Highlights
- •Ocrelizumab phase II trial extension data has 18-month post-drug follow-up.
- •Annualized relapse rate seems to remain low during the drug-free follow-up.
- •Infections and adverse events seem to be reduced during drug-free follow-up.
- •Extended interval dosing may be possible that maintains efficacy and allows for more successful vaccination to new infections.
- •Extended interval dosing may afford a drug-free pregnancy.
Abstract
Objective
Ocrelizumab inhibits relapsing multiple sclerosis when administered every six months.
Based on potential similar memory B cell depletion mechanisms with cladribine and
alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit
a duration of response exceeding the current licenced treatment interval.
Methods
Internet-located information from regulatory submissions and meeting reports relating
to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715)
were reviewed. This followed people (54–55/arm) with MS, who switched from placebo
or interferon-beta to ocrelizumab for three 600 mg treatment cycles (week 24, 48,
72) or people treated with ocrelizumab for four 600 mg treatment cycles (week 0–72),
followed by an 18 month treatment-free period.
Results
CD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion
of over 15 months. The reduced annualized relapse rate during the published efficacy
study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing
or T2 lesions detected in the treatment-free period. Importantly, within these extension
cohorts, there appeared to be fewer adverse events and infections events.
Conclusions
Ocrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment
cycles Therefore, it may be possible to reduce the frequency of dosing to maintain
efficacy, whilst limiting infection and other risks associated with continuous immunosuppression
and could allow more effective vaccination against new pathogens. Further studies
are now clearly required to determine whether this data is robust.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Multiple Sclerosis and Related DisordersAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study.Mult. Scler. 2019; 25: 235-245
- Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis.EBioMedicine. 2017; 16: 41-50
- Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of Alemtuzumab.JAMA Neurol. 2017; 74: 961-969
- Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.Brain. 2018; 141: 2834-2847
- Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial.Ann. Neurol. 2008; 63: 395-400
- Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis.Neurology. 2019; 93: e1778-e1786
- Experience with long-term rituximab use in a multiple sclerosis clinic.Mult scler J Exp Transl Clin. 2016; 2055217316672100
- Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.J Neurol. 2018; 265: 1199-1209
- Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions.Mult. Scler. 2019; 25 (65): 20-21
- Alemtuzumab depletion failure can occur in multiple sclerosis.Immunology. 2018; 154: 253-260
- Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program.PLoS ONE. 2014; 9: e87379
- Effects of ocrelizumab treatment in peripheral blood leukocyte subsets of primary progressive multiple sclerosis patients P686.Mult. Scler. 2019; 25 (S2): 341-342
- Ocrelizumab, a humanised anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomised, blinded, placebo-controlled, dose ranging study.Arth. Rheumatol. 2008; 58: 2652-2661
- Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study.Mult. Scler. 2018; 24: 1594-1604
- Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm.Curr. Opin. Neurol. 2018; 31: 233-243
- Week 144 results of a phase II, randomised, multicentre trial assessing the safety and efficacy of ocrelizumab in patients with relapsing-remitting multiple sclerosis (RRMS).Neurol. 2013; 80 (S31.004)
- Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.N Engl J Med. 2017; 376: 221-234
- Long-term reduction of relapse rate and confirmed disability progression after 5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis P590.Mult. Scler. 2018; 24: 285-286
- Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy.Neurology. 2017; 89: 1107-1116
- The human fetus and newborn: development of the immune response.Birth Defects Orig Artic Ser. 1983; 19: 289-294
- Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis.Neurology. 2019; 20: e133-e136
- Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity.Mult. Scler. Relat. Disord. 2020; 101468
- Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial.Lancet. 2011; 378: 1779-1787
- Long-term safety and efficacy of ocrelizumab in patients with relapsing–remitting multiple sclerosis: week 144 results of a Phase II, randomised, multicentre trial.Mult. Scler. J. 2012; 18: 140-141
- Less frequent rituximab retreatment maintains remission of neuromyelitis optica spectrum disorder, following long-term rituximab treatment.J. Neurol. Neurosurg. Psychiatry. 2018; (pii: jnnp-2018-318465)
- Pharmacokinetics, pharmacodynamics and exposure-response analyses of ocrelizumab in patients with multiple sclerosis.Neurol. 2019; 92: N4
- Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development.Clin. Dev. Immunol. 2008; 2008271363
- B cell depletion with ublituximab reshapes the T cell profile in multiple sclerosis patients.J. Neuroimmunol. 2019; 332: 187-197
- 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
- Fulminant hepatitis associated with echovirus 25 during treatment with ocrelizumab for multiple sclerosis.JAMA Neurol. 2019; 76: 866-867
- Tailoring B-cells depleting therapy in MS according to memory B-cells monitoring: a pilot study.Mult. Scler. 2019; 25 (P971): 509-510
Ocrevus European public assessment report. 7/01/2019 update. Summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf. Accessed 5 January 2020.
Ocrevus United States. New Drug Application. March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761053Orig1s000Lbl.pdf. Accessed 5 January 2020.
Ocrevus United States label. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label//761053lbl.pdf Accessed 5 January 2020.
- Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients.J. Immunol. 2014; 193: 580-586
- Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis.Arch. Neurol. 2010; 67: 707-714
- Features of Human CD3+CD20+ T Cells.J. Immunol. 2016; 197: 1111-1117
- Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis (S36.002).Neurology. 2018; 90: S36
- Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled.MR-monitored phase II trial. Neurology. 1997; 49: 351-357
- T-cell population changes and serious infection rates in the controlled periods of the pivotal phase III trials of ocrelizumab in multiple sclerosis P668.Mult. Scler. 2017; 23: 318-319
- Onset of secondary progressive MS after long-term rituximab therapy - a case report.Ann. Clin. Transl. Neurol. 2016; 4: 46-52
- WA21493-Phase II, multicenter, randomized parallel-group, partially blinded, placebo.Avonex® controlled dose finding study to evaluate the efficacy as measured by brain MRI lesions and safety of 2 dose regimens of ocrelizumab in patients with RRMS. 2016; (Report No. 1062910. March 2016)
- Extended interval dosing of natalizumab in multiple sclerosis.J. Neurol. Neurosurg. Psychiatry. 2016; 87: 885-889
- Disease-modifying therapies for relapsing-remitting and primary progressive multiple sclerosis: a cost-utility analysis.CNS Drugs. 2018; 32: 1145-1157
Article info
Publication history
Published online: June 08, 2020
Accepted:
June 8,
2020
Received in revised form:
June 1,
2020
Received:
March 14,
2020
Identification
Copyright
© 2020 Elsevier B.V. All rights reserved.
