Cenicriviroc Treatment for Adults with Non-Alcoholic Steatohepatitis: Year 2 Analysis of the Phase 2b

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Lefebvre, Guruprasad P. Aithal, Stephen A. Harrison, Manal F. Abdelmalek, Scott L.

1 Cenicriviroc Treatment for Adults with Non-Alcoholic Steatohepatitis: Year 2 Analysis of the Phase 2b CENTAUR Study Vlad Ratziu, Arun Sanyal, Sven Francque, Vincent Wai-Sun Wong, Rohit Loomba, Zachary Goodman, Eric Lefebvre, Guruprasad P. Aithal, Stephen A. Harrison, Manal F. Abdelmalek, Scott L. Friedman, Frank Tacke International Liver Congress 2018, European Association for the Study of the Liver (EASL) April 11 th -15 th, 2018 Paris, France 1

2 Disclosures Dr. Vlad Ratziu has provided consultancy for Allergan, Genfit, Intercept, Novartis, Boehringer Ingelheim, and Pfizer Dr. Ratziu has received grants from Gilead and Intercept 2

3 Background Cenicriviroc (CVC): an oral, once-daily, dual CCR2/5 antagonist C-C chemokine receptor type 2 (CCR2) and 5 (CCR5) promote recruitment of macrophages following liver injury and activation of collagen-producing hepatic stellate cells 1 8 CVC is a dual CCR2 and CCR5 antagonist with nanomolar potency 9 CVC has demonstrated anti-inflammatory and antifibrotic activity across multiple animal models of liver disease 9-13 CVC has shown good safety and tolerability in >1000 participants, including cirrhotic patients with mild-to-moderate hepatic impairment, with few AEs in studies extending 48 weeks AEs, adverse events; NASH, nonalcoholic steatohepatitis 1. Saiman Y, Front Physiol Zimmermann HW, Inflamm Allergy Drug Targets Seki E, Hepatology Seki E, J Clin Invest Miura K, Am J Physiol Gastrointest Liver Physiol Schwabe RF, Am J Physiol Gastrointest Liver Physiol Liaskou E, Hepatology Marra F, Gastroenterology Lefebvre E, PLoS ONE Krenkel O, Hepatology Mossanen JC, Hepatology Puengel T, PLoS ONE Yu D, Liver Int Thompson M, AIDS Lefebvre E, Clin Transl Sci Friedman SL, Hepatology

4 CENTAUR Study Design Phase 2b, Randomized, Double-Blind, -Controlled Study Baseline Year 1 (Primary Endpoint) Year 2 (Final Analysis) Arm A N=289 Randomization 2:1:1 Arm B Primary endpoint biopsy Final biopsy EXPLORATORY ANALYSES Arm C First Phase 2b study in NASH to collect 3 serial biopsies over a 2-year duration Key eligibility criteria Fibrosis stage 1-3 (NASH CRN), NASH diagnosis (NAS 4) Enriched for T2DM, high BMI with at least 1 criteria of MetS, or bridging fibrosis and/or NAS 5 Stratification factors: NAS (4 or 5) and fibrosis stage ( 2 or >2) Study conducted in the USA, EU, Australia, and Hong Kong BMI, body mass index; CVC, cenicriviroc; MetS, metabolic syndrome; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis; NASH CRN, NASH Clinical Research Network; T2DM, type 2 diabetes mellitus Friedman SL, Contemp Clin Trials 2016; NCT : Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis (CENTAUR). 4

CENTAUR Year 1 Results Proportion of participants, ITT (%) CVC demonstrated antifibrotic effect without impact on underlying steatohepatitis at Year 1 (ITT) Arm A vs.

5 CENTAUR Year 1 Results Proportion of participants, ITT (%) CVC demonstrated antifibrotic effect without impact on underlying steatohepatitis at Year 1 (ITT) Arm A vs. Arms B+C 25% 2-point improvement in NAS AND No worsening of fibrosis Complete resolution of NASH AND No worsening of fibrosis Improvement in fibrosis stage AND No worsening of NASH CVC 15% 19% p= % p= % 5% 6% p=0.50 8% 10% 0% n=144 n=145 n=144 n=145 n=144 n=145 Primary endpoint Key secondary endpoints (surrogate composite endpoints) CVC, cenicriviroc; ITT, intent-to-treat (missing data counted as failure); NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis Friedman SL, Hepatology 2017 Wong V, APASL Annual Meeting 2017 Lefebvre E, EASL-AASLD Meeting

6 Subject Disposition Assessed for eligibility (N=812) Underwent liver biopsy (n=610) Randomized (n=289) Excluded (n=523) Not meeting eligibility criteria (n=436) Withdrew consent (n=31) Lost to follow-up (n=12) Other reasons (n=44) Randomized: Baseline (N=289) (Month 0) Arm A (n=145) Arm B (n=72) Arm C (n=72) Entered treatment: Start of Year 2 (N=242) (Month 13) Arm A (n=121) Arm B (n=61) Arm C (n=60) Early withdrawal (n=12) Adverse event (n=5) Early withdrawal (n=2) Adverse event (n=1) Early withdrawal (n=2) Adverse event (n=0) Treatment completers: End of Year 2 (N=226) (Month 24) Arm A (n=109) Arm B (n=59) Arm C (n=58) Post-randomization biopsy at Year 2 Evaluable (n=99) Non-evaluable (n=4) Missing (n=42) Post-randomization biopsy at Year 2 Evaluable (n=60) Non-evaluable (n=0) Missing (n=12) Post-randomization biopsy at Year 2 Evaluable (n=54) Non-evaluable (n=2) Missing (n=16) 6

7 Study Participants Baseline characteristics of participants included in the Year 2 analysis CVC (Arm A) /CVC (Arm B) (Arm C) Total No. of participants at start of Year 2 (FAS) Participants with evaluable biopsies at Year 2, n (%) 99 (68.3) 60 (83.3) 54 (75.0) 213 (73.7) Demographics Age at screening, mean Female, n (%) 54 (44.6) 34 (55.7) 31 (51.7) 119 (49.2) White, n (%) 106 (87.6) 52 (85.2) 49 (81.7) 207 (85.5) Type 2 diabetes, n (%) 73 (60.3) 29 (47.5) 25 (41.7) 127 (52.5) BMI, mean (kg/m 2 ) NAS at Screening, n (%) 4 36 (29.8) 13 (21.3) 15 (25.0) 64 (26.4) 5 85 (70.2) 48 (78.7) 45 (75.0) 178 (73.6) NASH CRN Fibrosis stage, n (%) Stage 1 42 (34.7) 19 (31.1) 21 (35.0) 82 (33.9) Stage 2 33 (27.3) 18 (29.5) 15 (25.0) 66 (27.3) Stage 3 46 (38.0) 24 (39.3) 24 (40.0) 94 (38.8) FAS, Full analysis set (at Year 2); CVC = cenicriviroc; NASH, nonalcoholic steatohepatitis; NASH CRN, NASH Clinical Research Network; BMI, body mass index 7

8 Efficacy Endpoints Main comparisons of CENTAUR Year 2 analyses Histological endpoints Improvement in fibrosis ( 1 stage) Improvement in fibrosis ( 1 OR 2 stages) AND no worsening of NASH Baseline Year 1 Year 2 Arm A N=289 Randomization 2:1:1 Arm B Arm C Maintenance of antifibrotic response from Year 1 to Year 2 (Arm A vs. Arm C) Effects of 2 years of CVC treatment (Arm A vs. Arm C) Effects of 1 year of CVC treatment (pooled CVC data; Arms A + B vs. Arm C) Safety and tolerability of CVC vs. during Year 2 8

9 Efficacy Endpoints Main comparisons of CENTAUR Year 2 analyses Histological endpoints Improvement in fibrosis ( 1 stage) Improvement in fibrosis ( 1 OR 2 stages) AND no worsening of NASH Baseline Year 1 Year 2 Arm A N=289 Randomization 2:1:1 Arm B Arm C Maintenance of antifibrotic response from Year 1 to Year 2 (Arm A vs. Arm C) Effects of 2 years of CVC treatment (Arm A vs. Arm C) Effects of 1 year of CVC treatment (pooled CVC data; Arms A + B vs. Arm C) Safety and tolerability of CVC vs. during Year 2 9

Safety Endpoints Main comparisons of CENTAUR Year 2 analyses Histological endpoints Improvement in fibrosis ( 1 stage) Improvement in fibrosis ( 1 OR 2 stages) AND no worsening of NASH Baseline Year

10 Safety Endpoints Main comparisons of CENTAUR Year 2 analyses Histological endpoints Improvement in fibrosis ( 1 stage) Improvement in fibrosis ( 1 OR 2 stages) AND no worsening of NASH Baseline Year 1 Year 2 N=289 Randomization 2:1:1 Arm A Arm B Arm C Maintenance of antifibrotic response from Year 1 to Year 2 (Arm A vs. Arm C) Effects of 2 years of CVC treatment (Arm A vs. Arm C) Effects of 1 year of CVC treatment (pooled CVC data; Arms A + B vs. Arm C) Safety and tolerability of CVC vs. during Year 2 10

11 Proportion of participants, mitt (%) Results CVC treatment is associated with greater maintenance of antifibrotic response (Arm C) Response from Year 1 to Year 2 Arm A vs. Arm C CVC (Arm A) 100% Arm C, Overall Arm C, by fibrosis stage 100% Arm A, Overall Arm A, by fibrosis stage 80% 80% 86% n=12 60% 60% 60% 60% 40% 30% n=3 n=3 40% n=18 40% n=4 33% n=2 0% 0% 0% Total F3 F2 F1 0% Total F3 F2 F1 n=10 n=5 n=2 n=3 n=30 n=14 n=10 n=6 Maintained 1-stage improvement in fibrosis No change from Baseline Of 36 CVC responders at Year 1, 6 had missing Year 2 biopsy, 4 of whom were NASH CRN Stage 3 at baseline mitt, Modified intent-to-treat population: participants in the ITT population Worsened compared to Baseline 11

12 Proportion of participants, mitt (%) Results 1-stage antifibrotic response with CVC following 2 years of treatment Baseline to Year 2 Arm A vs. Arm C 30% 25% 22% p= % p=0.94 CVC Post-randomization biopsy at Year 2 n (%) CVC n (%) 15% 10% 17% 15% Randomized Evaluable 54 (75%) 99 (68.3%) Non-evaluable 2 (2.8%) 4 (2.8%) Missing* 16 (22.2%) 42 (29.0%) 5% 0% n=54 n=99 Improvement in fibrosis by 1 stage n=54 n=99 Improvement in fibrosis by 1 stage AND no worsening of NASH Percentages based on randomized participants *Participants with missing post-baseline biopsies were considered non-responders and excluded from the mitt analysis *Imbalance in missing liver biopsies at Year 2 predominantly affected Arm A 12 mitt, modified intent-to-treat population: participants in the ITT population with evaluable paired biopsies

13 Proportion of participants, mitt (%) Results 2-stage antifibrotic response with CVC after 1 and 2 years of treatment 14% 12% Arm A vs. Arm C (Subjects with Stage 2 or 3 Fibrosis) Baseline to Year 1 Baseline to Year 2 p=0.13 CVC 10% p= % 11% 8% 6% 4% 2% 3% 3% 0% n=38 n=82 Improvement in fibrosis by 2 stages AND no worsening of NASH mitt, Modified intent-to-treat population: participants in the ITT population with evaluable paired biopsies, excluding those with Stage 1 fibrosis at baseline n=34 n=65 13

Proportion of participants, mitt (%) Results Antifibrotic response in totality of participants treated with CVC for 1 year is consistent with Year 1 primary analysis findings 35% 30% Pooled CVC

14 Proportion of participants, mitt (%) Results Antifibrotic response in totality of participants treated with CVC for 1 year is consistent with Year 1 primary analysis findings 35% 30% Pooled CVC analysis Baseline to Year 1 (Arms A, C); Year 1 to Year 2 (Arm B) Arms A+B vs. Arm C p= % CVC 25% 15% p= % 10% 13% 5% 0% mitt, modified intent-to-treat population n=60 n=186 Improvement in fibrosis by 1 stage n=60 n=186 Improvement in fibrosis by 1 stage AND no worsening of NASH 14

15 Proportion of participants, mitt (%) Results Seesaw effect: substantial variability in fibrosis stage in placebo group Arm C Change in Fibrosis Stage from Baseline to Year 1 100% Change in Fibrosis Stage Year 1 to Year 2 Change in Fibrosis Stage from Baseline to Year 2 100% Improved Year 1 80% 10% 10% 22% 80% 80% 60% 45% Stable Year 1 8% 65% 27% 60% 56% 40% 40% 35% Worsened Year 1 27% 53% 22% 0% Baseline to Year 1 0% 0% 40% 60% 80% 100% Improved No change Worsened Baseline to Year 2 n=60 n=54 Data based on modified intent-to-treat population analysis set for Year 1 to Year 2 15

16 Results Mean change from baseline, FAS ChangeatDay720 ChangeatDay720 ChangeatDay720 Fibrinogen CVC treatment reduced markers of systemic inflammation at Year 2 Baseline to Year 2 Arm A vs. Arm C CVC IL-1β pg/ml [-0.06; 0.03] 95% CI IL-8 pg/ml [-1.2; 6.9] 95% CI hs-crp mg/l [-1.1; 0.1] 95% CI 40 Fibrinogen mg/dl [-58; -1] 95% CI Data based on Full Analysis Set; 95% confidence interval (CI) for the location shift (CVC minus placebo) by Hodges Lehmann estimation CVC, cenicriviroc; hs-crp, high-sensitivity C-reactive protein; IL-1β, interleukin-1 beta; IL-8, interleukin-8 Associated with CV Outcomes 16

17 Mean change from baseline ±SEM, (FAS) Results CVC treatment associated with rapid and sustained reductions in fibrinogen Fibrinogen (mg/dl) Arm C Arm B Arm A Study Days -70 FAS, full analysis set; SEM, standard error of the mean 17

18 Results CVC treatment was well tolerated over the second year of treatment CVC (Arm A) n (%) /CVC (Arm B) n (%) (Arm C) n (%) No. of Participants (SAS, N=242) Treatment-emergent adverse events 105 (86.8) 46 (75.4) 50 (83.3) Maximum severity grade Grade 1 (Mild) 40 (33.1) 25 (41.0) 22 (36.7) Grade 2 (Moderate) 47 (38.8) 17 (27.9) 19 (31.7) Grade 3 (Severe) 17 (14.0) 4 (6.6) 8 (13.3) Grade 4 (Life-threatening) 1 (0.8) 0 1 (1.7) Any study drug-related TEAE 19 (15.7) 6 (9.8) 9 (15.0) Discontinued study due to TEAE 5 (4.1) 0 0 Grade 2 drug-related TEAEs in 2% 10 (8.3) 0 3 (5.0) Alanine aminotransferase increased 3 (2.5) 0 2 (3.3) Treatment-emergent SAEs Any SAE 13 (10.7) 3 (4.9) 9 (15.0) Resulted in subject discontinuation 1 (0.8) 0 0 Any study drug-related SAE Death Treatment-emergent adverse events, n (%); N = number of participants in the Safety Analysis Set (SAS) Population at Year 2. Treatment-emergent adverse events included all events with a start date/time after the date of first dose of study medication during the treatment period. No deaths were reported during the course of the study up to database lock [1] An adverse event was considered related if the Investigator indicated the event was possibly, probably, or definitely related to study drug. CVC = cenicriviroc; SAE = serious adverse event; TEAE = treatment-emergent adverse event. 18

19 Summary and Conclusions Final results of the 2-Year Phase 2b CENTAUR study with CCR2/5 inhibitor Cenicriviroc Year 2 exploratory analyses corroborate cenicriviroc s antifibrotic activity in adults with NASH and liver fibrosis, supporting Year 1 primary analysis findings Twice as many cenicriviroc-treated participants achieving 1-stage improvement in fibrosis at Year 1 maintained this benefit at Year 2 compared to placebo, particularly in Stage 3 fibrosis A numerically greater proportion of cenicriviroc-treated participants achieved 2-stage improvement in fibrosis AND no worsening of NASH at Years 1 and 2 compared to placebo, further supporting cenicriviroc s antifibrotic mode of action Biomarker analyses over a 2-year period suggest that cenicriviroc continues to exert systemic anti-inflammatory activity, while being neutral on metabolic disturbances Safety and tolerability of cenicriviroc was comparable to placebo during the Year 2 treatment period, expanding on the substantial clinical safety database of this agent 19

20 Summary and Conclusions Final results of the 2-Year Phase 2b CENTAUR study with CCR2/5 inhibitor Cenicriviroc Key study limitations: Higher attrition rate (23%) than anticipated (15%) over 2 years Possibly associated with requirement of 3 serial biopsies over a 2 year period Imbalance in missing liver biopsy data predominantly affected Arm A, limiting current evaluation of Year 2 timepoint Substantial seesaw effect in fibrosis improvement observed in serial biopsies of participants receiving placebo for 2 years (Arm C) May reflect the natural history of NASH Highlights the need to identify prognostic biomarkers for patient selection Phase 3 evaluation of cenicriviroc for treatment of liver fibrosis associated with NASH is underway (NCT ) 20

Acknowledgments This study was sponsored by Allergan plc The

their families, the CENTAUR study investigators, research

Muller (A Wigg) R Skoien E Tse Belgium S Francque D Cassiman N

V de Ledinghen M Maynard D Samuel L Serfaty Germany Hong Kong Italy

van Boemmel T Wissniowski VW Wong A Craxὶ P Andreone S Fargion P

United Kingdom United States J Caballeria P Bellot A Fernandez

Abdelmalek S Alqahtani (M Sulkowski) B Aqel H Arnold L Balart M

M Fallon (MI Nevah Rubin) J Gallegos-Orozco R Hardi S Harrison (A

J Lalezari A Siddique R Loomba S Sigal A Martinez (J Park) C

21 Acknowledgments This study was sponsored by Allergan plc The sponsor and authors would like to thank study participants and their families, the CENTAUR study investigators, research coordinators, and study staff Australia G Farrell P Angus A Hodge K Muller (A Wigg) R Skoien E Tse Belgium S Francque D Cassiman N Lanthier C Moreno France V Ratziu J Boursier JP Bronowicki C Bureau V de Ledinghen M Maynard D Samuel L Serfaty Germany Hong Kong Italy Poland F Tacke M Demir J Kluwe A Pathil-Warth I Schiefke E Schott F van Boemmel T Wissniowski VW Wong A Craxὶ P Andreone S Fargion P Invernizzi (M Carbone) K Simon M Jablkowski E Janczewska Spain United Kingdom United States J Caballeria P Bellot A Fernandez Yunquera J Genesca G Soriano GP Aithal W Alazawi A Fowell M Abdelmalek S Alqahtani (M Sulkowski) B Aqel H Arnold L Balart M Bansal C Barish B Bilir M Chojkier H Conjeevaram JN Cooper K Corey M Fallon (MI Nevah Rubin) J Gallegos-Orozco R Hardi S Harrison (A Paredes) M Hernandez ME Jonas Z Kayali N Kemmer KV Kowdley R Krause J Lalezari A Siddique R Loomba S Sigal A Martinez (J Park) C McClain BS Smith S Moussa S Tarwater J Phillips P Thuluvath F Poordad JC Williams A Sanyal Z Younes N Shah D Zogg 21

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