Arrowhead misses the target in alpha-1 antitrypsin deficiency

The Takeda-partnered project fazirsiran shows an impressive reduction in mutant protein, but questions about fibrosis remain.

Anyone who had been hoping for a path to accelerated approval for Arrowhead and Takeda’s alpha-1 antitrypsin deficiency (AATD) project fazirsiran will have been disappointed today. Questions raised by mixed data from the mid-stage Sequoia trial will only be answered by a phase 3 study, slated to begin this month.

Sequoia showed impressive and dose-dependent reductions in mutant alpha-1 antitrypsin protein (Z-AAT) among the fazirsiran-treated patients with fibrosis at baseline. Half of these subjects also showed improvement in fibrosis; however, 38% of placebo patients also improved, setting up a nervous wait for the phase 3 trial, which will have fibrosis as its primary endpoint.

Arrowhead shares opened down 20% this morning.

Liver focus

AATD is an inherited condition causing no or very low levels of a protective enzyme inhibitor, alpha 1 antitrypsin, and can lead to lung and liver disease. With fazirsiran, an RNA interference project designed to reduce the production of Z-AAT, Arrowhead and Takeda are taking aim at the liver component.

All patients in Sequoia had the homozygous, or PiZZ, genotype; of 40 patients enrolled, 25 had baseline fibrosis, while 15 did not. They were randomised to receive fazirsiran dosed at 25mg, 100mg, 200mg or placebo.

Focusing on the fibrosis patients, 48-week mean reductions in serum Z-AAT levels were 74%, 89% and 94% respectively, versus a 9% increase with placebo.

Source: Company presentation

Liver Z-AAT levels also declined by a median of 94% across all doses, compared with a 26% increase for placebo.

However, on fibrosis the picture was much less clear cut. 50% of those receiving fazirsiran showed an improvement of one point or more – but 38% of patients on placebo also achieved this. And the proportion of patients with worsening of one point or more was similar across the groups: 25% for fazisiran and 22% for placebo.

Arrowhead investors had clearly been expecting greater separation here. During a company conference call today, Dr Virginia Clark of the University of Florida pointed to a natural history study in which around 39% of AATD patients showed fibrosis progression at three years, while only 15% improved.

Arrowhead and Takeda will be hoping for placebo numbers more like this when the phase 3 study reads out. That trial, which will be carried out by the Japan group, will enrol about 160 patients with stage F2 to F4 fibrosis. There was no detail on what fazirsiran dose would be used.

There is no approved treatment for AATD, but others are vying for a piece of this market. Mereo, which reported mid-stage data last year, is homing in on lung disease with alvelestat, while a phase 2 study of belcesiran, which Novo Nordisk picked up through its purchase of Dicerna, is enrolling liver disease patients.

Meanwhile, Vertex is taking a third shot here with VX-634, following two previous failures. It is not the only group to have fallen short: Centessa canned ZF874 last August after cases of elevated liver enzymes.

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