kinetics? And if we can’t beat the Swedes why can’t we join them?
ADIOS = ADaptIve Ocrelizumab dosing Study
There is mounting evidence from NMO and rheumatology that anti-CD20 therapies can be used as either a maintenance therapy or an immune reconstitution therapy (IRT). Another way of using them is to adjust the dose based on memory B-cell reconstitution (MBR) kinetics.
Adapting the dose of anti-CD20 therapies using MBR or as IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and possibly the ability to respond to vaccines. It could also lead to better family planning by being able to expand the treatment-free period safely. Another plus would be cost-saving for the NHS and the other healthcare systems.
We are therefore in the process of designing a new trial to test standard interval dosing (SID) of ocrelizumab vs. adaptive dosing either using an MBR or an IRT protocol. What do you think? If you were on ocrelizumab would you sign up for this study? The advantage for you is that it may make your treatment safer in the long-term and it will potentially save the NHS millions.
