Monday, 12 August 2013

Targeting B cells

Will the anti-B-cell therapies supplant alemtuzumab and natalizumab in MS? #MSBlog #MSResearch

"Although neuromyelitis optica (NMO) is a different disease to MS it is one of the disease that mimics MS; NMOers are frequently misdiagnosed as being MS. This is a problem as most of the DMTs licensed for treating MS make NMO worse. Therefore, it is reassuring to have a treatment strategy that works for both MS and NMO."

"Rituximab is a B cell depleting agent that works in MS. The phase 2 results were spectacular and shifted the paradigm in MS. The anecdotal experience from the off-label use of rituximab in MS has confirmed this; I have personally used rituximab in a handful of cases and have been very impressed with its ability to switch-off disease activity."

"Due to complex, scientific and business, reasons Genentech-Roche decided against taking rituximab forward in MS. Instead they decided  to develop the follow-on compound ocrelizumab. This latter decision will delay the access of an anti-CD20 therapy for MSers by about 4 years. At the time Genentech-Roche made  the decision not to develop rituximab and to go with ocrelizumab a lot of us felt this was unacceptable, because it would be denying or delaying MSers access to a very effective therapy.  Despite our protests the decision was made and the ocrelizumab program is now quite advanced. There are currently three phase 3 ocrelizumab studies running (two in RRMS and one in PPMS) that are due to report in late 2015 and early 2016. The question is not about whether or not ocrelizumab will be effective or not, but rather about safety. There is little doubt that ocrelizumab will be a highly effective DMT. Will it be safe? The rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE) ocrelizumab development programmes were halted due to safety concerns. Whether or not the same safety issues will arise in MS is yet to be ascertained. I suspect not as MSers are generally much healthier than people with severe RA and SLE. Ocrelizumab will also be an induction therapy and will be given every 6 months for at least 2 years. What is not known is how often redosing will be needed after completing the first 2 years of treatment. The phase 2 extension results presented at the AAN, by Prof. Hauser and suggest that the treatment effects may last at least 18 months, and may be longer, after the last dose. What this NMO study below provides is a framework for developing a redosing schedule based on the recovery of peripheral B cells counts."

"Why the paradigm shift? Anti-CD20 therapies target B cells by depleting them from the peripheral blood and to some extent from  the peripheral tissues. What nobody expected was for these therapies to be so effective in MS; MS was always considered to be a T-cell mediated disease. B cells are the immune cells that make antibodies and are also involved in other immune functions. The B cell is also the niche where EBV resides once you become infected with the virus. Therefore anti-CD20 therapies are also anti-EBV drugs; in fact rituximab is the only licensed drug to treat EBVassociated diseases. In short anti-CD20 therapies have multiple potential modes of action. The onset of action of anti-CD20 therapies is too quick, i.e. within weeks of dosing, for them to be having their effect via antibody production. Most of feel the mode of action anti-CD20 therapies in MS must be related to its impact on the other immunological functions or against EBV. Because of the latter I have branded the anti-CD20 therapies as being anti-EBV and challenge people in the field to prove that these drugs are not working via EBV. Unfortunately, to date no one has risen to the challenge."

"Apart from ocrelizumab (Roche) GSK is currently developing ofatumumab for MS; both drugs target CD20 on the surface of B-cells. Another target is CD19, which to me is even more appealing than CD20 as it is expressed on a larger number of cells including plasmablasts. At present we are recruiting RRMSers for a trial of MEDI-551, which is an antibody that depletes B cells via the CD19 receptor (http://multiple-sclerosis-research.blogspot.co.uk/2012/11/anti-cd19-and-multiple-sclerosis.html)."

"I am of the opinion that if no major safety signals emerge with the anti-CD20 and anti-CD19 therapies that these classes of drugs will supplant the other monoclonal antibodies. The good news is that PPMSers will get an answer with regard to whether or not this class of drug is effective in PPMS at the same time as RRMSers. Who said we are ignoring PPMS?"


Kim et al. A 5-Year Follow-up of Rituximab Treatment in Patients With Neuromyelitis Optica Spectrum Disorder. JAMA Neurol. 2013 Jul 29.

IMPORTANCE: A previous 2-year analysis of repeated rituximab treatment in NMOers (people with neuromyelitis optica (NMO)) revealed significant improvements in relapse rates and disability. This paper reports the findings from the longest follow-up of rituximab treatment in NMO, which provide reassurance regarding the long-term efficacy and safety of rituximab in NMO.

OBJECTIVE: To report the results of rituximab treatment in NMOers with relapsing NMO or NMO spectrum disorder (NMOSD) for a median of 60 months. 

DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series in an institutional referral center for MS, including 30 NMOers or NMOSDers.

INTERVENTIONS: After induction therapy, a single infusion of rituximab (375 mg/m2) as maintenance therapy was administered whenever the frequency of re-emerging CD27+ memory B cells in peripheral blood mononuclear cells, as measured with flow cytometry, exceeded 0.05% in the first 2 years and 0.1% thereafter. 

MAIN OUTCOMES AND MEASURES: Annualized relapse rate (ARR), disability (Expanded Disability Status Scale score), change in anti-aquaporin 4 antibody, and safety of rituximab treatment. 

RESULTS: Of 30 NMOers, 26 (87%) exhibited a marked reduction in ARR over 5 years (mean [SD] pretreatment vs posttreatment ARR, 2.4 [1.5] vs 0.3 [1.0]). Eighteen NMOers (60%) became relapse free after rituximab treatment. In 28 NMOers (93%), the disability was either improved or stabilized after rituximab treatment. No serious adverse events leading to discontinuation were observed during follow-up.

CONCLUSIONS AND RELEVANCE: Repeated treatment with rituximab in NMOers over a 5-period, using an individualized dosing schedule according to the frequency of re-emerging CD27+ memory B cells, leads to a sustained clinical response with no new adverse events.

CoI: multiple

Other posts of interest

14 Nov 2012
In response to a query re anti-CD19 treatment. Unfortunately, you can't access anti-CD19 treatment at present it is not a licensed therapy. However, we are doing a clinical trial of this agent so if you are interested you can ...

30 Jul 2013
BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. OBJECTIVES:To evaluate the efficacy and safety ...
04 Dec 2012
"In response to a comment regarding the safety of rituximab and ocrelizumab in MS. This poster was presented at ECTRIMS. This is very reassuring in that the anti-CD20 look as if they will be in the upper zone of efficacy and if ...
11 Nov 2012
Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in MSers with relapsing MS as a single agent. Our investigator-initiated phase II ...
04 May 2012
Then look in MSers and find that some B cells are producing more IL-6 and this excessive production of IL-6 is lost in B cells from rituzimab-treated individuals. This suggests that rituximab is killing the IL-6 producing B cells.

29 Jun 2011
In this observational study the investigators present clinical and spinal fluid findings in 3 patients with SPMS who were treated with rituximab, a drug that target the B-cell or the cell that produces antibodies, for at least 15 ...
08 Jun 2011
Rituximab is a monoclonal antibody that targets a surface protein on B cells called CD20. There is good phase 2 data on its effectiveness when given intravenously (i.e. via a peripheral vein) in RRMS and a subgroup of PPMS ...
13 Apr 2013
Reduced antibody formation after influenza vaccination in patients with neuromyelitis optica spectrum disorder treated with rituximab. Eur J Neurol. 2013 Mar 22. doi: 10.1111/ene.12132. [Epub ahead of print] BACKGROUND ...
04 Jun 2011
In the Rituximab study time to confirmed progression between Rituximab and placebo treated groups was not significant. However, subgroup analyses suggest selective B-cell depletion may affect disease progression in ...

06 Nov 2011
Anonymous Friday, November 25, 2011 10:38:00 am. Is Ocrelizumab a new product? I thought it is perhaps Rituximab with a new name. If it is a new product, then it will come dearly so for patients/payers-will it Gavin? Reply ...

16 Oct 2010
First anonymous- They both have the same targets, i.e. both are anti-CD20 monoclonal antibodies (MAb). However, Rituximab is a chimeric MAb (fusion with mouse protein) whereas Ocrelizumab is is humanised MAb. Making ...

19 comments:

  1. Prof G,

    Thanks for posting - I thought you might be having a day in bed!

    I'm really enjoying these longer posts, much better that the 'you're all getting dementia' stuff.

    2 Qs

    1. If the anti-B cell therapies are anti-EBV, does it negate the need for the Charcot project.
    2. I'd heard that Alemtuzumab also targets B cells. Is it as effective as Rituximab and it's offshoot at targeting B cells?

    Ps I assume Mouse is recovering after a booze- fest heavy metal weekend.


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    1. RE: "If the anti-B cell therapies are anti-EBV, does it negate the need for the Charcot project?"

      No not at all; all these drugs have side effects and EBV is not the only virus that needs targeting. If anti-CD20 is working via EBV we could devise a much more clever drug that only targets B-cells infected with the virus and not all B cells.

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    2. Re: "I'd heard that Alemtuzumab also targets B cells. Is it as effective as Rituximab and it's offshoot at targeting B cells?"

      All the highly effective therapies target B cells; it is what is common to all of their modes of action (mitoxantrone, alemtuzumab, cladribine, fingolimod, natalizumab, rituximab, ocrelizumab, etc.). The B cell is the where all the action is at.

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    3. I have PPMS and was very early on put on a year's intensive course of mitoxantrone that had no impact on my progression despite its so-called effects on B cell activity. I still continue to get worse.

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  2. Bar only a couple of endeavours, PPMS does seem to be massively overlooked. Everyone is hogging the middle ground, wanting to cash in on RRMS because that is a form of the disease which Big Pharma largely has made loads of money off as its natural pathology is one where short episodes of attack are comforted by naturally longer periods of remission. It is these periods of remission that invite dishonest entities to claim their drugs are the very thing responsible for such fortitude, yet if an MSer continues to relapse despite being on such miraculous drugs then these dishonest entities will claim the drugs were given too late to have made an impact.

    You say that alemtuzumab is worth the hefty price tag because relapses 'upset' the patient, but that sounds feeble to me. What we ought to be paying for is drugs that fix damage caused by progression for all MS victims. Until that is possible, you're wasting our time.

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    1. I'm guessing you haven't met Prof G at one of the research days or Dr Coles from Cambridge. I'm lucky to have contact with both. The idea that these guys are wasting our time is beyond belief. Thanks to Dr C we have a drug on the horizon that can substantially reduce inflammation / relapses. Thanks to Prof G we have trials looking at the possibility of EBV being the course and methods for studying the impact of neuroprotective agents. Probably best for you not to visit this blog if it's wasting your time.

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    2. The Charcot Project is suspect at best. MS is in a sufferer's chromosomes, it is in the very fabric of their makeup. It may be triggered by a virus but it is not caused by one. Experiments like the Charcot project have been a part of medical history and have failed. Medical historians will tell you so. Your interpretation of MS is too narrow. You need to read around more and not just depend on this blog for all your answers.

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    3. Anon 2:37 pm "MS is in a sufferer's chromosomes..."

      You sound like an arrogant scientist. What about the affect of migration? Is that in your chromosomes?

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    4. Please calm down; the refusal to look beyond the blinkers is what typifies most people's world view from within the current paradigm or dogma. We expect the Charcot Project to get some stick as it challenges the current dogma.

      Anon 2.37 you should read the literature on EBV and MS; you may, or may not, change your opinion about a viral cause.

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    5. Re: "What we ought to be paying for is drugs that fix damage caused by progression for all MS victims. Until that is possible, you're wasting our time."

      We don't have drugs that fix the damage; this is Sci-Fi at the moment. We do have drugs that stop further damage and allow your own nervous system to fix itself. The only problem is that your nervous system's ability to fix itself depends on how damaged it is. The earlier you stop the damage the better your chances of getting some repair. This is why highly effective treatments have limited effect in SPMSers; please note that I have deliberately said limited effect, not no effect.

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  3. It is a shame that Rituxan was pulled from clinical trial due to expiring patent in 2015. From all accounts this could be a game-changer. With the delay of up to 4 years what options are available to clinicians? Do you feel that HSCT therapy followed by alemtuzumab can be a viable option?

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    1. There is a rituximab trial for SPMS that is still recruiting:

      http://clinicaltrials.gov/ct2/show/NCT01212094?term=10-n-0212&rank=1

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    2. That study is at NIH in D.C. Too bad Rituxan can't be used off-label.

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    3. I am aware of this trial, but it won't lead to a license and hence it will difficult to prescribe. This is why we need a Big Pharma Alternative.

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  4. What about resveratrol? Has it similar effect as rituximab?
    I found this study:

    Resveratrol Prevents EBV Transformation and Inhibits the Outgrowth of EBV-Immortalized Human B Cells

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0051306

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  5. So is there any literature on what happens to MS sufferers that are treated with chemotherapy for Hodgkin's Lymphoma. Mixed Cellularity Hodgkins is caused by B cells infected by EBV.

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  6. At what intervals did they check CD27+ levels?
    Why CD27+ levels and not CD19?
    Is CD27 testing as easily available as CD19?

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  7. 1. Any differences in the 2 Opera phase 3 studies of Ocrelizumab in RRMS? In Methodology and Results?
    2. For ORATORIO study of Ocrelizumab in PPMS, why more patients had active disease on MRI compared to PPMS study with Rituxan? Was that based on entry selection criteria? Thanks!

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    1. 1. Opera 1 & 2 were mirror images I think and results were virutually identical I think..
      2. They learned from the rituximab trial how to get a positive

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