Takeda, Arrowhead hit one target for rare disease drug, but placebo overperformance sends biotech's shares tumbling

Takeda and Arrowhead Pharmaceuticals have met at least one mark in a phase 2 study of a liver disease drug called fazirsiran, but placebo overperformed on reducing liver scarring, sending the biotech’s shares down over 22% Monday morning.

Nevertheless, the partners are advancing the med to phase 3, albeit with a plan for a longer study period.

In the mid-stage SEQUOIA study, fazirsiran, also known as TAK-999 or ARO-AAT, reduced a marker of the rare genetic disorder alpha-1 antitrypsin deficiency (AATD-LD). The protein is made in the liver and helps protect the lungs from damage. Patients with the condition have a greater risk of lung and liver diseases.

Patients in the study had baseline fibrosis of the liver and received one of three doses, 25 mg, 100 mg, or 200 mg. The companies said in a Monday release that the therapy spurred a dose-dependent mean reduction in serum mutant alpha-1 antitrypsin protein (Z-AAT) at week 48 of 74%, 89%, and 94%, respectively, meaning all three doses reduced Z-AAT.

On a histological measure of Z-AAT accumulation called PAS-D globule burden, fazirsiran also caused a reduction from a baseline of 5.9 to 2.3, according to liver biopsy results. Portal inflammation, which is a sign of liver damage and disease, was also improved in 42% of patients, while only 7% experienced worsening.

The placebo group, on the flip side, saw no meaningful changes in baseline Z-AAT, a 26% increase in Z-AAT and no change in PAS-D globule burden. These patients also did not see an improvement in portal inflammation, while 44% worsened.

But on the fibrosis measure, placebo patients had 22% worsening and 38% improvement—meaning the control group nearly matched the fazirsiran arm.

This caveat to the data sent Arrowhead’s shares tumbling 22% to $29.20 on Monday morning, from a close of $37.38 on Friday.

Arrowhead and Takeda said the placebo performance finding “highlights the known variability on histologic fibrosis assessment.” The company said the data is consistent with an earlier open-label phase 2 study called AROAAT-2002.

As for safety, the companies said the therapy was well tolerated, with treatment-emergent adverse events in line with placebo. No discontinuations or premature study withdrawals from treatment-emergent events were reported in either group.

To fix the placebo performance problem, the companies plan to use a larger sample size in phase 3 in hopes of seeing a rate of improvement more in line with natural history studies in untreated AATD-LD patients.

Takeda plans to launch the randomized, double-blind, placebo-controlled TAK-999-3001 study this month to evaluate the safety and efficacy of fazirsiran for treating patients with alpha-1 antitrypsin deficiency–associated liver disease that has progressed to fibrosis. The trial will look for a decrease in baseline stage of histologic fibrosis on a liver biopsy performed at week 106. This represents a longer study duration compared to phase 2, which viewed results at week 48.

Back in April 2021, Takeda and Arrowhead reported that then-named ARO-AAT reduced scarring and slashed Z-AAT levels in patients.

The partners are working on the therapy through a $300 million up-front licensing deal signed in October 2020, which also includes $740 million in development, regulatory and commercial milestones.