Christine Xu1, Ying Liu1, Jennifer Sloane2, Remco Diab3, Hubert van Hoogstraten1, Hisham Abdallah4, Sreeraj Macha1 and Bhaskar Dasgupta5, 1Sanofi, Bridgewater, NJ, 2Sanofi, Cambridge, MA, 3Sanofi, Rotkreuz, Switzerland, 4Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 5Anglia Ruskin University, East Anglia, United Kingdom
Background/Purpose: Sarilumab blocks interleukin-6 (IL-6) from binding to the membrane-bound and soluble IL-6 receptor-α subunit (IL-6Rα). Sarilumab is now approved for both rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) in adult patients. The objectives of the exposure-response (E-R) analyses presented here are to characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationships of sarilumab exposure with key efficacy, and safety endpoints in patients with PMR.
Methods: The SAPHYR study (NCT03600818) assessed the efficacy and safety of sarilumab in patients with steroid resistant active PMR. Patients were randomized (1:1) to 52 weeks of treatment with sarilumab 200 mg every 2 weeks (q2w) + 14 weeks glucocorticoid (GC) tapering regimen or placebo q2w + 52 weeks GC tapering regimen. In the E-R analyses, the efficacy endpoints included the primary endpoint of the proportion of patients achieving sustained remission at Week 52 and the cumulative proportion (%) of patients who had rescue GC therapy during the 52-week treatment period; the safety endpoints included treatment-emergent adverse events (TEAEs), serious adverse events, adverse events of special interest, and absolute neutrophil count (ANC). PK-PD relationships were assessed using descriptive E-R analyses for the efficacy and safety endpoints and were explored graphically for biomarkers (IL-6, total soluble [s] IL-6Rα and C-reactive protein [CRP]) using the observed steady state trough concentrations (Ctrough) of sarilumab at Week 24. Descriptive E-R analyses were conducted by tertiles of sarilumab steady-state Ctrough. Results were compared with results in patients with RA when appropriate.
Results: Greater sarilumab Ctrough in patients with PMR was associated with an increase in total sIL-6Rα and a decrease in CRP levels and was similar in patients with PMR and RA.
There was a slight increase in the proportion of patients achieving sustained remission from the low to the medium tertile. The treatment effect approached a plateau with increasing Ctrough. However, higher Ctrough was not associated with decreased need for rescue therapy. No clear E-R relationships were observed between increasing sarilumab Ctrough and a higher incidence of TEAEs. There was a greater ANC reduction with an increase in sarilumab Ctrough; however, the effect appeared to reach a plateau at ~20 mg/L. In contrast, no higher proportion of patients with ANC < 1.0 Giga/L in patients with increasing sarilumab Ctrough was observed. These results in patients with PMR were consistent with those observed in patients with RA.
Conclusion: The PK-PD relationship between sarilumab exposure and efficacy, and safety endpoints demonstrated that the pharmacodynamic effect of sarilumab appeared to reach a plateau at Ctrough levels of 20 to 25 mg/L for target saturation, supporting a sarilumab dose of 200 mg q2w for the treatment of patients with PMR.
C. Xu: Sanofi, 3, 11; Y. Liu: Sanofi, 3, 11; J. Sloane: Sanofi, 3, 11; R. Diab: Sanofi, 3, 11; H. van Hoogstraten: Sanofi, 3, 11; H. Abdallah: Regeneron Pharmaceuticals, Inc., 3, 11; S. Macha: Sanofi, 3, 11; B. Dasgupta: AbbVie, 5, Cipla, 6, Roche Chugai, 2, 5, 6, Sanofi, 2, 5.
