Update on the HCV Antiviral Pipeline Todd S. Wills, MD SPNS HCV Treatment Expansion Initiative Evaluation and Technical Assistance Center Infectious Disease.

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Presentation transcript:

Update on the HCV Antiviral Pipeline Todd S. Wills, MD SPNS HCV Treatment Expansion Initiative Evaluation and Technical Assistance Center Infectious Disease Specialist

HCV Response Rates in HIV+ and HIV- Patients Treated With PegIFN/RBV APRICOT HIV Positive Overall SVR: 40% PRESCO HIV Positive Overall SVR: 50% Soriano V, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel AIDS. 2007;21: Patients With SVR (%) FRIED HIV Negative Overall SVR: 56% GT1/4GT2/3GT1/4GT2/3GT1/4GT2/3 48 Wks of Therapy, 600 mg RBV 24, 48, or 72 Wks of Therapy, Weight-Based RBV 48 Wks of Therapy, Weight-Based RBV n =

Potential HCV antiviral targets NS4A C E1E2/NS1NS2NS3NS5A NS5B NS4B 5’5’ 3’3’ RNA binding site Envelope glyco- proteins Signal peptide Serine protease/ helicase RNA dependent RNA polymerase Internal ribosomal entry site telaprevir, boceprevir

Response Terminology TermTime PointHCV RNA Level Rapid virologic response (RVR) Wk 4 of therapyUndetectable Early virologic response (EVR) Wk 12 of therapy≥ 2 log 10 IU decrease from baseline Complete early virologic response (cEVR) Wk 12 of therapyUndetectable Slow to respondWk 24 of therapyUndetectable (but with detectable HCV RNA at Wk 12) End of treatment response (EOT or ETR) End of therapyUndetectable Sustained virologic response (SVR) 6 mos posttherapyUndetectable

Adherence Triple therapy presents challenges with already busy schedules [143] –TID dosing –Food requirements Data show pegIFN/RBV adherence decreases over time [5] –Addition of PIs may exacerbate this trend 1. Telaprevir [package insert]. May Boceprevir [package insert]. May EMA. Boceprevir [package insert] EMA. Telaprevir [package insert] Lo Re V 3rd, et al. Ann Intern Med. 2011;155: from Clinical Care Options

Sulkowski M, et al. CROI Abstract 146LB. Study 110: High Rates of Early Response With TVR + PR in Coinfected Patients Similar efficacy results observed with or without concurrent ART Nausea, pruritus, dizziness, fever more common with TVR vs placebo Pharmacokinetic interactions with ATV or EFV not clinically significant Undetectable HCV RNA, Week 4 (ITT) Undetectable HCV RNA (%) Telaprevir + PRPR n/N = 5/7 12/169/1426/37 0/61/80/81/22 No ART EFV-based ART ATV/RTV-based ART Total Undetectable HCV RNA, Week 12 (ITT) Telaprevir + PRPR n/N = 5/7 12/168/1425/37 1/61/8 3/22 Undetectable HCV RNA (%)

Study 110 – SVR 12 Data Telaprevir Group N=38Placebo Group SVR1228/38 (74)10/22 (45) On Treatment Virologic Failure 3/38 (8)8/22 (36) Not Suppressed at End of Treatment 5/37 (14)9/22 (41) Relapse1/32 (3)2/13 (15) Dieterich D, et al. CROI 2012 Abstract 46

Telaprevir plus PegINF and Ribavirin in HIV/HCV Infected Patients – Side Effects Adverse EffectTVR+PRPR Pruritis or Itching39%9% Headache37%27% Nausea34%23% Skin Rash*34%23% Fever21%9% Anemia13%18% Depression21%9% Insomnia13%23% *no cases of severe rash Sherman, KE et al.. AASLD Conference November 2011 – Late Breaker Abstract 8

Boceprevir in Addition to Pegylated INF alfa 2a in HIV/HCV Patients on ARVs Sulkowski, M. CROI 2012 Abstract 47

Investigational Agents

PSI-7977 – Phase II Trial Data HCV uridine nucleotide analogue 12 WEEK TreatmentPSI-7977/P/R n=47 PSI 7977/P/R n=54 PSI 7977/R n=10 PSI-7977 n=10 EOT Week 1-4 Relapse1004 SVR > Wk 4 relapse0000 SVR pending SVR (11 pend)4 (6 pend)pending Genotype 1 Genotype 2/3 Lawritz, E. et al. J of Hepatology 54 (s1) 2012

TMC-435 – Phase IIb trial data HCV NS3/4A Protease Inhibitor (Once-Daily) Prior Treatment Failures TMC12/P R48 n=66 TMC24/ PR48 N=65 TMC48/P R48 N=66 TMC12/P R48 n-=66 TMC24/P R48 N=68 TMC48/PR 48 N=65 Pbo48/P R48 N=66 RVR Total44/66 (67) 38/65 (59) 35/66 (53) 41/66 (62) 46/68 (68) 43/65 (66) 1/66 (2) SVR Total46/66 (70) 43/65 (66) 40/66 (61) 44/66 (67) 49/68 (72) 52/65 (80) 15/66 (23) SVR Null6/16 (38) 9/16 (56) 8/18 (44) 9/17 (53) 7/17 (41)10/17 (59) 3/16 (19) SVR Partial16/23 (70) 11/23 (48) 12/22 (55) 15/23 (65) 18/24 (75) 19/22 (86) 2/23 (9) SVR Relapse 24/27 ( 89) 23/26 (89) 20/26 (77) 24/37 (89) 23/26 (89) 10/27 (37) 100 mg 150 mg P<0.001 vs placebo Zeuzem S., et al. J of Hepatology 54 (s1) 2012

Interferon Sparing Strategies ABT 450/r – ritonovir boosted HCV PI + ABT 072 – HCV polymerase inhibitor + Weight-based ribavirin Open label 12 week treatment trial 11 patients Interferon sparing 91% SVR24 One patient relapsed 8 weeks post Rx All patients were IL28B CC Lawitz, E. et al. Of Hepatology 56(s1) 2012

Interferon AND Ribavirin Sparing Strategies Daclatasvir (NS5A replication complex inhibitor) + Asunaprevir (HCV NS3 PI) Open label trial of both drugs in 43 prior null responders or with IFN/R intolerance Null Responders N=21 IFN/R Ineligible or Intolerant N=22 IL28B CC3/21 (14.3)16/22 (72.7) RVR11/21 (52.4)19/22 (86.4) cEVR19/21 (90.5)20/22 (90.9) EOT18/21 (85.7)16/22 (72.7) SVR 1219/21 (90.5)14/22 (63.6) Suzuki, F. et al. J of Hepatology 56 (s1) 2012