Vertex’s attempt to treat a rare genetic disease has hit another setback. The biotech tossed two more drug candidates onto the discard pile in response to underwhelming data but, following a playbook that has worked in other settings, plans to use the missteps to inform the next wave of preclinical prospects.
The disease, alpha-1 antitrypsin deficiency (AATD), is a long-standing area of interest for Vertex. Seeking to diversify beyond cystic fibrosis, the biotech has studied a series of molecules in the indication but has so far failed to find a winner. Vertex dropped VX-814 in 2020 after seeing elevated liver enzymes in phase 2. VX-864 joined its sibling on the scrapheap in 2021 after efficacy fell short of the target level.
Undeterred, Vertex moved VX-634 and VX-668 into first-in-human studies in 2022 and 2023, respectively. The new drug candidates ran into an old problem. Like VX-864 before them, the molecules were unable to clear Verex’s bar for further development.
Vertex said phase 1 biomarker analyses showed its two AAT correctors “would not deliver transformative efficacy for people with AATD.” Unable to go big, the biotech decided to go home, stopping work on the clinical-phase assets and focusing on its preclinical prospects. Vertex plans to use knowledge gained from VX-634 and VX-668 to optimize the small molecule corrector and other approaches in preclinical.
Vertex’s goal is to address the underlying cause of AATD and treat both the lung and liver symptoms seen in people with the most common form of the disease. The common form is driven by genetic changes that cause the body to produce misfolded AAT proteins that get trapped inside the liver. Trapped AAT drives liver disease. At the same time, low levels of AAT outside the liver lead to lung damage.
AAT correctors could prevent these problems by changing the shape of the misfolded protein, improving its function and preventing a pathway that drives liver fibrosis. Vertex’s VX-814 trial showed it is possible to significantly improve levels of functional AAT but the biotech is yet to reach its efficacy objectives.
History suggests Vertex may get there in the end. The biotech toiled unsuccessfully for years in pain but ultimately reported a pair of phase 3 wins for one of the several candidates it has tested in humans. Vertex is set to learn whether the FDA will approve the pain prospect, suzetrigine, in January 2025.