Vertex Stops Test of Rare Disease Drug, Dimming Pipeline Prospects

Vertex Pharmaceuticals is halting work on an experimental drug for a rare protein deficiency after safety problems were reported in Phase 2 testing.

The study was evaluating the small molecule, VX-814, as a treatment for alpha-1 antitrypsin deficiency, which can lead to liver and lung problems. After the markets closed Wednesday, Vertex (NASDAQ: [[ticker:VRTX]]) disclosed that elevated liver enzymes—eight times greater than normal—-were observed in four of the patients who received the drug i. The placebo-controlled study enrolled approximately 50 patients.

The liver enzyme levels are resolved or are resolving but Vertex also said that its analysis of how VX-814 moves within the body indicate that exposure levels were low. The company concluded it would not be feasible to safely reach levels at which the drug would produce meaningful increases in alpha-1 antitrypsin. Based on that analysis, the Boston-based company stopped the study. The company, however, is continuing a Phase 2 test of VX-864, a different small molecule that is also being evaluated as a potential treatment for the protein deficiency.

Alpha-1 antitrypsin is produced by the liver and circulates throughout the body. It protects organs, including the lungs, from enzymes that break down tissue. But a genetic mutation can lead to misfolded versions of the protein that don’t circulate and instead accumulate in the liver, damaging that organ. Meanwhile, insufficient levels of the protein lead to problems in the lungs.

Treatments for the lung disease associated with the protein deficiency aim to boost alpha-1 antitrypsin levels in the blood. Vertex had hoped to more directly address the disorder with a small molecule that would reach the liver and restore normal folding of alpha-1 antitrypsin. That’s a tall task, according to SVB Leerink analyst Geoffrey Porges.

“We believed that the hurdle for showing clinically meaningful effects in the lung was a high bar for a drug with activity confined to the liver, particularly when the corrected protein needed to circulate from the liver, through the entire circulation, to the lung, and then across the lung mucosa, before conferring its clinical effect,” he wrote in a Wednesday research note.

Vertex has been trying to expand its drug pipeline beyond its franchise of cystic fibrosis drugs. The alpha-1 antitrypsin drug candidate was considered a promising prospect. Even before that drug was sidelined, SVB Leerink viewed the Vertex pipeline as too small for a company of its size and value. In a separate research note Thursday morning , the investment firm says it expects the company will turn to dealmaking in the coming year to diversify its portfolio and pipeline. SVB Leerink cautions that the new Vertex management team does not have a track record in business development, and investors are “likely to be disappointed if those investments continue to stretch the boundaries of pharmacological feasibility.”

Until the release of the Phase 2 results for VX-814, Vertex was in contention with Arrowhead Pharmaceuticals (NASDAQ: [[ticker:ARWR]]) in the race to be the first to bring to patients an FDA-approved treatment for alpha-1 antitrypsin deficiency. The Arrowhead drug, ARO-AAT, employs RNA interference, a mechanism that stops a gene from producing a disease-causing protein. Unlike Vertex’s focus on addressing the lung disease associated with the protein deficiency, Arrowhead aims to address the liver problems. By stopping production of mutant alpha-1 antitrypsin, it’s hoped that the Arrowhead drug will give the liver the chance to heal.

In September, Arrowhead released encouraging data for its experimental “gene-silencing” therapy from a small group of patients in a Phase 2 test. Based on those data, Takeda Pharmaceutical (NYSE: [[ticker:TAK]]) last week agreed to pay Arrowhead $300 million up front to share commercialization rights in the US and secure rights to the drug in the rest of the world.

The Vertex results were not publicly known when the Takeda/Arrowhead alliance was announced. In a conference call last week, Asit Parikh, the executive in charge of Takeda’s gastroenterology division, was asked why did not wait until Vertex reported data for its alpha-1 antitrypsin drug before making the Arrowhead deal. Parikh responded that the approvals of other RNAi treatments have reduced the risk associated with that technology, while the competition in alpha-1 antitrypsin deficiency still has a lot to prove.

“I actually believe this is going to be the first drug out there for patients with this disease and I actually think it’s going to be the strongest drug out there based on what we know,” Parkih said of Arrowhead’s experimental treatment.

Image: iStock/TopStep2005