Background/Purpose

The pharmacokinetic (PK) and pharmacodynamic (PD) effects of two investigational monoclonal antibodies inhibiting type I IFN signaling –  sifalimumab or anifrolumab, specific for IFN-α or IFN-α receptor subunit 1 (IFNAR1), respectively were assessed in the blood of adult SLE Japanese patients. 

Methods

Two phase 2 randomized, open label, dose-escalation studies were conducted in adult Japanese patients with SLE – AZD2800C (sifalimumab; N=30) and AZD3461C (anifrolumab; N=17). Patients enrolled in both studies satisfied ACR classification criteria. AZD2800C included dose cohorts of 1, 3, and 10 mg/kg (mpk) administered intravenously (IV) every 4 weeks; 100 mg subcutaneously every 2 weeks; and 600 and 1200 mg IV every 4 weeks. AZD3461C included dose cohorts of 100, 300, and 1000 mg administered IV every 4 weeks. In both studies, blood specimens were collected for PK and PD assessment at multiple time points between predose and 169 days (anifrolumab) or 365 days (sifalimumab) after initial administration. Sifalimumab and anifrolumab concentrations were measured using a validated electrochemiluminescence assay and PK parameters were determined by noncompartmental analysis. Transcript profiling was conducted with qRT-PCR on a 21 IFN gene signature (IFNGS). 

Results

Sifalimumab exhibited linear pharmacokinetics with a half-life of about 20 days while, anifrolumab exhibited nonlinear pharmacokinetics. Trough concentrations of both sifalimumab and anifrolumab reached steady state by Day 84. In AZD2800C and AZD3461C, 97% and 88% of patients had elevated IFNGSs at baseline, respectively. In AZD2800C, maximum median suppression of the IFNGS was 63% with 1 mpk, 48% with 3 mpk, 67% with 10 mpk, 37% with 100 mg SC, 76% with 300 mg, and 61% with 1200 mg and was observed within 1 to 3 days of dosing with sifalimumab.  In AZD3461C, maximum median suppression of the IFNGS by anifrolumab was 6% in the 100 mg (day 85), 85% (day 169) in the 300 mg, and 97% (day 85) in the 1000 mg cohort, with sustained suppression (>70% and >95%) in the 300 and 1000 mg cohorts after days 141 and 29, respectively. The level of suppression correlated well with increased anifrolumab concentrations.  There were no major safety issues in the small sifalimumab  and anifrolumab Japanese open-label trials (AZD2800C and AZD3461C, respectively) at the dose regimens studied but there is inadequate data to fully characterize the safety profile adequately and overall safety needs to be confirmed in larger double-blind controlled studies.

Conclusion

Both sifalimumab and anifrolumab showed expected mechanism of action in SLE, with anifrolumab having increased and more sustained target suppression of the IFNGS in Japanese SLE patients compared to sifalimumab.

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ACR Meeting Abstracts - http://acrabstracts.org/abstract/target-modulation-of-a-type-i-interferon-ifn-gene-signature-with-sifalimumab-or-anifrolumab-in-systemic-lupus-erythematosus-sle-patients-in-two-open-label-phase-2-japanese-trials/