Integrated Safety and Tolerability of Daclatasvir plus Asunaprevir in Patients with Chronic HCV Genotype 1b Infection

( L. Wei ),( K. Chayama ),( W. L. Chuang ),( S. H. Bae ),( J. Y. Jang ),( R. Bhore ),( V. Vazquez ),( L. Mo ),( M. Linaberry ),( M. Treitel ),( H. Kumada ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The combination of daclatasvir (DCV) plus asunaprevir (ASV)has demonstrated high sustained virologic response (SVR) rates andis generally well tolerated in clinical studies. This integrated analysisevaluated the safety profile of DCV (60mg once daily) and ASV (100mgsoftgel capsule or 200mg tablets twice daily in genotype 1b (GT1b)infected patients enrolled in four phase 3 and two phase 2 clinicalstudies conducted globally, including Asia.Methods: Integrated safety data from 1218 treatment-naive or treatment-experienced patients were analyzed for adverse events (AEs),serious AEs, discontinuations due to AEs and grade 3/4 AEs andlaboratory abnormalities reported on-treatment.Results: Patients were 58% female, median age was 58 years and23% had compensated cirrhosis. DCV+ASV was associated with infrequentserious AEs and discontinuations due to AEs (Table). Twelvepatients reported treatment-related serious AEs. The most commonAEs (any grade) were diarrhea, nausea, fatigue, and headache. Onepatient died due to coronary heart disease (not treatment-related).The most common grade 3/4 laboratory abnormalities were aminotransferaseelevations (more frequent among Japanese patients); however,all grade 3/4 laboratory abnormality occurred in <5% of patientsoverall. Grade 3/4 total bilirubin elevations were reported in <1%of patients. The DCV+ASV safety profile was similar in patients withor without cirrhosis.Conclusions: DCV+ASV was generally well tolerated across globalnon-Asian patient populations and in Asian patients from Japan, mainlandChina, Korea, and Taiwan.

An Integrated Analysis of the Efficacy of Glecaparevir/ Pibrentasvir by Geographical Region

( Edward Gane ),( Kazuaki Chayama ),( Mudra Kapoor ),( Stuart K Roberts ),( Jeong Heo ),( Jia-horng Kao ),( Thomas Berg ),( Philippe J Zamor ),( Brian Conway ),( James Park ),( Sandra S Lovell ),( Rak 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The pangenotypic direct-acting antiviral (DAA) regimen glecaprevir (developed by AbbVie and Enanta) coformulated with pibrentasvir (G/P) is approved in the US, EU, and Japan to treat chronic HCV genotype (GT) 1-6 infection. In the US and EU, G/P is indicated for treatment-naïve, HCV genotype (GT) 1-6-infected patients without and with compensated cirrhosis for 8-week and 12-week treatment durations, respectively, and achieved SVR12 rates ≥95% across all six major GTs. In clinical studies, G/P exposures were similar across ethnicities; an integrated analysis of the efficacy of G/P by geographical region was conducted to assess the impact of geography and ethnicity on SVR12. Methods: Data were pooled from 9 phase 2 and 3 clinical studies; data from 2 additional phase 3 clinical studies conducted in Japan were pooled separately. Patients had HCV GT1-6 infection with or without compensated cirrhosis and were either HCV treatment-naïve or experienced with interferon (IFN) or pegIFN with or without ribavirin (RBV), sofosbuvir and RBV with or without pegIFN, or NS5A- and/or protease inhibitor-containing regimens. G/P (300 mg/120 mg) was orally dosed once-daily for 8, 12, or 16 weeks. The primary efficacy endpoint in all studies was SVR12. Safety and tolerability were assessed in all patients. Data from all 11 studies will be pooled for presentation. Results: In total, 2369 patients were included in the integrated analysis: 964 (41%) were enrolled in North America, 891 (38%) in Europe, and 514 (22%) enrolled and pooled from Taiwan, Korea, Australia, New Zealand, Chile, Israel, and South Africa; 332 additional patients were enrolled in Japan. The SVR12 results by region were 97% (935/964; 95% CI 95.9-98.1), 98% (876/891; 95% CI 97.5-99.1), and 96% (496/514; 95% CI 94.9-98.1) for patients enrolled in North America, Europe, and the other pooled countries, respectively. Patients enrolled in Japan achieved a 98% (325/332; 95% CI 95.7-99.0) SVR12 rate. Less than 1% of all patients had virologic failure. G/P was well-tolerated with a favorable safety profile; treatment discontinuations due to adverse events and cases of drug-induced liver injury were rare (<1%). Conclusions: G/P efficacy, safety and tolerability were consistently favorable regardless of baseline characteristics, suggesting that recently updated HCV treatment guidelines for the use of G/P in clinical practice can be applied to all ethnicities and geographical regions, without need for modification.

High Sustained Virologic Response with Daclatasvir plus Asunaprevir in HCV GT-1b Chinese, Korean and Taiwanese without Baseline NS5A Polymorphisms

( F. Mcphee ),( L. Wei ),( Q. Xie ),( Y. Suzuki ),( J. Toyota ),( Y. Karino ),( K. Chayama ),( Y. Kawakami ),( M. L. Yu ),( S. H. Ahn ),( N. Zhou ),( H. Kumada ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Daclatasvir (DCV) plus asunaprevir (ASV) has demonstrated highsustained virologic response (SVR) in HCV genotype (GT-)1b infection.NS5A-Y93H and NS5A-L31 resistance-associated polymorphisms(RAPs) to DCV are known to impact DCV+ASV response in GT-1b-infectedJapanese. The effect of RAPs on SVR at posttreatment week12 (SVR12) to DCV+ASV was explored in mainland Chinese, Korean,and Taiwanese.Methods: Pooled data from 2 studies of DCV (60 mg daily) + ASV(100 mg capsule, twice-daily) for 24 weeks in GT-1b-infected interferon/ribavirin-naive and -experienced patients from mainland China,Korea, and Taiwan. Similar Japanese data (4 studies; n=445) werepooled for comparison. SVR12 with versus without baseline Y93Hand/or L31 RAPs was compared by age (<65 vs ≥65 years), cirrhosisstatus, and baseline HCV-RNA.Results: SVR12 and baseline NS5A sequences were available for 282patients (126 mainland Chinese [45%〕, 80 Koreans [28%〕, 76Taiwanese [27%〕). NS5A-Y93H and/or -L31 RAPs were observed pretreatmentin 8% mainland Chinese, 14% Korean, and 18%Taiwanese patients, compared with 19% in Japanese. SVR12 in allnon-Japanese patients is shown (Figure); rates were broadly similarbetween countries and with Japanese data (Japanese: 96% overallwithout RAPs, 41% with RAPs). Responses were lower among patientswith baseline RAPs. By contrast, SVR12 in patients without RAPs washigh (92-100%), irrespective of cirrhosis, age, or baseline HCV-RNA.Conclusions: At least 95% of HCV GT-1b-infected patients from mainlandChina, Korea or Taiwan without baseline NS5A-Y93H or -L31polymorphisms who had HCV-RNA ≤7 log10 IU/mL achieved SVR12on DCV+ASV, regardless of cirrhosis status and age.

A Long-Term, Observational, Follow-Up Study of Patients Treated in Phase 2 and 3 Clinical Studies with Daclatasvir- Based Regimens: Efficacy and Safety Outcomes

( KR Reddy ),( S Pol ),( PJ Thuluvath ),( H Kumada ),( J Toyota ),( K Chayama ),( J Levin ),( E Lawitz ),( A Gadano ),( W Ghesquiere ),( G Gerken ),( M Brunetto ),( CY Peng ),( M Silva ),( S Strasser 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Background/aims: Daclatasvir plus other direct-acting antivirals (DAAs) and/or peg-interferon/ribavirin has achieved high rates of sustained virologic response (SVR) in multiple clinical studies of patients. This follow-up study evaluates the long-term efficacy and safety outcomes in these patients. Methods: : This 144-week observational study enrolled patients treated with ≥ 1 dose of daclatasvir within 6 months of either completing their parent studies or protocol availability at the study site. The study objectives were to evaluate SVR12 durability, persistence of emergent NS5A and NS3 substitutions in non-responders, and to characterize events of hepatic disease progression or hepatocellular carcinoma. Results: This study enrolled 1503 patients treated with DAA-only (n = 893) or interferon-containing (n = 610) regimens of daclatasvir, of whom 60% were male, 18% were aged ≥ 65 years, 87% had HCV genotype 1 infection, and 18% had cirrhosis. Overall, 1329/1489 evaluable patients archived SVR12 in parent studies; 1316 (99%) maintained SVR until their most recent follow-up visit. 12 responders relapsed after achieving SVR12 (9 on/before and 3 after post-treatment week 24); 1 was re-infected. Relapse occurred in 3/842 (0.4%) and 9/487 responders (2%) treated with DAA-only regimens and interferon-containing regimens, respectively. From parent study end of treatment, hepatic disease progression (n = 15) or new hepatocellular carcinoma (n = 23) were diagnosed in 36 patients (two had both); median time to diagnosis was 70 weeks (range, 0.4-206 weeks). These 36 patients were generally older (median, 61 years versus 56 years), more had cirrhosis at baseline (50% versus 18%), and most were infected with HCV genotype 1a (36%) or 1b (61%). Complete replacement of emergent NS5A, NS3 substitutions by wild-type sequences was observed in 27/157 (17%), 35/47 (74%) non-responders, respectively. Conclusions: The results suggest that SVR12 achieved with daclatasvir- based regimens is durable in the long term. Hepatic disease progression events and new hepatocellular carcinoma were infrequent.

Emergence and Persistence of NS5A and NS3 Resistance-Associated Substitutions in HCV Genotype 1b Patients Treated with Daclatasvir and Asunaprevir

( F. Mcphee ),( D. Hernandez ),( N. Zhou ),( F. Yu ),( B. Kienzle ),( Y. Zhao ),( M. Linaberry ),( S. Noviello ),( M. L. Yu ),( S. H. Ahn ),( Y. Karino ),( K. Chayama ),( H. Kumada ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: A pooled analysis of emergent RAS was performed in HCV genotype (GT-)1b-infected patients receiving daclatasvir and asunaprevir (DCV+ASV) and the persistence of DCV- and ASV-resistant substitutions through ≥post-treatment Week (PTWK)192 was assessed to understand the RAS profile and help guide potential retreatment options. Methods: HCV GT-1b-infected patients without a sustained virologic response (SVR) and with HCV RNA ≥1000 IU/mL on or after DCV+ASV treatment were included from 5 Phase 2 and 3 studies. Baseline and post-baseline plasma samples were sequenced at a sensitivity cut-off ł20%. To determine the persistence of emergent RAS, samples at the end of study (up to PTWK48) and/or from a 3-year long-term follow-up rollover study were sequenced (sensitivity cut-off ≥20%, and ≥1% for select samples). Results: 152 DCV+ASV-treated patients without SVR met the resistance testing criteria: 89% (136/152) had NS5A and 95% (145/152) had NS3 sequences at both baseline and virologic failure (VF). NS5A and NS3 RAS emerged in 99% (134/136) and 89% (129/145), respectively, at VF (Table). Overall, 93% (142/152) of patients with VF had both NS5A and NS3 sequence data at failure, of which 77% (109/142) had RAS at L31, Y93 and D168. Emergent NS5A RAS persisted at PTWK96 (92%;24/26) and ≥PTWK192 (100;7/7compared with 22% (6/27) and 14% (1/7), respectively, for emergent NS3 RAS. Replacement of emergent NS5A and NS3 RAS observed at VF occurred in 8% (2/26) of NS5A and 74% (17/23) of NS3 sequences at PTWK96 and in 0% (0/7) of NS5A and 86% (6/7) of NS3 sequences at ≥PTWK192. Conclusions: NS5A and NS3 RAS emerged in most patients treated with DCV+ASV who experienced VF, and NS5A RAS persisted post-treatment. Therapy options for DCV+ASV treatment failures may depend on the timing of retreatment: an NS3 inhibitor-containing regimen may be possible if NS3 RAS are no longer observed, while regimens not impacted by the NS5A-L31+Y93 and NS3-D168 RAS combination would offer an immediate alternative.