Vertex Scraps Two Phase I AATD Candidates Following Disappointing Data

Poor efficacy data for two early-stage candidates for the rare disease alpha-1 antitrypsin deficiency have convinced Vertex Pharmaceuticals to terminate their development.

Vertex Pharmaceuticals released its second-quarter financial report on Thursday, revealing that it has discontinued the development of two early-stage investigational therapies after underwhelming Phase I data.

The two assets—VX-634 and VX-668—were small molecule drug candidates being assessed for alpha-1 antitrypsin deficiency (AATD), a rare genetic disorder that affects the liver or the lungs and manifests as persistent jaundice, elevated liver enzymes, severe itching and easy bleeding. There are currently no approved treatments for AATD.

VX-634 and VX-668 were proposed as correctors of the misfolded Z-AAT protein, which in AATD accumulates in liver cells, leading to progressive organ dysfunction and fibrosis. Through this mechanism of action, the two candidates were thought to increase the secretion of functional AAT into the bloodstream, potentially addressing the effects of AATD on the lungs and liver.

However, Phase I data for VX-634 and VX-668 returned disappointing results showing that the candidates “would not deliver transformative efficacy for people with AATD,” according to Vertex. Despite trimming its pipeline, the company is “using the learnings” from VX-634 and VX-668 to inform the development of more effective therapies for AATD.

While its AATD portfolio continues to struggle, Vertex on Thursday touted the promising performance of its gene therapy Casgevy (exagamglogene autotemcel), indicated for sickle cell disease and transfusion-dependent beta-thalassemia. As of mid-July, Vertex has activated more than 35 authorized treatment centers globally and has harvested cells from around 20 patients up for treatment since Casgevy’s first approval in December 2023.

William Blair analyst Myles Minter in a note to investors said that Casgevy’s revenues will be recognized once the gene therapy has been infused into the patients, which could start in the third quarter of 2024, “followed by a greater influx of revenue in late 2024 and early 2025.” The investment firm expects Casgevy to make around $81.4 million this year.

As Vertex awaits Casgevy sales, its business continued to be anchored by its cystic fibrosis (CF) franchise, which in Q2 generated $2.65 billion in revenue, up from nearly $2.5 billion during the same period in 2023. Vertex’s CF earnings were generally in line with the consensus estimate of $2.66 billion, and a bit lower than William Blair’s forecast of $2.68 billion, according to Minter.

The biotech’s CF business will likely receive a boost early next year with the FDA’s potential approval of its Vanza triple combo regimen. In February 2024, Vertex announced that Vanza triple aced its pivotal Phase III program—consisting of three late-stage studies—demonstrating the investigational treatment was at least non-inferior to the currently approved CF therapy Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor).

In July 2024, the FDA accepted Vertex’s New Drug Application for Vanza triple in CF, with a target action date of Jan. 5, 2025.

Looking ahead to the rest of 2024, Vertex raised its total product revenue guidance to a range of $10.65 billion to $10.85 billion, up from a previous projection of $10.55 billion to $10.75 billion.

https://www.biospace.com/business/vertex-scraps-two-phase-i-aatd-candidates-following-disappointing-data