Rough times continued Friday at Arbutus Biopharma Corp. as it discontinued clinical development of AB-506, an oral capsid inhibitor, which is in a clinical trial for treating chronic hepatitis B. The decision was made when two healthy volunteers were found to have acute hepatitis.
"We intend to present results from the AB-506 phase Ia/IIb clinical trial along with further details regarding the two cases of acute hepatitis at an appropriate scientific meeting later in 2019," said Gaston Picchio, Arbutus' chief development officer.
The two cases of acute hepatitis were found in the phase Ia 28-day trial. Final results of the study were expected in the first half of 2020, with plans being made for a combination proof-of-concept phase II trial in patients with chronic hepatitis B.
The company also decided to postpone its combination study targeting the hepatitis B virus (HBV) using AB-506 and AB-729, a subcutaneously administered N-acetylgalactosamine conjugate, that had been set to begin in the first half of next year. However, Arbutus plans to select one of its remaining compounds for IND-enabling studies by the end of the year.
Burnaby, British Columbia-based Arbutus has struggled since its five-year market high of $25.61 per share on Jan. 30, 2015. The stock (NASDAQ:ABUS) closed down 28.6% Friday, with shares at $1.02.
The recent slide began last fall. Oct. 9, 2018, was a busy day at the company as it announced that HBV patients were poised to be dosed in the AB-506 trial "following successful execution of the healthy volunteer portion of the ongoing phase I clinical study." It also noted the appointment of Picchio as the new chief development officer.
But there was more, as it also announced a delay in starting a phase I trial for AB-452, a hepatitis B RNA destabilizer, a study the company had planned to start by year-end. In the meantime, the company planned to complete AB-452's ongoing nonclinical studies.
A steep drop in the share price, which had been $9.38 on Oct. 5, followed the announcements and, by Oct. 12, shares were going for $4.31. The downward drift continued into last week and deepened Friday.
Capsid inhibitors inhibit viral replication by stopping functional viral capsids from assembling and helping reduce new covalently closed circular DNA from forming. AB-506-001 is a double-blind, randomized, placebo-controlled, single and multiple dose trial evaluating the safety, tolerability and pharmacokinetics of AB-506 in healthy subjects and HBV-DNA-positive subjects with chronic HBV (CHB) infection. The healthy subject portion of the trial and two cohorts of CHB subjects were completed by mid-July. The healthy subject portion consisted of a single ascending-dose part in which subjects were randomized 6-to-2 (active-to-placebo), n=21, to receive AB-506 doses ranging from 30 mg to 1,000 mg, including investigation of food effect, and a multiple dose part in which subjects (randomized 10-to-2, n=12) received 400 mg of AB-506 once daily for 10 days.
In July, Arbutus reported no serious adverse events or clinically significant safety findings were to be found in the healthy subjects enrolled in the phase Ia/Ib trial. ALT levels and other liver function tests were found to be normal throughout the 10 days of dosing. Then, on Friday, Arbutus announced that it had stopped the study.
Also in July, Arbutus began the healthy subject portion of a single- and multiple-dose phase Ia/Ib study for AB-729, an RNAi agent that preclinical models showed to span all HBV transcripts, reduce all viral antigens, including HBV surface antigen expression, and inhibit HBV replication. The trial is for healthy subjects and those with CHB infection.
Last year, Genevant Sciences Ltd., with the help of $37.5 million seed money from Roivant Sciences Ltd., signed on to use Arbutus technology in its drive to get five to 10 RNA-based therapies into the clinic by next year. Genevant's birth built on a $116.4 million investment Roivant had committed to Arbutus in 2017. (See BioWorld, April 13, 2018.)