VX-864

Adapted from iStock, Drypsiak Vertex may have pivoted away from the space, but candidates in development by Arrowhead/Takeda, Wave, Korro and others could address the damage underlying alpha-1 antitrypsin deficiency and make today’s treatments a thing of the past. Alpha-1 antitrypsin deficiency is a genetic disorder that affects the liver and/or lungs. Approximately 1 in 3,500 people have two abnormal SERPINA1 genes for the alpha-1 antitrypsin (AAT) protein and are at risk of serious organ damage due to AATD. While M-AAT is produced in healthy humans to inhibit neutrophil elastase in the lungs, AATD patients produce Z-AAT, which does not inhibit neutrophil elastase as effectively. If too much neutrophil elastase builds up in the lungs or liver, the result is inflammation which, untreated, can lead to lifelong complications. The only currently approved treatment option for AATD is augmentation therapy , which entails delivering normal alpha-1 antitrypsin collected and purified from blood donors through weekly intravenous administration. But this treatment does not reverse pulmonary damage or stop the progression of liver damage. Multiple companies are developing candidates that would prevent or reverse this damage, and despite some setbacks in the field, in the next 5 to 10 years we could see augmentation therapy become a thing of the past. In August 2024 , Vertex Pharmaceuticals announced that the company would cease research into both of its investigational small molecules for AATD. While Vertex had hoped that VX-634 and VX-668 would treat the disease by correcting the AAT protein, the efficacy was not transformative enough. Along with Vertex’s November 2023 discontinuation of the development of VX-864 for AATD due to reports of rashes and elevated liver enzymes, these setbacks highlight some of the challenges associated with researching new treatments for AATD. Meanwhile, Arrowhead Pharmaceuticals and Takeda are recruiting for three Phase III trials for fazirsiran, an investigational subcutaneous first-in-class investigational RNA interference (RNAi) therapy for AATD-associated liver disease. While Phase II AROAAT-2002 results indicated that fazirsiran led to significant reductions in Z-AAT, the evidence for pulmonary efficacy and improvement is murky because the Phase II trial did not have a placebo arm and the median FEV1 and mean DLCOhbg—markers of pulmonary function—were stable over time in all subjects receiving experimental treatment compared to baseline. While these data do not show any signs of pulmonary decline, there is no sign of overall pulmonary improvement either. In addition, Sanofi is working on SAR447537, an AATD asset acquired from Inhibrx. Formerly known as INBRX-101 , SAR447537 is a fusion protein currently in the recruitment stage for Phase II trials involving AATD emphysema. In Phase I results, safety and pharmacokinetic data supported the intravenous use of SAR447537 every three or four weeks. However, efficacy data related to the liver are not available. In the in vivo base editing space, Beam Therapeutics is investigating the use of BEAM-302 to treat AATD. BEAM-302 is a liver-targeting lipid nanoparticle formulation that is currently undergoing Phase I/II trials and is formulated to be a one-time intravenous injection of an adenine base editor. When tested in rat and mouse models , toxic liver protein levels decreased. Finally, Wave Life Sciences, AIRNA and Korro Bio are competing in the early phases of preclinical/clinical research to develop AATD-targeting subcutaneous RNA-editing oligonucleotides. On Oct. 16, Wave reported positive proof-of-mechanism data from a Phase Ib/IIa trial of WVE-006 in AATD, while Korro Bio released preclinical data this month for its AATD investigational treatment, KRRO-110 . AIRNA had yet to release its adenosine deaminase acting on RNA (ADAR) preclinical data publicly as of July 2024. With all these investigational treatments aiming to transform the way AATD is treated, augmentation therapy could soon be obsolete. If efficacy data for RNA-based oligonucleotides is significant and points to clinical success, RNA-based oligonucleotides could hit the market as soon as four to five years from now. In the meantime, at the current trajectory, fazirsiran could reach the market as early as two to four years from now if all goes well. Given these developments in the AATD space, competition could heat up within the next decade as more efficacy data are released from therapies currently at earlier stages of development.