Effi cacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir ...
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E fficacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve Adults With HCV Genotype 1–6 and Aspartate Aminotransferase to Platelet Ra o Index (APRI) ≤1 Robert J Fontana 1 , Sabela Lens 2 , Stuart McPherson 3 , Magdy Elkhashab 4 , Krum Katzarov 5 , Ana Gabriela Pires dos Santos 6 , Zhenyi Xue 6 , Roger Trinh 6 , Lino Rodrigues Junior 6 , Ariel Porcalla 6 , Stefan Zeuzem 7 1 Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, United States; 2 Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, Barcelona, Spain; 3 Liver Unit, The Newcastle upon Tyne Hospitals NHS Foundaon and Trust and Newcastle University, United Kingdom; 4 Toronto Liver Centre, Toronto, Ontario, Canada; 5 Department of Gastroenterology, Hepato-Pancreato-Biliary (HPB) Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria; 6 AbbVie Inc., North Chicago, Illinois, United States; 7 JW Goethe University, Frankfurt, Germany INTRODUCTION • WHO global target of HCV eliminaon by 2030 depends on access to tesng and treatment with direct acng anvirals 1 • Linkage to care following HCV diagnosis is a gap in the HCV care cascade, in part due to need for specialists in the comprehensive and costly evaluaon for presence or absence of cirrhosis using either liver biopsy or transient elastography 1,2 • Aspartate aminotransferase to platelet rao index (APRI) is a low-cost, widely available, non-invasive method, for which APRI ≤1 has high negave predicve value (94%) for cirrhosis compared to biopsy 3,4 • Non-invasive markers, including APRI, may be used to assess for cirrhosis prior to HCV treatment according to WHO, EASL, Australian, and Canadian guidelines 5–8 G/P is Approved for Paents With HCV GT1–6 Infecon • 8-week duraon approved for treatment-naïve paents with HCV genotype (GT) 1–6 infecon and without cirrhosis 9 • Pangenotypic SVR12 rate of 98% in more than 2200 paents in registraonal studies • Potent against common polymorphisms (eg, Y93H in NS5A and Q80K in NS3) • Recent real-world results demonstrate that G/P achieved high SVR12 rates consistent with those observed in clinical trials 10,11 • Favorable safety profile irrespecve of baseline factors Glecaprevir pangenotypic NS3/4A protease inhibitor Pibrentasvir pangenotypic NS5A inhibitor Coformulated: G/P r tre ea at t tm me en nt t t-n na aï ï ï ïv ve e p pa a e en nt t t ts s w wi i i i it t t th h h h h H H H H HC CV g 98% in more than 2200 paents in reg C C C C Co o o o o of f f f f o o o or r r r m m m m mu u u u u u ul l l l a a a a a a at t t t t e e e e ed d d d d: : : : : G G G G G G/ / / / / P P P P GLE PIB G/P dosed as 3 pills taken once daily with food for a total dose of 300 mg/120 mg. Glecaprevir was idenfied by AbbVie and Enanta. OBJECTIVE Evaluate whether treatment-naïve paents with APRI ≤1 would achieve high SVR12 rates with 8-week G/P regimen. METHODS • Phase 3, open label, single-arm, mulcenter study conducted from August 7th, 2017 to August 13th, 2018 – Paents were enrolled in Bulgaria, Canada, France, Germany, Poland, Puerto Rico, Russia, Spain, United Kingdom, and United States of America • Data were analyzed on an intent-to-treat (ITT) populaon (all paents who received ≥1 dose of G/P) and on a modified ITT (mITT) populaon (excluding paents who did not achieve SVR12 for reasons other than virologic failure, like missing SVR12 data or premature G/P disconnuaon) – Virologic failure included any virologic breakthrough during treatment or post-treatment relapse • APRI was assessed at screening using the following formula: U T S A ( L ) U T S A (ULN ) ( L ) 10 9 APRI = Platelet Count ( L ) × 100 Presented at The Liver Meeng of the American Associaon for the Study of Liver Diseases (AASLD), November 9–13, 2018, San Francisco, California, United States FRI-653 REFERENCES 1. World Health Organizaon. Global Hepas Report. Geneva, Switzerland. 2017. 2. Calvaruso V, et al. Is global eliminaon of HCV realisc? Liver Internaonal. 2018;38 (Suppl. 1):40–6. 3. Chou R and Wasson N. Blood tests to diagnose fibrosis or cirrhosis in paents with chronic hepas C virus infecon. Annals of Internal Medicine. 2018;158(11):807–20. 4. Kelly ML, et al. Capacity of non-invasive hepac fibrosis algorithms to replace transient elastography to exclude cirrhosis in people with hepas C virus infecon: A mul-centre observaonal study. PLoS ONE. 2018;13:e0192763. 5. World Health Organizaon. Guidelines for the care and treatment of persons diagnosed with chronic hepas C infecon. Geneva, Switzerland. 2018. 6. European Associaon for the Study of the Liver. EASL Recommendaons on Treatment of Hepas C 2018. J Hepatol. 2018;69:461–511. 7. Hepas C Virus Infecon Consensus Statement Working Group. Australian recommendaons for the management of hepas C virus infecon: a consensus statement (September 2018). Melbourne: Gastroenterological Society of Australia, 2018. 8. Shah H, et al. The management of chronic hepas C: 2018 guideline update from the Canadian Associaon for the Study of the Liver. CMAJ. 2018;190(22):E677–87. 9. MAVYRET [US Package Insert]/MAVIRET [SmPC], AbbVie 2017. 10. T Berg, U Naumann, A Stoehr, et al. GS-007, EASL/ILC, April 13, 2018. 11. R D’Ambrosio, L Pasulo, M Puo, et al. GS-013, EASL/ILC, April 14, 2018. 12. Kamil RJ, et al. Case-control study evaluang compeng risk factors for angioedema in a high-risk populaon. Laryngoscope. 2016;126(8):1823–30. DISCLOSURES Robert J Fontana: Research support from BMS, Gilead, AbbVie; Consulng: Alynam. Stuart McPherson: Consultancy/speakers fees: AbbVie, Allergan, BMS, Gilead, MSD, Novars. Sabela Lens: Advisor: Janssen, Gilead, AbbVie. Magdy Elkhashab: Grant support from AbbVie; Advisor for AbbVie. Stefan Zeuzem: Consultancies for AbbVie, BMS, Gilead, Janssen, Merck. Krum Katzarov: nothing to disclose. Ana Gabriela Pires dos Santos, Roger Trinh, Zhenyi Xue, Lino Rodrigues Junior, and Ariel Porcalla are employees of AbbVie Inc. and may hold stock or stock opons. AbbVie sponsored the study (NCT03212521), contributed to its design and collecon, analysis, and interpretaon of the data, and parcipated in the wring, review, and approval of the abstract. All authors had access to relevant data. Glecaprevir was idenfied by AbbVie and Enanta. PATIENTS • The Baseline Demographics and Disease Characteriscs are summarized in Table 1 for both the mITT and ITT populaons • Among the 230 paents in the ITT populaon, 99 (43%) had a history of a psychiatric disorder Table 1. Baseline Demographics and Disease Characteris cs Characteristic mITT population N = 222 ITT population N = 230 Male, n (%) 111 (50) 117 (51) Race, n (%) White 202 (91) 207 (90) Black or African American 10 (5) 13 (6) Asian 10 (5) 10 (4) Hispanic or Latino ethnic origin, n (%) 23 (10) 25 (11) Age, median (range), years 48 (19–82) 48 (19–82) Age ≥65 years old, n (%) 23 (10) 25 (11) BMI, median (range), kg/m 2 25.3 (16. 9–55.6) 25.2 (16. 9–55.6) Baseline HCV RNA level, median (range), log 10 IU/mL 6.3 (2.2–7.7) 6.3 (2.2–7.7) Baseline HCV RNA ≥1 million IU/mL, n (%) 141 (64) 146 (63) HCV genotype, n (%) GT1 145 (65) 151 (66) GT1a 77 (35) 82 (36) GT1b 67 (30) 68 (30) GT2 33 (15) 33 (14) GT3 33 (15) 35 (15) GT4 9 (4) 9 (4) GT6 2 (<1) 2 (<1) Key baseline polymorphisms, n (%)* Any NS3 polymorphism 1 (<1) 1 (<1) Any NS5A polymorphism 68 (31) 71 (31) Screening APRI, median (range) 0.41 (0.13–1.0) 0.41 (0.`1.0) Screening APRI, n (%) ≤0.5 136 (61) 140 (61) 0.5–0.7 54 (24) 57 (25) 0.71–1.0 32 (14) 33 (14) Blinded Fibrotest, median (range) † 0.26 (0.02–0.87) 0.26 (0.02–0.87) Platelet count, median (range), count/10 9 /L 243 (126–462) 243 (126–483) HIV co-infection, n (%) ‡ 8 (4) 10 (4) CD4+ T-cell count, median (range), cells/mm 3§ 762 (444–1199) 692 (444–1199) History of injection drug use, n (%) 83 (37) 87 (38) Within the last 12 months 5 (2) 6 (3) More than 12 months ago 78 (35) 81 (35) On stable opiate substitution, n (%) 19 (9) 19 (8) History of diabetes, n (%) 7 (3) 9 (4) History of depression or bipolar disorder, n (%) 43 (19) 45 (20) BMI, body-mass index; HCV, hepas C virus; GT, genotype; APRI, Aspartate aminotransferase to platelet rao; HIV, human immunodeficiency virus. *Includes any baseline resistance-associated variants in NS3 (155, 156, and 168) or NS5A (24, 28, 30, 31, 58, 92, and 93) at a 15% detecon threshold. No paents had both a NS3 and a NS5A key resistance-associated variant. † Performed at baseline, blinded to the invesgators and therefore, not used for paent eligibility. ‡ All paents with HIV co-infecon were anretroviral therapy-naïve. § Only assessed in the 10 HIV/HCV co-infected paents. EFFICACY • The primary efficacy endpoint was met, with an overall SVR12 rate in the mITT populaon of 100% (222/222, 95%CI = 98.3–100) (Figure 2) • The sequenal secondary endpoint was also met, with an overall SVR12 rate in the ITT populaon of 96.5% (222/230, 95%CI = 94.2–98.9). Eight (3%) paents did not achieve SVR12 due to non-virologic failure reasons (Figure 2) • No paents experienced on-treatment virologic failure or post-treatment relapse • High SVR12 rates were observed in all HCV genotypes (Figure 3) • Nighty-nine percent (202/204) of paents were adherent to the treatment (≥80% and ≤120% adherence) among paents with available data at all treatment visits 44073-HCV-FRI-653 — AASLD 2018 — AbbVie — proof 4 (rjh) — october 26, 2018 the henderson company 6020 keating avenue, chicago illinois 60646 (847) 979-8051 CREATED @ 100% ACKNOWLEDGEMENTS • The authors would like to express their gratude to the paents and their families, invesgators, and coordinators who made this study possible. • Medical wring support was provided by Dan O’Brien, PhD, of AbbVie. METHODS Έ CONTINUEDΉ Figure 1. Study Design BL Weeks SVR12 G/P 300/120 mg 8-week treatment (N = 230) GT1–6, TN, and APRI ≤1 Post-treatment Week 12 8 Open-label Treatment Screening BL, baseline; G/P, glecaprevir/pibrentasvir; SVR12, sustained virologic response at post-treatment Week 12; TN, treatment-naïve; APRI, aspartate aminotransferase to platelet rao index; GT, genotype. KEY INCLUSION CRITERIA • Adult male or female, at least 18 years old at the me of screening • HCV treatment naïve with chronic HCV genotype (GT) 1, 2, 3, 4, 5, or 6 infecon (mixed GT and indeterminate GT were acceptable) • Posive an-HCV Ab and HCV RNA ≥1000 IU/mL for ≥6 months prior to and at screening • APRI score ≤1 at the me of screening • HIV-1 negave or HIV-1 posive (naïve or on stable qualifying anretroviral therapy) KEY EXCLUSION CRITERIA • Any prior evidence of cirrhosis; however, formal assessment for cirrhosis was not required • Presence of hepas B or hepatocellular carcinoma • ALT or AST >10 × upper limit of normal (ULN) • Direct bilirubin >ULN • Platelet count <150 000 cells/mm 3 • Albumin <lower limit of normal • Creanine clearance (Cockcroſt -Gault) <30 mL/min • History of organ transplantaon ENDPOINTS AND ANALYSES Sequenal E fficacy Endpoints (fixed sequence tesng procedure): Primary Efficacy Endpoint Secondary Efficacy Endpoints Percentage of paents with SVR12 in the ITT populaon • Efficacy will be established if the lower bound of the 95%CI is greater than the threshold of 91.4%, based on the mITT threshold minus an expected 1% rate of non-virological SVR failures Percentage of paents with SVR12 (HCV RNA <LLOQ 12 weeks aer the last dose of study drug) in the mITT populaon • Efficacy will be established if the lower bound of the 95% confidence interval (95%CI) is greater than the threshold of 92.4%, based on the historical rate observed in GLE/PIB registraonal studies in treatment-naïve, non-cirrhoc subjects (98.4%) minus a margin of 6% Non-sequenal Endpoints: Secondary Efficacy Endpoints • Percentage of paents with on-treatment virologic failure in ITT populaon • Percentage of paents with post-treatment relapse in ITT populaon Addional Assessments: Safety Assessments Adverse events (AEs) † and key laboratory abnormalies were assessed in ITT populaon • Treatment adherence* conducted in ITT populaon • Number and percentage of paents with viral suppression (HCV RNA <LLOQ) at treatment visits in paents with available data Addional Analyses SVR12, sustained virologic response at 12 week post-treatment; HCV, hepas C virus; LLOQ, lower limit of quanficaon; ITT, intent-to-treat; CI, confidence interval; mITT, modified ITT; AE, adverse event. *Treatment adherence defined as use of ≥80% and ≤120% of the expected total number of tablets. † Includes AEs leading to treatment disconnuaons, AEs occurring in ≥5% of paents, serious AEs, and DAA-related serious AEs. Figure 2. E fficacy of 8-week G/P Regimen in HCV Treatment-naïve Paents With APRI ≤1 mITT ITT 0 20 40 80 100 222 222 222 230 100 97 Breakthrough Relapse Premature G/P d/c Missing SVR 12 0 0 N/A N/A Reason for non-response, n (%) 0 0 3 (1%)* 5 (2%) † % Paents With SVR12 mITT, modified intent-to-treat; ITT, intent-to-treat; SVR12, sustained virologic response at 12-week post-treatment; CI, confidence interval; G/P, glecaprevir/pibrentasvir; d/c disconnuaon. Doed lines indicate threshold above which lower bound of 95%CI must be greater than in mITT and ITT populaons in order to meet primary and secondary endpoint, respecvely. *Includes 2 paents who prematurely disconnued due to a serious AE (see Table 3). † All 5 paents missing SVR12 data had no detectable HCV RNA at end of treatment. Table 2. Number and Percentage of Paents With Viral Suppression Over Time Viral Suppression at Treatment Visit, n/N (%)* 8-week G/P treatment Week 4 214/225 (95) Week 8 (EOT) 211/211 (100) Final treatment visit † 226/226 (100) G/P, glecaprevir/pibrentasvir; EOT, end of treatment. *Viral suppression reported as number and percentage of paents with HCV RNA less than lower limit of quanficaon at each post-baseline treatment visit in paents with available SVR data. †The last visit for a paent during G/P treatment. Figure 3. E fficacy by Genotype for 8-week G/P Regimen in HCV Treatment-naïve Paents With APRI ≤1 GT1 GT2 GT3 GT4 GT6 0 20 40 60 80 100 HCV Genotype mITT ITT 146 146 146 152 32 32 33 33 33 35 9 9 2 2 2 2 100 96 100 100 94 100 100 100 32 32 100 9 9 100 % Paents With SVR12 mITT, modified intent-to-treat; ITT, intent-to-treat; GT, genotype; SVR12, sustained virologic response at 12-week post-treatment; HCV, hepas C virus. SAFETY • Overall, 124 (54%) paents experienced an AE, of which 8 (3%) paents had a grade 3 or higher AE (Table 3) • Two (1%) paents experienced serious AEs of angioedema that led to premature G/P disconnuaon – Both were African American and former drug users (both risk factors for angioedema) and were taking an ACE inhibitor (lisinopril), a common cause of drug-induced angioedema 12 • The most common AEs (occurring in ≥5% of all paents) were headache (13%) and fague (7%) • No grade ≥3 laboratory abnormalies in ALT, AST, or total bilirubin were observed RESULTS Table 3. Adverse Events and Laboratory Abnormalies Event, n (%) ITT population N = 230 Any AE 124 (54) Grade ≥3 AE 8 (3) Serious AE 4 (2) DAA-related* serious AE 2 (1) † AE leading to premature G/P discontinuation 2 (1) † AEs occurring in ≥5% of all patients by preferred term Headache 29 (13) Fatigue 17 (7) Laboratory abnormalities (Grade ≥3) ALT >5 × ULN ‡ 0 AST >5 × ULN 0 Total bilirubin >3 × ULN 0 Deaths 0 G/P, glecaprevir/pibrentasvir; AE, adverse event; DAA, direct acng anviral; ALT, alanine aminotransferase; ULN, upper limit of normal; AST, aspartate aminotransferase. *As assessed by the invesgator. † Two paents experienced a serious AE of angioedema leading to premature G/P disconnuaon on Days 8 and 15, respecvely. ‡ Post-nadir increase in grade to Grade ≥3. Scan QR code to download an electronic version of this presentaon (poster 653) and other AbbVie AASLD 2018 Scienfic Presentaons. To obtain a QR code reader, go to your device app store and search for “QR code reader.” QR code expiraon: 27 November 2018. CONCLUSIONS The study met its primary and secondary efficacy endpoints with SVR12 rates of 100% and 96.5% in mITT and ITT populaons, respecvely – No virologic failures were observed in treatment-naïve HCV GT1–6- infected paents with an APRI ≤1 treated with 8-week G/P regimen G/P was well-tolerated with no Grade ≥3 laboratory abnormalies in ALT, AST, and total bilirubin, as well as with low rates of serious AEs (2%) and AEs leading to premature G/P disconnuaon (1%) Treang paents infected with HCV GTs 1–6 and with an APRI score of ≤1 with 8 weeks of G/P was highly efficacious and well tolerated Paents with APRI ≤1 and no prior evidence of cirrhosis can be successfully treated with G/P for 8 weeks, suggesng that APRI can be used in simplified HCV management strategies LIMITATIONS • This was a single-arm, open-label trial without a placebo arm; however, the use of objecve measures for efficacy (SVR12) and the comparison with a pre-specified threshold considering historical reference SVR12 rates (efficacy observed in the registraonal program) migates this concern PRESENTATION NOTES Data to be presented at AASLD 2018 on EXPEDITION-8 (LB-7) that assessed safety and efficacy of 8-week G/P regimen in treatment-naïve paents with compensated cirrhosis and HCV GT1, 2, 4–6 infecon.
Transcript of Effi cacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir ...
Effi cacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve Adults With HCV Genotype 1–6 and Aspartate Aminotransferase to Platelet Rati o Index (APRI) ≤1Robert J Fontana1, Sabela Lens2, Stuart McPherson3, Magdy Elkhashab4, Krum Katzarov5, Ana Gabriela Pires dos Santos6, Zhenyi Xue6, Roger Trinh6, Lino Rodrigues Junior6, Ariel Porcalla6, Stefan Zeuzem7
1Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, United States; 2Liver Unit, Hospital Clinic, IDIBAPS and CIBERehd, Barcelona, Spain; 3Liver Unit, The Newcastle upon Tyne Hospitals NHS Foundati on and Trust and Newcastle University, United Kingdom; 4Toronto Liver Centre, Toronto, Ontario, Canada; 5Department of Gastroenterology, Hepato-Pancreato-Biliary (HPB) Surgery and Transplantology, Military Medical Academy, Sofi a, Bulgaria; 6AbbVie Inc., North Chicago, Illinois, United States; 7JW Goethe University, Frankfurt, Germany
INTRODUCTION• WHO global target of HCV eliminati on by 2030 depends on access to testi ng
and treatment with direct acti ng anti virals1
• Linkage to care following HCV diagnosis is a gap in the HCV care cascade, in part due to need for specialists in the comprehensive and costly evaluati on for presence or absence of cirrhosis using either liver biopsy or transient elastography1,2
• Aspartate aminotransferase to platelet rati o index (APRI) is a low-cost, widely available, non-invasive method, for which APRI ≤1 has high negati ve predicti ve value (94%) for cirrhosis compared to biopsy3,4
• Non-invasive markers, including APRI, may be used to assess for cirrhosis prior to HCV treatment according to WHO, EASL, Australian, and Canadian guidelines5–8
G/P is Approved for Pati ents With HCV GT1–6 Infecti on
• 8-week dura�on approved for treatment-naïve pa�ents with HCV genotype (GT) 1–6 infec�on and without cirrhosis9
• Pangenotypic SVR12 rate of 98% in more than 2200 pa�ents in registra�onal studies
• Potent against common polymorphisms (eg, Y93H in NS5A and Q80K in NS3)
• Recent real-world results demonstrate that G/P achieved high SVR12 rates consistent with those observed in clinical trials10,11
• Favorable safety profile irrespec�ve of baseline factors
Glecaprevirpangenotypic NS3/4A
protease inhibitor
Pibrentasvirpangenotypic NS5A
inhibitor
Coformulated: G/P
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98% in more than 2200 pa�ents in reg
CCCCCoooooofffffoooorrrrmmmmmuuuuuuullllaaaaaaattttteeeeeddddd::::: GGGGGG/////PPPP
GLE PIB
G/P dosed as 3 pills taken once daily with food for a total dose of 300 mg/120 mg.Glecaprevir was identi fi ed by AbbVie and Enanta.
OBJECTIVEEvaluate whether treatment-naïve pati ents with APRI ≤1 would achieve high SVR12 rates with 8-week G/P regimen.
METHODS• Phase 3, open label, single-arm, multi center study conducted from August
7th, 2017 to August 13th, 2018
– Pati ents were enrolled in Bulgaria, Canada, France, Germany, Poland, Puerto Rico, Russia, Spain, United Kingdom, and United States of America
• Data were analyzed on an intent-to-treat (ITT) populati on (all pati ents who received ≥1 dose of G/P) and on a modifi ed ITT (mITT) populati on (excluding pati ents who did not achieve SVR12 for reasons other than virologic failure, like missing SVR12 data or premature G/P disconti nuati on)
– Virologic failure included any virologic breakthrough during treatment or post-treatment relapse
• APRI was assessed at screening using the following formula:
U TSA (L )
U TSA (ULN ) (L )
109
APRI =
Platelet Count ( L )
× 100
Presented at The Liver Meeti ng of the American Associati on for the Study of Liver Diseases (AASLD), November 9–13, 2018, San Francisco, California, United States
FRI-653
REFERENCES 1. World Health Organizati on. Global Hepati ti s Report. Geneva, Switzerland. 2017.
2. Calvaruso V, et al. Is global eliminati on of HCV realisti c? Liver Internati onal. 2018;38 (Suppl. 1):40–6.
3. Chou R and Wasson N. Blood tests to diagnose fi brosis or cirrhosis in pati ents with chronic hepati ti s C virus infecti on. Annals of Internal Medicine. 2018;158(11):807–20.
4. Kelly ML, et al. Capacity of non-invasive hepati c fi brosis algorithms to replace transient elastography to exclude cirrhosis in people with hepati ti s C virus infecti on: A multi -centre observati onal study. PLoS ONE. 2018;13:e0192763.
5. World Health Organizati on. Guidelines for the care and treatment of persons diagnosed with chronic hepati ti s C infecti on. Geneva, Switzerland. 2018.
6. European Associati on for the Study of the Liver. EASL Recommendati ons on Treatment of Hepati ti s C 2018. J Hepatol. 2018;69:461–511.
7. Hepati ti s C Virus Infecti on Consensus Statement Working Group. Australian recommendati ons for the management of hepati ti s C virus infecti on: a consensus statement (September 2018). Melbourne: Gastroenterological Society of Australia, 2018.
8. Shah H, et al. The management of chronic hepati ti s C: 2018 guideline update from the Canadian Associati on for the Study of the Liver. CMAJ. 2018;190(22):E677–87.
9. MAVYRET [US Package Insert]/MAVIRET [SmPC], AbbVie 2017.
10. T Berg, U Naumann, A Stoehr, et al. GS-007, EASL/ILC, April 13, 2018.
11. R D’Ambrosio, L Pasulo, M Puoti , et al. GS-013, EASL/ILC, April 14, 2018.
12. Kamil RJ, et al. Case-control study evaluati ng competi ng risk factors for angioedema in a high-risk populati on. Laryngoscope. 2016;126(8):1823–30.
DISCLOSURESRobert J Fontana: Research support from BMS, Gilead, AbbVie; Consulti ng: Alynam. Stuart McPherson: Consultancy/speakers fees: AbbVie, Allergan, BMS, Gilead, MSD, Novarti s. Sabela Lens: Advisor: Janssen, Gilead, AbbVie. Magdy Elkhashab: Grant support from AbbVie; Advisor for AbbVie. Stefan Zeuzem: Consultancies for AbbVie, BMS, Gilead, Janssen, Merck. Krum Katzarov: nothing to disclose. Ana Gabriela Pires dos Santos, Roger Trinh, Zhenyi Xue, Lino Rodrigues Junior, and Ariel Porcalla are employees of AbbVie Inc. and may hold stock or stock opti ons.
AbbVie sponsored the study (NCT03212521), contributed to its design and collecti on, analysis, and interpretati on of the data, and parti cipated in the writi ng, review, and approval of the abstract. All authors had access to relevant data. Glecaprevir was identi fi ed by AbbVie and Enanta.
PATIENTS
• The Baseline Demographics and Disease Characteristi cs are summarized in Table 1 for both the mITT and ITT populati ons
• Among the 230 pati ents in the ITT populati on, 99 (43%) had a history of a psychiatric disorder
Table 1. Baseline Demographics and Disease Characteristi cs
CharacteristicmITT population
N = 222ITT population
N = 230
Male, n (%) 111 (50) 117 (51)
Race, n (%)
White 202 (91) 207 (90)
Black or African American 10 (5) 13 (6)
Asian 10 (5) 10 (4)
Hispanic or Latino ethnic origin, n (%) 23 (10) 25 (11)
Age, median (range), years 48 (19–82) 48 (19–82)
Age ≥65 years old, n (%) 23 (10) 25 (11)
BMI, median (range), kg/m2 25.3 (16. 9–55.6) 25.2 (16. 9–55.6)
Baseline HCV RNA level, median (range), log10
IU/mL 6.3 (2.2–7.7) 6.3 (2.2–7.7)
Baseline HCV RNA ≥1 million IU/mL, n (%) 141 (64) 146 (63)
HCV genotype, n (%)
GT1 145 (65) 151 (66)
GT1a 77 (35) 82 (36)
GT1b 67 (30) 68 (30)
GT2 33 (15) 33 (14)
GT3 33 (15) 35 (15)
GT4 9 (4) 9 (4)
GT6 2 (<1) 2 (<1)
Key baseline polymorphisms, n (%)*
Any NS3 polymorphism 1 (<1) 1 (<1)
Any NS5A polymorphism 68 (31) 71 (31)
Screening APRI, median (range) 0.41 (0.13–1.0) 0.41 (0.`1.0)
Screening APRI, n (%)
≤0.5 136 (61) 140 (61)
0.5–0.7 54 (24) 57 (25)
0.71–1.0 32 (14) 33 (14)
Blinded Fibrotest, median (range)† 0.26 (0.02–0.87) 0.26 (0.02–0.87)
Platelet count, median (range), count/109/L 243 (126–462) 243 (126–483)
HIV co-infection, n (%)‡ 8 (4) 10 (4)
CD4+ T-cell count, median (range), cells/mm3§ 762 (444–1199) 692 (444–1199)
History of injection drug use, n (%) 83 (37) 87 (38)
Within the last 12 months 5 (2) 6 (3)
More than 12 months ago 78 (35) 81 (35)
On stable opiate substitution, n (%) 19 (9) 19 (8)
History of diabetes, n (%) 7 (3) 9 (4)
History of depression or bipolar disorder, n (%) 43 (19) 45 (20)
BMI, body-mass index; HCV, hepati ti s C virus; GT, genotype; APRI, Aspartate aminotransferase to platelet rati o; HIV, human immunodefi ciency virus.*Includes any baseline resistance-associated variants in NS3 (155, 156, and 168) or NS5A (24, 28, 30, 31, 58, 92, and 93) at a 15% detecti on threshold. No pati ents had both a NS3 and a NS5A key resistance-associated variant.†Performed at baseline, blinded to the investi gators and therefore, not used for pati ent eligibility.‡All pati ents with HIV co-infecti on were anti retroviral therapy-naïve.§Only assessed in the 10 HIV/HCV co-infected pati ents.
EFFICACY
• The primary effi cacy endpoint was met, with an overall SVR12 rate in the mITT populati on of 100% (222/222, 95%CI = 98.3–100) (Figure 2)
• The sequenti al secondary endpoint was also met, with an overall SVR12 rate in the ITT populati on of 96.5% (222/230, 95%CI = 94.2–98.9). Eight (3%) pati ents did not achieve SVR12 due to non-virologic failure reasons (Figure 2)
• No pati ents experienced on-treatment virologic failure or post-treatment relapse
• High SVR12 rates were observed in all HCV genotypes (Figure 3)
• Nighty-nine percent (202/204) of pati ents were adherent to the treatment (≥80% and ≤120% adherence) among pati ents with available data at all treatment visits
44073-HCV-FRI-653 — AASLD 2018 — AbbVie — proof 4 (rjh) — october 26, 2018the henderson company 6020 keating avenue, chicago illinois 60646 (847) 979-8051 CREATED @ 100%
ACKNOWLEDGEMENTS • The authors would like to express their grati tude to the pati ents and their families,
investi gators, and coordinators who made this study possible.
• Medical writi ng support was provided by Dan O’Brien, PhD, of AbbVie.
METHODS CONTINUED
Figure 1. Study Design
BL
Weeks
SVR12G/P
300/120 mg8-week treatment (N = 230)
GT1–6, TN, and APRI ≤1
Post-treatmentWeek 12
8
Open-label Treatment
Screening
BL, baseline; G/P, glecaprevir/pibrentasvir; SVR12, sustained virologic response at post-treatment Week 12; TN, treatment-naïve; APRI, aspartate aminotransferase to platelet rati o index; GT, genotype.
KEY INCLUSION CRITERIA
• Adult male or female, at least 18 years old at the ti me of screening
• HCV treatment naïve with chronic HCV genotype (GT) 1, 2, 3, 4, 5, or 6 infecti on (mixed GT and indeterminate GT were acceptable)
• Positi ve anti -HCV Ab and HCV RNA ≥1000 IU/mL for ≥6 months prior to and at screening
• APRI score ≤1 at the ti me of screening
• HIV-1 negati ve or HIV-1 positi ve (naïve or on stable qualifying anti retroviral therapy)
KEY EXCLUSION CRITERIA
• Any prior evidence of cirrhosis; however, formal assessment for cirrhosis was not required
• Presence of hepati ti s B or hepatocellular carcinoma
• ALT or AST >10 × upper limit of normal (ULN)
• Direct bilirubin >ULN
• Platelet count <150 000 cells/mm3
• Albumin <lower limit of normal
• Creati nine clearance (Cockcroft -Gault) <30 mL/min
• History of organ transplantati on
ENDPOINTS AND ANALYSES
Sequenti al Effi cacy Endpoints (fi xed sequence testi ng procedure):
Primary Efficacy Endpoint
Secondary EfficacyEndpoints
Percentage of pa�ents with SVR12 in the ITT popula�on• Efficacy will be established if the lower bound of the
95%CI is greater than the threshold of 91.4%, based on the mITT threshold minus an expected 1% rate of non-virological SVR failures
Percentage of pa�ents with SVR12 (HCV RNA <LLOQ 12 weeks a�er the last dose of study drug) in the mITT popula�on• Efficacy will be established if the lower bound of the
95% confidence interval (95%CI) is greater than the threshold of 92.4%, based on the historical rate observed in GLE/PIB registra�onal studies in treatment-naïve, non-cirrho�c subjects (98.4%) minus a margin of 6%
Non-sequenti al Endpoints:
Secondary EfficacyEndpoints
• Percentage of pa�ents with on-treatment virologic failure in ITT popula�on
• Percentage of pa�ents with post-treatment relapse in ITT popula�on
Additi onal Assessments:
Safety Assessments Adverse events (AEs)† and key laboratory abnormali�es were assessed in ITT popula�on
• Treatment adherence* conducted in ITT popula�on
• Number and percentage of pa�ents with viral suppression (HCV RNA <LLOQ) at treatment visits in pa�ents with available data
Addi�onalAnalyses
SVR12, sustained virologic response at 12 week post-treatment; HCV, hepati ti s C virus; LLOQ, lower limit of quanti fi cati on; ITT, intent-to-treat; CI, confi dence interval; mITT, modifi ed ITT; AE, adverse event.*Treatment adherence defi ned as use of ≥80% and ≤120% of the expected total number of tablets.†Includes AEs leading to treatment disconti nuati ons, AEs occurring in ≥5% of pati ents, serious AEs, and DAA-related serious AEs.
Figure 2. Effi cacy of 8-week G/P Regimen in HCV Treatment-naïve Pati ents With APRI ≤1
mITT ITT0
20
40
80
100
222222
222230
100 97
BreakthroughRelapsePremature G/P d/cMissing SVR12
00
N/AN/A
Reason fornon-response, n (%)
00
3 (1%)*5 (2%)†
% P
a�en
ts W
ith
SVR1
2
mITT, modifi ed intent-to-treat; ITT, intent-to-treat; SVR12, sustained virologic response at 12-week post-treatment; CI, confi dence interval; G/P, glecaprevir/pibrentasvir; d/c disconti nuati on.Dott ed lines indicate threshold above which lower bound of 95%CI must be greater than in mITT and ITT populati ons in order to meet primary and secondary endpoint, respecti vely.*Includes 2 pati ents who prematurely disconti nued due to a serious AE (see Table 3).†All 5 pati ents missing SVR12 data had no detectable HCV RNA at end of treatment.
Table 2. Number and Percentage of Pati ents With Viral Suppression Over TimeViral Suppression at Treatment Visit, n/N (%)* 8-week G/P treatment
Week 4 214/225 (95)
Week 8 (EOT) 211/211 (100)
Final treatment visit† 226/226 (100)
G/P, glecaprevir/pibrentasvir; EOT, end of treatment.*Viral suppression reported as number and percentage of pati ents with HCV RNA less than lower limit of quanti fi cati on at each post-baseline treatment visit in pati ents with available SVR data.†The last visit for a pati ent during G/P treatment.
Figure 3. Effi cacy by Genotype for 8-week G/P Regimen in HCV Treatment-naïve Pati ents With APRI ≤1
GT1 GT2 GT3 GT4 GT60
20
40
60
80
100
HCV GenotypemITT ITT
146146
146152
3232
3333
3335
99
22
22
100 96 100 100 94 100 100 100
3232
100
99
100
% P
a�en
ts W
ith
SVR1
2
mITT, modifi ed intent-to-treat; ITT, intent-to-treat; GT, genotype; SVR12, sustained virologic response at 12-week post-treatment; HCV, hepati ti s C virus.
SAFETY
• Overall, 124 (54%) pati ents experienced an AE, of which 8 (3%) pati ents had a grade 3 or higher AE (Table 3)
• Two (1%) pati ents experienced serious AEs of angioedema that led to premature G/P disconti nuati on
– Both were African American and former drug users (both risk factors for angioedema) and were taking an ACE inhibitor (lisinopril), a common cause of drug-induced angioedema12
• The most common AEs (occurring in ≥5% of all pati ents) were headache (13%) and fati gue (7%)
• No grade ≥3 laboratory abnormaliti es in ALT, AST, or total bilirubin were observed
RESULTSTable 3. Adverse Events and Laboratory Abnormaliti es
Event, n (%)ITT population
N = 230
Any AE 124 (54)
Grade ≥3 AE 8 (3)
Serious AE 4 (2)
DAA-related* serious AE 2 (1)†
AE leading to premature G/P discontinuation 2 (1)†
AEs occurring in ≥5% of all patients by preferred term
Headache 29 (13)
Fatigue 17 (7)
Laboratory abnormalities (Grade ≥3)
ALT >5 × ULN‡ 0
AST >5 × ULN 0
Total bilirubin >3 × ULN 0
Deaths 0
G/P, glecaprevir/pibrentasvir; AE, adverse event; DAA, direct acti ng anti viral; ALT, alanine aminotransferase; ULN, upper limit of normal; AST, aspartate aminotransferase.*As assessed by the investi gator.†Two pati ents experienced a serious AE of angioedema leading to premature G/P disconti nuati on on Days 8 and 15, respecti vely.‡Post-nadir increase in grade to Grade ≥3.
Scan QR code to download an electronic version of this presentati on (poster 653) and other AbbVie AASLD 2018 Scienti fi c Presentati ons. To obtain a QR code reader, go to your device app store and search for “QR code reader.” QR code expirati on: 27 November 2018.
CONCLUSIONS The study met its primary and secondary effi cacy endpoints with SVR12 rates of 100% and 96.5% in mITT and ITT populati ons, respecti vely
– No virologic failures were observed in treatment-naïve HCV GT1–6-infected pati ents with an APRI ≤1 treated with 8-week G/P regimen
G/P was well-tolerated with no Grade ≥3 laboratory abnormaliti es in ALT, AST, and total bilirubin, as well as with low rates of serious AEs (2%) and AEs leading to premature G/P disconti nuati on (1%)
Treati ng pati ents infected with HCV GTs 1–6 and with an APRI score of ≤1 with 8 weeks of G/P was highly effi cacious and well tolerated
Pati ents with APRI ≤1 and no prior evidence of cirrhosis can be successfully treated with G/P for 8 weeks, suggesti ng that APRI can be used in simplifi ed HCV management strategies
LIMITATIONS• This was a single-arm, open-label trial without a placebo arm; however,
the use of objecti ve measures for effi cacy (SVR12) and the comparison with a pre-specifi ed threshold considering historical reference SVR12 rates (effi cacy observed in the registrati onal program) miti gates this concern
PRESENTATION NOTESData to be presented at AASLD 2018 on EXPEDITION-8 (LB-7) that assessed safety and effi cacy of 8-week G/P regimen in treatment-naïve pati ents with compensated cirrhosis and HCV GT1, 2, 4–6 infecti on.
