The B-cell line up

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https://ars.els-cdn.com/content/image/1-s2.0-S2211034821000535-gr2_lrg.jpg
Figure: Anti-CD20s (A) rituximab (yellow), (B) ocrelizumab (red), (C) ofatumumb (green), (D) ublituximab (brown)

The B-cell line up for MS now reads: rituximab, ocrelizumab, ofatumumab, and ublituximab. A fair number of you believe that these four treatments embody some magical powers, but I am about to demystify some of these beliefs and explain the science behind them. The three main take away points fall under mode of action, efficacy, and side effects.

Firstly, they all target CD20 found on the surface of B cells leading to B-cell depletion (Figure above outlines their targets on the CD20 receptor).

Secondly, although there are no head to head studies, their efficacy as measured using MRI activity (GAD enhancing lesions) is similar. They all perform well.

Thirdly, the incidence of infections post-immunosuppression are similar across the groups: nasopharyngitis, upper respiratory tract infections and urinary tract infection being the commonest. B cell recovery occurs the quickest with ofatumumab. And mostly likely because of B-cell depletion, there is also a cancer read out; they are best avoided with a strong family history of cancers or previous malignancy.

If you’d like to know the specifics from the individual clinical trials for these drugs, Cotchett et al. have compile a comprehensive table for you:

Table 1. summary of clinical trial data

StudyStudy DesignEfficacyAdverse Effects
Clinical trials studying rituximab
Naismith et al.
(Naismith et al., 2010)
MS subtype: RMS
Trial design: 52-week, MRI blind, RTX add on, phase II trial for patients relapsing while on injectables
Subject groups:
30 subjects received 375 mg/m2 RTX IV weekly at weeks 1, 2, 3 and 4.
Baseline characteristics of patients:
Age, median:: 43.5 years (range: 20-53)
Disease duration, median: 7.5 years (range: 2-32)
EDSS, mean: 4.7
Number of Gd lesions, mean: 2.81
T2 lesion volume, mean: 25.87 cm3
MRI Measurements:
• 74% of post treatment MRI scans did not show GdE activity vs 26% of GdE activity free MRI scans at baseline.
• An 88% reduction was seen in the mean number of enhancing lesions per month with RTX.
• A 78% decrease in mean volume enhancing lesions per month was seen following RTX treatment.
Clinical Measurements:
• EDSS remained stable in 27 subjects. Improvements were seen in 7 subjects and a decline was seen in 2 subjects.
IRRs:
• 11/30 subjects had minor IRRs.
• 2/30 subjects had infusion related reactions that led them to discontinue the trial.
Hauser et al. (HERMES)
(Hauser et al., 2008)
ClinicalTrials.
gov number: NCT00097188
MS subtype: RRMS
Trial design: Phase II, randomized, double blind, 48-week trial
Subject groups:
69 subjects received 1000 mg IV RTX and
35 subjects received placebo on days 1 and 15
Baseline characteristics of patients:
Age, mean: 39.6-41.5 years
Time since diagnosis, mean: 6.2-6.9 years
EDSS, median: 2.5
Number of GdE lesions, mean: 0.3-2.1
MRI Measurements:
• A significant reduction was seen in counts of total and total new GdE lesions at weeks 12, 16, 20 and 24 compared to placebo.
• A 91% relative reduction in GdE lesions was seen in the RTX group.
• A greater reduction in the volume of T2 lesions was seen in the RTX group than the placebo group from baseline to weeks 24 and 36.
Clinical Measurements:
• Significantly less subjects in the RTX group had relapses at weeks 24 and 48 compared to placebo.
• The proportion of patients with relapses was lower in the RTX group at week 24 and week 48 compared to placebo.
IRRs:
• More subjects in the RTX group (78.3%) had AE in the 24 hours following the first infusion than seen in placebo group (40%).
Infections:
• Infections were reported in 71.4% of the RTX group and 69.6% of placebo.
• 2.9% of RTX group had infection associated serious adverse events compared of 5.7% of placebo.
Neoplasms:
• 1 case of malignant thyroid neoplasm was reported in the RTX group.
Hawker et al. (OLYMPUS)
(Hawker et al., 2009)
ClinicalTrials.
gov number: NCT00087529
MS subtype: PPMS
Trial design: Phase II/III, randomized, double-blind, placebo-controlled trial.
Subject groups:
• 292 subjects received 1,000 mg IV RTX and 147 subjects received placebo on weeks 0, 2, 24, 26, 48, 50, 72 and 74.
Baseline characteristics of patients:
Age, mean: 49.9 years
Time since diagnosis, mean: 4.0 years
EDSS, mean: 4.8
0 Total GdE lesions: 75.5% of patients
T2 lesion volume, mean: 9,173.25 mm3
MRI Measurements:
• Subjects in the RTX group had significantly less increase in T2 lesions volume from baseline to week 96 compared to placebo.
• Brain volume change was not significantly different between groups (p=0.62).
Clinical Measurements:
• No significant difference to CDP was found between groups (p=0.1442). However, subgroup analyses of subjects under 51 years of age or those with gadolinium lesions at baseline showed a delay in time to CDP compared to placebo (p=0.010, p=0.007, respectively)
IRRs:
• 67.1% of subjects in the RTX group experienced IRRs on first infusion, compared to 23.1% of placebo.
Infections:
• Total infection associated events & serious events were reported in 68.2% of the RTX group and 65.3% of the placebo group.
• Serious infections associated events were reported in 4.5% of RTX group and less than 1% of placebo.
Bar-Or et al.
(Bar-Or et al., 2008)
MS subtype: RRMS
Trial design: open label, 72-week, phase I trial.
Subject groups:
26 subjects received 1000 mg IV RTX on weeks 0, 2, 24 and 26.
Baseline characteristics of patients:
Age, mean: 40.4 years
Time since diagnosis, mean: 5.4 years
EDSS, mean: 2.3
Total Gd lesion count, mean: 1.3
T2 lesion volume, mean: 8566.4 mm3
MRI Measurements:
• The mean number of GdE lesions decreased from 1.31 at trial entry to 0.73 at week 4, 0.04 at week 48 and 0 at week 72.
• The mean number of new T2 lesions declined from 0.92 at week 4 to 0 at week 72.
Clinical Measurements:
• 80.8% of patients were relapse free during the 72-week period
• The mean relapse rate from baseline to week 24 was 0.25 and 0.22 from baseline to week 72.
IRRs:
• 65.4% of subjects experienced IRRs during the study.
• 42% of subjects had an IRR following the first infusion.
Infections:
• 61.5% of subjects experienced infection, all of which were mild to moderate.
Clinical trials studying ocrelizumab
Kappos et al.
(Kappos et al., 2011)
ClinicalTrials.
gov number: NCT00676715
MS subtype: RRMS
Trial design: phase II, randomized, double-blind, 48-week, placebo-controlled trial.
Subject subgroups:
subjects received 600 mg IV OCR (n=55), 2000 mg OCR (n=55), or placebo (n=54) in 2 doses on days 1 and 15. 54 subjects received IFN ß-1a once a week. At week 24 the placebo, 600 mg and IFN ß-1a groups received 600 mg OCR. The 2000 mg group received 1000 mg.
Baseline characteristics of patients:
Age, mean: 35.6- 38.1 years

Time since diagnosis, mean: 2.7- 4.4 years
EDSS, mean: 3.1-3.5
Absence of T1 GdE lesions: 49-66% of patients
T2 lesion volume, mean: 8951- 13973 mm3
MRI Measurements:
• At week 24 the number of GdE T1 lesions was 89% lower in the 600 mg group and 96% lower in the 2000 mg group.
• The number of new & persisting GdE lesions were significantly lower in both OCR groups than placebo.
• The change in total volume of T2 lesions was not significantly different between groups at week 24.
Clinical Measurements:
• Over 24 weeks the ARR was 80% lower in the 600 mg group and 73% lower in 2000 mg group.
IRRs:
• 35, 44, and 9 percent of subjects had IRRs following the first infusion in the 600 mg, 2000 mg and placebo groups respectively.
• IRRs were reported in 51.85% of placebo, 45.45% of 600 mg,
52.73% of 1000 mg, & 37.04% of IFN ß-1a
Infections:
• Incidence of serious infection were similar between both OCR groups and placebo. From weeks 0 to 24 serious infections occurred in 2% of the placebo group. From weeks 24 to 48, serious infections occurred in 2% of patients in the following groups: placebo, 600 mg OCR, and IFN ß-1a. No serious infections occurred in the 2,000 mg OCR group.
Neoplasms:
• 1 case of breast cancer and 1 case of squamous cell carcinoma were reported in the higher dose OCR group.
Hauser et al. (OPERA I & II)
(Hauser et al., 2017)
ClinicalTrials.
gov numbers: NCT01247324 and NCT01412333, respectively
MS subtype: RMS
Trial design: Two identical, parallel phase III, 96-week trials
Subject subgroups:
Across both trials, 827 subjects received 600 mg IV OCR every 24 weeks and 829 received 44 μg SQ IFN ß-1a 3 times per week for 96 weeks. All patients received 100 mg IV methylprednisolone before each infusion. Prophylaxis with analgesic or antipyretics and an antihistamine was recommended.
Baseline characteristics of patients:
Age, mean: 36.9-37.4 years
Time since diagnosis, mean: 3.71-4.15 years
EDSS, mean: 2.75-2.86
Absence of T1 GdE lesions: 57.5-61.9% of patients
T2 lesion volume, mean: 9.74-10.85 cm3
Normalized brain volume, mean: 1499.18-1503.90 cm3
MRI Measurements:
• The total mean number of T1 GdE lesions was 94% (OPERA I) and 95% (OPERA II) lower in the OCR groups.
• The total mean number of new or newly enlarged hyperintense T2 lesions was 77% (OPERA I) and 83% (OPERA II) lower in the OCR groups.
Clinical Measurements:
• The ARR was 46% (OPERA I) and 47% (OPERA II) lower with OCR.
• Across both trials, 9.1% of subjects in the OCR group had confirmed disease progression at 12 weeks (a 40% lower risk), vs 13.6% in IFN ß-1a.
IRRs:
• Across both trials, 34.3% of subjects in the OCR group experienced IRRs compared to 9.7% in IFN ß-1a.
Infections:
• 56.9% (OPERA I) & 60.2% (OPERA II) of OCR patients had infections vs IFN ß-1a 54.3% (OPERA I) & 60.2% (OPERA II). Most common infections: URI, nasopharyngitis & UTI.
• Serious infections occurred in 1.2% (OPERA I) and 1.4% (OPERA II) of the OCR group and 2.9% (OPERA I) and 2.9% (OPERA II) of the IFN ß-1a group.
Neoplasms:
• Across both trials, neoplasms were reported in 0.5% of the OCR group and 0.2% in the IFN ß-1a group. 2 of the cases in the OCR group were invasive ductal breast carcinoma.
• 5 additional neoplasms were reported in the open label extension period. 2 of these cases were breast cancer.
Montalban et al. (ORATORIO)
(Montalban et al., 2017)
ClinicalTrials.
gov number: NCT01194570
MS subtype: PPMS
Trial design: phase III, 120-week, double blind trial.
Subject subgroups: 488 received 600 mg IV OCR (as 2 × 300 mg infusions) 14 days apart every 24 weeks. 244 subjects received placebo at the same time points. All subjects were given 100 mg IV methylprednisolone prior to each infusion. Optional prophylactic analgesics or antipyretics and antihistamine was recommended.
Baseline characteristics of patients: Age, mean: 44.4-44.7 years
Time since diagnosis, mean: 2.8-2.9 years
EDSS, mean: 4.7
Absence of T1 GdE lesions: 72.5-75.3% of patients
T2 lesion volume, mean: 10.9-12.7 cm3
Normalized brain volume, mean: 1462.9-1469.9 cm3
MRI Measurements:
• The volume of hyperintense T2 lesions decreased by 3.4% in the OCR group and increased by 7.4% in placebo from baseline to week 120.
• A smaller percentage of brain volume loss from week 24 to week 120 was seen in the OCR group (0.90%) than in the placebo group (1.09%).
Clinical Measurements:
• 32.9% of OCR patients had 12 week confirmed disability progression compared to 39.3% of placebo.
• OCR group showed a 38.9% mean change from baseline to week 120 in the timed 25-foot walk compared to a 55.1% change in placebo.
IRRs:
• More subjects in the OCR group (39.9%) reported at least 1 IRR than those in placebo group (25.5%).
Infections:
• 71.4% of OCR patients had infections vs 69.9% of placebo. Most common nasopharyngitis, UTI, influenza & URI.
• Serious infections occurred in 6.2% of OCR group and 5.9% of placebo group.
Neoplasms:
• Neoplasms were found in 2.3% of subjects in the OCR group and 0.8% of placebo. In OCR, 4 of the 11 cases were of breast cancer.
• 2 additional cases of neoplasm were detected during the open label extension phase.
Clinical trials studying ofatumumab
Sorensen et al.
(Sorensen et al., 2014)
ClinicalTrials. gov number: NCT00640328
MS subtype: RRMS
Trial design: phase II, randomized, double- blind, 48-week, placebo-controlled study.
Subject subgroups: subjects received 2 IV OFA infusions (100 mg, n=8; 300 mg, n=11; or 700 mg, n=7) or placebo (n=12) 2 weeks apart. At week 24 subjects underwent alternate treatment.
All subjects received Acetaminophen, an antihistamine & a corticosteroid prior to each infusion.
Baseline characteristics of patients:
Age, mean: 36.0-36.3 years
Time since diagnosis, mean: 1.7-3.8 years
EDSS, mean: 1.0-1.3
Number of new T1 GdE lesions: 0.2- 2.2
Number of new and/or enlarging T2 lesions: 0.3-1.5
MRI Measurements:
• Significant reductions in the number of new T1 GdE lesions, total T1 GdE lesions and new and/or enlarging T2 lesions were seen in the OFA groups compared to placebo from weeks 8 to 24.
• From weeks 8 to 24, the total number of T1 GdE lesions decreased by 99% from week 8 to 24 in the OFA group.
Clinical Measurements:
• 19% of patients in the OFA group relapsed from weeks 0 to 24 compared to 25% of placebo.
IRRs:
• IRRs were more common in the OFA group than in placebo. The most common IRR was rash.
Infections:
• Infections were reported in 38.5% of OFA subjects and 50% of placebo subjects from weeks 0 to 24.
• One serious infection (Influenza) occurred in the placebo group during the first period of trial.
Bar-Or et al. (MIRROR)
(Bar-Or et al., 2018)
ClinicalTrials. gov number: NCT01457924
MS subtype: RRMS
Trial design: phase IIb double-blind, 48-week study.
Subject subgroups:
34 subjects received 3 mg OFA every 12 weeks, 32 subjects received 30 mg every 12 weeks, 34 subjects received 60 mg every 12 weeks, 64 subjects received 60 mg every 4 weeks, 62 subjects received placebo. At week 12 the placebo group received 3 mg OFA.
Acetaminophen and an antihistamine were given prior to each injection.
Baseline characteristics of patients:
Age, mean: 37.2 years
Disease duration, mean: 4.38 years
MRI with active lesions (last 12 months): 43% of patients
MRI Measurements:
• A 65% reduction in the cumulative number of new GdE lesions in all OFA groups vs placebo from weeks 0 to 12.
• From weeks 4 to 12 the reduction in rate of new GdE lesions ranged from 71% to 92% across OFA groups vs placebo.
Clinical Measurements:
• Over the 24-week treatment period, 9% to 22% of subjects across OFA groups relapsed vs 25% of placebo.
IRRs:
• IRRs were reported in 52% of OFA subjects and 15% of placebo.
Infections:
• The incidence of infection was similar across treatment groups.
Neoplasms:
• 1 case of malignant melanoma in the 60 mg OFA group was reported in the follow up phase.
ASCLEPIOS I and II
(Hauser et al., 2020)
ClinicalTrials. gov number: NCT02792218
and NCT02792231,
respectively
MS subtype: RMS
Trial design: Two parallel, randomized double-blind, double-dummy, phase III trials.
Subject subgroups: Across both trials 946 subjects received 20 mg SQ OFA every 4 weeks after receiving 20 mg loading doses at days 1, 7 and 14. 936 subjects received 14 mg oral teriflunomide daily. Subjects in the OFA group received oral placebo and subjects in the teriflunomide group received SQ placebo. The first injection was given by a health care provider on the trial site. The following 2 injections were self-administered on the trial site under the supervision of a health care provider who trained patients on use. Ability to administer the injection had to be documented before patients were authorized to do so at home. Premedication with acetaminophen and/or antihistamines was recommended. Premedication with steroids was only recommended for the first injection.
Baseline characteristics of patients:
Age, mean: 37.8- 38.9 years
Time since diagnosis, mean: 5.48-5.77 years
EDSS, mean: 2.86-2.97
0 total T1 GdE lesions: 56.1-63.4% of patients
T2 lesion volume, mean: 12.0-14.3 cm3
Normalized brain volume, mean:1439-1446 cm3
MRI Measurements:
• The mean number of GdE lesions on T1-weighted MRI was 0.01 with OFA and 0.45 with teriflunomide in ASCLEPIOS I (97% relative reduction with OFA). The corresponding values in ASCLEPIOS II were 0.03 and 0.51 (94% relative reduction).
• Serum neurofilament light chain was 7% lower at 3 months, 27% lower at 12 months and 23% lower at 24 months than teriflunomide in ASCLEPIOS I. Corresponding values in ASCLEPIOS II were 11%, 26% and 24%.
• The annualized rate of brain volume loss did not differ significantly between subjects treated with OFA or teriflunomide (ASCLEPIOS I: -0.28% with OFA, -0.35% with teriflunomide. ASCLEPIOS II: -0.29% with OFA, -0.35% with teriflunomide).
Clinical Measurements:
• The adjusted ARR was 0.11 (50.5% relative reduction) in subjects given OFA and 0.22 in subjects given teriflunomide in ASCLEPIOS I (difference: -0.11). The corresponding values in ASCLEPIOS II were 0.10 (58.5% relative reduction) and 0.25 (difference: -0.15).
IRRs:
• IRRs were reported in 20.2% of OFA subjects vs 15.0% of teriflunomide subjects (placebo injection).
Infections:
• Serious infections occurred in 2.5% of OFA subjects and 1.8% of teriflunomide subjects.
• Appendicitis occurred in 8 (0.8%) patients who received OFA and 2 (0.2%) patients who received teriflunomide
Neoplasms:
• Neoplasms were detected in 0.5% of OFA subjects. One case each of malignant melanoma in situ, recurrent non-Hodgkin’s lymphoma, invasive breast carcinoma and two cases of basal cell carcinoma. Neoplasms were detected in 0.4% of teriflunomide subjects. Once case each of cervical carcinoma and fibrosarcoma and two cases of basal cell carcinoma.
Clinical Trials with Ublituximab
Fox et al.
(Fox et al., 2020)
ClinicalTrials. gov number: NCT02738775
MS subtype: RMS
Trial design: Phase II, 48-week, placebo-controlled trial.
Subject subgroups:
Subjects received 3 UTX infusions (150 mg over 1-4 hours on day 1 and 450-600 mg over 1-3 hours on day 15 and week 24) in 6 dosing cohorts.
• 36 subjects received UTX. 13 subjects received placebo. Subjects in the placebo group received UTX after the placebo phase.
• An oral antihistamine and an oral corticosteroid were administered 30 minutes prior to UTX.
Baseline characteristics of patients:
Age, mean: 40 years
Disease duration, mean: 7.7 years
EDSS, mean: 2.44
Number of GdE lesions, mean: 3.63
T2 lesion volume, mean: 14.87 cm3
MRI Measurements:
• At weeks 24 and 48 no new or persisting T1 GdE lesions were seen in any patients.
• A 10.6% decline in volume of T2-weighted lesions was seen by week 48.
Clinical Measurements:
• 93% of subjects were relapse free during the study.
• 17% of subjects met criteria for 24-week confirmed disability improvement.
IRRs:
• 50% of patients experienced IRRs. All IRRS were grade 1 or 2 in severity.
•77% of the 141 UTX infusions did not result in an IRR.
Infections:
• The most common infection was upper respiratory tract infection, occurring in 15% of subjects.

Abbreviations: MRI= magnetic resonance imaging, IV= intravenous, SQ= subcutaneous, IRRs= Infusion/Injection related reactions, ARR= annualized relapse rate, GdE= Gadolinium enhancing, RTX= rituximab, OCR= ocrelizumab, OFA=ofatumumab, UTX= ublituximab, EDSS= expanded disability status scale, clinical disease progression= CDP.

Abstract

Mult Scler Relat Disord. 2021 Jan 22;49:102787. doi: 10.1016/j.msard.2021.102787. Online ahead of print.

Comparison of the Efficacy and Safety of Anti-CD20 B Cells Depleting Drugs in Multiple Sclerosis

Kelly R CotchettBonnie N Dittel Ahmed Z Obeidat

Rituximab, ocrelizumab, ofatumumab and ublituximab are disease modifying therapies (DMT) currently used in the treatment of multiple sclerosis (MS) or are in advanced stages of clinical trials. These monoclonal antibodies deplete B cells by targeting the cell surface protein CD20. This review highlights the similarities and major differences between the four agents. We summarize data from various clinical trials of each of these therapeutics and discuss their efficacy and safety. Additional considerations regarding the route of administration and cost are presented. Among the four therapeutics, only ocrelizumab is approved for primary progressive (PP) MS. Infusion/injection related reactions (IRRs) are the most common adverse events associated with all four therapeutics. In phase III trials of ocrelizumab and ofatumumab, the incidence of IRRs was lower with ofatumumab. Ofatumumab is unique among the four therapeutics due to its availability as a subcutaneous injection (SQ). Although SQ administration may be appealing for some patients it may raise concerns regarding medication compliance among physicians. Phase II trials studying ublituximab for the treatment of RMS yielded promising results. Phase III trials are currently comparing the efficacy of ublituximab to teriflunomide.

About the author

Neuro Doc Gnanapavan

7 comments

  • Hi

    Are there any medium to long term side effects to B cell depleting drug use? Such as a lag or black spot for memory B cells.

    And are there any studies into short course on B cell depletion therapy’s around 2/3 years then move onto a DMT that may have less medium/longer term side effects.

    Regards

    • Are there…Answer is yes. There are side effects for all teatments..one is concerned about infection risks. The study I would like to see is 1-2 years on DMT and then watch and wait maybe someone will fund the ADIOS trial.

      • My use of there and their 🙈

        Yes makes sense due to B cell depletion therapy’s effectiveness at shutting down inflammation as you know, then a monitor and or a maintenance or a therapy such as DMF after the course of B cell depletion more longer term.

        • “B cell depletion therapy’s around 2/3 years then move onto a DMT that may have less medium/longer term side effects.”

          The side effect from long term b cell therapy is just ms progression/secondary progressive state. Some people have been sold bill of goods that ocrevus/rituximab is the cure for ms..Hauser developed bcell therapies about year 2000 at UCSF and this is study is from his people and patient….”Onset of secondary progressive MS after long‐term rituximab therapy – a case report”

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221476/

          ” A fair number of you believe that these four treatments embody some magical powers, but I am about to demystify some of these beliefs and explain the science behind them. “..Neuro Doc Gnanapavan.

          ..NDG…No illusions from Prof. G…and myself…about the Emperor’s Clothes as we didn’t drink the Kool Aid..”Why-is-everyone-drunk-on-anti-cd20-kool-aid”

          https://multiple-sclerosis-research.org/2019/03/why-is-everyone-drunk-on-anti-cd20-kool-aid/

          • I think most of us on CD20 are quite familiar with this case. You should be aware this is a single case which does not necessarily indicate everyone’s disease course. Further, this case represents a different situation where CD20+ was administrated 10 years+ after onset. Last, the increasing number of T. spinal leasions could be interperated as diesease activity breakout – could be ADA than lack of long term efficacy.

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