Given on a three-weekly schedule, efdoralprin alfa lifted mean fAAT trough levels by a margin more than three-fold larger than weekly plasma-derived AAT (pdAAT), clearing the primary endpoint at p<0.0001. Every key secondary measure cleared the same statistical bar. Patients on the three-weekly regimen spent the full 32 weeks of the trial above the lower bound of the normal fAAT range (23.8 μM); those on standard-of-care pdAAT cleared that threshold on only 41% of days — a contrast Sanofi is positioning as evidence that a longer-acting recombinant approach could reset expectations for how consistently patients can be kept in range.

AATD is a rare inherited disorder in which patients produce too little — or none — of the AAT protein that ordinarily buffers the lungs against inflammatory damage. Left untreated, the deficit can drive progressive loss of lung tissue and, in many cases, emphysema, which is responsible for as much as 72% of mortality in this population and represents the most prevalent form of COPD. Roughly nine in ten people with AATD are thought never to be diagnosed. Plasma-derived therapy has anchored treatment for close to 40 years; efdoralprin alfa is a recombinant protein engineered along a different pharmacological path.

“AATD presents a persistent clinical challenge. Widespread lack of awareness of the condition as a genetic cause of some forms of COPD leaves many patients under-served. Without treatment to address the underlying AAT protein deficiency, these patients are unable to maintain protective protein levels and become vulnerable to progressive lung disease,” said Igor Barjaktarevic, MD, PhD, Associate Professor, David Geffen School of Medicine at UCLA, Los Angeles, CA, US and principal investigator on the ElevAATe Phase 2 study. “The ElevAATE data suggest efdoralprin alfa, through its mechanism of action, may be able to restore normal AAT levels and keep patients in that range for longer than the standard-of-care therapy, helping to address an unmet need of this disease with a restorative recombinant approach.”

“The data demonstrate efdoralprin alfa, a restorative recombinant therapy designed to achieve a longer half-life than standard of care augmentation therapy, has the potential to raise and sustain fAAT levels within normal range with less frequent dosing. This could represent an important advancement in the treatment of AATD-related emphysema, offering patients new hope in a disease state where innovation has been limited over the past 40 years,” said Christopher Corsico, Global Head of Development at Sanofi.

Discussions with regulators about the program’s next steps are underway. Efdoralprin alfa already holds Fast Track and Orphan Drug status with the FDA and Orphan Designation from the EMA, and longer-term outcomes are being captured in the ElevAATe open-label extension study.