Relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with systemic lupus erythematosus

Yen Lin Chia, Jianchun Zhang, Raj Tummala, Tomas Rouse, Richard A Furie, Eric F Morand, Yen Lin Chia, Jianchun Zhang, Raj Tummala, Tomas Rouse, Richard A Furie, Eric F Morand

Abstract

Objectives: To characterize the relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with moderate to severe SLE despite standard therapy, using pooled data from two phase 3 trials.

Methods: TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks). For the exposure-response analysis, BILAG-based Composite Lupus Assessment (BICLA) or SLE Responder Index [SRI(4)] response rates at week 52 in each quartile/tertile of average anifrolumab serum concentration (Cave) were compared for anifrolumab and placebo in all-comers, patients who completed treatment, and IFN gene signature (IFNGS)-high patients who completed treatment, using average marginal effect logistic regression. Relationships between exposure and key safety events were assessed graphically.

Results: Of patients in TULIP-1/TULIP-2 who received anifrolumab (150 mg, n = 91; 300 mg, n = 356) or placebo (n = 366), 574 completed treatment, of whom 470 were IFNGS high. In the exposure-efficacy analyses, BICLA and SRI(4) treatment differences favouring anifrolumab 300 mg vs placebo were observed across Cave subgroups and all analysis populations. Logistic regression identified Cave as a significant covariate for predicted BICLA response, as higher anifrolumab Cave predicted greater efficacy. There was no evidence of exposure-driven incidence of key safety events through week 52 in patients receiving anifrolumab 150 or 300 mg.

Conclusion: While higher Cave predicted greater efficacy, consistent positive benefit favouring anifrolumab 300 mg vs placebo was observed in BICLA and SRI(4) responses across Cave subgroups in the TULIP trials. There was no evidence of exposure-driven safety events.

Clinicaltrial.gov numbers: NCT02446912, NCT02446899.

Keywords: anifrolumab; autoimmunity; biologic therapies; clearance; efficacy; exposure–response; population pharmacokinetics; safety; systematic lupus erythematosus.

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Figures

Fig . 1
Fig. 1
BICLA response at week 52 by analysis of populations in TULIP-1 and TULIP-2 Data were from the pooled exposure–response analysis set. Response rates and treatment difference for BICLA were calculated using the AME approach based on logistic regression models by treating quartile/median groups along with placebo group as one covariate, and stratification factors by SLEDAI-2K score at screening (vs ≥10 points), day 1 glucocorticoid dose (<10 mg/day vs ≥10 mg/day prednisone or equivalent), and type I IFNGS at screening (high vs low), whenever applicable. Tertiles (µg/ml) were defined as: G1 <31.2, G2 ≥31.2 to <43.8 and G3 ≥43.8; quartiles (µg/ml) were defined as: Q1 <27.6, Q2 ≥27.6 to <39.2, Q3 ≥39.2 to <49.8 and Q4 ≥49.8. AME: average marginal effect; BICLA: BILAG-based Composite Lupus Assessment; G: tertile; IFNGS: type I IFN gene signature; n: number of patients; N: number of patients in group; Q: quartile; SLEDAI-2K: SLE Disease Activity Index 2000.
Fig . 2
Fig. 2
Predicted BICLA response at week 52 in all patients and IFNGS-high patients who completed treatment Data were from the pooled exposure–response analysis set. Two hundred and twenty-seven IFNGS-high patients receiving placebo were included in the model but are not shown; Cave was set to 0 μg/ml. (A) All patients; (B) IFNGS-high patients. BICLA: BILAG–based Composite Lupus Assessment; Cave: average serum concentration; IFNGS: type I IFN gene signature; n: number of patients; Obs: observed; SLEDAI-2K: SLE Disease Activity Index 2000.
Fig . 3
Fig. 3
SRI(4) response at week 52 by analysis populations in TULIP-1 and TULIP-2 Data were from the pooled exposure–response analysis set. Response rates and treatment difference for SRI(4) were calculated using the AME approach based on logistic regression models by treating quartile/median groups along with placebo group as one covariate, and stratification factors by SLEDAI-2K score at screening (vs ≥10 points), day 1 oral glucocorticoid dose (<10 mg/day vs ≥10 mg/day prednisone or equivalent) and type I IFNGS at screening (high vs low), whenever applicable. Tertiles (µg/ml) were defined as: G1 <31.2, G2 ≥31.2 to <43.8 and G3 ≥43.8; quartiles (µg/ml) were defined as: Q1 <27.6, Q2 ≥27.6 to <39.2, Q3 ≥39.2 to <49.8 and Q4 ≥49.8. AME: average marginal effect; G: tertile; IFNGS: type I IFN gene signature; n: number of patients; N: number of patients in group; Q: quartile; SLEDAI-2K: SLE Disease Activity Index 2000; SRI(4): SLE Responder Index of ≥4.
Fig . 4
Fig. 4
Predicted SRI(4) response at week 52 in all patients and IFNGS-high patients who completed treatment Data were from the pooled exposure–response analysis set. Two hundred and seventy-six placebo patients (A) and 227 IFNGS-high placebo patients (B) from pooled TULIP trials who completed the treatment were included in the model but are not shown; Cave was set to 0 μg/ml. Cave: average serum concentration; IFNGS: type I IFN gene signature; n: number of patients; Obs: observed; SLEDAI-2K: SLE Disease Activity Index 2000; SRI(4): SLE Responder Index ≥4.
Fig . 5
Fig. 5
Incidence of key adverse events by PK medians/quartiles in all-comers in TULIP-1 and TULIP-2 Data were from the pooled exposure–response analysis set. The overall incidence rate included the patients excluded from the exposure–response analysis set. (A) Herpes zoster; (B) non-opportunisitic serious infections; (C) infusion-related reactions; (D) hypersensitivity. Cave: average anifrolumab concentrations up to the first incidence of serious infection or end of treatment; Cmax: latest anifrolumab peak concentrations at the end of infusion prior to first incidence of infusion-related events or end of treatment; n: number of patients; PK: pharmacokinetic.

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