- Email: [email protected]
pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection
ORAL PRESENTATIONS it improved insulin sensitivity, lipids, adiponectin, and fibrosis biomarkers. This Phase 2 study evaluated the safety, tolerability, and efficacy of BMS-986036 in NASH patients. Methods: This was a multicenter, randomised (1:1:1), double-blind, placebo-controlled study in adults with body mass index ≥25 kg/m2, biopsy-confirmed NASH (F1-F3), and hepatic fat fraction ≥10%, assessed by magnetic resonance imaging – proton density fat fraction (MRI-PDFF). Randomisation was stratified by diabetes status. Patients received subcutaneous injections of BMS-986036 10 mg daily (QD), BMS-986036 20 mg weekly (QW), or placebo QD for 16 weeks. The primary efficacy endpoint was absolute change in MRI-PDFF at Week 16; exploratory endpoints included serum pro-C3 (N-terminal type III collagen propeptide, a fibrosis biomarker), ALT, AST, and, in a subset of patients, liver stiffness, assessed by MR elastography (MRE). Results: 74 patients were treated (median age, 51.5 years; women, 65%; type 2 diabetes, 38%; mean hepatic fat fraction, 19.5%). Baseline characteristics, including histology, imaging, and biochemical parameters, were comparable among groups. 68 patients had MRI-PDFF data at both Baseline and Week 16. At Week 16, both BMS-986036 regimens significantly reduced MRI-PDFF versus placebo and improved pro-C3, MRE, adiponectin, ALT and AST (Table). The most frequent AEs in BMS-986036-treated patients were diarrhea (17% vs. 8% [ placebo]), nausea (15% vs. 8%), and frequent bowel movements (10% vs. 0%); most of these were mild, none was severe. Serious AEs occurred in 2 patients; none was considered treatment-related. There were no deaths and no discontinuations due to AEs.
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National Taiwan University Hospital, Taipei, Taiwan; 9The Liver Institute at Methodist Dallas, Dallas; 10University of Pennsylvania, Philadelphia; 11 Cedars Sinai Medical Center, Los Angeles, United States; 12Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, Barcelona, Spain E-mail: [email protected] Background and Aims: Safe and effective ribavirin (RBV)-free HCV treatment options for transplant recipients remain a high priority. Coformulated glecaprevir (identified by AbbVie and Enanta) and pibrentasvir (G/P) have negligible renal excretion and demonstrate high rates of sustained virologic response (SVR) at post-treatment week 12 (PTW12; SVR12) in patients with HCV genotype (GT) 1–6 infection. This study evaluated the safety and efficacy of G/P in adult patients with chronic HCV GT 1–6 infection who have received a liver or renal transplant. Methods: MAGELLAN-2 is a phase 3, single arm, open-label, multicenter study conducted in patients at least 3 months posttransplant. Patients without cirrhosis who were HCV treatment-naïve or, with the exception of GT3 patients, treatment experienced with interferon (IFN), pegIFN±RBV, or sofosbuvir with RBV±pegIFN received G/P (300 mg/120 mg) for 12 weeks. The primary endpoint compared the proportion of patients with SVR12 to a historical standard of care SVR12 rate. Results: One hundred patients were enrolled; Table 1 shows baseline demographics. In patients with available data, 89/90 achieved SVR at PTW4 (SVR4), with one virologic failure in a treatment-naïve, GT3infected patient who relapsed at PTW4. With the exception of the one patient with virologic failure, all patients had undetectable HCV RNA at their last visit. The most common adverse events (AE) were headache and fatigue (Table 2). One patient discontinued G/P due to a serious AE of cerebrovascular accident unrelated to G/P, but achieved SVR4. One patient had a mild liver transplant rejection, continued treatment, and achieved SVR12. Immunosuppression monitoring and dose adjustments were consistent with the standard-of-care. SVR12 and available data on baseline NS3 and NS5A polymorphisms will be presented. Table 1: Baseline Demographics and Disease Characteristics G/P 12 Weeks N = 100
Characteristic
Conclusions: BMS-986036, QD and QW for 16 weeks, compared with placebo, significantly decreased hepatic fat fraction in patients with NASH (F1-F3). BMS-986036 also improved biomarkers of fibrosis (MRE and pro-C3), adiponectin, and markers of hepatic injury (ALT and AST). These results suggest that BMS-986036 has beneficial effects on steatosis, liver injury, and fibrosis in NASH.
LBO-03 MAGELLAN-2: safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection N. Reau1, P.Y. Kwo2, S. Rhee3, R.S. Brown, Jr4, K. Agarwal5, P. Angus6, E. Gane7, J.-H. Kao8, P.S. Mantry9, K.R. Reddy10, T.T. Tran11, Y.B. Hu3, A. Gulati3, T.I. Ng3, E.O. Dumas3, N. Shulman3, R. Trinh3, X. Forns12. 1 Rush University Medical Center, Chicago; 2Stanford University School of Medicine, Palo Alto; 3AbbVie Inc., North Chicago; 4Center for Liver Disease and Transplantation, Weill Cornell Medical College, New York, United States; 5Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom; 6University of Melbourne, Melbourne, Australia; 7University of Auckland, Auckland, New Zealand;
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Male, n /% White race* Genotype 1/2/3/4/5/6, n Age, median (range), years BMI, median (range), kg/m2 HCV treatment-experienced, n/% IFN-based, n/% SOF-based, n/% Treatment experience pre-transplant, n/% Treatment experience post-transplant, n/% HCV RNA, median (range), log10 IU/mL F0-F1/F2/F3 Fibrosis, n Liver transplant, n/% Kidney transplant, n/% Time since transplant, median (range), months eGFR, median (range), mL/min/1.73 m2 Baseline immunosuppressant medication, n/% Tacrolimus Mycophenolic acid Cyclosporine Prednisone Prednisolone Everolimus Azathioprine Sirolimus
75 78 57/13/24/4/0/2 60 (39–78) 26.01 (17.44–42.45) 34 31 1 24 10 6.5 (4–7.6) 78/5/14† 80 20 55.6 (4.2–545.3) 62.3 (28.7–132.2) 66 29 14 13 10 7 6 6
G/P, glecaprevir/pibrentasvir; BMI, body mass index; HCV, hepatitis C virus; eGFR, estimated glomerular filtration rate. *Race was self-reported. † Data missing for 3 patients.
Journal of Hepatology 2017 vol. 66 | S63–S94
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,
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National Taiwan University Hospital, Taipei, Taiwan; 9The Liver Institute at Methodist Dallas, Dallas; 10University of Pennsylvania, Philadelphia; 11 Cedars Sinai Medical Center, Los Angeles, United States; 12Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, Barcelona, Spain E-mail: [email protected] Background and Aims: Safe and effective ribavirin (RBV)-free HCV treatment options for transplant recipients remain a high priority. Coformulated glecaprevir (identified by AbbVie and Enanta) and pibrentasvir (G/P) have negligible renal excretion and demonstrate high rates of sustained virologic response (SVR) at post-treatment week 12 (PTW12; SVR12) in patients with HCV genotype (GT) 1–6 infection. This study evaluated the safety and efficacy of G/P in adult patients with chronic HCV GT 1–6 infection who have received a liver or renal transplant. Methods: MAGELLAN-2 is a phase 3, single arm, open-label, multicenter study conducted in patients at least 3 months posttransplant. Patients without cirrhosis who were HCV treatment-naïve or, with the exception of GT3 patients, treatment experienced with interferon (IFN), pegIFN±RBV, or sofosbuvir with RBV±pegIFN received G/P (300 mg/120 mg) for 12 weeks. The primary endpoint compared the proportion of patients with SVR12 to a historical standard of care SVR12 rate. Results: One hundred patients were enrolled; Table 1 shows baseline demographics. In patients with available data, 89/90 achieved SVR at PTW4 (SVR4), with one virologic failure in a treatment-naïve, GT3infected patient who relapsed at PTW4. With the exception of the one patient with virologic failure, all patients had undetectable HCV RNA at their last visit. The most common adverse events (AE) were headache and fatigue (Table 2). One patient discontinued G/P due to a serious AE of cerebrovascular accident unrelated to G/P, but achieved SVR4. One patient had a mild liver transplant rejection, continued treatment, and achieved SVR12. Immunosuppression monitoring and dose adjustments were consistent with the standard-of-care. SVR12 and available data on baseline NS3 and NS5A polymorphisms will be presented. Table 1: Baseline Demographics and Disease Characteristics G/P 12 Weeks N = 100
Characteristic
Conclusions: BMS-986036, QD and QW for 16 weeks, compared with placebo, significantly decreased hepatic fat fraction in patients with NASH (F1-F3). BMS-986036 also improved biomarkers of fibrosis (MRE and pro-C3), adiponectin, and markers of hepatic injury (ALT and AST). These results suggest that BMS-986036 has beneficial effects on steatosis, liver injury, and fibrosis in NASH.
LBO-03 MAGELLAN-2: safety and efficacy of glecaprevir/pibrentasvir in liver or renal transplant adults with chronic hepatitis C genotype 1–6 infection N. Reau1, P.Y. Kwo2, S. Rhee3, R.S. Brown, Jr4, K. Agarwal5, P. Angus6, E. Gane7, J.-H. Kao8, P.S. Mantry9, K.R. Reddy10, T.T. Tran11, Y.B. Hu3, A. Gulati3, T.I. Ng3, E.O. Dumas3, N. Shulman3, R. Trinh3, X. Forns12. 1 Rush University Medical Center, Chicago; 2Stanford University School of Medicine, Palo Alto; 3AbbVie Inc., North Chicago; 4Center for Liver Disease and Transplantation, Weill Cornell Medical College, New York, United States; 5Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom; 6University of Melbourne, Melbourne, Australia; 7University of Auckland, Auckland, New Zealand;
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Male, n /% White race* Genotype 1/2/3/4/5/6, n Age, median (range), years BMI, median (range), kg/m2 HCV treatment-experienced, n/% IFN-based, n/% SOF-based, n/% Treatment experience pre-transplant, n/% Treatment experience post-transplant, n/% HCV RNA, median (range), log10 IU/mL F0-F1/F2/F3 Fibrosis, n Liver transplant, n/% Kidney transplant, n/% Time since transplant, median (range), months eGFR, median (range), mL/min/1.73 m2 Baseline immunosuppressant medication, n/% Tacrolimus Mycophenolic acid Cyclosporine Prednisone Prednisolone Everolimus Azathioprine Sirolimus
75 78 57/13/24/4/0/2 60 (39–78) 26.01 (17.44–42.45) 34 31 1 24 10 6.5 (4–7.6) 78/5/14† 80 20 55.6 (4.2–545.3) 62.3 (28.7–132.2) 66 29 14 13 10 7 6 6
G/P, glecaprevir/pibrentasvir; BMI, body mass index; HCV, hepatitis C virus; eGFR, estimated glomerular filtration rate. *Race was self-reported. † Data missing for 3 patients.
Journal of Hepatology 2017 vol. 66 | S63–S94
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,
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