B101-07 Efdoralprin Alfa vs. Plasma-derived Alpha-1 Proteinase Inhibitor (pdA1PI) Augmentation Therapy in Adults With Alpha-1 Antitrypsin Deficiency (AATD) Emphysema: Results From Phase 2 ElevAATe Trial

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.