Efdoralprin Alfa Normalizes Alpha-1 Antitrypsin Levels in Phase 2 ElevAATe

A recombinant alpha-1 antitrypsin (AAT) therapy administered every 3 to 4 weeks achieved significantly greater functional AAT levels than the current standard of care in adults with an AATD deficiency and emphysema, according to phase 2 ElevAATe data presented at the 2026 American Thoracic Society (ATS) International Conference in Orlando, Florida.1 In an on-site interview with HCPLive, Igor Barjaktarevic, MD, PhD, of UCLA Health, shared that these findings mark a meaningful step forward for a field that has relied on plasma-derived products for nearly 4 decades.

“Normal alpha-1 antitrypsin levels should be our goal," he said, "…and hopefully…we're going to prove that targeting normal will actually have a way more significant clinical impact on disease progression."

Alpha-1 antitrypsin deficiency affects approximately 80,000 to 100,000 people in the United States.2 Despite being a diagnosable genetic disorder, the majority of affected individuals remain undiagnosed, often presenting with COPD or asthma without the underlying genetic etiology being recognized. Major societies, including ATS, have recommended routine screening for > 20 years.3

Current plasma-derived augmentation therapies remain the standard of care but require weekly intravenous infusions, depend on blood donation supply chains, and do not maintain patients within the physiologic normal range of functional AAT throughout the dosing interval.1 The short half-life of plasma-derived products means levels rise after infusion and fall below normal before the next dose.

The ElevAATe trial enrolled 97 adults with antigenic AAT < 11 µM and confirmed emphysema.1 Participants were randomized 2:2:1 to receive efdoralprin alfa at 120 mg/kg every 3 weeks, efdoralprin alfa at 120 mg/kg every 4 weeks, or plasma-derived alpha-1 proteinase inhibitor (pdA1PI; Zemaira) at the FDA-approved dose of 60 mg/kg weekly for 32 weeks.

All primary and key secondary endpoints were met with both efdoralprin alfa dosing regimens. For the primary endpoint, change from baseline to steady-state functional AAT trough concentration measured by anti-neutrophil elastase capacity, least squares mean changes were 24.1 µM in the Q3W group and 16.8 µM in the Q4W group, compared with 7.6 µM for weekly pdA1PI. Both comparisons were statistically significant (P <.0001).1

For the key secondary endpoint of average functional AAT concentration at steady state, least squares mean changes were 32.9 µM (Q3W) and 26.0 µM (Q4W), versus 17.9 µM for pdA1PI. The proportion of days patients spent above the lower limit of normal was 100% for the Q3W group and 89.3% for Q4W, compared with 40.8% for weekly pdA1PI, meaning patients on standard of care were below the physiologic threshold for more than half of the treatment period.1

Both efdoralprin alfa regimens were well tolerated, with a safety profile comparable to pdA1PI. There were no treatment discontinuations attributable to treatment-emergent adverse events. Transient, non-neutralizing anti-drug antibodies were detected in 2 of 79 efdoralprin alfa-treated participants (2.5%).1

Barjaktarevic said while the pharmacokinetic data are encouraging, longer-term clinical outcomes data are still needed. An open-label extension of up to 3 years is currently enrolling patients rolling over from the phase 2 trial.1

Editor’s note: Reported disclosures for Barjaktarevic include GENZYME CORPORATION, Mylan Specialty L.P., AstraZeneca UK Limited, Grifols USA, Takeda Pharmaceuticals U.S.A., Regeneron Pharmaceuticals., Aero US, and more.

References

1. Barjaktarevic I, Diago C, Brown C, et al. 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. Poster presented at ATS 2026 in Orlando, Florida, on May 18. https://ats2026.d365.events/education/sessions/25c0ded1-ea4d-4921-a32b-eb72e63b4660

2. Learn About Alpha-1 Antitrypsin Deficiency. American Lung Association. Accessed May 28, 2026. https://www.lung.org/lung-health-diseases/lung-disease-lookup/alpha-1-antitrypsin-deficiency/learn-about-alpha-1-antitrypsin-defiency

3. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. doi:10.1164/rccm.168.7.818