- An experimental RNA-based medicine developed by Arrowhead Pharmaceuticals reduced levels of a mutant protein in patients with a rare liver disorder by up to 94% in a Phase 2 clinical trial, the company reported Monday. The drug’s effects on liver scarring were less pronounced, with 50% of participants improving compared with 38% among patients given a placebo.
- With partner Takeda, Arrowhead executives also announced the design of a Phase 3 trial that will be larger and twice as long in duration than Wall Street analysts had expected. The trial design will increase expected research and development costs, as well as push back the medicine’s potential market launch.
- Arrowhead shares fell by as much as 30% in morning trading before recovering somewhat. The company in November reported it has enough cash to fund operations for at least 12 months.
Arrowhead’s drug, called fazirsiran, is designed to treat alpha-1 antitrypsin deficiency, a genetic condition in which a mutant form of the namesake protein accumulates in liver cells, causing fibrosis and cirrhosis.
Alpha-1 antitrypsin, or AAT, deficiency has become a target of several drugmakers, including Vertex Pharmaceuticals, Dicerna Pharmaceuticals and Wave Life Sciences. The last two have been targets of recent dealmaking, with Novo Nordisk announcing an acquisition of Dicerna and GSK licensing Wave’s AAT drug.
The data announced Monday came from a trial of 42 patients with AAT deficiency, who were randomized to receive one of three doses of fazirsiran or placebo. The trial’s main goal was a reduction in a key mutant form of AAT.
On that measure, fazirsiran appears to help, with a median reduction of the mutant protein of 94% at the end of 48 weeks in patients given the highest dose. By comparison, those receiving a placebo had “no meaningful change,” Arrowhead said.
A secondary goal was reduction by one point on a gauge of liver fibrosis called METAVIR, which researchers assessed using a liver biopsy. Fifty percent of the patients given fazirsiran reached this goal, versus 38% of placebo patients did. That finding “introduces risk” to the Phase 3 trial, Cantor Fitzgerald analyst Prakhar Agrawal wrote in a Jan. 9 note to clients.
Arrowhead said the fibrosis data for the placbeo group “highlights the known variability” of liver fibrosis assessment. “With a larger sample size, like in the planned Phase 3 study, the rate of improvement in patients receiving placebo may more closely approximate results from natural history studies of untreated patients,” the company said in a statement.
It’s not the first time researchers have seen disappointing results from an experimental drug for AAT deficiency. Vertex, for example, pulled the plug on one in 2021, prompting it to develop a second-generation agent.
The planned Phase 3 trial will enroll 160 patients, half of whom will receive fazirsiran and half of whom will receive a placebo. The trial’s main goal will be the one-point reduction in liver fibrosis, measured after 106 weeks.
Investors had been expecting Takeda, which will run the Phase 3 trial, to measure that fibrosis improvement at 52 weeks. “Thus the long duration of [the] Phase 3 trial will likely push out timelines of launch by at least one year,” Agrawal wrote.