Overviews of Therapies in Development for HCV. Interferon-free Regimens

Transcription

1 Overviews of Therapies in Development for HCV Interferon-free Regimens David R Nelson MD Professor and Associate Dean Director, Clinical and Translational Science Institute University of Florida Gainesville, USA

2 Disclosures Research relationships: Abbott, BI, BMS, Genentech/Roche, Gilead, Merck, Vertex Off-label use and therapies in development will be discussed

3 Outline Why we need all oral treatments Limitations of IFN-containing regimen Building all oral regimens Historical perspective Current drugs in development Safety, efficacy, etc Clinical trial data Timelines and treatment paradigms

4 Limitations of Current Interferon-based Therapy Limitations: Tolerability / adverse events Suboptimal efficacy in subgroups Cirrhotics, African Americans, IL28B CT/TT Duration of therapy weeks Complicated treatment regimens <20% of HCV-infected pts have undergone IFN-based therapy 134,934 HCV-infected veterans, 16,043 (11%) were prescribed IFN-containing regimens; only 22% completed therapy 1 1. Liver Int Feb;30(2):240-50

5 Milestones For Oral HCV Therapy First DAA: proof of concept (BILN 2061) DAA monotherapy limited by resistance (TVR/BOC) First all oral viral suppression: INFORM (PI + Nuc) First SVR with all oral (DAC + ASU) High SVR with all oral First approved all oral regimen

6 DAAs in Active Phase 2/3 Development Protease Inhibitors Asunaprevir (BMS) BI (Boehringer) Simeprevir (Janssen/Tibotec) ABT-450/r (Abbott) ACH-1625 (Achillion) Danoprevir/r (Roche) Vaniprevir (Merck) MK-5172 (Merck) GS-9451 (Gilead) Nucleoside inhibitors Sofosbuvir (GS-7977, Gilead) Mericitabine (Roche) IDX-184 (Idenix, on hold) ALS-2200 (Alios/Vertex) Non-nucleoside inhibitor ABT-072 (Abbott) ABT-333 (Abbott) BI (Boehringer) BMS Setrobuvir (Anadys) Tegobuvir (Gilead) VX-222 (Vertex) PPI-383 (Presidio) NS5A inhibitors Daclatasvir (BMS) GS-5885 (Gilead) ABT-267 (Abbott) GSK (GSK) ACH-3102 (Achillion) MK-8742 (Merck)

7 Safety Concerns with Rapid DAA Development Protease Inhibitors BILN 2061: cardiac toxicity IDX-320: hepatotoxicity Nucleoside inhibitors BMS (INX189): cardiac and renal toxicity IDX-184 & 19368: on hold given same active metabolite PSI-938: hepatotoxicty R1626: bone marrow toxicity Non-nucleoside inhibitors NM283 (Valopicitabine): GI toxicity GS 9190: cardiac/qt HCV-796: hepatotoxicity Host agents Alisporivir: pancreatitis

8 The Ideal All Oral Regimen Potent Pangenotypic Safe and well tolerated Once daily dosing 1 co-formulated pill No drug-drug interactions Inexpensive

9 1: 1 st generation 2: 2 nd generation DAA Profiles Resistance profile Pan-genotypic efficacy Efficacy Adverse events DAA NS3 1 NS3 2 NS5A nuc NS5B non-nuc NS5B Good profile Average profile Least favorable profile

10 All Oral HCV Clinical Trial Highlights

11 Electron 1 : IFN-free arms Impact of Ribavirin and IFN-responsiveness Wk 0 Wk 4 Wk 8 Wk 12 SVR 4 n=10 n=10 n=25 GS RBV (G2/3 Treatment Naïve) GS-7977 (G2/3 Treatment Naïve) GS RBV (GT 2/3 Treatment-Experienced) 100 % 60 % 80 % n=25 GS RBV (GT 1 Treatment-Naive) 88 % n=10 GS RBV (GT 1 Null Responders) 11 % n=19 QUANTUM 2 GS RBV (GT 1 Treatment-Naive) 59% 1. Gane E, et al. AASLD 2011 and EASL2012; 2. Gilead press release April 2012 (16 % IL28B CC vs 44% in ELECTRON)

12 GS-7977 (NI) + Daclatasvir (NS5A) Treatment naïve, Gen 1/2/3, non-cirrhotic SVR4 (G1) SVR4 (G2/3) GS Daclatasvir G1 (n=44) G2/3 (n=44) GS Daclatasvir + RBV GS-7977 GS Daclatasvir Sulkowski, M, et al. EASL weeks No impact of RBV or host/viral factors on viral response

13 PILOT and Co-PILOT Pilot: G1, treatment naïve, IL28BCC, non-cirrhotic ABT-450/r +ABT-072 +RBV Co-Pilot: G1, non-cirrhotic Naive Treatment Experienced ABT mg/r + ABT-333 +RBV ABT mg/r + ABT-333 +RBV ABT mg/r + ABT-333 +RBV SVR12 (%) Pilot 1 Co-Pilot /10 n=11 n=19 n=14 n=17 weeks Lawitz E, et al. EASL Abstract Poordad F, et al. EASL Abstract 1399 ABT-450: NS3 inhibitor ABT-072 and -333: nonnucleoside inhibitor r: ritonavir

14 Daclatasvir (NS5A) + Asunaprevir (PI) Pts: Gen1b, non-cirrhotic Null responder IFN ineligible and intolerant Null responder IFN intolerant Daclatasvir + Asunaprevir Daclatasvir + Asunaprevir SVR24 (%) weeks N=21 9/10 n=22 Suzuki F, et al. EASL Abstract 14 Among pts with breakthrough (7%) or relapse (9%), low plasma concentrations of DAC and ASU

15 SOUND-C2: Higher SVR12 in Pts With GT 1b HCV, IL28B CC, BID Dosing Gen 1, naïve 10% cirrhosis 0 weeks 28 BI mg QD + BI mg BID + RBV (n = 78) SVR12 (%) n/n = 0 1a non-cc 1a CC 1b non-cc HCV Subtype and IL28B Genotype 1b CC Zeuzem S, et al. EASL Abstract 101. BI : protease inhibitor BI : non-nucleoside inhibitor

16 First All Oral HCV Regimens Likely Available in Nucleoside-based regimens Sofosbuvir + RBV (G2/3, select G1) Sofosbuvir + Daclatasvir (off-label) Sofosbuvir + PI (TMC 435) (off-label) Sofosbuvir + GS RBV (pan-genotype) Non-nucleoside based regimens Daclatasvir + Asunaprevir (G1b) ABT-450/r + ABT ABT RBV (G1) BI BI RBV (G1, select)

17 Integration of New HCV Agents into Optimal All Oral Treatment Paradigms SVR will be high (80-100%) with short duration (12-24 weeks) Depends on potency and barrier to resistance of the combination Challenges for new regimens Identifying predictors of response and optimal duration Selecting patients for best treatment regimen ~ 1a v 1b, IL28B CC v CT/TT, cirrhosis v mild fibrosis Tailoring duration of therapy ~ 12 weeks for easy to cure (naive, non-cirrhotic, IL28B CC) ~ weeks for harder to cure (cirrhotic, 1a, IL28BTT/TC) Minimising and managing resistance Minimising and managing toxicity