Medical Innovation Exchange

Vertex drops phase 2 lung therapy, rethinks DMD drug’s journey towards clinic

Vertex Pharmaceuticals may be looking forward to a “milestone-rich period coming up,” but one candidate will no longer be joining the biotech on its journey while another will be delayed into the clinic.

The company is discontinuing its alpha-1 antitrypsin (AAT) deficiency therapy, dubbed VX-864, “due to non-serious rash events in some patients,” Vertex revealed in its third quarter earnings release.

Patients with AATD have a mutation that causes them to produce abnormal forms of the AAT protein. These misfolded proteins get trapped in the liver instead of being released into the blood like normal AAT proteins. The buildup of abnormal AAT in the liver, coupled with low levels of AAT in the blood, can result in liver and lung disease.

VX-864 is a “corrector molecule” designed to prevent the misfolding of AAT and increase plasma levels of AAT. Vertex had already decided against moving the therapy into late-stage development back in 2021. Despite all three dose levels of VX-864 beating placebo when it came to boosting patients’ plasma AAT levels in a phase 2 study, the company decided that the drug’s effect was so small that it was unlikely to “translate into substantial clinical benefit.”

However, that didn’t stop Vertex from launching a fresh phase 2 study the following year to assess the impact of longer-term treatment on polymer clearance from the liver. The study was sparked by an analysis of the previous mid-stage trial, which had revealed that VX-864 reduced levels of Z-polymer in the blood, Vertex explained at the time. Researchers have investigated Z-polymer as a potential biomarker for ATTD outcomes.

But it seems that this last remaining avenue of exploration for VX-864 has now also been closed due to the reports of rash. In yesterday’s release, Vertex highlighted that it would continue to enroll and dose healthy volunteers in its two other AAT correctors, VX-634 and VX-668. This “next wave” of investigational therapies for the autosomal recessive inherited disease have “significantly improved potency and drug-like properties compared with the first-generation AATD correctors,” the company added.

Vertex’s plans to enter the notoriously tricky Duchenne muscular dystrophy (DMD) space also seem to be stalled for the time being. A week after Sarepta saw its stock tank when its approved DMD gene therapy Elevidys failed to hit the primary goal of a pivotal study, Vertex said it won’t be rushing into the clinic in this indication anytime soon.

Vertex has been investigating whether the muscle degenerative condition can be treated by delivering CRISPR/Cas9 gene-editing technology to the muscle cells with a virus, AAV9. The aim is to change the targeted DNA sequence to restore dystrophin protein expression.

But the company said today that after considering the pre-clinical data generated so far, it’s decided that additional in vitro and animal studies of the delivery system for the therapy are needed before it moves into human testing.

“Consistent with its portfolio approach to research and development, Vertex is also using the learnings from its first-generation vectors to design next-generation delivery systems for in vivo gene editing in DMD,” the company added.

Still, the slow pace of the DMD work and the discontinuation of Vertex’s original AATD bet are small fry compared to the FDA’s upcoming decision on exa-cel. Should the agency give a positive verdict on the CRISPR Therapeutics-partnered prospect in sickle cell disease on December 8—which analysts seem pretty confident of—it will mark the first-ever CRISPR gene editing-based therapy to make it to market.

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