New Antiviral Therapy for HCV: Progress Toward Cure

Transcription

1 New Antiviral Therapy for HCV: Progress Toward Cure Raymond T. Chung, MD Director of Hepatology Vice Chief, GI Unit MGH Worldwide Prevalence of HCV HCV Genomic Organization 5 UTR region 9.6 kb RNA 3 UTR region Polyprotein C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Protease Serine Helicase Protease Polyprotein Processing C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Protease Serine Helicase Serine RNA-dependent Glycoproteins Protease Protease RNA polymerase Cofactor F McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 28; 48:

2 HCV life cycle Moradpour, Nat Rev Microbiol 27;5:453 HCV Genotypes and Subtypes Developed countries 2 Americas + Western Europe South Africa Middle East North Africa U.S. 1 75% (45%SVR) 2,3 25% (8%SVR) IVDU 3 Simmonds P, Journal of Hepatology, 1999 Asia 6 What s in Our Therapeutic Armamentarium? PEG-interferon- and ribavirin Agents directly targeting viral functions (DAAs) NS3/4A protease inhibitors NS5B polymerase inhibitors Nucleoside Nonnucleoside NS5A inhibitors Other viral targets Other inteferons Agents targeting host cofactors Lipid synthesis inhibitors Cyclophilin antagonists mirna inhibitors Pharmacogenomics (IL28B) 2

3 Proposed antiviral effects of interferonalpha Hundreds of ISGs induced Include PKR, OAS, ISG15 Inhibit viral protein, RNA synthesis HCV has evolved multiple subversive mechanisms Ribavirin: proposed mechanisms of action Guanosine analogue with antiviral properties against RNA and DNA viruses Only minimal antiviral effects on HCV as monotherapy Augments IFN s antiviral effects Best available evidence supports independent immunomodulatory effects Enhances IFN-stimulated genes Clinically minimizes IFN relapse rates PEG-IFN- and RBV Produce SVR in About Half of Patients with HCV % 4 34% 42% 39% 2 6% 16% IFN 6 m IFN 12 m IFN/RBV 6 m IFN/RBV 12 m Peg-IFN 12 m Peg-IFN/ RBV 12 m Adapted from Strader DB, et al. Hepatology. 24;39:

4 The good news: a sustained response is truly sustained % 98.8% 99.1% 1% 99.% mean F/U yrs All PEG Mono therapy PEG RBV Abnormal ALT PEG RBV Normal ALT PEG +/-RBV HCV HIV Swain M, et al. Gastroenterology 21;139:1593 SVR Postpones Liver Complications in Persons with Advanced HCV Fibrosis n=479, median f/u 2.1Y (.8-4.9) Liver Failure, % Hepatocellular Carcinoma, % 5 yr occurrence: SVR % No SVR 13.3% ( %) P=.1 5-year 5 yr occurrence: SVR: 9.2% (CI, (-19.6%).%-19.6%) NO No SVR: SVR 13.1% 13.1% (CI, ( %) 7.6%-18.6%) P =.192 (log likelihood) P=.192 NO SVR NO SVR SVR SVR Veldt BJ, et al. Ann Intern Med 27;147: The bad news: limited effectiveness Multiple adverse effects Neuropsychiatric Hematologic Autoimmune Limited tolerability Contraindications Promise of therapy therefore elusive to many Challenge to find shorter duration, inherently more tolerable regimens 4

5 Targets for Direct Acting Antivirals (DAA) C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Protease Serine Helicase Serine RNA-dependent Glycoproteins Protease Protease RNA polymerase Cofactor NS3-4A protease inhibitors NS5B polymerase inhibitors nucleoside analogs non-nucleoside analogs McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 28; 48:17-12 Potential HCV Targets Adapted from Bartenschlager RJ. Presented at 43 rd Annual Meeting of the European Association for the Study of the Liver (EASL) Milan, Italy, April 28. Potential HCV Targets Adapted from Bartenschlager RJ. Presented at 43rd Annual Meeting of the European Association for the Study of the Liver (EASL) Milan, Italy, April 28. 5

6 The NS3-4A Protease Chymotrypsin-like serine protease (vs. HIV-1 aspartyl protease) Activation by NS4A Cleavage of viral downstream targets at cys/tyr ser/ala boundary Shallow substrate-binding cleft poses challenges to small molecule development Kim JL, et al. Cell. 1996;87: Adapted from Bartenschlager RJ. 43 rd EASL Milan, Italy, April 28 Peptidomimetics Act to Inhibit NS3-4A NS3-4A + End product inhibition of NS3-4A enzymatic activity P6-P1 hexapeptide can be mimicked Ingalinella P, et al. Biochemistry. 1998;37: Peptidomimetic NS3-4A Inhibitors Macrocyclic (also Danoprevir, TMC43535) Telaprevir / Linear Boceprevir / Linear Adapted from Bartenschlager RJ. Presented at 43rd Annual Meeting of the European Association for the Study of the Liver (EASL) Milan, Italy, April 28. 6

7 Median Log HCV RNA Median HCV RNA (log 1 IU/ML) Median HCV RNA (log 1 IU/ML) Potent Antiviral Effect of an HCV Protease Inhibitor Study Time (in Days) Placebo TPV 45 mg q8h TPV 75 mg q8h TPV 125 mg q12h Reesink HW, et al. Gastro. 26;131: Low Barrier to Resistance of an HCV Protease Inhibitor Resistant variants Study Time (in Days) Placebo TPV 45 mg q8h TPV 75 mg q8h TPV 125 mg q12h Reesink HW, et al. Gastro. 26;131: Dynamics of Viral Variants Plateau Group Telaprevir Dosing Period Postdosing Long-Term Follow-up Baseline EOD 14 days Follow-up 7 1 days postdosing Long-term follow-up 3 7 months postdosing WT 36/ WT WT WT 36/155 V36 R155 IC WT M/A/L K/T/S/M T54A 36/155 A156V/T 36/156 5 fold change Adapted from Kieffer T, et al. 41st EASL. April 26-3, 26. Abstract 12. 7

8 SVR (%) SVR (%) Add on to SOC: Phase 2 Trials of HCV NS3-4A protease inhibitors in HCV-1 Response PROVE1 (24 wks) PROVE2 (24 wks) SPRINT-1 (28 wks) (no leadin/leadin) SPRINT-1 (48 wks) (no leadin/leadin) SOC Peg/RBV (48 wks) RVR 81% 69% 39% 37% 8-15% SVR 61% 68% 54/56% 67/75% 38-48% PROVE1: TPV + Peg-2a/ RBV 12 wks then Peg/RBV 12 wks if RVR (24W) PROVE2: TPV + Peg-2a /RBV 12 wks then PegRBV 12 wks (24W) SPRINT-1: Boceprevir + Peg-2b + RBV for 24/28 weeks or 44/48 weeks with or without a 4-wk lead in period of PEG-2b + RBV McHutchison J, et al. NEJM 29;36: Hezode C et al, NEJM 29;36: Kwo P, et al. Lancet 21; 376:75-16 PROVE2: Truncation of therapy is feasible with addition of a PI P =.1 P >.2 P = Relapse, % PegIFN/RBV + Placebo 48w (n=82) TPV 12w+ PegIFN/RBV 24w (n=81) TPV 12w+ PegIFN/RBV 12w (n=82) TPV 12w+ PegIFN 12w (n=78) Hezode C et al, NEJM 29;36: ADVANCE: Telaprevir with Response Guided Therapy in naïve HCV-1 ervr = HCV Yes 24W, No 48W TPV 75 mg q8h; PEG-2a; WB RBV 1 8 P <.1 P < ervr, % Relapse, % DC for rash, % DC for AE,% PegIFN/RBV + Placebo 48w (n=361) TPV 12w+ PegIFN/RBV RGT (n=363) TPV 8w+ PegIFN/RBV RGT (n=364) Jacobson I et al, AASLD 21; abstract 211 8

9 SVR (%) SVR (%) ADVANCE: Telaprevir with Response Guided Therapy in naïve HCV-1 ervr = HCV Yes 24W, No 48W TPV 75 mg q8h; PEG-2a; WB RBV 1 8 P <.1 P < ervr, % Relapse, % DC rash, T or P/all % DC any AE,% PegIFN/RBV + Placebo 48w (n=361) / 4 TPV 12w+ PegIFN/RBV RGT (n=363) /1.4 7 TPV 8w+ PegIFN/RBV RGT (n=364) /.5 8 Jacobson I et al, AASLD 21; abstract 211 ILLUMINATE: Randomized trial of short vs. long duration Rx after ervr Gt 1 naive (N=54) Peg2a /WB RBV/TPV x 12 wks +12 wks P/R (n=162) Wk 4, 12 HCV RNA (-) 65.2% (n=352) Randomize +36 wks P/R (n=16) met noninferiority criteria A truncated PEG/RBV/TPV regimen preserves high rates of SVR following ervr SVR 92% SVR 87% Sherman K et al, AASLD 21; abstract LB-2 SPRINT-2: Boceprevir Response Guided Therapy in naïve HCV Ph 3, BOC 8 tid, PEG-2b, WB RBV P =.4 P <.1 P <.1 P = Non-black Black W8-24RNA(-), % PPV for SVR, % Relapse, % Anemia,% LI +Peg/RBV + Placebo 48w (n=311/52) NR NR LI+24Peg/RBV BOC +/- 2 Peg/RBV (n=316/52) LI +44Peg/RBV/ BOC (n=311/55) Poordad F et al, AASLD 21; LB-4. Bronowicki J et al, LB

10 SVR (%) RESPOND-2: Boceprevir in treatmentexperienced HCV Ph 3, BOC 8 tid, PEG-2b, WB RBV 21 P <.1 P < Overall Prior RR Prior NR Relapse, % DC for AE,% Peg/RBV 48w (n=51/29 RR/NR) 32 3 LI+ P/R/BOC x32w +/-12W P/R RGT (n=15/57 RR/NR) 15 8 LI +44 P/R/BOC (n=13/58 RR/NR) Bacon B et al, AASLD 21; Abstract 216 REALIZE: Phase 3 Trial of Telaprevir in treatment-experienced HCV-1 Previous Response Overall Null Response W12) Partial Response W12, *P<.1 vs SOC but RNA+ W24) Relapse T12PR48 or LI +TPR12+ PR32 (pooled) 65%* (346/53) 31%* (46/147) SOC (PR48) 17% (22/132) 5% (2/37) 57%* (55/97) 15% (4/27) 86%* (245/286) 24% (16/68) Vertex Press Release, Sept 7, 21 PILLAR Study: TMC435 + PegIFN/RBV Proportion of Patients Achieving Virologic Response Week 4 Week 12 *** *** *** *** *** *** *** *** TMC 12/ TMC 24/ TMC 12/ TMC 24/ Pbo 24/ TMC 12/ TMC 24/ TMC 12/ TMC 24/ Pbo 24/ PR24 PR24 PR24 PR24 PR48 PR24 PR24 PR24 PR24 PR48 75 mg 75 mg 15 mg 15 mg 75 mg 75 mg 15 mg 15 mg (n=77) (n=75) (n=76) (n=75) (n=75) (n=78) (n=73) (n=77) (n=77) (n=74) <25 IU/mL undetectable <25 IU/mL detectable >25 IU/ml Fried MW, et al. AASLD 21; Abst. LB-5. 1

11 Mean(+/- SE) Change in Plasma HCV RNA (log 1 IU/mL) from Baseline PILLAR Study: Role of IL28B Genotype Placebo Week CC CT TT All TMC 435 (75 mg) All TMC 435 (15 mg) Week Week Fried MW, et al. AASLD 21; Abst. LB-5. SILEN-C1: BI PegIFN/RBV with or without 3-day lead-in ervr SVR Relapse PR BI mg LI BI mg LI BI mg No LI Sulkowski et al. EASL 211 NS5B RNA-dependent RNA Polymerase Multiple Sites of Action GS-919 Benzimidazoles JTK-3 Nucleosides R1626 RG7128 MK-68 Benzothiadiazines A Benzofurans HCV-796 Thiophenes VCH-759 Nucs: high barrier, high fitness cost NNI: low barrier, low fitness cost 11

12 Response (%) PROPEL: 12 wk interim analysis of PEG/RBV/RG7128 Phase 2, PEG-2a, WB RBV 49 Peg/RBV 48w (n=84) No excess AEs over SOC RG7128 5bid x12w PR24 (n=8) No rebound or resistance observed RG7128 1bid x8w PR24 (n=81) RG7128 1bid x12w PR24 (n=82) 62 8 RG7128 1bid x12w PR48 (n=81) RVR cevr JUMP-C RGT study interim data: 6% ervr 76% SVR Jensen D et al, AASLD 21; Abstract 81; Pockros P et al, EASL 211 An NS5A inhibitor has potent activity against HCV NS5A: no known enzymatic function, indispensable for RNA replication, viral assembly Chemical screening BMS single ascending dose study in gt 1 naïve pts -3.6 after 1 mg dose non-overlapping resistance profile with PI, pol-inhibitors Gao M et al. Nature 21;465:96-1 NS5A inhibitor + PegIFN/RBV 1 8 SVR PR (n=12) NS5A 1 mg (n=12) NS5A 1 mg (n=12) NS5A 6 mg (n=12) Pol et al. EASL

13 Platelets (GI/L) Total Neutrophils (GI/L) Hemoglobin (g/l) Percentage of patients ± 95% CI IFNs alpha and lambda IFN- : type III IFN vs type I IFN- Share convergent signal transduction Limited receptor distribution (hepatocytes, immune cells) More limited AE profile? PEG-IFN- 1 as therapeutic O Brien TR. Nat Genetics 29;41:148 Virologic response by IL28B Genotype in patients with HCV Genotypes 1, 4 RVR Solid bars: CC Hatched bars: CT/TT cevr μg 18 μg 24 μg 18 μg 12 μg 18 μg 24 μg 18 μg PegIFN-λ PegIFN-α-2a PegIFN-λ PegIFN-α-2a n = Zeuzem et al. EASL 211 Changes in Hematologic Parameters Over Time and PegIFN and RBV Dose Reductions LLN PegIFN-λ 12 µg PegIFN-λ 18 µg PegIFN-λ 24 µg PegIFN-α-2a LLN 15 LLN Study Week PegIFN-λ PegIFN α-2a 12 µg 18 µg 24 µg 18 µg Lab Toxicity, % (N=128) (N=131) (N=134) (N=133) Hemoglobin low RBV dose reduction, % (due to Hb abnormality) Neutrophils Low Platelets Low 14.4 PegIFN dose reduction, % (due to hematologic abnormality) 17.3 Zeuzem et al. EASL

14 Log 1 HCV-RNA (IU/mL) Pros, Cons of Direct Acting Antivirals Class Potency Barrier to Resistance Protease inhibitors High Low Nuc Polymerase inhibitors Nonnuc Polymerase inhibitors NS5A inhibitors High Toxicity and Interactions Rash Anemia Bilirubin Mitochondrial Nuc interactions (ART, RBV) Comments 2 nd gen PIs: better barrier, pangenotypic Single target Moderatehigh Low- Moderate Low variable Many targets Moderate- High Moderate Multiple antiviral MOA Ideal DAA cocktail will combine high potency with high barrier to resistance A Combination of DAAs Could Eliminate Resistant Variants Target Variant NS3 Linear NS3 Macrocyclic NS5A inhibitor NS5B nucleoside NS5B Palm NS5B Thumb NS5B Finger IFN RBV V36M R S S S S S S S S NS3 Protease NS5A T54A R S S S S S S S S R155K R R S S S S S S S A156T R R S S S S S S S D168V S R S S S S S S S L28V S S R S S S S S S Y93H S S R S S S S S S S282T S S S R S S S S S C316Y S S S S R S S S S NS5B M414T S S S S R S S S S R422K S S S S S R S S S M423T S S S S S R S S S P495S S S S S S S R S S S = Susceptible (< 4 fold shift in HCV replicon EC5) R = Resistant (>4 fold increase in EC5) Proof of concept for combining two DAAs: INFORM RG danoprevir (n=73) Day LLOQ = lower limit of quantification by TaqMan Assay (<4 IU/mL) LLOD = lower limit of detection by TaqMan Assay (<15 IU/mL) Placebo LLOQ LLOD Gane EJ, et al. Lancet 21; Oct 14, epub ahead of print 14

15 Other DAA combinations in early trials Rationale: exploit replication dependence of HCV RG7128 (Nuc) + danoprevir (PI) (Gane, Lancet 21) Telaprevir (PI) + VX222 (NN) +/- PEG/RBV BMS6532 (PI) + BMS7952 (NS5A) +/- PEG/RBV (Lok, AASLD LB-8) GS919 (NN) + GS9256 (PI) +/- RBV (Zeuzem, AASLD LB-1) BI21335 (PI) + BI27127 (NN) + RBV (Zeuzem, AASLD LB-7) IDX184 (Nuc) + IDX32 (PI) Modeling: SVR possible with DAAs if barrier high Gane EJ, et al. Lancet 21; Oct 14, epub ahead of print Rong L et al, Science Transl Med 21; 2:3ra32 A Full Pipeline: Other DAAs in Clinical Testing (Phase) Protease inhibitors TMC435 (2) Danoprevir (2) MK79 (2) BI21335 (2) BMS6532 (2) GS9256 (2) ACH1625 (2) IDX32 (2) PHX1766 (1) Nuc pol inhibitors IDX184 (2) PSI7977 (2) RG7348 (1) Nonnuc pol inhibitors GS919 (2) ANA598 (2) VCH759 (2) Filibuvir (2) VX222 (2) ABT333, 72 (2) BI27127 (1) ABT83793 (1) NS5A inhibitors BMS 7952 (2) PPI461 (1) NS4B inhibitors clemizole (1) Entry ITX561 (2) MBL-HCV1 (2) At least 4 proteins participate in HCV entry Fusion Ploss A et al. Nature 29;457:882 Pietschmann T. Nature 29;457:797 15

16 Other viral targets: HCV Entry Inhibitors In development: inhibitors of CD81, claudin-1, occludin-1 Possible role in cell-to-cell spread Potentially promising approach to prevent de novo HCV infection Phase 2 study of MBL-HCV-1: MAb vs. HCV E2 protein to prevent allograft reinfection Ploss A et al, Nature 29; 457:882 Other Targets: Host Cofactors for Viral Replication Exploit strategies to block host accessory factors in the viral lifecycle Advantage: high barrier to viral resistance Disadvantage: host cellular toxicity Growing list of potential targets Cyclophilin A MicroRNAs Lipid biosynthesis Cyclophilin Antagonists Cyclophilin A blocks incorporation of NS5B into replication complex CsA active vs HCV in culture models CsA blocks cyclophilin A but also inhibits calcineurin immunosuppression Non-immunosuppressive antagonists DEBIO 25 (-3.6 log w/ monotherapy in HCV/HIV) SCY635 (-2.3 log w/ monotherapy in HCV) high barrier to resistance broadly active across genotypes Phase 2 studies Watashi K, et al. Mol Cell. 25;19: Liu Z et al, J Virol 29;83:6554. Flisiak R, et al. Hepatology. 28;47: Hopkins S et al, EASL

17 mir122 Antagomirs micrornas regulate host mrnas mir122 is predominant liver mirna, required for HCV replication SPC3649: mir122 antagomir reduced HCV by 2-3 log in chimpanzees No breakthrough, resistance observed during 12 weeks of Rx Suggests utility for nonresponders and DAA failures Phase 1 studies Lanford RE et al, Science 21; 327: Host factors: HCV replication requires cholesterol intermediates Wang C, et al. Mol Cell. 25;18:425 Ye J, PLoS Pathogens 27;3:e18 Statins exert strong antiviral effect in vitro HMGR inhibitors: strong antiviral effect in replicon Reversible with geranylgeraniol However, no HCV activity alone at std clinical doses Best IC 5 vs HCV = 1 M (vs IC 5 for HMGR = 1nM) Higher concentrations may be necessary for GG depletion Synergy with IFN in replicon Combo with DAA agents additive, and prevents or delays resistance Rationale for combination trial Ikeda M, et al. Hepatology 26;44:117 Kim SS et al, Gastroenterology 27;132:311 O Leary JG et al, Hepatology 27;45:895 Delang L et al, Hepatology. 29;5:6 17

18 A SNP in IL28B (IFN 3) predicts treatment response in HCV Ge D et al, Nature : IFNs alpha and lambda O Brien TR. Nature Genetics 29;41:148 The new waves of HCV therapy Wave 1 ( ): add-on Rx 1 st generation PIs + SOC: naïve and experienced Naives consider empiric Rx (as with gt 2/3) Experienced offer Rx (particularly R/R, PR) Nulls stratify by stage Wave 2 ( ): the better mousetrap Substitution of 2 nd generation PIs, nucs (better PK, tolerability) Substitution of better tolerated IFNs 4 drug regimens for P/R/PI failures Phase 3 (216-22): the holy grail Oral cocktails of DAAs, host cofactor inhibitors, RBV Many roads to the same destination! 18

19 Summary DAAs are the future of HCV therapy Protease inhibitors have potent activity but select resistant variants Nucleosides have potent activity and high genetic barrier but potential interaction concerns Nonnucs have moderate activity, many sites, but low barrier to resistance NS5A inhibitors also potent, nonoverlapping resistance Host cofactor inhibitors have high barrier to resistance, but may have greater toxicity concerns Selection of agents with complementary MOA and resistance profiles will be desirable Must provide rapid suppression, minimize resistance Combine high barrier compounds with potent low barrier compounds IFN-sparing regimens will be possible in future (6-1yr) Role of pharmacogenomics in decision making 19