Sanofi says drug for rare disease AATD tops standard care
A phase 2 trial of Sanofi's experimental therapy for alpha-1 antitrypsin deficiency (AATD) has raised the hope of an improvement on the decades-old standard of care for the rare disease.
The 97-patient ElevAATe study compared efdoralprin alfa to current plasma-based therapy for AATD, an inherited disorder whose main consequence is life-threatening pulmonary emphysema and damage to other organs such as the liver.
Sanofi's drug, formerly known as INBRX-101, is a recombinant form of the AAT enzyme that is defective in the disease, an alternative to the enzyme derived from the plasma of healthy donors, that has been engineered to have a longer half-life in the body. The company acquired it as part of the $2.2 billion takeover of Inhibrx in 2024.
The ElevAATE results showed that an infusion of efdoralprin alfa given every three weeks was more effective than weekly infusions of a plasma-derived product, CSL Behring's Zemaira (alpha1-proteinase inhibitor [human]), at increasing trough levels of functional alpha-1 antitrypsin (fAAT) in adults with AATD that has progressed to emphysema.
In patients dosed at three-week intervals with efdoralprin alfa, fAAT levels remained above the normal threshold (23.8 μM) for 100% of days during the 32-week study, compared to 41% of days in patients treated with Zemaira.
The finding feeds the hope that extended and more reliable enzyme replacement could reduce or even eliminate the lung decline seen with AATD and significantly improve patient quality of life.
A four-weekly dose of the experimental drug was less effective than the three-weekly regimen in the study, but still outperformed the plasma-derived product. Sanofi said it will now discuss next steps for the drug with global regulatory authorities.
Around 235,000 people worldwide live with AATD, with nearly 100,000 people in the US alone, but it is estimated that 90% of people living with the rare disease are undiagnosed, said the company.
"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," according to ElevAATE's principal investigator, Igor Barjaktarevic, of UCLA in Los Angeles, US.
"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," he said, adding that efdoralprin alfa could help to "address an unmet need of this disease with a restorative recombinant approach."
Sanofi's enzyme replacement therapy approach is just one of several being pursued by the pharma industry for AATD.
Mereo Biopharma's oral therapy alvelestat, a neutrophil elastase inhibitor, has shown promising activity in phase 2 testing and is being prepared for a phase 3 trial as the UK company tries to find development and commercial partners for the project.
Meanwhile, other companies – including Wave Life Sciences, Arrowhead Pharma/Takeda, AIRNA, Beam Therapeutics, and CRISPR Therapeutics – are developing therapies that attempt to correct the underlying genetic mutations in AATD.
Among these, Arrowhead and Takeda's fazirsiran is in phase 3 for liver disease caused by AATD, while Wave's WVE-006 – formerly partnered with GSK – cleared a phase 1/2 trial in 2024 and is currently in mid-stage testing. Beam's BEAM-302 candidate has shown early promise in a phase 1/2 trial, while CRISPR's CTX460 and AIRNA's AIR-001 are still in preclinical testing.
