Abstract Rationale Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that can lead to reduced serum functional alpha-1 antitrypsin (fAAT), unopposed neutrophil elastase activity, lung damage, and emphysema. Current standard of care is weekly augmentation therapy with infused plasma-derived alpha-1 proteinase inhibitor (pdA1PI). Efdoralprin alfa (SAR447537), an AAT-Fc fusion protein with a longer half-life than pdA1PI, is a restorative recombinant therapy being investigated for AATD-associated emphysema. Methods ElevAATe (NCT05856331) was a phase 2, double-blind, randomized, active-control, parallel- group study evaluating the pharmacokinetics, pharmacodynamics, immunogenicity, and safety of efdoralprin alfa compared to pdA1PI (Zemaira) in adults with antigenic AAT 11μM and emphysema. Participants (N = 97) were randomized 2:2:1 to receive efdoralprin alfa 120mg/kg every-3-weeks (Q3W; n = 41), efdoralprin alfa 120mg/kg every-4-weeks (Q4W; n = 38), or pdA1PI at the FDA-approved dose of 60mg/kg weekly (n = 18) for 32 weeks. Randomization was stratified by baseline antigenic AAT levels and post-bronchodilator percent predicted forced expiratory volume in 1 second recorded at screening. The primary endpoint was change from baseline to steady-state in fAAT trough concentration (Ctrough), measured by anti-neutrophil elastase capacity. Key secondary endpoints were change from baseline to steady-state in fAAT average concentration (Cavg) and percentage of days with fAAT above the lower limit of normal (LLN) range during steady-state. Results All primary and key secondary endpoints were met by efdoralprin alfa Q3W and Q4W. Least squares (LS) mean change (95% confidence interval CI) in fAAT Ctrough was greater with efdoralprin alfa Q3W and Q4W (24.1μM 22.8μM, 25.3μM and 16.8μM 15.5μM, 18.1μM, respectively) than with pdA1PI (7.6μM 6.0μM, 9.3μM). LS mean difference of efdoralprin alfa Q3W and Q4W vs. pdA1PI was 16.4μM and 9.2μM, respectively (both p 0.0001). Median fAAT trough concentrations are reported (Figure). Significant improvements were observed in key secondary endpoints. LS mean change (95% CI) in fAAT Cavg was 32.9μM (31.7μM, 34.2μM) and 26.0μM (24.6μM, 27.3μM), respectively, for efdoralprin alfa Q3W and Q4W vs. 17.9μM (16.2μM, 19.6μM) for pdA1PI. Median days above LLN were 100% (efdoralprin alfa Q3W) and 89.3% (Q4W) vs. 40.8% (pdA1PI). Efdoralprin alfa Q3W and Q4W were well tolerated and demonstrated a safety profile comparable to pdA1PI. There were no treatment discontinuations due to treatment-emergent adverse events. Transient, non-neutralizing anti-drug antibodies against efdoralprin alfa were detected in 2/79 (2.5%) efdoralprin alfa-treated participants. Conclusions Efdoralprin alfa, a recombinant restorative therapy, significantly increased fAAT levels to the physiologically normal range compared to the weekly administered, standard-of-care augmentation therapy, while demonstrating a favorable safety profile. This abstract is funded by: Sanofi
Barjaktarevic et al. (Fri,) studied this question.