Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study

Amit Bar-Or, Heinz Wiendl, Xavier Montalban, Enrique Alvarez, Maria Davydovskaya, Silvia R Delgado, Evgeniy P Evdoshenko, Natasa Giedraitiene, Katrin Gross-Paju, Sulev Haldre, Craig E Herrman, Guillermo Izquierdo, Guntis Karelis, Fritz Leutmezer, Miroslav Mares, Jose E Meca-Lallana, Dalia Mickeviciene, Jacqueline Nicholas, Derrick S Robertson, Denis V Sazonov, Kenneth Sharlin, Bharathy Sundaram, Natalia Totolyan, Marta Vachova, Martin Valis, Morten Bagger, Dieter A Häring, Inga Ludwig, Roman Willi, Martin Zalesak, Wendy Su, Martin Merschhemke, Edward J Fox, Amit Bar-Or, Heinz Wiendl, Xavier Montalban, Enrique Alvarez, Maria Davydovskaya, Silvia R Delgado, Evgeniy P Evdoshenko, Natasa Giedraitiene, Katrin Gross-Paju, Sulev Haldre, Craig E Herrman, Guillermo Izquierdo, Guntis Karelis, Fritz Leutmezer, Miroslav Mares, Jose E Meca-Lallana, Dalia Mickeviciene, Jacqueline Nicholas, Derrick S Robertson, Denis V Sazonov, Kenneth Sharlin, Bharathy Sundaram, Natalia Totolyan, Marta Vachova, Martin Valis, Morten Bagger, Dieter A Häring, Inga Ludwig, Roman Willi, Martin Zalesak, Wendy Su, Martin Merschhemke, Edward J Fox

Abstract

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.

Keywords: Ofatumumab; autoinjector pen; bioequivalence; multiple sclerosis; pharmacokinetics; pre-filled syringe.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.B-O. reports grants and personal fees from Biogen Idec and Genentech; and personal fees from Atara Biotherapeutics, Brainstorm, Celgene/Receptos, GlaxoSmithKline, Janssen/Actelion, MAPI Pharma, MedImmune, Merck/EMD Serono, Novartis, Roche, and Sanofi Genzyme, outside the submitted work. H.W. reports grants and personal fees from AbbVie, Biogen, Merck Serono, and Sanofi Genzyme; personal fees from Actelion, Alexion, Evgen, F. Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Immunic, Lundbeck, MedDay Pharmaceuticals, Novartis, Roche Pharma AG, Teva, and WebMD Global; and grants from Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, European Union, Fresenius Foundation, German Ministry for Education and Research (BMBF), GlaxoSmithKline, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, NRW Ministry of Education and Research, PML Consortium, RE Children’s Foundation, and Swiss MS Society, outside the submitted work. X.M. reports personal fees and non financial support from Actelion, Biogen, Celgene, Excemed, F. Hoffmann-La Roche, Merck Serono, MSIF, National Multiple Sclerosis Society (NMSS), Novartis, Sanofi Genzyme, and Teva, outside the submitted work. E.A. reports compensation for activities such as advisory boards, lectures, and consultancy from Actelion/Janssen, Alexion, Bayer, Biogen, Celgene/Bristol Myers Squibb, EMD Serono/Merck, Genentech/Roche, Genzyme, Novartis, Sanofi, and TG Therapeutics; and research support from Biogen, Genentech/Roche, National Institutes of Health (NIH), NMSS, Novartis, Patient-Centered Outcomes Research Initiative, Rocky Mountain MS Center, and TG Therapeutics. M.D. reports grants and consulting or speaking fees from Biogen Idec, Celgene/Receptos, Janssen/Actelion, Merck/EMD Serono, Novartis, Roche, and Sanofi Genzyme; S.R.D. reports grants and consulting fees from Novartis; and grants from MAPI Pharma, NIH/NINDS, and NMSS, outside the submitted work. E.P.E. reports grants and consulting or speaking fees from Biogen Idec, Celgene/Receptos, Janssen/Actelion, MedImmune, Merck/EMD Serono, Novartis, Roche, and Sanofi Genzyme. N.G. reports grants and consulting fees from Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. K.G-P. reports grants and consulting fees from Merck/EMD Serono, Novartis, Roche, Sanofi Genzyme, and Teva. S.H. reports grants and consulting fees from Merck/EMD Serono, Roche, Sanofi Genzyme, and Teva. C.E.H. has nothing to disclose. G.I. reports receiving fees for participating in speaker bureaus and/or advisory boards from Actelion, Bayer, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi, and Teva. G.K. has nothing to disclose. F.L. reports grants and personal fees from Biogen and Novartis; and personal fees from Celgene, MedDay, Merck, Roche, Sanofi Genzyme, and Teva. M.M.1 has nothing to disclose. J.E.M-L. reports grants and consulting or speaking fees from Almirall, Biogen, Bristol Myers Squibb, Genzyme, Merck, Novartis, Roche, and Teva. D.M. reports grants and consulting fees from Merck/EMD Serono, Novartis, Roche, and Sanofi Genzyme, outside the submitted work. J.N. reports grants and consulting fees from Alexion, Biogen Idec, Genentech, Genzyme, and Novartis; consulting fees from EMD Serono and Greenwich Biosciences; and speaking fees from Biogen Idec, Consortium of Multiple Sclerosis Centers (CMSC), EMD Serono, Genentech, Novartis, and Viela Bio. D.S.R. reports grant support from Janssen, MedDay Pharmaceuticals, Patient-Centered Outcomes Research Institute, and TG Therapeutics; grants and personal fees from Biogen, EMD Serono, Genentech, Mallinckrodt, Novartis, Prime CME, and Sanofi Genzyme; and personal fees from Alexion, Bristol Myers Squibb, CMSC, and Multiple Sclerosis Association of America. D.V.S. reports personal fees from BIOCAD and Novartis. K.S. reports receiving fees for participating in speakers bureaus from AbbVie and Biohaven Pharmaceuticals. B.S. has nothing to disclose. N.T. reports institutional research fees and personal fees from Actelion/Janssen, Alexion, BIOCAD (Russia), Generium (Russia), MAPI Pharma, Merck, Novartis, Receptos, Roche, Sanofi, and TG Therapeutics. M.V.1 reports speaker fees and consultant fees from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. M.V.2 reports compensation for travel, speaker fees, and consultant fees from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. M.B., D.A.H., I.L., R.W., M.Z., W.S., and M.M.2 are employees of Novartis Pharma AG. E.J.F. reports compensation for research, consulting, speakers bureau, and/or advisory work from AbbVie, Alexion, Biogen, Bristol Myers Squibb, Chugai, EMD Serono, Genentech/Roche, MedDay, Novartis, Sanofi Genzyme, and TG Therapeutics.

Figures

Figure 1.
Figure 1.
APLIOS patient flow chart. One patient in the PFS-abdomen group discontinued the study following a Grade-2 AE (blood IgM level decreased). Two patients in the PFS-abdomen group, including the patient who discontinued the study, did not contribute to the bioequivalence analysis because they missed the dose at Week 8 and had no data available for the dosing interval (Weeks 8–12). AE: adverse event; AI: autoinjector; PFS: pre-filled syringe; PK, pharmacokinetic.
Figure 2.
Figure 2.
Plasma concentrations of ofatumumab by nominal visit. The blue vertical arrows indicate the timing of dose administration. The shaded region indicates the Week 8−12 dosing interval that was considered for bioequivalence testing. AI: autoinjector; PFS: pre-filled syringe.
Figure 3.
Figure 3.
(a) Median number of B-cells over 12 weeks with subcutaneous ofatumumab 20 mg (N = 284), (b) proportion of patients with B-cells < 10 µL over time (N = 284), and (c) proportion of patients with B-cells < 10 µL over time stratified by body-weight quartile. The blue vertical arrows indicate the timing of dose administration. The analysis considered data until 30 days after the last injection. The shaded bands in parts (a) and (b) are 95% confidence intervals calculated using the Clopper–Pearson method. Q: quartile.
Figure 4.
Figure 4.
(a) Number of new or persistent Gd+ T1 lesions and (b) proportion of patients free of Gd+ T1 lesions over 12 weeks with ofatumumab treatment. Pre-dose MRI assessments are displayed as time 0 on the x-axis. The analysis considers scans collected until 30 days after the last injection date. Gd+ T1 lesion counts from scans collected in the 14 days after termination of steroid therapy are excluded from the analysis. The shaded bands are 95% confidence intervals calculated (a) from bootstrap and (b) using the Clopper–Pearson method. Gd+: gadolinium-enhancing.

References

    1. Hauser SL, Bar-Or A, Cohen JA, et al.. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med 2020; 383: 546–557.
    1. Hauser SL, Bar-Or A, Comi G, et al.. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376: 221–234.
    1. Hauser SL, Waubant E, Arnold DL, et al.. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358: 676–688.
    1. Du FH, Mills EA, Mao-Draayer Y. Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. Auto Immun Highlights 2017; 8: 12.
    1. Kaplon H, Reichert JM. Antibodies to watch in 2021. MAbs 2021; 13(1): 1860476.
    1. Lin TS. Ofatumumab: A novel monoclonal anti-CD20 antibody. Pharmgenomics Pers Med 2010; 3: 51–59.
    1. Engelberts PJ, Voorhorst M, Schuurman J, et al.. Type I CD20 antibodies recruit the B cell receptor for complement-dependent lysis of malignant B cells. J Immunol 2016; 197: 4829–4837.
    1. Semple KM, Gonzaléz CM, Zarr M, et al.. Evaluation of the ability of immune humanized mice to demonstrate CD20-specific cytotoxicity induced by ofatumumab. Clin Transl Sci 2019; 12(3): 283–290.
    1. Samjoo IA, Worthington E, Drudge C, et al.. Comparison of ofatumumab and other disease-modifying therapies for relapsing multiple sclerosis: A network meta-analysis. J Comp Eff Res 2020; 9(18): 1255–1274.
    1. Cohen JA, Coles AJ, Arnold DL, et al.. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012; 380: 1819–1828.
    1. Coles AJ, Twyman CL, Arnold DL, et al.. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839.
    1. Kapoor R, Ho PR, Campbell N, et al.. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): A phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol 2018; 17(5): 405–415.
    1. Polman CH, O’Connor PW, Havrdova E, et al.. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910.
    1. Genentech Inc. Ocrevus (prescribing information). San Francisco, CA: Genentech, Inc., (2017, accessed 28 January 2021).
    1. European Medicines Agency. International Conference on Harmonisation: Guideline for good clinical practice E6(R2), (2016, accessed 28 January 2021).
    1. World Medical Association. WMA Declaration of Helsinki—ethical principles for medical research involving human subjects, (2018, accessed 4 November 2020).
    1. Polman CH, Reingold SC, Banwell B, et al.. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2): 292–302.
    1. Lublin FD, Reingold SC, Cohen JA, et al.. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014; 83: 278–286.
    1. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, (2017, accessed 12 March 2020).
    1. US Food and Drug Administration. Guidance document: Statistical approaches to establishing bioequivalence, (2001, accessed 12 February 2020).
    1. Davit BM, Chen ML, Conner DP, et al.. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration. AAPS J 2012; 14(4): 915–924.
    1. Genentech. Ocrevus (Clinical Pharmacology and Biopharmaceutics Review). Genentech, (2016, accessed 9 November 2020).
    1. Kähäri L, Fair-Mäkelä R, Auvinen K, et al.. Transcytosis route mediates rapid delivery of intact antibodies to draining lymph nodes. J Clin Invest 2019; 129: 3086–3102.
    1. Theil D, Smith P, Huck C, et al.. Imaging mass cytometry and single-cell genomics reveal differential depletion and repletion of B-cell populations following ofatumumab treatment in cynomolgus monkeys. Front Immunol 2019; 10: 1340.
    1. Mayer L, Kappos L, Racke MK, et al.. Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies. Mult Scler Relat Disord 2019; 30: 236–243.
    1. Stoner KL, Harder H, Fallowfield LJ, et al.. Intravenous versus subcutaneous drug administration. Which do patients prefer? A systematic review. Patient 2015; 8: 145–153.
    1. Cramer JA, Cuffel BJ, Divan V, et al.. Patient satisfaction with an injection device for multiple sclerosis treatment. Acta Neurol Scand 2006; 113(3): 156–162.

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