Aus dem Annual 2016
Concluded Phase 2 Clinical Trial in PBC
A4250 was previously evaluated in an investigator-initiated Phase 2 clinical trial for the treatment of PBC. We facilitated the
trial, which was concluded in the fourth quarter of 2016, primarily to provide additional learning on the effects of A4250 in patients
with cholestatic liver disease to guide future development and to address feedback received from the FDA at a pre-investigational new
drug, or IND, meeting regarding the need to generate data in adults with cholestatic liver disease prior to initiating clinical
development in children in the United States. PBC is a chronic disease of the liver in which the bile ducts become inflamed and are
slowly destroyed. When bile ducts are damaged, bile acids can build up in the liver, leading to irreversible cirrhosis. As cirrhosis
progresses and the amount of scar tissue in the liver increases, the liver loses its ability to function. Cirrhosis also prevents blood from
the intestines from returning to the heart.
The trial was an open label, crossover study designed to evaluate the safety and tolerability of A4250, the efficacy of A4250 in
relieving pruritus and the effects of A4250 on liver biochemistry and bile acid metabolism in patients with PBC and cholestatic
pruritus. The investigator conducted the trial at two sites in Sweden. The trial design provided for enrollment of adult patients who had
not responded adequately to at least six months of treatment with UDCA and who met specified criteria for elevated serum levels of
ALP and for itching.
In the trial, patients initially continued their existing regimen of either cholestyramine or colestipol for four weeks. After a two-
week washout period, patients in the first cohort received a 1.5 mg once daily oral dose of A4250 for one week and a 3 mg once daily
oral dose of A4250 for the succeeding three weeks. A4250 was administered in a powder formulation in a capsule, and patients who
did not tolerate the higher dose could revert to the lower dose at the discretion of the investigator. After another two-week washout
period beginning at the end of the four-week A4250 treatment period, patients again returned to their initial dosing regimen of either
cholestyramine or colestipol for four weeks.
Following completion of the first cohort, the investigator began to enroll a second cohort of six patients into the trial to receive a
lower daily dose of A4250 than patients in the first cohort received. However, the investigator experienced recruitment delays for the
second cohort and determined to conclude the study prior to completion of the second cohort, citing GI side effects.
The primary endpoint of the trial was the incidence of treatment-emergent SAEs during the treatment period. The VAS-itch, a
commonly used tool to assess pruritus based on a linear 10-point scale, was one of the exploratory efficacy endpoints in the trial.
Based on data from the trial that we received from the investigator, nine patients received A4250 and all of them reported a
substantial reduction in pruritus, assessed by the VAS-itch scale, at the time of the first assessment (one week). The reduction in
pruritus was sustained throughout the remaining period of participation in the trial with dosing with A4250, and pruritus levels
returned to pre-A4250 levels when dosing was stopped.
Two of the five patients in the first cohort dropped out of the trial due to diarrhea, an effect consistent with the IBAT inhibition
mechanism. Three of the four patients in the abbreviated second cohort of the trial dropped out prior to completion of the four-week
dosing period due to GI side effects, including diarrhea, abdominal pain and, in one case, bleeding.
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