Vertex may have misjudged the data that regulators will want to see before approving one of the company’s most prized pipeline drugs.On Monday, the Food and Drug Administration held a workshop on developing medicines for alpha-1 antitrypsin deficiency, a genetic disorder where lack of a protein called AAT causes lung and liver damage. Vertex aims to treat the disorder with VX-814, an experimental therapy that should yield Phase 2 proof-of-concept results by next year.Older treatments for the disease gained approval based on how much AAT was in patients’ plasma. Vertex has said VX-814 could be initially cleared for market based on that measure, yet equity analysts who covered Wednesday’s workshop aren’t so sure. They now believe the FDA will be looking for functional data like improved liver and lung health, which could make a pivotal trial for Vertex’s drug “larger and longer than anticipated,” according to Geoffrey Porges of SVB Leerink.
Investors have pushed Vertex about what diseases it will target beyond cystic fibrosis. On the company’s second quarter earnings call, executives were quick to tout the positive effect VX-814 showed in preclinical testing, and how the drug was quickly advancing into Phase 2.
R&D chief Reshma Kewalramani, who is poised to be Vertex’s new CEO, said the mid-stage study would be of “very reasonable” size and duration because its main goal revolves around AAT levels and activity. Yet that data may not be enough for regulators.
Slides from the meeting cited by Porges show that the FDA wants future AAT deficiency clinical trials to show “substantial evidence of clinical effectiveness.” To do so, the drug in question should demonstrate a positive trend on endpoints like FEV1, an indicator of lung health that measures how much air a person can breathe out in one second.
Porges argues that such endpoints present a challenge to Vertex and other AAT deficiency drugmakers, since few patients are diagnosed with the disease and, presumably, only a fraction of them would be enrolled in clinical trials.
A functional endpoint rather than a biomarker endpoint could extend a pivotal study of VX-814 from several months in duration to several years by Porges’ estimates. It would also “significantly increase the patient sample required, as the pre-test assumptions and variability would be less well-known than for a standard assay of serum AAT levels.”
While data requirements may become tougher, Jefferies analyst Michael Yee pointed out potential bright spots. The FDA, he noted, will consider the “totality of data” when making approval decisions. It might also allow investigators to use a larger p-value when evaluating the statistical significance of a drug’s effect, he said.
The FDA hasn’t yet published any guidance to drugmakers on development of drugs for AAT deficiency, but Porges expects that to change soon. Whether or not biomarker endpoints are considered should go some ways to determining how long Vertex’s road to a new drug might take.