- Email: [email protected]
The Ileal Bile Acid Transport inhibitor A4250 decreases pruritus and serum bile acids in cholestatic liver diseases – an ongoing multiple dose, open-label, multicentre study
ORAL PRESENTATIONS Table 2: Safety and Tolerability
Treatment-Emergent Event, n/%
G/P 12 weeks N = 10 0
Serious AEs AEs leading to study drug D/C Deaths AEs occurring in >10% of patients Headache Fatigue Nausea Laboratory Abnormalities ALT, grade ≥3 (>5 × ULN) Total bilirubin, grade ≥3 (>3 × ULN) Creatinine, grade ≥3 (>3 × ULN)
6* 1 0
Patient reported diary data documented improvement of VAS-itch score (VASi) in 14/19 cases during treatment (fig 1A and 1B). The dose with the greatest improvement showed a mean decrease of 2.86 from baseline. Four-week, once-daily treatment with A4250 reduced mean levels of s-BA in all cohorts. Substantial reductions in 7/9 PFIC patients (ranging from 43% to 98%) were observed (fig 1C). A4250 also reduced s-BA in the 11 non-PFIC patients, but to a lesser extent than in PFIC patients (fig 1D).
20 20 11 2 1 1
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. *Of these, one SAE of sinusitis was deemed possibly related to G/P
Conclusions: Once-daily G/P for 12 weeks is a well-tolerated, RBVfree treatment option for transplant patients with HCV infection, regardless of prior IFN or sofosbuvir treatment experience, with high SVR4 rates observed to date. LBO-04 The Ileal Bile Acid Transport inhibitor A4250 decreases pruritus and serum bile acids in cholestatic liver diseases – an ongoing multiple dose, open-label, multicentre study U. Baumann1, F. Lacaille2, E. Sturm3, E. Gonzalès4, H. Arnell5, M.H. Jørgensen6, R.J. Thompson7, M. Ekelund8, J.P. Mattsson9, E. Lindström9, P.-G. Gillberg9, K. Torfgård 9, P.N. Soni10. 1Klinik fϋr Pädiatrische Nieren-, Leber- und Stoffwechselerkrankungen, Medizinische Hochshule Hannover, Hannover, Germany; 2Pediatric Gastroenterology Hepatology-Nutrition, Necker-Enfants Maladies Hospital, Paris, France; 3Pediatric Gastroenterology and Hepatology, University Childreń s Hospital Tuebingen, Tϋbingen, Germany; 4Pediatric Hepatology and Liver Transplantation, University Hospitals of Paris-Sud, Bicetre, France; 5Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; 6Pediatric and Adoloscent Medicine, Rigshospitalet, Copenhagen, Denmark; 7Institute of Liver Studies, King’s College London, London, United Kingdom; 8Department of Clinical Sciences Lund, Surgery, Lund University, Faculty of Medicine, Lund; 9Albireo Pharma, Gothenburg, Sweden; 10Albireo Pharma, Boston, United States E-mail: [email protected] Background and Aims: Ileal bile acid transporter (IBAT) inhibition is a novel therapeutic concept for cholestatic pruritus and the progression of cholestatic liver disease. A4250, a potent, selective inhibitor of IBAT, is minimally absorbed by the gut and binds reversibly to IBAT to decrease the enteric reuptake of bile acids (BA). The aim of this phase II study in children with cholestatic pruritus was to assess safety and tolerability of A4250 and to explore changes in serum-BA and pruritus after 4 weeks of treatment. Methods: This study evaluated 5 doses to date (0.01–0.2 mg/kg) with four patients at each dose level. Patients with cholestatic disease and intractable pruritus were administered a single dose of A4250 and pharmacokinetics were determined. If no safety concerns were present and low systemic exposure was confirmed the patients started a 4-week, once-daily oral treatment with A4250. Itching was measured by a visual itch score (VAS 0–10) using a diary. Patients were permitted background therapy with UDCA or rifampicin. Results: Nineteen patients (8 females) aged 1–17 years were enrolled (one patient was re-entered as per protocol): PFIC (1, 2 or 3), 9; Alagille, 6; Biliary atresia, 3; Intrahepatic cholestasis, 1. No SAEs were reported. Most AEs were mild, transient and assessed as unrelated to study medication including increased transaminases.
Conclusions: A4250 was safe, well tolerated and reduced s-BA and pruritus in a range of cholestatic diseases. It has the potential to be a significant and novel advance for the treatment of pediatric cholestatic diseases. LBO-05 Controlled attenuation parameter as an additional tool for the non-invasive prediction of first clinical decompensation in compensated advanced chronic liver disease C. Margini1, G. Murgia1, G. Stirnimann1, A. De Gottardi1, N. Semmo1, S. Casu1, J. Bosch1, J.-F. Dufour1, A. Berzigotti1. 1Hepatology, UVCM, Inselspital, University of Bern, Bern, Switzerland E-mail: [email protected] Background and Aims: In compensated advanced chronic liver disease (cACLD) liver stiffness (LS) ≥21 kPa predicts portal hypertension and onset of first clinical decompensation. Since obesity is an additional negative prognostic factor, controlled attenuation parameter (CAP), which provides quantitative data related to liver fat content, might be an objective tool to improve risk stratification obtained by LS alone in cACLD. Methods: Consecutive patients with cACLD (LS ≥10 kPa; Baveno criteria) with available CAP observed between 09/2013 and 09/2015 and with a minimum 6 months follow-up were included. Patients with previous or ongoing liver decompensation, vascular liver diseases, HCC outside Milano criteria, LS with IQR/M >0.30 or AST >300 IU/ml were excluded. First clinical decompensation, death and OLT were identified on follow-up. Steatosis was excluded by CAP <220 dB/m (90% sensitive threshold) and ruled-in by CAP ≥220 dB/m. Cox Regression analysis was used to assess the association between LS, CAP and decompensation. Results: We included 193 fully compensated ACLD patients with a mean follow-up of 19 months (males 65%; viral etiology 58%; Child score 5.4 ± 0.8; platelets 164 ± 64 G/L; LS 21.1 ± 14.1 kPa; LS ≥21 kPa in 33.2%; CAP 255 ± 62 dB/m; CAP ≥220 dB/m in 68.4%). 18 patients developed first decompensation and 7 died. Patients who decompensated on follow-up had higher LS (33.6 ± 19.2 vs.19.8 ± 13.0,
Journal of Hepatology 2017 vol. 66 | S63–S94
S91
Treatment-Emergent Event, n/%
G/P 12 weeks N = 10 0
Serious AEs AEs leading to study drug D/C Deaths AEs occurring in >10% of patients Headache Fatigue Nausea Laboratory Abnormalities ALT, grade ≥3 (>5 × ULN) Total bilirubin, grade ≥3 (>3 × ULN) Creatinine, grade ≥3 (>3 × ULN)
6* 1 0
Patient reported diary data documented improvement of VAS-itch score (VASi) in 14/19 cases during treatment (fig 1A and 1B). The dose with the greatest improvement showed a mean decrease of 2.86 from baseline. Four-week, once-daily treatment with A4250 reduced mean levels of s-BA in all cohorts. Substantial reductions in 7/9 PFIC patients (ranging from 43% to 98%) were observed (fig 1C). A4250 also reduced s-BA in the 11 non-PFIC patients, but to a lesser extent than in PFIC patients (fig 1D).
20 20 11 2 1 1
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. *Of these, one SAE of sinusitis was deemed possibly related to G/P
Conclusions: Once-daily G/P for 12 weeks is a well-tolerated, RBVfree treatment option for transplant patients with HCV infection, regardless of prior IFN or sofosbuvir treatment experience, with high SVR4 rates observed to date. LBO-04 The Ileal Bile Acid Transport inhibitor A4250 decreases pruritus and serum bile acids in cholestatic liver diseases – an ongoing multiple dose, open-label, multicentre study U. Baumann1, F. Lacaille2, E. Sturm3, E. Gonzalès4, H. Arnell5, M.H. Jørgensen6, R.J. Thompson7, M. Ekelund8, J.P. Mattsson9, E. Lindström9, P.-G. Gillberg9, K. Torfgård 9, P.N. Soni10. 1Klinik fϋr Pädiatrische Nieren-, Leber- und Stoffwechselerkrankungen, Medizinische Hochshule Hannover, Hannover, Germany; 2Pediatric Gastroenterology Hepatology-Nutrition, Necker-Enfants Maladies Hospital, Paris, France; 3Pediatric Gastroenterology and Hepatology, University Childreń s Hospital Tuebingen, Tϋbingen, Germany; 4Pediatric Hepatology and Liver Transplantation, University Hospitals of Paris-Sud, Bicetre, France; 5Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden; 6Pediatric and Adoloscent Medicine, Rigshospitalet, Copenhagen, Denmark; 7Institute of Liver Studies, King’s College London, London, United Kingdom; 8Department of Clinical Sciences Lund, Surgery, Lund University, Faculty of Medicine, Lund; 9Albireo Pharma, Gothenburg, Sweden; 10Albireo Pharma, Boston, United States E-mail: [email protected] Background and Aims: Ileal bile acid transporter (IBAT) inhibition is a novel therapeutic concept for cholestatic pruritus and the progression of cholestatic liver disease. A4250, a potent, selective inhibitor of IBAT, is minimally absorbed by the gut and binds reversibly to IBAT to decrease the enteric reuptake of bile acids (BA). The aim of this phase II study in children with cholestatic pruritus was to assess safety and tolerability of A4250 and to explore changes in serum-BA and pruritus after 4 weeks of treatment. Methods: This study evaluated 5 doses to date (0.01–0.2 mg/kg) with four patients at each dose level. Patients with cholestatic disease and intractable pruritus were administered a single dose of A4250 and pharmacokinetics were determined. If no safety concerns were present and low systemic exposure was confirmed the patients started a 4-week, once-daily oral treatment with A4250. Itching was measured by a visual itch score (VAS 0–10) using a diary. Patients were permitted background therapy with UDCA or rifampicin. Results: Nineteen patients (8 females) aged 1–17 years were enrolled (one patient was re-entered as per protocol): PFIC (1, 2 or 3), 9; Alagille, 6; Biliary atresia, 3; Intrahepatic cholestasis, 1. No SAEs were reported. Most AEs were mild, transient and assessed as unrelated to study medication including increased transaminases.
Conclusions: A4250 was safe, well tolerated and reduced s-BA and pruritus in a range of cholestatic diseases. It has the potential to be a significant and novel advance for the treatment of pediatric cholestatic diseases. LBO-05 Controlled attenuation parameter as an additional tool for the non-invasive prediction of first clinical decompensation in compensated advanced chronic liver disease C. Margini1, G. Murgia1, G. Stirnimann1, A. De Gottardi1, N. Semmo1, S. Casu1, J. Bosch1, J.-F. Dufour1, A. Berzigotti1. 1Hepatology, UVCM, Inselspital, University of Bern, Bern, Switzerland E-mail: [email protected] Background and Aims: In compensated advanced chronic liver disease (cACLD) liver stiffness (LS) ≥21 kPa predicts portal hypertension and onset of first clinical decompensation. Since obesity is an additional negative prognostic factor, controlled attenuation parameter (CAP), which provides quantitative data related to liver fat content, might be an objective tool to improve risk stratification obtained by LS alone in cACLD. Methods: Consecutive patients with cACLD (LS ≥10 kPa; Baveno criteria) with available CAP observed between 09/2013 and 09/2015 and with a minimum 6 months follow-up were included. Patients with previous or ongoing liver decompensation, vascular liver diseases, HCC outside Milano criteria, LS with IQR/M >0.30 or AST >300 IU/ml were excluded. First clinical decompensation, death and OLT were identified on follow-up. Steatosis was excluded by CAP <220 dB/m (90% sensitive threshold) and ruled-in by CAP ≥220 dB/m. Cox Regression analysis was used to assess the association between LS, CAP and decompensation. Results: We included 193 fully compensated ACLD patients with a mean follow-up of 19 months (males 65%; viral etiology 58%; Child score 5.4 ± 0.8; platelets 164 ± 64 G/L; LS 21.1 ± 14.1 kPa; LS ≥21 kPa in 33.2%; CAP 255 ± 62 dB/m; CAP ≥220 dB/m in 68.4%). 18 patients developed first decompensation and 7 died. Patients who decompensated on follow-up had higher LS (33.6 ± 19.2 vs.19.8 ± 13.0,
Journal of Hepatology 2017 vol. 66 | S63–S94
S91