Anti-CD20 trial for Intra thecal Rituximab started whilst another stopped for lack of efficacy

Today we have a B cell flavoured day at ACTRIMS as CD20 depletion is at the forefront
If one person has an idea another is having it at the same time. 

Leptomeningeal inflammation and Intrathecal Rituximab in Progressive MSDr. Peter A Calabresi, MD, Johns Hopkins University, Baltimore, MD

While many treatment options exist for the relapsing form of MS, there are no effective therapies for progressive MS. Pathological studies have shown the presence of leptomeningeal inflammation (LMI) in people with MS and it is more prevalent in primary and secondary progressive MS. LMI is linked to increased gray matter demyelination and increased sub-pial lesion load, suggesting a possible role for LMI in disease progression. Identifying this process in vivo has been a challenge, but recent studies have shown that time-delayed post-contrast FLAIR sequences can demonstrate leptomeningeal lesions that correspond to areas of inflammation with lymphocyte aggregates seen on autopsy. These lesions appear to remain stable over time and are seen more frequently in people with progressive MS.

Our data suggest that in the late stages of the relapsing remitting experimental autoimmune encephalitis (EAE) model in SJL mice, contrast-enhancing lesions emerge in the meninges overlying the cerebral cortex. These lesions persist over time and consist of B and T lymphocytes, suggesting a process that may be similar to LMI seen in people with MS, which could facilitate screening of therapies designed to target this type of inflammation.

Since anti-CD20 is already FDA approved and has been given intrathecally (IT) to people with MS, we have commenced a clinical trial of IT Rituximab in people with progressive MS who have two baseline MRIs demonstrating leptomeningeal enhancement (LME). Since LME is a persistent process for years, unlike white matter enhancing lesions, any reduction of LME on MRI would be meaningful. The design of the clinical trial and enrollment to date will be discussed.

But as a trial starts another is stopped prematurely because it isn’t going to work

Intrathecal Rituximab in progressive MS stopped for insufficient inhibition of CNS inflammation: a randomized, double-blind, placebo-controlled studyDr. Mika Komori, MD, PhD, Dr. YenChih Lin, PhD, Dr. Irene Cortese, MD, Mr. Andrew Blake, Ms. Joan Ohayon, CNRP, Ms. Jamie Cherup, RN MSN CRNP, Dr. Dragan Maric, PhD, Dr. Peter Kosa, PhD, Dr. Tianxia Wu, PhD and Dr. Bibiana Bielekova, MD, National Institutes of Health, Bethesda, MD
Background: The lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS) may be caused by the unreachable compartmentalized inflammation in the central nervous system (CNS).
Objectives: The double blind combination of Rituximab by IntraVenous and IntraThecal injection versus placebo in patients with Low-Inflammatory Secondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: 1. Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and 2. If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?
Methods: Patients aged 18-65 years were randomly assigned (2:1; randomization sequence table balanced for age) to rituximab (n=18) or placebo (n=9). Protocol-stipulated interim analysis of serum and cerebrospinal fluid (CSF) biomarkers in patients who completed the induction dose of study drug quantified the efficacy of B cell depletion.
Results: The selected rituximab regimen failed to reach criteria for continuation of the trial. Changes in B cell-related CSF biomarkers (soluble CD21 [sCD21] and B-cell activating factor [BAFF]) occurred only in the active-treatment arm. While the mobile pool of CSF B cells was depleted by a median of -79.71% (p= 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, p<0·0001). Consequently, the T cell specific CSF biomarker sCD27 also decreased only slightly (-10.97 %, p=0.0005), while a marker of axonal damage, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement and paucity of cytotoxic CD56dim NK cells contribute to decreased efficacy of rituximab in the CNS.
Conclusion: Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that the RIVITALISE trial would be underpowered to reliably measure efficacy on clinical outcomes.

In other trials of intrathecal rituximab it shows that most of the antibody put in the CSF ends up  in the blood and it depletes the B cell pool in blood. However eliminating B cells from the CNS is not achieved

Is the intial trial doomed even before it starts?

Again 3-4 underpowered studies verses a joined-up definative answer…same old same old:-(

If you are going for this approach would it not be best to target the Plamsa cells which do not express CD20, ensuring that the antibody is complement fixating and that complement s around and not killing by Antibody-dependent cellular cytotoxicity that need other cells to do the killing

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  • What is the evidence that B-cells in the CNS is driving the progressive phase of the disease?

    It seems maybe this is not the culprit, so even if you could eliminate oligoclonal bands in progressive disease (not likely with any therapy) it seems maybe this is not the problem in this stage of the disease.

  • I believe that you are right and the b cell and progression is part of a red herring. It is a hypothesis that b cells drive progression. There is no question of lesions on the surface of the brain and it is clear that antibodies in CSF can be damaging. The b cell follicles are debatable but people with Ms have oligoclonal b cell activation. Get rid of them and if MS goes away then QED. Likewise target innate inflammation and progression stops QED. However go about it half cocked and you end up with cock-up. Rituximab is never going to get at the plasma cells so it won't answer the question. 5 min of thought process rather than suck it and see. sometimes that works but generally it doesn't. Just because you can doesn't mean you should and if it puts the cause backwards then it is bad news.
    However Tally Ho is the clinical mantra maybe it is better to try and fail than not to try at all.

    • Apologies if I'm oversimplifying, but is this not a relatively cheap/easy thing to test? I thought we already have licensed drugs that deactivate microglia, and licensed drugs that delete plasma cells… Is there now quick and dirty way to test this idea by taking some rapidly progressing SPMSers and prescribing off label?

      Appreciate the need for a full trial before it's made widely available, but are you not allowed to do a human "proof of concept" trial first?

      What happens in the mices?

    • Is it cheap to test…Not really cheap to test they were taking 5 year study at ACTRIMS so thats 7-8 years with recruitment and a few million.
      Deactivting Microglial maybe in our hands mimocyline isn't that good and depelting plasma cells is possible with antibodies but you have to delivery them there are some drugs too. However how do you do a quick trial? PROXIMUS is recruiting very, very slowly

    • I guess what I'm saying is that we're all banging on about the relevance of OCBs to progression, and how the current therapies swerve them, whilst sitting on a bunch of drugs (new and old) that can delete plasma cells with pretty decent efficacy…

      Surely there'd be some prestige for academia in being the first lab to reverse OCBs in MS. And you wouldn't need to wait 8 years to know – you'd see it pretty quick from a couple of lumbar punctures, right?

      I don't know what it would cost to give 50 or so PPMS patients an intrathecal mab and a couple of LPs… Couple of hundred grand?

      Surely pharma would donate the drug for free on the basis that, if successful (and it seems a decent prospect that it would be), they've got a new market for their drug of essentially 80% of anyone who has any type of MS…

      Same story with microglial activation. There are apparently drugs out there that can reduce it, you have a means now to measure it on MRI, there's a strong correlation with disease stage/severity/pathology, so why doesn't someone just do the experiment already – even if just in a prototype/proof of concept way – to see if they can improve on the natural history? Small, agile, fail fast kind of methodology.

    • I commented to some friends with MS who had MS and resided in the UK who tried to enroll in PROXIMUS. But I think some people are afraid to participate in clinical trials, whatever maybe because they feel as "guinea pigs"…
      I see a lot of complaints about studies with animal testing models, I also don't like this, but that's how science moves.
      If you don't test a substance, ir a hypothesis, you will not know if it really works or not, or if you screwed up the test process, etc …

  • Can you comment on MIS416? Seems like it is having success addressing innate immunity. I've been progressive for over 8 years and my neuro is pretty frustrated with my decision not to take Rituxan.

    • There is a presentation at AAN about this going through phase i s a option with so it is someway off becming available. If you are active then there is supportive evidence for any CD20

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