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 (C_trough) of sarilumab at Week 24. Descriptive E-R analyses were conducted by tertiles of sarilumab steady-state C_trough. Results were compared with results in patients with RA when appropriate.

Results: Greater sarilumab C_trough 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 C_trough. However, higher C_trough was not associated with decreased need for rescue therapy. No clear E-R relationships were observed between increasing sarilumab C_trough and a higher incidence of TEAEs. There was a greater ANC reduction with an increase in sarilumab C_trough; 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 C_trough 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 C_trough 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exposure-response-analysis-of-sarilumab-in-patients-with-polymyalgia-rheumatica/