https://doi.org/10.1177/1177392817737515 Drug Target Insights Volume 11: 1–3 © The Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1177392817737515 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Background and Introduction In March 2017, ocrelizumab (OCR) was approved by the Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis (MS) and primary-progressive multi- ple sclerosis. It is a humanized anti-CD20 monoclonal antibody (MAb) molecule that leads the MAb revolution in the treatment of MS. To understand OCR and its pharmacodynamics, a closer look at rituximab (RTX) helps one to decode OCR dosing. Published literature suggests that RTX is a chimeric (human/ murine) MAb directed against the human CD20 molecule1 and promotes cytotoxicity and apoptosis. It was approved by the FDA for the treatment of rheumatoid arthritis (RA) in 2006 and was the first therapeutic B-cell–depleting chimeric MAb to be used in MS with success. Diseases such as MS, RA, neuromyeli- tis optica/neuromyelitis optica spectrum disorder (NMO/ NMOSD), systemic lupus erythematosus, peripheral neuropa- thies, antimyelin-associated glycoprotein neuropathy, chronic inflammatory demyelinating polyneuropathy, subacute ataxic neuropathy without paraproteinemia, myasthenia gravis, opso- clonus-myoclonus syndrome, and inflammatory myopathies have been treated using anti-CD20 MAbs. Both OCR and RTX bind to an extracellular CD20 epitope on B cells whose binding site overlaps between each drug. Following CD19 cell counts as a surrogate marker for CD20 cells in the peripheral blood in patients with RA, NMOSD, and MS on RTX therapy helps us understand how the dosing of OCR dosing may be optimized in the treatment of MS. In general, RTX treatment produces a rapid depletion of CD20 cells from the circulation but does not directly target pro-B cells, their precursors, or plasma cells.2–3 As RTX interferes with flow cytometric analysis of CD20 cells, CD19 cells, which carry a similar expression profile, are typically used as surrogate markers to schedule reinfusion based on CD19 cell counts. It is thought that RTX binding to CD20 enables cells to mediate trogocytosis or “shaving” causing internalization of the RTX-CD20 complex and accompanying cell membrane through an Fcγ receptor–dependent mechanism4–5—this pro- cess is thought to interfere with the flow cytometric analysis of CD20 cells, and therefore, CD19 cell counts serve as the sur- rogate marker to monitor treatment efficiency of anti-CD20 cell therapies. The depth of B-cell depletion is variable among patients, but restoration of the B-cell repertoire takes between 9 and 12 months from the last perfusion of RTX.6 In patients with RA, treatment with RTX induces depletion of peripheral B lymphocytes, with many patients demonstrat- ing near complete depletion (CD19 counts are <20 cells/μL or below the lower limit of quantification) within 2 weeks after receiving the first dose of the drug. Some patients show periph- eral B-cell depletion that lasts for at least 6 months. Up to ~4% of patients with RA had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of RTX. Equally important, some patients may need more infusions than a 6-month re-administration schedule. The reconstitution of peripheral blood B cells after RTX therapy in patients with RA was noted after a mean of 8 months posttreatment.7 Anti-CD20 Cell Therapies in Multiple Sclerosis—A Fixed Dosing Schedule for Ocrelizumab is Overkill Jagannadha Avasarala1,2 1Department of Medicine, Division of Neurology, USC School of Medicine Greenville, Greenville, SC, USA. 2Department of Internal Medicine, Division of Neurology, USC School of Medicine and UMG-Neuroscience Associates, Greenville, SC, USA. ABSTRACT: Anti-CD 20 therapies have found significant uses in multiple sclerosis (MS). Based singularly on the accumulated evidence with the use of rituximab (RTX; Rituxan, Genentech, and Biogen) in neuroimmunological diseases, ocrelizumab (OCR; Ocrevus, Genentech) was developed as a treatment option for MS and selectively targets CD20 B cells, a cell surface antigen found on pre-B cells, mature, and memory B cells, but not on lymphoid stem cells and plasma cells. On the basis of indirect evidence, elimination of the antigen-presenting capabilities and antigen nonspecific immune functions of B cells appear to be central to the therapeutic efficacy of anti-CD20 B-cell therapies. An important question is this—Why does the drug need to be dosed at fixed intervals and not based on a measurable endpoint, such as tracking peripheral CD20 cell counts? There is minimal scientific validity in infusing the drug every 6 months particularly if CD20 cell counts are negligible in the peripheral blood. In this analysis, a case is made for following CD19 cell populations as a surrogate for CD20 cells on a monthly basis to guide OCR redosing parameters and does not follow a scheduled dosing parameter. KeywORDS: Ocrelizumab, Multiple Sclerosis, CD19/20 cells, anti-CD therapies, Rituxan, Dosing schedules, Ocrevus, Neuromyelitis optica spectrum disorder ReCeIVeD: June 30, 2017. ACCePTeD: September 4, 2017. PeeR ReVIew: Two peer reviewers contributed to the peer review report. Reviewers’ reports totaled 230 words, excluding any confidential comments to the academic editor. TyPe: Rapid Communication FunDIng: The author(s) received no financial support for the research, authorship, and/or publication of this article. DeClARATIOn OF COnFlICTIng InTeReSTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. CORReSPOnDIng AuTHOR: Jagannadha Avasarala, UMG-Neuroscience Associates, Greenville, SC 29615, USA. Email: javasarala@ghs.org 737515DTI0010.1177/1177392817737515Drug Target InsightsAvasarala research-article2017 https://uk.sagepub.com/en-gb/journals-permissions mailto:javasarala@ghs.org 2 Drug Target Insights In a study involving 107 patients with MS, 105 (98.1%) had at least 1 follow-up CD20 count after the first RTX adminis- tration and follow-up levels occurred at an average of 138.3 ± 121.4 days apart.8 The CD20 counts of patients who received 1000 mg with a concurrent 1000 mg dose 2 weeks later were above 0 by 6 months in 20% of patients, whereas 3% of patients had a CD20 count above 2% of baseline numbers. Of patients receiving a single RTX 1000 mg dose, 20% had a CD20 count above 0 by 6 months, and 5% of patients had >2% by 6 months. This small, observational study in one MS care clinic clearly showed how widely different the repopulation of CD20 counts were, suggesting that a fixed time scheduling is perhaps not optimal. Given the wide spectrum of unpredicta- ble B-cell suppression, it is impossible to predict how each individual patient would respond to RTX and what the opti- mal dosing interval ought to be in each patient. A more obvi- ous question is whether scheduled RTX infusions are required when CD20 counts are negligible—what is the target cell when counts are less than 20 cells/μL and what is the rationale for reinfusion? There are no hard data to support this treat- ment regimen. In another disease model, the treatment of NMO/NMOSD with RTX tightly scheduled every 6 to 9 months to prevent relapses was not globally successful either9–11 casting doubt on the theory that treatment protocols should follow a scheduled dosing pattern. In addition, Greenberg and colleagues9 retro- spectively reviewed RTX dosing in an NMO clinical cohort and concluded that patients should be redosed prior to evi- dence of B-cell reconstitution by CD20 counts which is prob- ably optimal and individualized. Pellkofer and colleagues also reviewed RTX experience in patients with NMO, and based on their results concluded that a fixed dosing schedule every 69 months was advisable.11 Studies have also shown that drugs such as RTX also deplete anti-CD20 T cells demonstrating that peripheral depletion of all CD20 cells contributes to suppression of disease.12 Taken together, studies in RA, MS, and NMOSD have demonstrated why a fixed dosing schedule with RTX may not be optimal. In the case of RTX, the package insert clearly notes that redosing for patients with RA is based on (1) clinical evaluation or (2) every 24 weeks. However, no such options exist for the use of OCR in patients with MS and dosing schedules are fixed. Discussion The scheduled dosing of OCR for both forms of MS is slated at 6-month intervals. Because OCR avidly targets CD20 cell populations and depletes them and as their numbers can be monitored by peripheral blood counts of CD19 cells, it remains poorly understood why OCR needs to be reinfused at sched- uled intervals regardless of CD20 cell counts. In addition, in up to 1% (12/1311) of all patients with MS in clinical trials, relapsing and primary-progressive types, antidrug antibodies (ADAs), and particularly neutralizing antibodies appeared in 2 patients, clearing OCR faster and rendering B-cell repletion quicker. This is one other reason why following CD20 cells are prudent. Additional validity and strength of my analysis come from the original data submitted to the Center for Drug Evaluation and Research as shown in Figures 1 and 2 which depict CD19 cell populations in clinical trials at <20 cells/μL, the lower limit of quantification, at 24 weeks postinfusion. These results are derived from the Clinical Pharmacology and Biopharmaceutics Review (application no. 761053Orig1s000), the document that was originally submitted to the FDA for evaluation and approval of Ocrevus. Finally, in the package insert for OCR, one of the statements warns not to administer subsequent doses if the separation between doses is not at least 5 months. This statement is pithy but ignores the fact that repopulation of CD20 cells could also remain undetectable at 6 months postinfusion. Hence, to correctly assess the need to reinfuse, following monthly CD19 cell counts is a small price to pay both in the scientific and literal sense. In addition, data on long-term OCR therapy are lacking and concern regarding prolonged B-cell depletion remains; these could come to light in postmarketing data. Figure 1. Median peripheral blood B-cell profiles following intravenous ocrelizumab (OCR) administration in subjects with rheumatoid arthritis in study ACT2847g. Avasarala 3 Specifically, OCR is an expensive biologic that promises to deliver clinical benefit. However, the long-term safety of repeated OCR treatment remains unknown and there is no scientific validity to giving the drug when CD20 cells are nonexistent in the periphery at counts below 20 cells/μL. Any effective treat- ment strategy that aims to minimize unnecessary patient expo- sure to the drug helps with patient safety and allows for significant cost savings to the patient and third-party payers. Therefore, the following recommendations are suggested. (1) If the disease activity stabilizes both clinically and from a radiological perspective, less frequent retreatment might be sufficient to prevent relapses, although the correlation between clinical/radiological criteria to disease activity is not a linear relationship and therefore must be individualized based on monthly CD20 cell counts by monitoring CD19 cells. (2) Alternatively, CD20 cell counts must be monitored monthly on a routine basis irrespective of clinical or radiological status and reinfusion of the drug carried out after the cell population rebounds to ≥20 cells/μL; this holds true also for patients who develop ADAs that can neutralize OCR activityin which case the CD19 cell count would repopulate. Author Contributions JA: Idea/conceptualization, data collection/collation and anal- ysis, as well as write-up of the manuscript and submission. R efeR enCes 1. Browning JL. B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov. 2006;5:564–576. 2. Edwards JC, Cambridge G. Prospects for B-cell-targeted therapy in autoim- mune disease. Rheumatol. (Oxford). 2005;44:151–156. 3. Hoyer BF, Manz RA, Radbruch A, Hiepe F. Long-lived plasma cells and their contribution to autoimmunity. Ann N Y Acad Sci. 2005;1050:124–133. 4. Beum PV, Kennedy AD, Williams ME, Lindofer MA, Taylor RP. The shaving reaction: rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes. J Immunol. 2006;176:2600–2609. 5. Pedersen AE, Jungersen MB, Pedersen CD. Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies. Immunology. 2011;133:239–245. 6. Dass S, Rawstron AC, Vital EM, Henshaw K, McGonagle D, Emery P. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum. 2008;58:2993–2999. 7. Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheuma- toid arthritis. Arthritis Rheum. 2006;54:613–620. 8. Barra ME, Soni D, Huy Vo K, Chitnis T, Stankiewicz JM. Experience with long-term rituximab use in a multiple sclerosis clinic [published online ahead of print October 9, 2016]. Mult Scler J Exp Transl and Clin. doi:10.1177/ 2055217316672100. 9. Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol. 2008;65: 1443–1448. 10. Greenberg BM, Graves D, Remington G, et al. Rituximab dosing and monitor- ing strategies in neuromyelitis optica patients: creating strategies for therapeutic success. Mult Scler J. 2012;18:1022–1026. 11. Pellkofer HL, Krumbholz M, Berthele A, et al. Long term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurol. 2011;76:1310–1315. 12. Palanichamy A, Jahn S, Nickles D, et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J of Immunol. 2014;193:580–586. Figure 2. Median B-cell count in study WA25046 (primary-progressive multiple sclerosis). OCR indicates ocrelizumab.