Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder affecting approximately 1 in 3,500 people, impacting the liver and lungs. Patients with two abnormal SERPINA1 genes produce Z-AAT, which is less effective at inhibiting neutrophil elastase, leading to inflammation and potential organ damage. The current standard treatment, augmentation therapy, involves weekly intravenous infusions of normal alpha-1 antitrypsin from blood donors but does not reverse existing damage. Several companies are developing innovative therapies that could transform AATD treatment in the coming years.
Challenges and Setbacks in AATD Drug Development
Vertex Pharmaceuticals recently discontinued research on two investigational small molecules, VX-634 and VX-668, after disappointing efficacy data. This decision followed the earlier discontinuation of VX-864 due to reports of rashes and elevated liver enzymes. These setbacks highlight the challenges in developing effective AATD treatments.
Fazirsiran: An RNAi Therapy in Phase III Trials
Arrowhead Pharmaceuticals and Takeda are currently recruiting for three Phase III trials of fazirsiran, a subcutaneous RNA interference (RNAi) therapy targeting AATD-associated liver disease. Phase II results (AROAAT-2002) indicated that fazirsiran significantly reduced Z-AAT levels. However, pulmonary efficacy data remains unclear, as the Phase II trial lacked a placebo arm, and pulmonary function markers remained stable without showing improvement.
Sanofi's SAR447537: A Fusion Protein Approach
Sanofi is developing SAR447537, formerly INBRX-101, a fusion protein currently in Phase II trials for AATD emphysema. Phase I results supported intravenous administration every three to four weeks, demonstrating favorable safety and pharmacokinetic profiles. Data regarding liver-related efficacy are still pending.
Base Editing with BEAM-302
Beam Therapeutics is exploring BEAM-302, a liver-targeting lipid nanoparticle formulation designed for a one-time intravenous injection of an adenine base editor. Preclinical studies in rat and mouse models showed a reduction in toxic liver protein levels. BEAM-302 is currently in Phase I/II trials.
RNA-Editing Oligonucleotides: Early-Stage Innovation
Wave Life Sciences, AIRNA, and Korro Bio are in the early stages of developing AATD-targeting subcutaneous RNA-editing oligonucleotides. Wave Life Sciences recently reported positive proof-of-mechanism data from a Phase Ib/IIa trial of WVE-006, while Korro Bio released preclinical data for KRRO-110. AIRNA is also developing an adenosine deaminase acting on RNA (ADAR) therapy for AATD.
The Future of AATD Treatment
With numerous investigational treatments in development, augmentation therapy could become obsolete. If RNA-based oligonucleotide therapies demonstrate significant efficacy, they could potentially reach the market within the next four to five years. Fazirsiran could potentially be available even sooner, within two to four years, assuming successful trial outcomes. The AATD treatment landscape is poised for significant advancements, potentially leading to increased competition and improved patient outcomes.
