Vertex Pharmaceuticals on Thursday said it would not be advancing VX-864 into late-stage testing as a potential treatment for patients with alpha-1 antitrypsin deficiency (AATD) despite the drug having achieved the primary endpoint in a Phase II study. "These data provide clear evidence that an oral small molecule corrector designed to promote the proper folding of the mutant Z-AAT protein can increase plasma levels of functional AAT," the company said, but "the magnitude of treatment effect observed in this study is unlikely to translate into substantial clinical benefit." Shares fell as much as 15% on the news.
Last October, Vertex shelved plans to further develop VX-814, another AATD candidate it was working on, after several participants in a Phase II study experienced elevated liver enzymes. The company stated at the time that it would concentrate instead on VX-864, which it said was structurally distinct from VX-814.
The latest Phase II study enrolled 44 AATD adult patients with the PiZZ genotype who were randomised to one of three doses of VX-864 or placebo for 28 days. Baseline functional AAT levels among the 37 patients who were given the treatment ranged from 3.8 to 4.1 micromolar. The primary endpoint was mean change from baseline in plasma functional AAT levels at day 28 compared to placebo.
According to the company, VX-864 led to "rapid, consistent and statistically significant" gains in mean functional AAT compared to placebo across all dose groups, increasing to 6.1 to 6.3 micromolar among treated patients, although that was not enough to make much of a difference clinically. There was also a 28-day follow-up period after the last dose of treatment during which Vertex said plasma functional AAT levels returned to baseline, "consistent with the half-life of native AAT protein and further confirming the biological activity of VX-864."
From a safety standpoint, Vertex said VX-864 was well tolerated, with mostly mild or moderate side effects. There were also no discontinuations due to adverse events (AEs) and no serious AEs considered related to the drug. Moreover, the company said liver function test results were similar between the placebo and VX-864 treated groups.
"This is the first time that dosing of a small molecule corrector of the Z-AAT protein resulted in significant elevations in both functional and antigenic levels of AAT in people with AATD," noted Carmen Bozic, head of global medicines development and medical affairs. She said Vertex is working to "translate the learnings from this study to optimise the next set of small molecule correctors" that the company is hoping to move into the clinic in 2022.
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