Anti-CD20 What are the Manufacturers Doing?

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Anti-CD20 is a highly popular treatment for MS as the only one approved across the subtypes and so whilst the manufacturers were no doubt rubbing their hands with glee with the sales in 2019…in 2020/2021 along came COVID-19 and anti-CD20 has become the poster child for bad news, COVID-19 wise. It has been reported to make COVID-19 worse and to block the vaccination response. So how do you counter this?

With Data

To their credit the manufacturers of anti-CD20 were quick to respond and have been putting their views and their data into the public domain. As for the disease worsening elements one has to remember the effects are small even if there is a risk and remember Bad News Sells Space. Therefore there is always the possibility of reporting bias. Adverse events are more likely to be reported than someone having a good experience. So it may not be true

Friseel (Sweden ECTRIM 2021) No association between rituximab infusion timing nor cumulative dose and hospitalization for COVID-19: Evidence from the nationwide COMBAT-MS Cohort

As it is open access you can have a read of the CD20 story and OK you have to rememeber rule number one of Pharma club is don’t talk about any problem with your product :-).

Rosetta Pedotti, Erwan Muros-Le Rouzic, Catarina Raposo, Sven Schippling, Nikki Jessop. Understanding the impacts of COVID-19 pandemic in people with multiple sclerosis treated with ocrelizumab MASARDS 2021 in press

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to major challenges in the therapeutic management of patients living with multiple sclerosis (pwMS), particularly regarding the use of disease-modifying therapies. Despite an extraordinary scientific effort to study SARS-CoV-2 in pwMS, the heterogeneity of COVID-19 manifestations, immunological mechanisms induced by the natural infection or the vaccines, and the extent of protection through the vaccines remain major knowledge gaps. Here, we describe the scientific evidence generation plan developed by Roche/Genentech to better understand the impact of the COVID-19 pandemic in pwMS treated with the B-cell depleting monoclonal antibody ocrelizumab.

They say

“There is commonly a reporting bias for more significant outcomes, which may result in an overrepresentation of more severe cases. For example, positive PCR in asymptomatic patients is usually not reported as AE and no testing has been mandated in our clinical trials”

“In addition, the correlation between antibody titres and COVID-19 severity is still controversial and the absence of antibodies, the serum titers of which vary over time, appears not to translate into absence of immunity”

“We are collaborating with several academic partners with the common goal of characterizing the immune response against SARS-CoV-2 following infection in pwMS treated with ocrelizumab”

Indeed they say they they have studies ongoing in Germany, Israel, Italy, Switzerland, USA. The USA study has surfaced on MedRxiv and one wonders when the others will appear, maybe ECTRIMS (see below) maybe in JAMA Neurology which does not allow preprinting but changes the manuscript and re draws all the figures and so takes months to surface so not a good choice if you are in a race to get it out there. Maybe the Italian study is part there maybe there are others. This in addition other studies in the pipleline or those that have surfaced.

M Freier (Germany) ECTRIMS 2021 Humoral and cell-based responses following SARS-CoV-2 mRNA vaccination of patients with multiple sclerosis on B-cell depleting therapy.

We will have confirmation in 400 people that there is a T cell response and there is some B cell response in some people depending on which assay and which SARS-COV-2 antigen you test and maybe use the ultra sensisitive assays to say positive…tick. However, there are already studies in hundreds of anti-CD20 vacinees that suggest otherwise.

Sadly I have to say by the time they arrive people will be saying “Who cares we know this already”.

I have been a referee of a paper doing the rounds for about 5-7 months it was new when it was submitted, but it has been refereed (not by me) into boredom, so by the time it arrives, there are about twenty papers saying the same thing but in larger groups in a more definative way so all it is good for is a jigsaw piece in an meta analysis such as the one below. It will hardly a citation classic:-(

As such we have a review of the state of play of what happens with COVID-19 and the answer is not much but you can see the data is strongest with anti-CD20 antibodies and this shows you that it is frequently used.

Cabreira V, Abreu P, Soares-Dos-Reis R, Guimarães J, Sá MJ. Multiple Sclerosis, Disease-Modifying Therapies and COVID-19: A Systematic Review on Immune Response and Vaccination Recommendations. Vaccines. 2021; 9:773. doi: 10.3390/vaccines9070773.

Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze vaccine response dynamics. A systematic review on COVID-19 course and outcomes in patients receiving different DMTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Emerging data on SARS-CoV-2 vaccines was used to elaborate recommendations. Data from 4417 patients suggest that MS per se do not portend a higher risk of severe COVID-19. As for the general population, advanced age, comorbidities, and higher disability significantly impact COVID-19 outcomes. Most DMTs have a negligible influence on COVID-19 incidence and outcome, while for those causing severe lymphopenia and hypogammaglobulinemia, such as anti-CD20 therapies, there might be a tendency of increased hospitalization, worse outcomes and a higher risk of re-infection. Blunted immune responses have been reported for many DMTs, with vaccination implications. Clinical evidence does not support an increased risk of MS relapse or vaccination failure, but vaccination timing needs to be individually tailored. For cladribine and alemtuzumab, it is recommended to wait 3-6 months after the last cycle until vaccination. For the general anti-CD20 therapies, vaccination must be deferred toward the end of the cycle and the next dose administered at least 4-6 weeks after completing vaccination. Serological status after vaccination is highly encouraged. Growing clinical evidence and continuous surveillance are extremely important to continue guiding future treatment strategies and vaccination protocols.

CoI: Multiple and I have had honoraria in the Past from the manufacturers of anti-CD20 so don’t take my word on any of the above if you wish

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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MouseDoctor

12 comments

  • Thank you very much for the continuous updates, MD. I’m slowly turning optimistic for Covid, vaccination and anti-CD20. Let’s hope T cells are king and abundant in vac responses.

  • That last figure is terrifying… Why are almost 2000 of the 4400 MS patients on low-efficacy therapies like beta interferon? What kind of purge is going to be necessary to clean up the neurology field and ensure that neurologists stop harming their patients?

    • beta interferon 218, GA 269 and teri 251 = 738 + DMF = 738 + 603/108 = 1449 + fingo = 1449 + 414 = 1863

    • Most newly diagnosed are prescribed with a high-efficacy. Many patients on lower to medium efficacy are diagnosed before OCR became available, and tolerate relatively well on their current DMT. Maybe it is not wise to test how well one will do on a lower-efficacy drug at diagnose, but many patients doing relatively well will be reluctant to switch therapy. Don’t always blame neruos under treating. Someone consistently overtreating in my opinion is also a quack and could potentially cause more damage (sadly we don’t know if both sides are correct or not.)

  • Thanks MD for your tireless reporting to us! I really appreciate it. I’m a little bit confused as to whether anti CD20 ers do or don’t get a T cell response now after so many papers though?!

  • As to Anonymous’s comment regarding interferons- As the 1st and only treatment in 1995, I started with Betaseron (Interferon 1B) every other day and continued for 20 years. I was NEDA about as soon as I started, and had a relapse only after I changed to Avonex for a brief 6 month stint. (Avonex being a weaker and more convenient interferon.) Although the MS was aggressive in my early days (I own a wheelchair now stored away), the MS essentially seemed to stop. Now 63 and no longer on any DMT, nothing seems to be going on. If I am smoldering, it is a slow smolder, and lets be honest, my “best years are behind me” anyway. I consider my former treatment to have gotten me here in essentially one piece. As to O, I was on that for a year and stopped, on my own intuition, when the whole covid mess heated up in Europe in 2020. I am happy about that decision; I am doing well.

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