AMSTERDAM — A novel approach for cholestatic pruritus, ileal bile acid transporter inhibition, was associated with improvement in pruritus in nearly three-quarters of children and adolescents, according to data presented at the International Liver Congress.
“Pediatric liver disease is a very diverse entity,” Ulrich Baumann, MD, of Klinik fr Pädiatrische Nieren-, Leber- und Stoffwechselerkrankungen, Medizinische Hochshule Hannover, in Germany, said in his presentation. “It often progresses to end-stage disease if left untreated, but there are currently no approved drug treatments.”
Surgical interventions include liver transplantation and biliary diversion surgery. The novel compound, A4250, is a selective inhibitor of ileal bile acid transporter (IBAT).
“The new compound tries to imitate the effect of surgery with minimal systemic exposure,” Baumann said. He added that it binds reversibly to IBAT and causes a reduction in enteric reuptake of bile acids.
In the current study, researchers assessed the safety and tolerability in five doses of the drug (0.01 mg/kg, 0.03 mg/kg, 0.06 mg/kg, 0.1 mg/kg and 0.2 mg/kg). Four patients aged 1 to 17 years were treated at each dosing level, with 19 patients comprising the cohort.
There were nine patients with progressive familial intrahepatic cholestasis (PFIC), six with alagille, three with biliary artresia and one patient with intrahepatic cholestasis.
Changes in serum BA and pruritus at 4 weeks underwent analysis.
Itching improved in 14 of the 19 patients. Among nine patients with PFIC, the baseline VAS itch score was 6.2 ± 0.7, which decreased to 3.8 ± 1.1 at end of therapy. In the non-PFIC group (n = 10), itch score improved from 6.2 ± 0.6 at baseline to 4.7 ± 0.9 at end of therapy. A decrease of 2.86 from baseline was the largest individual improvement reported.
For serum bile acids in the PFIC group, the baseline score was 278 ± 59 µmol/L, compared with 110 ± 50 µmol/L at end of treatment. For the non-PFIC group, serum bile acid levels improved from 193 ± 46 µmol/L at baseline to 120 ± 36 µmol/L at end of treatment.
The study was conducted at seven centers in Europe. There were 11 boys and eight girls included in the analysis. The median age was 6 years. Most patients received concomitant therapy. “Baseline data showed advanced liver disease,” Baumann said.
He concluded that the drug was well-tolerated and demonstrated a favorable safety profile. “All patients completed treatment,” he said. “A4250 has the potential to become a significant and novel advance in the treatment of PFIC and other pediatric cholestatic liver diseases.” – by Rob Volansky
Reference: Baumann U, et al. Abstract LBO-04. Presented at: International Liver Congress; April 19-24, 2017; Amsterdam.
Disclosure: Baumann reports receiving grants from Alexion, Alnylam, Astellas, MSD and Novartis.