Study Design - GT 1 Retreatment

Transcription

1 Retreatment of Patients Who Failed 8 or 12 Weeks of Ledipasvir/Sofosbuvir-Based Regimens With Ledipasvir/Sofosbuvir for 24 Weeks Eric Lawitz, Steven Flamm, Jenny C. Yang, Phillip S. Pang, Yanni Zhu, Evguenia Svarovskaia, John G. McHutchison, David Wyles, Paul Pockros Abstract O5 Study Design - GT 1 Retreatment Wk Wk 12 Wk 24 Wk 36 SOF failures (n=51) LDV/SOF + RBV 98% SVR12 1 LDV/SOF failures (n=41) LDV/SOF SVR12 SOF failures (advanced liver disease) LDV/SOF + RBV SVR12

2 Demographics and Baseline Characteristics GT 1 Retreatment LDV/SOF 24 Weeks N=41 Mean age, y (range) 58 (35 71) Male, n (%) 34 (83) Black/African American, n (%) 1 (24) IL28B non-cc, n (%) 38 (93) GT 1a, n (%) 34 (83) Mean HCV RNA, log 1 IU/mL (range) 6.2 ( ) Cirrhosis, n (%) 19 (46) Presence of NS5A RAVs 15 (79) Prior HCV treatment, n (%) LDV/SOF ± RBV 33 () LDV/SOF + GS () Prior HCV treatment duration, n (%) 8 weeks 3 (73) Presence of NS5A RAVs 19 (63) 12 weeks 11 (27) Presence of NS5A RAVs 11 () Results: On-Treatment Viral Kinetics and SVR GT 1 Retreatment One patient experienced on-treatment breakthrough at Week 16 HCV RNA <LLOQ (%) /41 39/41 41/41 4/41 3/41 29/41 Wk 1 Wk 4 Wk 8 EOT SVR4 SVR12 EOT, end of treatment. Error bars represent 95% confidence intervals.

3 SVR12 by Subgroup - GT 1 Retreatment All 11 patients without NS5A RAVs received 8 weeks of prior treatment SVR12 (%) /22 14/19 24/3 5/11 11/11 18/3 No Yes 8 wks 12 wks No Yes Cirrhosis Prior Treatment Duration Baseline NS5A RAVs SVR12 by Baseline NS5A RAVs GT 1 Retreatment SVR12 (%) /11 11/16 7/14 None 1 2 Number of NS5A RAV(s) 5/5 4/5 2/6 Q3R or M28T* L31M Y93H/N Type of Single NS5A RAV *M28T (n=1).

4 NS5B Resistance Analysis Baseline No NS5B resistance associated (S282T) or treatmentemergent (L159F, V321A) variants were detected At virologic failure 4 of 12 (33%) patients had NS5B variants detected S282T (n=2) L159F (n=1) Double-mutant S282T + L159F (n=1) Conclusions - GT 1 Retreatment 71% of patients who failed prior LDV/SOF-containing regimens achieved SVR12 when retreated with LDV/SOF for 24 weeks The presence of baseline NS5A RAV(s), which was more likely to develop with longer prior LDV/SOF treatment, was associated with virologic failure Emergence of S282T was observed in 3 of 12 virologic failure patients Retreatment with LDV/SOF is feasible in patients who have failed prior LDV/SOF-based regimens

5 Grazoprevir (Gzr)/Elbasvir (Ebr) Plus Ribavirin (Rbv) For Chronic Hepatitis C Virus Genotype-1 Infection After Failure Of Combination Therapy Containing A Direct-acting Antiviral Agent Xavier Forns, Stuart Gordon, Eli Zuckerman, Eric Lawitz, Jose Luis Calieja, Harald Hofer, Christopher Gilbert, John Palcza, Anita Howe, Dark DiNubile, Michael Robertson, Janice Wahl, Eliav Barr, Maria Buti Abstract O1 Background HCV NS3/4A inhibitor mg, once-daily, oral HCV NS5A inhibitor 5 mg, once-daily, oral Grazoprevir (MK-5172) Elbasvir (MK-8742) Broad in vitro activity against most HCV genotypes 1-3 Retains in vitro activity against many clinically relevant RAVs 1-3 All-oral, once daily regimen RAV = resistance-associated variant. 1. Summa V, et al. Antimicrobial Agent Chemother 12; 56: Coburn CA, et al. ChemMedChem 13: 8: Harper S, et al. ACS Med Chem Lett. 12; 3:

6 Study Design N = 79 GZR mg + EBR 5 mg + RBV 1 Endpoint: SVR12 Follow-up D1 TW4 TW8 TW12 FUW4 FUW8 FUW12 FUW16 FUW FUW24 Patients with chronic HCV GT1 infection who had failed >4 wks of triple therapy with PR + BOC, TPV, or SMV ~% of participants to have experienced VF on prior triple therapy Compensated cirrhosis* limited to <4% of study population Staging of liver disease by biopsy or non-invasive methods Study treatment: GZR mg + EBR 5mg + weight-based RBV x 12 weeks NS3 & NS5A RAVs identified by population sequencing at baseline & VF Baseline Characteristics Evaluable Patients All Treated Patients (N = 79) Baseline NS3 RAVs (N = 34) No Baseline NS3 RAVs (N=44) Mean (median) age, years 54.4 (55) 53.9 (55.) 54.6 (56.5) Male gender, n (%) 46 (58.2) 21 (61.8) 24 (54.5) HCV genotype, n (%) GT1a 3 (38.) 23 (67.6) 7 (15.9) GT1b 49 (62.) 11 (32.4) 37 (84.1) Cirrhosis, n (%) 34 (43.) 15 (44.1) 19 (43.2) Prior DAA experience, n (%) Boceprevir 28 (35.4) 1 (29.4) 17 (38.6) Telaprevir 43 (54.4) 19 (55.9) 24 (54.5) Simeprevir 8 (1.1) 5 (14.7) 3 (6.8) Past history of virologic failure 66 (83.5) 32 (94.1) 33 (75.)

7 Efficacy Endpoints Over Time (Full Analysis Set) Response Rate, %[95% Cl] 6 4 % 97.5% 96.2% 95.5% % [95.4, ] 79/79 [91.2, 99.7] [89.3, 99.2] [87.3, 99.1] 77/79 76/79 63/66 EOT response SVR4 All patients Prior virologic failure SVR12 [75.3,.] 13/13 Prior nonvirologic failure Emergent RAVs Coincident With Virologic Failure Infecting HCV Subgenotype Prior PI Type of Failure on GZR/EBR Follow-up Visit when VF was Diagnosed Resistance Associated Variants At Baseline At Failure NS3 NS5A NS3 NS5A 1a BOC Relapse FUW4 QK, R155T, D168N Wild Type QK, R155T, D168N, A156T/A M28T, Q3H, Y93H 1b TPV Relapse FUW8 T54S L31M T54S, Y56F, QL, A156T/A, V17I L31M, Y93H 1a TPV Relapse FUW4 V36L, R155K H58D V36L, R155K, A156T, D168N, V158V/A Q3R, H58D Treatment emergent RAVs shown in red bold

8 Summary GZR + EBR + RBV x 12 weeks resulted in SVR12 in 76/79 patients (96.2%) who had failed previous PR plus an earlier-generation PI SVR12 was attained in 63/66 (95.5%) patients with a history of VF SVR12 was attained in 31/34 (91.2%) patients harboring baseline NS3 RAVs conferring decreased susceptibility to 1st-generation Pls GZR + EBR + RBV was generally well tolerated Only 1 patient stopped study treatment (AE unrelated to study treatment) No serious drug related AEs