Sanofi (Nasdaq: SNY) reported Phase II data showing efdoralprin alfa, a recombinant human AAT-Fc fusion protein, outperformed standard-of-care plasma-derived augmentation therapy in normalizing functional alpha-1 antitrypsin levels in adults with alpha-1 antitrypsin deficiency-related (AATD) emphysema. Specifically, the Q3W dosing arm achieved mean trough increases more than three times greater than weekly plasma-derived therapy.
The ElevAATe trial is a double-blind, randomized, active-controlled Phase II study enrolling 97 adults with AATD-related emphysema, randomized 2:2:1 to efdoralprin alfa every three weeks, efdoralprin alfa every four weeks, or plasma-derived AAT augmentation therapy once weekly over 32 weeks.
The primary endpoint — mean change in serum functional AAT trough concentrations from baseline to steady state at week 32 — showed a least-squares mean increase of 24.1 µM (95% CI: 22.8–25.3) for the Q3W arm versus 7.6 µM (95% CI: 6.0–9.3) for the plasma-derived comparator (p < 0.0001). The Q4W arm produced a mean increase of 16.8 µM (95% CI: 15.5–18.1), also superior to the comparator (p < 0.0001).
On the key secondary endpoint measuring the proportion of days that steady-state functional AAT levels remained above the lower limit of the normal range (23.8 µM), the Q3W arm achieved 100% of days above threshold throughout the 32-week study, compared to 40.8% of days for patients receiving weekly plasma-derived augmentation therapy. The Q4W arm achieved 89.3% of days above threshold. All key secondary endpoints met statistical significance at p < 0.0001.
Efdoralprin alfa was well tolerated. No participants in either active arm discontinued due to treatment-emergent adverse events. The most common adverse events across all arms were COPD exacerbations, headache, and COVID-19 infection. Grade ≥ 2 COPD exacerbations — captured as an adverse event of special interest — occurred numerically less often in the Q3W arm (26.8%) than in the Q4W (42.1%) or plasma-derived therapy arms (44.4%). Anti-drug antibodies were detected in two participants and were transient and non-neutralizing.
Why the efdoralprin alfa AATD data matter
AATD is a rare inherited condition caused by mutations in the SERPINA1 gene, resulting in low or absent circulating AAT protein. Without adequate functional AAT levels, neutrophil elastase and other serine proteases go unchecked, progressively degrading alveolar tissue and driving emphysema — the most common form of COPD in this population, accounting for up to 72% of deaths in AATD. An estimated 235,000 people worldwide carry the diagnosis, with approximately 100,000 in the US, though roughly 90% of affected individuals are believed to remain undiagnosed.
Plasma-derived augmentation therapy has been the only available alpha-1 antitrypsin deficiency treatment since 1987 but does not consistently sustain functional AAT levels within the normal range, depends on human plasma supply, and requires weekly clinical visits. The ElevAATe data suggest that a recombinant protein therapy approach, engineered with an Fc fusion to extend half-life, can address the pharmacokinetic shortcomings of plasma-derived therapy by maintaining patients within the normal functional AAT range continuously rather than intermittently.