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Abstract Number: 1398

Sarilumab and Tocilizumab Receptor Occupancy (RO), and Effects on C-Reactive Protein (CRP) Levels, in Patients with Rheumatoid Arthritis (RA)

Christine Xu1, Patrick Nolain 2, Qiang Lu 3, Anne Paccaly 4, Melitza Iglesias-Rodriguez 5, Gregory St John 6, Chad Nivens 4, Rafael Maldonado 7, Tomonori Ishii 8, Ernest Choy 9 and Vanaja Kanamaluru 3, 1Sanofi, Bridgewater, NJ, 2Sanofi-Aventis, Montpellier, France, 3Sanofi, Bridgewater, 4Regeneron Pharmaceuticals, Inc., Tarrytown, 5Sanofi Genzyme, Cambridge, MA, 6Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 7Pompeu Fabra University, Barcelona, Spain, 8Tohoku University Hospital, Sendai, Japan, 9Cardiff University School of Medicine, Cardiff, United Kingdom

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: C-reactive protein (CRP), IL-6R signaling, pharmacokinetics, rheumatoid arthritis (RA) and tocilizumab

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Session Information

Date: Monday, November 11, 2019

Session Title: RA – Treatments Poster II: Established Treatments

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: The in vitro binding affinity of sarilumab (KD 61.9 pM) for the human interleukin-6 receptor (IL-6R) is 15–22-fold higher than that of tocilizumab. This study evaluated the relationship between IL-6R receptor occupancy (RO), pharmacodynamic (PD) variables (eg CRP), and the potential clinical relevance of the differences between sarilumab and tocilizumab.

Methods: Binding to soluble IL-6R (sIL-6R) in vivo translates into the quasi-steady-state target-mediated drug disposition pharmacokinetics (PK) and indirect-response PD model with inhibition of elimination of sIL‑6R and unbound sIL-6R concentration for both sarilumab and tocilizumab. PK/PD models simulated sIL-6R RO over time for: sarilumab 200 and 150 mg subcutaneously (SC) once every 2 weeks (q2w); tocilizumab 162 mg SC q2w and once every week (qw); and tocilizumab 4 and 8 mg/kg intravenously (IV) once every 4 weeks (q4w). RO profiles were compared with changes in CRP levels following administration of sarilumab SC and tocilizumab IV in patients with RA (ASCERTAIN; NCT01768572); during the study period, 60.8% of patients receiving tocilizumab required a dose increase from 4 to 8 mg/kg IV q4w, based on clinical response.

Results: Sarilumab 200 mg SC q2w achieved >90% RO after the first dose, which was maintained over the dosing interval throughout the 24-week treatment period; at 150 mg SC q2w, RO was >90% from the second dose onwards. Tocilizumab 162 mg SC q2w achieved RO >90% after the first dose but this decreased to < 50% before the second dose. The RO for tocilizumab 4 mg/kg IV q4w was >99% after the first dose at Week 1 but decreased over the dosing interval to < 50% before the second dose. At trough steady state (Week 24), RO was greater with sarilumab 200 mg SC q2w (98%) and 150 mg SC q2w (94%) versus tocilizumab 162 mg SC q2w (84%) and 4 mg/kg IV q4w (60%). At the higher dose (8 mg/kg IV q4w) or dosing frequency (162 mg SC qw), tocilizumab maintained RO ≥99% at steady state, similar to sarilumab 200 mg SC q2w. CRP levels were inversely associated with RO at trough in patients with RA; the greatest suppression in CRP levels occurred with sarilumab SC (either dose) or with the tocilizumab 8 mg/kg IV q4w (Figure). Proportionally smaller CRP reductions were observed with tocilizumab 4 mg/kg IV q4w, consistent with the lower RO of tocilizumab at this dose.

Conclusion: The higher IL-6R binding affinity of sarilumab translated into higher RO and greater reduction in CRP levels when compared with tocilizumab. Sarilumab 200 mg SC q2w led to a rapid and sustained suppression of CRP over the 24-week treatment course; the higher dose (IV) or increased dosing frequency (SC) of tocilizumab was required to maintain the same degree of RO and CRP suppression. CRP may be a useful tool in clinical practice for patients treated with an IL-6R blocker.


Disclosure: C. Xu, Sanofi, 1, 3; P. Nolain, Sanofi, 1, 3; Q. Lu, Sanofi, 1, 3; A. Paccaly, Regeneron, 1, 3, Amgen, 1; M. Iglesias-Rodriguez, Sanofi Genzyme, 1, 3; G. St John, Regeneron, 1, 3, 4, Regeneron Pharmaceuticals, Inc, 1, 3; C. Nivens, Regeneron, 1, 3, 4; R. Maldonado, Sanofi, 2, 5, 8, Esteve, 2, 5, 8, Almirall, 2, 5, 8, GSK, 2, 5, 8, Boehringer, 2, 5, 8, Lundbeck, 2, 5, 8, Grünenthal, 2, 5, 8, UPSA, 2, 5, 8, Uphjon, 2, 5, 8, Uriach, 2, 5, 8, Ferrer, 2, 5, Janus, 2, 5, Aelis, 2, 4, 5, Spherium, 2, 5, Pharmaleads, 2, 5, BRAINco, 2, 5, Phytoplant, 2, 5, Rhodes, 2, 5, GW Pharma, 2, 5; T. Ishii, Abbvie, 8, Asahi, 8, Astellas, 8, Chugai, 8, Daiichi-Sankyo, 8, Eisai, 8, GSK, 2, 5, Janssen, 2, 5, 8, Kasei Pharma, 8, Mitsubishi-Tanabe, 8, Ono, 8, Pfizer, 8, Sanofi, 8, Takeda, 8, Teijin, 8, UCB, 8; E. Choy, AbbVie, 5, Abbvie, Roche, Chugai, Amgen, Eli Lilly, Janssen, Novartis, Regeneron, R-Pharm and Sanofi, 5, Amgen, 2, 5, 8, Amgen, Roche, Chugai, Bristol-Myers Squibb, Eli-Lilly Janssen, Pfizer, Regeneron, Sanofi and UCB., 8, AstraZeneca, 5, Bio-Cancer, 2, Bio-Cancer, Biogen, Novartis, Sanofi, Roche, Pfizer and UCB, 2, Biogen, 2, 5, BMS, 5, 8, Boehringer Ingelheim, 5, 8, Celgene, 5, Chugai Pharma, 2, 5, Eli Lilly, 5, 8, Ferring Pharmaceuticals, 2, 5, GSK, 5, Hospira, 5, 8, Janssen, 5, Jazz Pharmaceuticals, 5, Merck Sharp & Dohme, 5, 8, Merrimack Pharmaceutical, 5, Napp, 5, Novartis, 2, 5, 8, Novimmune, 2, 5, ObsEva, 5, Pfizer, 2, 5, 8, Regeneron, 5, 8, Roche, 2, 5, 8, R-Pharm, 5, Sanofi, 2, 5, 8, SynAct Pharma, 5, Tonix, 5, Union Chimique Belge, 2, 5, 8; V. Kanamaluru, Sanofi, 1, 3.

To cite this abstract in AMA style:

Xu C, Nolain P, Lu Q, Paccaly A, Iglesias-Rodriguez M, St John G, Nivens C, Maldonado R, Ishii T, Choy E, Kanamaluru V. Sarilumab and Tocilizumab Receptor Occupancy (RO), and Effects on C-Reactive Protein (CRP) Levels, in Patients with Rheumatoid Arthritis (RA) [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/sarilumab-and-tocilizumab-receptor-occupancy-ro-and-effects-on-c-reactive-protein-crp-levels-in-patients-with-rheumatoid-arthritis-ra/. Accessed January 28, 2023.
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