B cell depletion with ofatumumab and a new-kid-on the (CD20) block with the appearence of “Ubli” at ECTRIMS2021


Ofatumumab antibody depletes B cells. Sure it is going to deplete them T cells too . It depletes B cells, so no surprise there (see below). It is given every month to wipe away the B cells in the blood. What does it do to memory B cells? I have no idea but would say that it is likely.

What does it do to CD20 T cells…I probably would answer “I don’t care” but if the Guru of B cells II, is correct then I should.

Ofatumumab is a human antibody targeting human CD20 on B (and a few T cells). That is given as a monthly treatment injected under the skin. This can be given at home and this study shows an autoinjector, so abit like the autoinjector you use with beta interferons.

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study.Bar-Or A, Wiendl H, Montalban X, Alvarez E, Davydovskaya M, Delgado SR, Evdoshenko EP, Giedraitiene N, Gross-Paju K, Haldre S, Herrman CE, Izquierdo G, Karelis G, Leutmezer F, Mares M, Meca-Lallana JE, Mickeviciene D, Nicholas J, Robertson DS, Sazonov DV, Sharlin K, Sundaram B, Totolyan N, Vachova M, Valis M, Bagger M, Häring DA, Ludwig I, Willi R, Zalesak M, Su W, Merschhemke M, Fox EJ.Mult Scler. 2021 Oct 4:13524585211044479. doi: 10.1177/13524585211044479.

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS).

Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion.

Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed.

Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated.

Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

However the question is what happened once the trial was stopped. How quickly do cells come back. Based on what I have read , it is quicker than with ocrelizumab. However, will this be true after a few years of ofatumumab?

ProfG has made the case that “big” (large body Mass Index) people may be underdosed when it comes to controlling progression. Will this be the case with ofatumumab?

However there may be more CD20 choice and that is because ublituxumab (“ubli” as Prof Steinman named it) will be on the way soon, once approved by the regulators. Ubli is a chimeric antibody meaning it is three quarter human one quarter mouse abit like rituximab. It is engineered to enhance killing, so it does the job abit like ocrelizumab, but what advantage does it have over ocrelizumab?

This is given as an infusion too. However ocrelizumab is humanised (about 95% and 5% mouse) and so is less likely to make anti-drug antibodies than “ubli”. However we weren’t told about anti-drug antibodies in the presentation. It’s only hope is that it is very good at blocking antibody formation, but then it will block the COVID-19 vaccination.

It is dosed at 450mg and so only takes an hour for the infusion versus about 2 hour, historically it was 3.hours with ocrelizumab bit the quicker was approved last year.

Will this be priced below the other anti-CD20, to make it look attractive? This is not my concern. I am more interested in the science. Does it target memory B cells. I bet the answer is yes too

117 – Phase 3 results of the ULTIMATE I & II global studies: ublituximab versus teriflunomide in relapsing multiple sclerosis. Lawrence Steinman et al.

Introduction: Ublituximab (UTX), a novel monoclonal antibody (mAb) targeting CD20, is glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC), allowing for lower doses and 1-hour infusions after the first infusion.
Objectives: ULTIMATE I & II are identical Phase 3, randomized, multi-center, double-blind, active-control studies evaluating the efficacy/safety of UTX in patients with relapsing multiple sclerosis (RMS). Herein, for the first time, we report key study endpoints which include cognition, brain volume, multiple sclerosis functional composite (MSFC), and additional safety data.
Methods: Patients were randomized (1:1) to receive either 450mg UTX via a 1-hour intravenous infusion every 24 weeks (following day 1 infusion of 150mg) or 14mg oral teriflunomide once-daily for 96 weeks. Eligible patients had a diagnosis of RMS, an Expanded Disability Status Scale (EDSS) score of 0-5.5, and ranged in age from 18-55 years.
 1094 patients were randomized in 10 countries. In the ULTIMATE I (N=549) and II (N=545) studies, administration of UTX significantly reduced annualized relapse rate (ARR) by 59.4% (p<0.0001) and 49.1% (p=0.0022) relative to teriflunomide, respectively. Contrast enhancing T1 lesions were decreased by 96.7% and 96.5%, while new/enlarging T2 lesions decreased by 92.4% and 90.0%, respectively (p<0.0001 for all). A pooled analysis of confirmed disability improvement (CDI) over teriflunomide at 12 and 24 weeks both demonstrated significant improvement, with increases of 116% (p=0.0003) and 103% (p=0.0026), respectively. A pooled analysis of confirmed disability progression (CDP) from both ULTIMATE studies at 12 and 24 weeks showed a 15.7% (p=0.5099) and 34.3% (p=0.1716) reduction for UTX compared to teriflunomide. Rates of no evidence of disease activity (NEDA) increased by 197% (p<0.0001) and 277% (p<0.0001). UTX showed improvement on MSFC in both studies, 76.3% (p=0.0484) and 89.5% (p=0.0171). Additional data on cognitive impairment (SDMT) and brain volume metrics will be reported. Adverse events were as expected, with the most commonly reported adverse event for UTX being infusion-related reactions.
Conclusions: The favorable efficacy and safety results of ULTMATE I & II demonstrate the potential of UTX, the first 1-hour anti-CD20 infusion, in RMS patients.

COI multiple

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  • How did the debate on ECTIMS2021 about indefinite use of anti-CD20 go? Is there a video published or summary/results?

    • DrT kicked some Buttt and won hands down, but I suspect her opponent ProfP was really in the same camp….Roche no doubt scrubbed ProfG off their christmas card list for suggesting the title of the debate as I supect we are going to see more personalised dosing

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