Sanofi announced positive results from its global ElevAATe phase 2 study, demonstrating that efdoralprin alfa (SAR447537) met all primary and key secondary endpoints in treating adults with alpha-1 antitrypsin deficiency (AATD) emphysema. The investigational recombinant human alpha-1 antitrypsin (AAT)-Fc fusion protein showed statistically significant superiority over standard plasma-derived therapy when administered every three or four weeks.
Study Results and Clinical Significance
The phase 2 study enrolled 97 patients randomized 2:2:1 to receive efdoralprin alfa every three weeks (Q3W), every four weeks (Q4W), or plasma-derived augmentation therapy once weekly. At week 32, efdoralprin alfa demonstrated a statistically significant greater mean increase in functional AAT levels within normal range as measured by trough concentrations at steady state compared to weekly plasma-derived therapy (p<0.0001).
The study also met key secondary endpoints, showing superior mean increase in functional AAT average concentration and higher percentage of days above the lower limit of the normal range for both Q3W and Q4W dosing regimens.
"These data demonstrate that efdoralprin alfa achieved consistently higher normal functional AAT levels, with less frequent dosing, compared to a current standard of care," said Christopher Corsico, Global Head of Development at Sanofi. "This is particularly meaningful as maintaining protective protein levels is the cornerstone of pulmonary management of AATD and currently available treatments require weekly therapeutic infusions."
Addressing Treatment Limitations
Igor Barjaktarevic, MD, PhD, Associate Professor at David Geffen School of Medicine at UCLA and primary investigator on the ElevAATe study, highlighted the clinical significance of these findings. "With the current standard of care, patients reach but do not maintain normal protein levels between the infusions, leaving a remaining unmet need," he explained. "Achieving and maintaining normal AAT levels with less frequent dosing and with complete independence from blood donation programs would be a welcome change to the current treatment experience for people living with AATD."
The recombinant therapy was well tolerated with a similar adverse event profile to plasma-derived therapy. Additional safety follow-up will be assessed in the ElevAATe OLE phase 2 study (NCT05897424).
Disease Background and Unmet Need
AATD is a rare, inherited disorder characterized by low levels or absence of AAT, a protein produced by the liver that protects the lungs from inflammation and damage. The disease causes progressive deterioration of lung and liver tissue, with affected individuals often experiencing lung damage and developing COPD, including emphysema. In severe cases, patients may require lung transplantation.
Approximately 235,000 people worldwide live with AATD, including nearly 100,000 in the United States, though about 90% of individuals with the condition are likely undiagnosed. Plasma-derived therapies were introduced in 1987, but no new therapies have been developed since then.
Regulatory Status and Next Steps
Efdoralprin alfa has received fast track and orphan drug designation from the US Food and Drug Administration for treating AATD emphysema. The investigational treatment is designed to restore functional AAT levels to the normal range and inhibit neutrophil elastase, an enzyme that can cause lung tissue damage in AATD patients.
Sanofi plans to present the data at an upcoming medical meeting and engage with global regulatory authorities regarding appropriate next steps for the development program. The company positions these results as reinforcing efdoralprin alfa's potential to be the first restorative recombinant therapy that normalizes and maintains functional AAT levels in this patient population.
