#ECTRIMS2021: ocrelizumab the game-changer

Barts-MS rose-tinted-odometer: ★★★★★★★
The first  7-star ‘Teal Blue Monday’ #367588

The next in the series of #ECTRIMS2021 long-term follow-up posts. This is the 7.5 year follow-up of the ocrelizumab OPERA 1&2 (relapsing MS) cohort. The efficacy data looks very impressive. 

  1. Annualised relapse rates well below one in 10 years or 0.1 p.a.

2. 82% of ocrelizumab treated subjects had no confirmed disability progression.

3. Less than 7% of ocrelizumab treated subjects needed a walking stick compared to 10% of subjects randomised to interferon for 2-years before switching to ocrelizumab. Sadly, the 2 years on interferon have come at a price; time really is brain and spinal cord. This data like most contemporary data sets make a strong case for flipping the pyramid. 

4. The safety of ocrelizumab looks similar to what it was 2-years ago. The risk of serious infections is 1.73 per 100 patient-years of follow-up; i.e. in 1,000 patients on ocrelizumab, 17 will have a serious infection per year. This needs to be balanced against the COVID-19 data showing a doubling of risk of severe COVID-19 in ocrelizumab-treated subjects and an ~80% chance of not seroconverting when being vaccinated with one of the COVID-19 vaccines.

Unfortunately, no end-organ damage data (brain volume loss) to present, but this will come in time.

It is clear that anti-CD20 therapies are a real game-changer when it comes to the management of MS; i.e. very high efficacy therapies, in terms of switching off MRI activity and relapses, with a relatively good short and long term safety profile. 

ECTRIMS-2021_OPERA-OLE-7.5-years-Poster_VA3-2

Giovannoni et al. Long-term  reduction  of  relapse  rate  and  confirmed  disability  progression  after  7.5  years  of ocrelizumab  treatment  in  patients  with  relapsing  multiple  sclerosis  in  the  OPERA  OLE. ECTRIMS 2021, P723. 

Introduction:  The  efficacy  and  safety  of  ocrelizumab  (OCR)  in  relapsing  multiple  sclerosis  (RMS)  were demonstrated  in  the  96-week  contro led  double-blind  period  (DBP)  of  the  Phase  I  OPERA  I  (NCT01247324) and  OPERA  I (NCT01412333)  trials.

Aims:  To  assess  the  efficacy  of  switching  from  interferon  (IFN)  β-1a  or  maintaining  OCR  therapy  on  disease activity  and  confirmed  disability  progression  (CDP)  after  5.5  years  of  fo low-up  in  the  open-label  extension (OLE)  of  OPERA  I  and  OPERA  I.

Methods:  In  the  DBP  of  OPERA  I  and OPERA  I, patients  were  randomised  to  receive  OCR  or  IFN  β-1a. Patients  completing  the  DBP  either  continued  OCR  (OCR-OCR)  or  switched  from  IFN  β-1a  to  OCR  (IFN-OCR) when  entering  the  OLE.  Adjusted  annualised  relapse  rate  (ARR),  time  to  onset  of  48-week  CDP  (CDP48)  and time  to  48-week  confirmed  Expanded  Disability  Status  Scale  score  ≥6.0  (time  to  require  a  walking  aid)  were analysed  up  to  Week  384.

Results:  Overa l,  76.3%  of  patients  who  entered  the  OLE  period  completed  OLE  Year  5.5.  Adjusted  ARR decreased  year-on-year  from  the  pre-switch  year  to  OLE  Year  5.5  in  IFN-OCR  switchers  (pre-switch,  0.20;  OLE Year  1,  0.10;  OLE  Year  5.5,  0.03)  and  was  maintained  at  low  levels  in  OCR-OCR  continuers  (pre-switch,  0.12; OLE  Year  1,  0.10;  OLE  Year  5.5,  0.03).  Rates  of  CDP48  were  lower  in  OCR-OCR  continuers  vs  IFN-OCR switchers  at  the  end  of  the  DBP  (4.1%  vs  8.5%  [Δ=4.4%;  p<0.001])  and  numerica ly  lower  at  OLE  Year  5.5 (17.9%  vs  21.5%  [Δ=3.5%;  p=0.118]).  Rates  of  patients  requiring  a  walking  aid  were  lower  in  OCR-OCR continuers  vs  IFN-OCR  switchers  at  the  end  of  the  DBP  (0.8%  vs  3.1%  [Δ=2.4%;  p=0.001])  and  numerica ly lower  at  OLE  Year  5.5  (6.6%  vs  9.5%  [Δ=2.9%;  p=0.060]).  Over  the  DBP  and  OLE  periods,  the  risk  of  CDP48 was  23%  lower  (overa l  percent  of  patients  with  CDP48  in  OCR-OCR  vs  IFN-OCR:  14.5%  vs  16.4%;  HR [95%CI]:  0.77  [0.60–0.98];  p=0.034)  and  the  risk  of  requiring  a  walking  aid  was  35%  lower  (overa l  percent  of patients  requiring  a  walking  aid  in  OCR-OCR  vs  IFN-OCR:  5.2%  vs  7.0%;  HR  [95%CI]:  0.65  [0.44–0.97]; p=0.034)  in  OCR-OCR  continuers  vs  IFN-OCR  switchers.

Conclusions:  Switching  from  IFN  β-1a  to  ocrelizumab  at  the  start  of  the  OLE  period  was  associated  with  a rapid  and  robust  reduction  in  ARR  that  was  maintained  through  the  5.5-year  fo low-up  of  the  OLE  period.Compared  with  patients  switching  to  ocrelizumab  at  the  OLE,  patients  initiating  ocrelizumab  2  years  earlier had  a  significantly  reduced  risk  of  requiring  a  walking  aid  and  48-week  CDP.

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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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Clash of the Titans: the HILO study

Barts-MS rose-tinted-odometer: ★★★ (I am seeing blue and Spanish yellow today) 
Roche blue (#0066CC) & Novartis Spanish Yellow (#F7B516)

Yes, I really do think that intrathecal (within the meninges that cover the brain and spinal cord) or CNS resident B-cells and plasma cells are pathogenic in MS. In other words, the cytokine or chemicals B-cells and plasma cells produce, in particular their antibodies, are what is driving some of the pathologies of smouldering MS. The evidence to support this hypothesis is well rehearsed on this blog and is the reason why we are testing high-dose ocrelizumab (more CNS penetrant) vs. standard-dose ocrelizumab (less CNS penetrant) against each other in two head-2-head studies. It is also the reason we are testing cladribine’s (CLADRIPLAS and CLAD-B) and ixazomib’s (SIZOMUS) effects in intrathecal B and plasma cell markers. Yes, I really do think we need to scrub the CNS clean of B-cells, plasma cells and their products, in particular the oligoclonal IgG bands. 

I am therefore proposing a new study; the HIgh-dose versus LOw-dose anti-CD20 study or HILO Study. 

In this study, I propose testing high-dose or double-dose ocrelizumab vs. standard or intermediate-dose ocrelizumab vs. low-dose ofatumumab against each other over two years and measure their impact on end-organ damage markers (slowly expanding lesions and brain volume loss) and on CSF markers of B-cell, plasma cell and microglial activity. The latter will include free kappa and lambda immunoglobulin light chains, OCBs, soluble CD14, etc. This will answer at least from a biomarker question whether or not we need CNS penetration of anti-CD20 monoclonal antibodies to target this component of smouldering MS. The following would also answer the question of whether or not you as a person with MS would want to be treated with high-dose or low-dose anti-CD20 therapy? 

Would you want to be randomised into this study?

This study would be a clash of the titans; Roche vs. Novartis. Who would win? It really is not that important as Novartis is a major shareholder in Roche and hence when Roche makes a profit so does Novartis. The real winners will be people with MS, the data will allow them to make an informed decision about whether or not they want to go beyond NEIDA (no evident inflammatory disease activity) and be on a treatment that tackles the smouldering B-cell and plasma-cell driven processes within their brains and spinal cords. 

SHOULD WE DO THE HILO STUDY? 

Conflicts of Interest

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Preventive Neurology

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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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Smouldering MS – not all bad news

Barts-MS rose-tinted-odometer: ★★★★★ (today’s colour is Delta Red Iron Oxide #9b2f1c)

One of the smouldering MS dogmas that have entered the MS lexicon is that the iron-rimmed slowly expanding MS lesions (SELs) go on enlarging and destroying or shredding the brain tissue around it forever. Another dogma states these SELs don’t respond to current DMTs. The good news is that both of these statements are probably incorrect. 

In the recently published longitudinal MRI study below iron rims around lesions gradually diminished with time. However, having these iron rim lesions is not good news in that they are significantly more destructive than non-iron rimmed MS lesions. The question I have is what drives these lesions to form? Knowing the answer to this question will tell us what is causing MS.

The second study below demonstrates that ocrelizumab significantly reduces the expansion of slowly expanding/evolving lesions. This suggests that these lesions may be driven by intrathecal or CNS-derived immunoglobulins. This is why we are doing the high-dose ocrelizumab, SIZOMUS (ixazomib) and CHARIOT-MS (cladribine) studies to see if reducing intrathecal B and plasma cell activity has an impact on smouldering MS.

If the former studies are positive, who would want to go onto a lower-dose anti-CD20 therapy (standard-dose ocrelizumab, ofatumumab, rituximab, ublituximab)? Please note that although these lower dose anti-CD20 therapies are very effective at stopping relapses and focal MRI activity this is not MS. The real MS is smouldering MS and what we see with end-organ damage markers. This is why if I had MS I would choose a DMT that offered the best chance of normalising my brain volume loss and I would volunteer for the SIZOMUS trial. 

The good news is that these two studies below show that the so-called chronic active lesions or SELs evolve over many years after their initial formation and that they may be modifiable with DMTs. Let’s celebrate these facts. 

Iron-rimmed lesion of SEL expanding over 7 years; image from BRAIN.

Dal-Bianco et al. Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI. Brain. 2021 Apr 12;144(3):833-847.

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation periods were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

Ocrelizumab reduces the increase in the volume of SELs compared to placebo; image from BRAIN.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain. 2019 Sep 1;142(9):2787-2799.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

How many ofatumumab doses should I miss?

Barts-MS rose-tinted-odometer: ★★★ (It feels like a sky blue rainy Friday =  #87ceeb)

“Prof G how many of my monthly ofatumumab injections should I miss to guarantee that I will have an adequate antibody response to the COVID-19 vaccine?”

This was the gist of one of the direct messages I received on Twitter from a person with MS living in the US. 

I really don’t know. However, I have tried extrapolating data from the repopulation kinetics of ofatumumab given 3-monthly and the modelling data below on ocrelizumab and rituximab. For ocrelizumab and rituximab to have 80% confidence it requires at least 9 months from the last infusion to the first vaccination to have a >50% chance of seroconversion in response to an RNA-based COVID-19 vaccine. This equates to missing close to one dose of ocrelizumab or rituximab as you have to wait 9 months then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommencing your 6-monthly infusions. i.e. ~11 months after your last infusion. Although Mike Famulare has treated rituximab and ocrelizumab as being equipotent in his modelling I suspect he is wrong and the gap for ocrelizumab may in fact have to be substantially longer. I predict that the average person will need to wait about 11-12 months post their last infusion of ocrelizumab to be confident of an antibody response.

As ofatumumab, is a lower dose anti-CD20, with more rapid B-cell repopulation kinetics than ocrelizumab or rituximab (see figure below). I estimate that you will need to wait about 6 months from your last injection before being vaccinated and you would then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommending your monthly injections. i.e. ~8 months later. As this is all based on modelling I suspect in real life you will simply need to wait for peripheral blood B-cell reconstitution to occur before being vaccinated. The problem with the latter is how high do your peripheral B-cells have to be before being vaccinated; more than 3, 5, 10, 20, 50 or 80 CD19+ B-cells per mm3? Clearly, this is something that needs further study and I would urge Pharma or one of the MS groups interested in answering this question to do the study.  Let’s call it the ‘Peripheral B-cell Threshold Vaccine Study‘ or the ‘PerBeC Vax Study‘.

I want to reiterate that vaccine immunity is not only about B-cell and antibody immunity, T-cells also have an important role to play. Granted that if you don’t make antibodies it indicates that your follicular T-helper cells memory may not be that great, but this does not tell you about other CD4+ and CD8+ T-cell memory responses. Therefore, please be patient until these data emerge. 

My message remains the same; #GetVaccinatedASAP. During this phase of the pandemic, some immunity is better than no immunity. The risk associated with getting COVID-19, particularly if you are on a B-cell depleting agent, far outweighs the risks associated with vaccination. 

covid_vax_seroconversion_probability_vs_time_since_BCDT.png
Seroconversion rate following complete COVID-19 vaccination vs. time since most recent b-cell depleting therapy (BCDT). Best fit, 80%, and 95% confidence interval shows logistic regresssion model of seroconversion probability over time.

Mike Famulare. Seroconversion after COVID-19 vaccination in patients using B-cell depleting therapies to manage multiple sclerosis increases with time between treatment and vaccination. Github v0.2 03 June 2021.

B-cell depleting therapies (BCDT) such as ocrelizumab and rituximab used for the management of multiple sclerosis are associated with reduced seroconversion rates following COVID-19 vaccination. In this note, I reanalyze data from the literature to examine how the probability of seroconversion depends on the time interval between the last BCDT dose and the first vaccine dose. While uncertainty is high due to limited data, the results show that the seroconversion probability increases with time. Under a Bayesian interpretation of logistic regression, I estimate with 80% confidence that it requires at least 9 months from last BCDT to first vaccination to have a >50% chance of seroconversion following complete mRNA vaccination, with large uncertainty on when higher confidence of seroconversion can be expected. Among subjects who do seroconvert following vaccination, anti-Spike IgG levels correlate with time since last BCDT. Limited data indicate that levels comparable with immunocompetent response can be achieved with intervals of 12 or more months between BCDT and vaccination. With combined data from multiple sources, I argue that time development of the seroconversion probability and antibody response parallels that of CD19+ and naive B-cell repopulation following BCDT, suggesting that monitoring B-cell repopulation will be useful at the individual level for optimizing vaccine response while maintaining adequate MS control.

Pharmacodynamic response showing dose-response depletion of CD19 B cells and repletion kinetics (safety population). The median time to repletion based on Kaplan-Meier estimates was ≈11 months for the ofatumumab 3 and 30 mg every 12 weeks groups and ≈14 months for the ofatumumab 60 mg every 12 and 4 weeks groups.

Bar-Or et al.Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018 Sep 11;91(11):538. 

Objective: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).

Methods: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.

Results: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.

Conclusion: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.

Classification of evidence: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

Trial registration: ClinicalTrials.gov NCT01457924.

Conflicts of Interest

Preventive Neurology

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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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

#MSCOVID19: Cladribine 3 vs. Ocrelizumab 1 vs. Fingolimod 0

Barts-MS rose-tinted-odometer: ★★★★★

Finally, the early Israeli COVID-19 vaccine seroconversion rates are out as a peer-reviewed publication. This data is not new but comes with being vetted by the scientific community and hence can be quoted and discussed at scientific meetings.

Protective humoral immunity was 97.9% in healthy subjects, 100% untreated pwMS, 100% in cladribine-treated pwMS, 22.7% in ocrelizumab-treated pwMS and 3.8% in fingolimod-treated pwMS. As I have said before this is only half the story and we need to know what happens on the T-cell side. 

IgG antibodies to the virus implies a good T-cell response as well; this is because to class switching to IgG happens in the germinal centres with T-cell help. The corollary does not necessarily hold, i.e. if you don’t make IgG antibodies you can’t assume that vaccine-induced T-cell responses are absent. This is why I predict, based on the fact that both ocrelizumab and fingolimod treated pwMS recover from COVID-19 implying their T-cells are working and helping to clear the virus, that both ocrelizumab- and fingolimod-treated patients are likely to have some T-cell immunity to SARS-CoV-2 spike protein post-vaccination. 

Please note this is a prediction and we will need to wait for more detailed immunological studies. Even if patients on these agents have some T-cell responses the question will remain whether this blunted vaccine-induced immunity against SARS-CoV-2 will be sufficient to protect these patients against getting COVID-19 or repeated episodes of COVID-19? This question will take much longer to answer, but I suspect this limited immunity won’t be sufficient because vaccine immunity is likely to wane with time and new immune escape variants of SARS-CoV2 will emerge. Already public health officials are planning for rounds of booster vaccines to cover new variants. What this means is that vaccine-readiness will become uppermost in the minds of pwMS and HCPs when deciding on which DMTs to choose for particular patients.

The good news is that if you have MS and have been treated with cladribine there is no blunting of vaccine-induced responses. This is not surprising and was predicted based on the immunology of cladribine and justifies my previous blog post taking the NMSS to task on their ill thought out initial COVID-19 vaccine guidelines. Fortunately, these have been updated and pwMS on cladribine can be confident to go ahead with getting vaccinated ASAP. 

Figures from Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

I would extrapolate the ocrelizumab vaccine data to the other anti-CD20 therapies, i.e. rituximab, ofatumumab and ublituximab, but not necessarily the fingolimod data to the other S1P modulators. There is evidence that fingolimod not only traps lymphocytes in lymph nodes but also depletes lymphocytes. In comparison to fingolimod, ozanimod and ponesimod deplete lymphocytes less intensely and at least for ponesimod, the recovery of lymphocytes is very rapid implying lymphocytes are not depleted on this drug.  So I would not be surprised if ponesimod, and possibly ozanimod, have less of an effect on vaccine responses than fingolimod. As for siponimod, I predict it will be closer to fingolimod in terms of its effect on neoantigen (new antigen) vaccine responses such as the COVID-19 vaccines. 

Does this data change anything about my current practice? No, not really, it is entirely in keeping with what I predicted. My advice is still #GetVaccinatedASAP. This data however may impact what treatment patients with MS decide to start off on; if vaccine responses are important to you, say for travel and/or work reasons, you may want to avoid S1P modulators and anti-CD20 therapies.

Please note I have put on my rose-tinted glasses; the sun is shining outside and spring is wonderful 😉

Achiron et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

Background and Aims: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.

Methods: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.

Results: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.

Conclusions: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

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Preventive Neurology

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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 the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

#MSCOVID19: T-cell response on ocrelizumab

Barts-MS rose-tinted-odometer: ★★★★★

As you know the vast majority of pwMS on anti-CD20 therapy who get COVID-19 or for that matter any other viral infection recover. In other words, their immune systems work despite blunted or absent B-cell or antibody responses. This study presented yesterday at the AAN meeting confirms that ocrelizumab-treated patients who get COVID-19 have good robust T-cell responses. Almost all of these patients also had antibody responses to the virus. The ocrelizumab-treated cases that fail to seroconvert may therefore represent a publication bias. However, as this study doesn’t include the 5% of subjects on ocrelizumab who succumb to COVID-19 we can’t assume this applies to all ocrelizumabers.

It will be interesting to see these results replicated with the COVID-19 vaccines. Although wild-type infection with SARS-CoV-2 is likely to provide a more robust immunological challenge than a COVID-19 vaccine, I can’t see why the vaccine won’t induce T-cell responses as well. The question will be how few patients fail to respond to the vaccine at both an antibody and T-cell level.

I am sure a large number of ocrelizumabers or anti-CD20ers and their HCPs will be relieved to see these results (or not).

Kister et al. Preliminary Results of Ongoing, Prospective Study of Antibody and T-Cell Responses to SARS-CoV-2 in Patients With MS on Ocrelizumab or Other Disease-Modifying Therapies. AAN 2021

Objective: 1. To assess SARS-CoV-2 seropositivity in 1,000 patients with multiple sclerosis (MS) and its association with demographic and disease-related characteristics, and disease-modifying therapy (DMT); 2. To evaluate the persistence of antibody and T-cell responses in a subset of these patients who were receiving ocrelizumab (OCR), other DMT or no DMT at the time of COVID-19 infection. Background: Since March 2020, ˜15% of patients attending NYU MS Care Center (NYUMSCC) in New York City had COVID-19. It is unknown whether DMTs affect the persistence of antibody and T-cell responses to SARS-CoV-2. 

Design/Methods: Patients from NYUMSCC were invited to undergo serologic assessment using Elecsys Anti-SARS-CoV-2 (Roche Diagnostics) and multiplex bead-based immunoassays of antibody responses to SARS-CoV-2 nucleocapsid and spike proteins. A subset of patients with or without COVID-19 history underwent a study of T-cell responses to SARS-CoV-2 spike protein using IFN-? enzyme-linked immunosorbent spot (Invitrogen) and TruCulture (Myriad RBM) spike protein assays and live virus immunofluorescence-based microneutralization assay. 

Results: Since January 2021, 100 unvaccinated patients with MS were enrolled (mean 41 years; 63% female; 45% non-white; 35% on OCR; 26% had COVID-19). Antibody and T-cell results were available for 40 patients (26 on OCR; 17 had COVID-19, median 10 months before sampling). Of the 40, Elecsys Anti- SARS-CoV-2 assay identified all but 2 COVID-19+ patients, and multiplex bead-based assay identified all but 1 COVID-19+ patient as seropositive. Neither assay had false positives. T-cell activation based on induced IFN-gamma secretion was observed in 10/17 COVID-19+ patients and 1 patient without COVID-19 history who developed PCR-confirmed COVID-19 five days after sampling. Anti-SARS-CoV-2 antibody response was detected in 4/5 and T-cell response in 3/5 OCR-treated COVID-19+ patients. 

Conclusions: Preliminary results suggest persistent humoral and T-cell immune memory to SARS-CoV-2 up to 10 months following infection even in B-cell depleted patients with MS. Updated results will be presented.

Conflicts of Interest

Preventive Neurology

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Disclaimer: Please note that the opinions expressed here 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.

Should we abandon the ADIOS study?

Barts-MS rose-tinted-odometer: ★★★

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.

Deepak P et al. Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2. MedRxiv https://doi.org/10.1101/2021.04.05.21254656.

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.

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#MSCOVID19: ABN Guidance Update

Barts-MS rose-tinted-odometer: ★★★

The ABN have updated their COVID-19 guidelines, which are beginning to move towards the evidence. However, the guidance on cladribine is not supported by the evidence nor the science, i.e. how cladribine actually works and its impacts the immune system.

The latest guidance states “the risk of severe COVID-10 disease is increased for many months after ocrelizumab and cladribine”. I am not sure there is evidence to support the statement about cladribine. Ocrelizumab and other anti-CD20 therapies are given continuously and hence the risk does not go away. However, cladribine is an immune reconstitution therapy and is reversible. Even in the depletion phase of treatment, the level of immunodepletion is modest, particularly for CD8+ T cells (see slide show below) and innate immunity is left intact. In our opinion, this pattern of immunodepletion is not sufficient to pose a risk to people with MS treated with cladribine and is supported by the emerging pharmacovigilance data.

The good news is that the guidelines state that for both ocrelizumab and cladribine “self-isolation for all that time is not appropriate except for individuals with multiple other risk factors”, which is compatible with our practice.

I am also reassured that their guidance has also softened for alemtuzumab; i.e. “we would anticipate pwMS being advised to strictly self-isolate for at least four weeks after an alemtuzumab administration”. This has been our practice since we started dosing alemtuzumab again. The rationale for the 4 week time period I assume is based on the impact of alemtuzumab on innate immunity and is supported by trial data; i.e. the viral infection risk falls rapidly after four weeks, presumably because monocyte counts recover.

The ABN is also recommending two weeks of self-isolation after high-dose steroids, which is pragmatic advice based on the risk of severe COVID-19 identified in the Italian registry studies.

The new guidance has also made a comment about vaccine readiness; “patients contemplating ocrelizumab should be advised that they may not be able to receive a future SARS CoV2 vaccine if it is a live vaccine, and they may not respond immunologically to a dead or inactivated vaccine. Consideration should be given to delaying ocrelizumab re-treatment”. It is interesting that none of the other DMTs is specifically mentioned when it comes to vaccine readiness. I am sure live viral vaccines will also be contraindicated in patients on S1P modulators (fingolimod and siponimod) and on some of the other immunosuppressive DMTs such as natalizumab and possibly even teriflunomide based on their current SmPCs.

The interesting thing about vaccine readiness is we don’t know about how important T-cell responses are in relation to these emerging vaccines and whether or not people on anti-CD20 therapies will mount an adequate protective T-cell response to the SARS-CoV-2 spike protein and other antigens. Everyone focuses on antibody responses when they may not be that important in protective anti-SARS-CoV-2 immunity.

I am sure we haven’t heard the last on MS DMTs and vaccine readiness. This is why I would urge all the DMT manufacturers to do the necessary studies to provide us with the necessary evidence-base to make clinical decisions.

Barts-MS Journal Club: vaccine responses on ocrelizumab

Dr Ide Smets discusses the Veloce study and its implications for managing MS.

Bar-Or et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology October 06, 2020; 95 (14) 

Objective: The phase IIIb VELOCE study (NCT02545868) assessed responses to selected vaccines in ocrelizumab (OCR)-treated patients with relapsing multiple sclerosis.

Methods: Patients were randomized 2:1 into Group OCR (n=68; OCR 600mg); or Control (n=34;interferon-β or no disease-modifying therapy). All received tetanus toxoid (TT)-containing vaccine, Pneumovax® (23-PPV) and keyhole limpet hemocyanin (KLH). Group OCR was subdivided into OCR1 (n=33) and OCR2 (n=35) at randomization. OCR1 received Prevnar® (13-PCV) 4 weeks after 23-PPV; OCR2 and Control received influenza vaccine. Vaccinations started 12 weeks after OCR initiation (Group OCR) or on Day 1 (Control).

Results: Positive response rate to TT vaccine at 8 weeks was 23.9% in OCR vs 54.5% in Control. Positive response rate to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in OCR and 100% in Control. Prevnar® did not enhance response to pneumococcal serotypes in common with Pneumovax®. Humoral response to KLH was decreased in OCR vs Control. Seroprotection rates at 4 weeks against five influenza strains ranged from 55.6–80.0% in OCR2 and 75.0–97.0% in Control.

Conclusion: Peripherally B-cell depleted OCR recipients mounted attenuated humoral responses to clinically relevant vaccines and the neoantigen, KLH, suggesting use of standard non-live vaccines while on OCR treatment remains a consideration. For seasonal influenza vaccines, it is recommended to vaccinate patients on OCR, as a potentially protective humoral response, even if attenuated, can be expected. Classification of evidence This study provides Class II evidence confirming that the humoral response to non-live vaccines in patients with RMS following ocrelizumab treatment is attenuated compared with untreated or interferon-β–treated patients, though can still be expected to be protective.

CoI: multiple

Anti-CD20 Derisk Study

Barts-MS rose-tinted-odometer: ★★★★★

Did you watch the anti-CD20 debate on the triMS-online platform yesterday? The question that was asked was ‘Can we use anti-CD20 therapies as immune reconstitution therapies rather than maintenance therapies?’. I am not sure the debaters answered the question. 

When I asked Anders Svenningsson, who is probably the world’s biggest adopter of anti-CD20 therapy as a treatment for MS, whether or not someone with MS could stay on anti-CD20 for life, he hesitated before saying ‘YES and NO’. His reason? SAFETY. He described things they were doing to try and reduce the risk of hypogammaglobulinaemia and infections in their patients on longterm anti-CD20 therapy. I am not sure it will work. Interestingly, he suggested stopping  anti-CD20 therapy when pwMS get to 55-60 years of age when the risks of treatment outweigh the benefits. In other words, Anders Svenningsson is saying we can’t leave pwMS on anti-CD20 lifelong. 

I have been making this exact point on this blog for several years and that is why I have proposed the ADIOS and iTeri studies as ways to derisk long-term anti-CD20 therapies. However, I have been thinking are there any other DMTs we could use after anti-CD20 that would potentially work to derisk the hypogammaglobulinaemia and tackle the cause of MS. I suspect yes. Fumarates, as monotherapy, or in combination with a neuroprotective therapy, also makes sense. The difficulty is what will be the primary outcome of such a trial and how would you do power calculations? 

Maybe we could use a non-inferiority design and make safety the primary outcome. Would regulators buy that in addition to non-inferiority as a secondary outcome?

There are not many companies who have the resources, motivation and know-how to do such a study. Roche-Genentech and Novartis would not as this would eat into their franchise. In my opinion, the only company with big enough bollocks and know-how to take this on would be Biogen. Would they be interested?

This is potentially an opportunity for them to come up with a new combination pill of one of their fumarate formulations with an add-on neuroprotective. DMF will maintain MS in remission post-anti-CD20 and the neuroprotective will tackle smouldering MS, which is something anti-CD20 therapies don’t do. A fumarate-neuroprotection combination may actually not only show improved safety but superiority on end-organ damage markers (brain volume loss etc.). 

The hypothesis is that if B-cells and in particular memory B-cells are driving MS then starting DMF for example before memory B-cell reconstitution occurs may actually make MS more responsive to fumarates. Add in a combination, to generate new intellectual property (Biogen need this as their fumarate patents are being challenged) and you have a new DMT.

If successful this new combination pill will probably become the most prescribed DMT in MS. Why? To quote Anders Svenningsson you can’t really remain on anti-CD20 lifelong so if you have to derisk an anti-CD20 at some stage. So why not do it before you develop hypogammaglobulinaemia? As more than 50% of MS patients will be treated with anti-CD20 therapy in the near future this combination therapy could potentially capture more than 50% of the market.

If you are on an anti-CD20 therapy (ocrelizumab, rituximab or ofatumumab) would you volunteer to participate in the DERISK study below?  

CoI: multiple

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