Rare Daily Staff

Vertex Pharmaceuticals reported that although results from a phase 2 proof-of-concept study of VX-864 for the treatment of patients with alpha-1 antitrypsin deficiency provided proof-of-mechanism, the magnitude of treatment effect observed in this study was unlikely to translate into substantial clinical benefit.

As such, Vertex said it will not advance VX-864 into late-stage development and instead will advance additional novel small molecule correctors with the potential for increased clinical efficacy into the clinic. Vertex shares fell 12.5 percent on the news in after hours trading.

“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. We are encouraged by the clear separation of AAT levels in the VX-864 treated groups versus placebo and the favorable safety profile,” said Carmen Bozic, executive vice president, Global Medicines Development and Medical Affairs, and chief medical officer at Vertex. “Based on these findings, we remain committed to developing transformative treatments for AATD and are working with urgency to translate the learnings from this study to optimize the next set of small molecule correctors so that we can fully realize the potential that this class of molecules may hold for people living with this disease.”

AATD is a rare, genetic disease characterized by a protein folding defect that can lead to liver and lung disease. AATD is caused by changes in the SERPINA1 gene that encodes the AAT protein. In the most common form of AATD, which occurs in people with a PiZZ genotype, these changes to SERPINA1 cause the body to produce misfolded AAT protein that gets trapped inside the liver, where most AAT is made. This leads to low levels of AAT protein in the blood, which can allow inflammation to proceed unchecked and damage the lungs. The accumulation of defective AAT in the liver can also lead to liver disease. There is currently no cure for AATD. There are also no treatments that target the underlying protein folding defect that is the cause of the disease.

The phase 2 study was a randomized, double-blind, placebo-controlled study of the efficacy and safety of VX-864 in people with the PiZZ genotype. People were randomized to one of three dose groups of VX-864 or placebo for 28 days. In addition, there was a 28-day follow-up period after the last dose of treatment. The primary outcome measures were the mean change from baseline in plasma fAAT levels at day 28 compared to placebo as well as safety and tolerability of VX-864.

The study met its primary endpoint, with all VX-864 dose groups demonstrating highly statistically significant increases in plasma fAAT levels from baseline compared to placebo at day 28 of treatment. Treatment with VX-864 resulted in a mean increase of 2.2 to 2.3 micromolar in fAAT levels across the three dose groups studied compared to placebo. All dose groups showed a rapid increase in fAAT by day 7 which was sustained over 28 days of treatment. Similar statistically significant increases in antigenic AAT levels were observed compared to placebo, with a mean increase of 2.7 to 3.5 micromolar across the three dose groups studied. Plasma fAAT levels returned to baseline, in the 28-day safety follow-up period following VX-864 discontinuation, consistent with the half-life of native AAT protein and further confirming the biological activity of VX-864.

VX-864 was generally well tolerated with all but one patient completing treatment. There were no discontinuations due to adverse events (AEs) and there were no serious adverse events (SAEs) considered related to study drug. Most AEs were mild or moderate in severity and not treatment limiting. The most common AEs in VX-864 treated patients were diarrhea and nausea. Liver function test (LFT) results were similar between the placebo and VX-864 treated groups, and there was no evidence of any impact on LFT results with VX-864.

The results of the VX-864 study demonstrated proof-of-mechanism with a rapid, consistent, and clear effect on functional and antigenic AAT levels and a safety profile consistent with no mechanism-related toxicity. Vertex said the data collected are anticipated to enable optimization of it’s small molecule corrector approach in AATD and the rapid progression of a portfolio of new molecules with the potential for greater clinical efficacy into the clinic in 2022.

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