The Pipeline of New HCV Therapies: What to Expect in the Next 5 Years Nancy Reau, MD Associate Professor University of Chicago
Learning Objectives Upon completion of this presentation, learners should be better able to: Understand the evolving landscape of hepatitis C therapy and the preliminary efficacy This presentation includes discussion of investigational agents.
Do you think that HCV therapy will be all oral in the next 5 years? 1. Yes for all patients 2. Yes for most patients 3. Yes for a few patients 4. No - not for any patients
Do you think that HCV will be treated by primary care physicians in the next 5 years? 1. Yes for nearly all patients 2. Yes for most patients 3. Yes for rare patients 4. No PCPs will not treat HCV
Ideal Therapy? Affordable Pan- Genotypic Convenient Daily or twice a day dosing Easy: short duration, simple rules No Drug Interactions Potent Safe Oral >80% SVR
Why SOC needs to be all oral Interferon toxicity Interferon incapable Interferon intolerant Interferon null responders Limited treatment access due to expertise required In the U.S., there are ~4000-6000 treaters, but 80% of patients are treated by 20% of physicians
Can all oral therapy change the treatment paradigm? Perhaps the most important question
Promising Therapeutic Targets for Direct Acting Antiviral Drug Development Poordad, J Viral Hep, 2012;19:449 464 Structural Proteins Hepatitis C Virus Polyprotein Core E1 E2 P7 NS2 NS3 4A NS4B NS5A NS5B Non-Structural Proteins Protease Inhibitors NS5A Inhibitors NS5B Nucleoside Inhibitors NS5B Non-Nucleoside Inhibitors High Potency Multi-genotypic coverage Intermediate to high barrier to resistance High Potency Multi-genotypic coverage Low to intermediate barrier to resistance Intermediate Potency Pan-genotypic coverage High barrier to resistance Intermediate Potency Limited genotypic coverage Low barrier to resistance
Slide compliments of Donald Jensen New Drug Development Protease inhibitors Polymerase inhibitors Others Approval Boceprevir Telaprevir Phase III BI-1335 TMC-435 GS-7977 BMS790052 Deb025 RG7227r ABT-450r RG-7128 ABT-333 VX222 Peg-rIL29 Phase II GS-9451 MK-5172 BMS650032 ACH-1625 IDX184 ABT-072 GS5885 PSI-938 GS-9190 ANA-773 INX189 Filibuvir Locteron GSK-5852 GS-9456 GI-5005 PPI-461 Phase I SCH900518 IDX136 PHX-1766 GSK625433 IDX375 ANA-598 VCH916 ABT267 PSI-7851 MX-3235 Silibin SCY-635 CTS-1027 NIM811 Preclinical
INTERFERON CONTAINING NOVEL REGIMENS
Patients (%) Six Weeks of a NS5A Inhibitor (GS-5885), Protease Inhibitor (GS-9451) plus Peginterferon/Ribavirin (PR) Achieves High SVR4 Rates in genotype 1 IL28B CC Treatment Naïve HCV Patients: Interim Results of a Prospective, Randomized Trial PR+GS-5885+GS-9451 (Arm 1) SVR4 SVR12 100 vs PR (Arm 2) 100 100 Arm 1: If HCV RNA <LLQ (vrvr) at Week 2 with Week 4 RVR, re-randomized to receive 6 or 12 weeks Arm 2: If HCV RNA<LLQ at Week 4, received 24 weeks of PR Quad therapy for 24 weeks for vrvr failures in Arm 1, RVR failures in Arm 2 80 60 40 20 0 94 81 50/53 39/48 59/59 40/40 6 weeks 12 weeks Virologic Response GS-5885 + GS-9451 + PEG/RBV Week 1 (n=94) 51/90 (54%) Week 2 (n =91) 81/86 (95%) Week 4 (n=74) 71/71(100%) Week 6 (n=64) 64/64 (100%) Thompson AJ, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 759.
MATTERHORN Study: Phase II Study of Partials and Nulls Randomized (1:1:1), open-label, multicentre, parallel study of 2 cohorts Stratification: G1a/G1b Cohort A: G1 Prior Partial Responders n=52 IFN-free: MCB + DNVr + RBV Follow-up G1a pts added PR and are excluded from this analysis n=49 Triple: DNVr + PR Follow-up n=50 QUAD: MCB + DNVr + PR Follow-up Cohort B: G1 Prior Null Responders n=77 IFN-free: MCB + DNVr + RBV Follow-up G1a pts added PR and are excluded from this analysis n=77 QUAD: MCB + DNVr + PR Follow-up n=74 QUAD: MCB + DNVr + PR PR Follow-up Ongoing 0 12 24 36 48 72 Weeks DNVr = danoprevir/ritonavir 100 mg/100 mg BID; MCB = mericitabine 1000 mg BID; PR = peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 1000 mg or 1200 mg/day Feld JJ, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 81. ClinicalTrials.gov Identifier: NCT01331850
Virological Response (% Patients) Virological Response (% Patients) MATTERHORN Study: High SVR in Genotype 1 Null responders Efficacy of IFN-free Treatment for G1b 100 80 60 40 20 0 Feld JJ, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 81. 87 44 EOT SVR4 SVR12 EOT SVR4 SVR12 Efficacy of DNVr +PR and QUAD for 24 Weeks Triple: DNVr+PR QUAD: DNVr+MCB+PR 100 80 60 40 20 0 *Awaiting f/u on 1 pt in A2 and 2 patients in B2, all EOT responders Prior Partial Response 39 20/23 10/23 9/23 28/32 21/31 17/31 94 94 Prior Partial Response 67 90 +MCB =30% 46 86 88 96 Prior Null Response 68 55 Prior Null Response 85 84 46*/49 47/50 32/48 45/50 27/48 43/50 73/76* 63/74 62/74 EOT SVR4 SVR12 EOT SVR4 SVR12
Patients with an SVR12, % SVR12 by Subtype: Addition of MCB Improves SVR12 in G1a by 45% Triple DNVr + P/R QUAD: DNVr + MCB + P/R 100 90 80 91 Genotype 1b 96 100 Genotype 1a QUAD 70 75 73 60 50 + MCB = 45% 40 30 20 30 10 0 19/21 25/26 30/30 8/27 18/24 32/44 Partial Responders Partial Responders Null Responders Partial Responders Partial Responders Null Responders Feld JJ, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 81.
SVR in G1 Null Responders with DCV (NS5A) and ASV (NS3) ± PR N=101 null responders Mean viral load 6.5 log G1b: A1 2: 100% B1 3: 14% F3 or higher 15-41% One IL28B CC (A1) Prior null responders to PR n=18 n=20 n=20 A1 (DUAL): DCV 60 mg QD + ASV 200 mg BID (G1b only) A2 (DUAL): DCV 60 mg QD + ASV 200 mg QD (G1b only) B1 (QUAD): DCV 60 mg QD + ASV 200 mg BID + PR (G1a/1b) Week 24 SVR12 Primary endpoint SVR48 Follow-Up Follow-Up Follow-Up QUAD n=21 B2 (QUAD): DCV 60 mg QD + ASV 200 mg QD + PR (G1a/1b) Follow-Up n=22 B3 (TRIPLE): DCV 60 mg QD + ASV 200 mg BID + RBV (G1a/1b) Follow-Up Week 12 SVR4 SVR24 Lok AS, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 79.
HCV RNA < LLOQ (% Patients) DUAL and QUAD Therapy 100 80 60 40 20 100 A1: DCV + ASV 200 mg BID A2: DCV + ASV 200 mg QD B1: DCV + ASV 200 mg BID + PR B2: DCV + ASV 200 mg QD + PR 85 95 95 100 100 100 95 89 89 65 65 1b 1b 90* QUAD 95 0 n = 18 20 18 20 18 20 NA NA 20 21 20 21 20 21 20 21 Week 4 EOTR (Week 24) SVR4 SVR24 2 patients relapsed 1 at PT Week 4 (B1); 1 at PT Week 12 (B2) Safety DUAL: Headache and diarrhea most common AEs QUAD: Addition of IFN AEs Resistance: Failure results in dual class (NS5A and NS3) resistance *1 pt missed 24 wk follow up failure on ITT analysis Lok AS, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 79.
Interferon-free, oral direct acting antiviral regimens
Protease or Nucleoside as Backbone? Protease inhibititor backbone ± NS5A inhibitor ± non-nucleoside polymerase inhibitor ± ribavirin Danoprevir/r + mericitabine + ribavirin Genentech Telaprevir + VX-222 + ribavirin Vertex Faldaprevir + BI7227 + ribavirin Boerhinger Ingelheim ABT450/r + ABT267 + ABT333 ± ribavirin Abbott Asunaprevir + daclatasvir ± BMS-325 BMS Nucleotide analogue polymerase inhibitor backbone with ribavirin or NS5A inhibitor/ribavirin Sofosbuvir + daclatasvir ± ribavirin Sofosbuvir + ribavirin Sofosbuvir + GS5885 + ribavirin Sofosbuvir + simeprevir
Virological Response (% Patients) Virological Response (% Patients) MATTERHORN Study: High SVR in Genotype 1 Null responders Efficacy of IFN-free Treatment for G1b 100 80 60 40 20 0 Feld JJ, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 81. 87 44 EOT SVR4 SVR12 EOT SVR4 SVR12 Efficacy of DNVr +PR and QUAD for 24 Weeks Triple: DNVr+PR QUAD: DNVr+MCB+PR 100 80 60 40 20 0 *Awaiting f/u on 1 pt in A2 and 2 patients in B2, all EOT responders Prior Partial Response 39 20/23 10/23 9/23 28/32 21/31 17/31 94 94 Prior Partial Response 67 90 +MCB =30% 46 86 88 96 Prior Null Response 68 55 Prior Null Response 85 84 46*/49 47/50 32/48 45/50 27/48 43/50 73/76* 63/74 62/74 EOT SVR4 SVR12 EOT SVR4 SVR12
ZENITH Study: VX-222 + Telaprevir + Ribavirin Phase 2b Treatment-naïve Genotype 1 Genotype 1b (n=23) VX-222 (400 mg bid) + Telaprevir (1125 mg bid) + RBV Follow-Up* PR* Genotype 1a (n=23) VX-222 (400 mg bid) + Telaprevir (1125 mg bid) + RBV Follow-Up* PR* Week 0 12* 24 36 PR: pegifn + RBV (weight-based dosing: 1000-1200 mg). HCV RNA >5 log 10 IU/mL; no cirrhosis (nonblack: 83%) *Patients undetectable HCV RNA at weeks 2 and 8 discontinue treatment at week 12. Patients with detectable HCV RNA at week 2 or 8 started PR at week 12 (until 24 weeks of PR are received). Jacobson IM, et al. Hepatology. 2012;56(supp 4):308A. Abstract 231.
Patients (%) ZENITH: Interim SVR12 Results VX-222 + telaprevir + RBV 100 100% 80 60 67% 40 20 0 Genotype 1b (n=5) Genotype 1a (n=4) Jacobson IM, et al. Hepatology. 2012;56(supp 4):308A. Abstract 231.
Faldaprevir (PI) + Non-nucloside polymerase inhibitor with or without ribavirin (16, 28 or40 weeks) (n=81) Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV Follow-up (n=80) Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV Follow-up (n=77) Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV Follow-up (n=78) (n=46) Faldaprevir 120 mg QD + BI 207127 600 mg BID + RBV Faldaprevir 120 mg QD + BI 207127 600 mg TID, no RBV Follow-up Follow-up Day 1 Week 16 Week 28 Week 40 Phase IIb, multicenter, open-label, randomized (1:1:1:1:1)a Treatment-naïve patients with chronic HCV GT-1 Stratified by GT-1 subtype (1a vs 1b) and IL28B (CC vs non-cc) Compensated cirrhosis included, 18 75 years of age, HCV RNA >100 000 IU/mL Stopping rule: HCV RNA detectable between Weeks 6 and 8 Primary endpoint: SVR 12 weeks after treatment completion A Randomization to the non-rbv arm stopped early (FDA request based on perceived increased risk of breakthrough with other interferon-free and RBV-free combinations) First dose of faldaprevir = 240 mg and BI 207127 = 1200 mg RBV dose, 1000 mg/day (<75 kg body weight) or 1200 mg/day ( 75 kg body weight) BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; SVR, sustained virologic response; TID, three-times daily Soriano V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 84.
SVR 12 (%) 100 SVR12 According to HCV Subtype (ITT) GT-1a GT-1b 80 60 40 38 75 69 44 47 56 43 85 57 20 0 ITT n/n BI 207127 dosing Duration (weeks) RBV 13/34 TID 16 + 35/47 14/32 33/48 16/34 24/43 13/30 41/48 2/18 16/28 TID 28 + TID 40 + BID 28 + 11 TID 28 - ITT, intention-to-treat All groups received faldaprevir 120 mg QD for the same duration as BI 207127 (16, 28, or 40 weeks) Soriano V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 84.
SVR (%) SOUND-C2 Study sub-analysis: Efficacy and Safety of the IFN-free Combination of BI 201335 + BI 207127 ± RBV in Treatment-naive G1 Patients with Compensated Liver Cirrhosis SOUND-C2 (N=362); 33 patients (9%) had liver cirrhosis (liver biopsy or Fibroscan) Pooled data from pts who received BI 207127 TID + RBV (TID16W, TID28W and TID40W) BI 7127 dosing Duration (weeks) RBV +/- 100 90 80 70 60 50 40 30 20 10 0 45 57 TID 16, 28 & 40 + Cirrhosis 50 BID 28 + 80 G1a G1b TID 28-33 68 43 42 TID 16, 28 & 40 + No Cirrhosis 3/7 8/14 2/4 4/5 0/0 1/3 40/93 84/124 11/26 37/43 2/18 15/25 BID 28 + 86 11 TID 28-60 Soriano V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 84.
Null Responder Treatment-naïve N 80 ABT450/r (PI) + ABT267 (NS5A)+/- ABT333 (NNI) +- RBV in Treatment Naive and Null Responders Regimen/Duration ABT-450 ABT-267 ABT-333 RBV ABT-450/r Dose (QD) 150/100 41 ABT-450 ABT-267 ABT-333 RBV 150/100 79 ABT-450 ABT-267 ABT-333 RBV 100/100,200/100 79 ABT-450 ABT-267 ABT-333 150/100 79 ABT-450 ABT-267 ABT-333 RBV 100/100,150/100 80 ABT-450 ABT-267 ABT-333 RBV 100/100,150/100 Wk 0 Wk 8 Wk 12 Wk 24 45 ABT-450 ABT-267 ABT-333 RBV 200/100 45 ABT-450 ABT-267 ABT-333 RBV 100/100,150/100 43 ABT-450 ABT-267 ABT-333 RBV 100/100,150/100 ABT-267 25mg QD; ABT-333 400mg BID; RBV weight-based 1000-1200 mg daily dose divided BID All patients to be followed through 48 weeks post-treatment Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-1.
SVR12 Rates (ITT) for 8- and 12-Week Arms Percentage of patients (ITT) achieving SVR 12 100 90 80 70 60 50 40 30 20 10 0 PI NS5A NNI RBV 88.6 85.4 ABT-450 ABT-267 ABT-333 RBV Naïve 450+267+333+RBV 8 Week Naïve 450+333+RBV Naïve 450+267+RBV Naïve RBV-free Naïve 450+267+333+RBV 12 Week Null 450+267+RBV Null 450+267+333+RBV 12 Week ABT-450 ABT-333 RBV 89.9 88.5 ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 Treatment-naϊve Patients 97.4 ABT-450 ABT-267 ABT-333 RBV 88.6 93.3 N=80 N=41 N=79 N=79 N=79 N=45 N=45 8 weeks 12 weeks 12 weeks ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV Null Responders Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-1.
Daclatasvir (NS5A) + Asunaprevir (PI) + Non-nucleoside polymerase inhibitor (no ribavirin) Primary Endpoint: SVR 12 Part 1 Part 2 Group 1 Group 2 Group 3 Group 4 DCV + ASV + BMS-791325 75 mg DCV + ASV + BMS-791325 75 mg DCV + ASV + BMS-791325 150 mg DCV + ASV + BMS-791325 150 mg 12-week follow-up 12-week follow-up 12-week follow-up 12-week follow-up Additional follow-up to SVR 48 Study Week 0 12 24 36 Patients: treatment-naïve, non-cirrhotic, HCV GT 1 stratified by subtype 1a/1b Treatment: DCV 60 mg QD + ASV 200 mg BID + BMS-791325 either 75 mg BID (Part 1) or 150 mg BID (Part 2) HCV RNA endpoints: per FDA guidance, HCV RNA < LLOQTD = target detected but below the assay lower limit of quantitation (LLOQ; 25 IU/mL); LLOQTND = below LLOQ and target not detected (previously referenced as HCV RNA undetectable or < LOD; 10 IU/mL for this study) Primary endpoint: HCV RNA < LLOQ 12 weeks post treatment (SVR12) Modified intent-to-treat analysis: missing, breakthrough, or relapse = failure Interim analysis: Part 1 results reported through post treatment week 4 (Group 1; SVR4) or post treatment week 12 (Group 2; SVR12); Part 2 enrolled and ongoing, results not yet available Everson G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB.-3.
Patients achieving endpoint (%) HCV RNA Endpoints: Modified Intention-to-Treat Analysis 24-Week Treatment Group 1, N = 16 12-Week Treatment Group 2, N = 16 100 80 60 40 20 HCV RNA < LLOQ TD or TND HCV RNA < LLOQ TD or TND Missing data Missing data 100 94 94 a 94 100 88 100 94 94 % < LLOQ 100 80 60 40 20 0 4 12 EOT PT 4 (SVR 4 ) b 0 Study Week b 4 12 EOT PT 4 PT 12 (SVR 4 ) (SVR 12 ) a Includes 1 patient with HCV RNA 118 IU/mL at last on-treatment visit but < LLOQTND 2 and 4 weeks post treatment (SVR4). b EOT, end of treatment; includes patients who discontinued prior to the protocol-defined last treatment visit. < LLOQTD or TND, HCV RNA below assay lower limit of quantitation (25 IU/mL) and target detected (LLOQTD) or target not detected (LLOQTND; HCV RNA < LOD 10 IU/mL, previously reported as HCV RNA undetectable); PT, posttreatment. Everson G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB.-3.
Nucleoside or Protease as Backbone? Protease inhibititor backbone ± NS5A inhibitor ± nonnucleoside polymerase inhibitor ± ribavirin Telaprevir + VX-222 + ribavirin Faldaprevir + BI7227 + ribavirin ABT450/r + ABT267 + ABT333 ± ribavirin Asunaprevir + daclatasvir ± BMS-325 Nucleotide analogue polymerase inhibitor backbone with ribavirin or NS5A inhibitor/ribavirin Sofosbuvir + ribavirin Sofosbuvir + daclatasvir ± ribavirin Sofosbuvir + GS5885 + ribavirin Sofosbuvir + simeprevir
ELECTRON Study: Sofosbuvir + Ribavirin Phase 2b Treatment-Naïve Genotype 2, 3 (n=10) Sofosbuvir 400 mg qd + PR Follow-Up Null Responders Genotype 1 (n=10) Sofosbuvir 400 mg qd + RBV Follow-Up Treatment-Naïve Genotype 1 (n=25) Sofosbuvir 400 mg qd + RBV Follow-Up Treatment-Experienced Genotype 2, 3 (n=25) Sofosbuvir 400 mg qd + RBV Follow-Up Week 0 4 8 12 24 Sofosbuvir (NS3/4A inhibitor). PR: pegifn + RBV. HCV RNA >50,000 IU/mL. No cirrhosis. Weight-based ribavirin dosing (800-1200 mg). Gane EJ, et al. N Engl J Med. 2013;368:34-44.
Patients (%) ELECTRON: SVR in HCV Genotype 2/3 100% 100% SVR12 SVR24 68% NR Treatment-Naïve Sofosbuvir + RBV 8 weeks (n=10) Treatment-Experienced Sofosbuvir + RBV 12 weeks (n=25) Gane EJ, et al. N Engl J Med. 2013;368:34-44.
7977 G2/3 Studies Study Regimen Genotype Criteria Cirrhosis SVR Positron 7977+RBV G2/3 207 IFN intolerants yes G2: 93% G3 61% Fission Fusion 7977+RBV 12 vs P/R24 7977+RBV 12 vs 16 wks G2/3 500 patients Naive G2/3 200 Treatment experienced 20% 67% overall vs 67% G2 97% v 78% G3 56% v 63% yes 73% in 16 wk (63 in G3, 94 in G2) 50% in 12 wk (30 in G3, 86 in G2)
Patients (%) ELECTRON : SVR in HCV 1 84% SVR12 SVR24 NR Treatment-Naïve Sofosbuvir + RBV 12 weeks (n=25) 10% NR Null Responders Sofosbuvir + RBV 12 weeks (n=10) Gane EJ, et al. N Engl J Med. 2013;368:34-44.
NIAID Study: Sofosbuvir + RBV in Washington DC Baseline Demographics GS-7977+1200mg RBV N=10 GS-7977+1200mg RBV N=25 GS-7977+ 600mg RBV N=25 Median age (range) 54 (30-65) 54 (30-65) 55 (26-78) Male sex(%) 4 (40%) 20 (80%) 14 (56%) Genotype 1a(%) 6 (60%) 20 (80%) 16 (64%) African American (%) 9 (90%) 18 (72%) 23 (92%) Median BMI (range) 26 (22-43) 18 (72%) 23 (92%) IL28B CT/TT (%) 6 (67%) 21 (84%) 21 (84%) Median HCV RNA log (IQR) 6.85 (5.80-7.21) 6.16 (5.37-6.41) 6.05 (5.49-6.36) Advanced fibrosis (%) 0 6 (24%) 7 (28%) Osinusi A, et al. AASLD 2012, Boston, #LB-4
% with HCV RNA <LLOQ (ITT) Treatment Response: NUC plus RBV for 24 weeks 1200 mg RBV: 75% SVR4 (mitt) 600 mg RBV: 64% SVR4 (mitt) 100 96 96 96 96 88 88 80 72 60 56 40 20 0 Wk 4 Wk 12 ETR SVR 4 Full dose RBV Low dose RBV 1 drop out at week 3 3 drop outs by week 8 Osinusi A, et al. AASLD 2012, Boston, #LB-4
Sofosbuvir + Daclatasvir + Ribavirin Phase 2a Treatment-naïve Genotype 2/3 LI* Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=16) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=14) Follow-Up Genotype 1 LI* Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=15) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=15) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=15) Follow-Up Follow-Up Follow-Up Follow-Up Week 0 12 24 48 *LI: 7-day lead-in with sofosbuvir 400 mg qd. HCV RNA >50K IU/mL, no cirrhosis. Primary outcome: SVR12. Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
Patients (%) Sofosbuvir + Daclatasvir + Ribavirin: SVR24 in G2/3 100 88% 100% 93% 80 60 40 20 0 LI/SOF/ DCV (n=16) SOF/DCV (n=14) SOF/DCV + RBV (n=14) LI: 7-day lead-in with sofosbuvir 400 mg qd. Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
Patients (%) Sofosbuvir + Daclatasvir + Ribavirin: SVR24 in G1 100 93% 100% 100% 80 60 40 20 0 LI/SOF/ DCV (n=15) SOF/DCV (n=14) SOF/DCV + RBV (n=15) LI: 7-day lead-in with sofosbuvir 400 mg qd. Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
Patients (%) 12-Week Treatment SVR4 (G1) 100 98% 95% 80 60 40 20 0 SOF/DCV (n=41) SOF/DCV + RBV (n=41) Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
Sofosbuvir + GS5885 and/or RBV: New Zealand Treatment Population Response Sofosbuvir + GS5885 + RBV for 12 weeks Sofosbuvir + GS5885 + RBV for 12 weeks GT 1 treatment-naive GT 1 Nulls 100% (25/25) SVR4 100% (3/3) SVR4 Gane E, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 229.
COSMOS: SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders F0-F2 fibrosis SMV 150 mg QD + AOF 400 mg QD w/wo RBV 1000-1200 mg Lawitz CROI 2013 March
COSMOS: Efficacy SVR8 100 90 80 70 60 50 40 30 20 10 0 SMV+SOF+RBV 24 SMV+SOF 24 SMV+SOF+RBV 12 SMV+SOF 12 SVR8 95% GT1a, 100 GT1b Lawitz CROI 2013 March
The early leaders: What we know and what we don t Protease/r NS5A Non-nuc Ribavirin Nuc NS5A/PI Ribavirin DATA No Data 3 pill regimen (5 drugs) 12 weeks Genotype 1 G1 naïve 98% SVR G1 nulls 93% SVR G1 cirrhotics G2/3 2 pill regimen (3 drugs) 12 weeks Genotype 1,?2/3/4 G1 naïve 100% SVR G1 nulls 100% SVR G2/3 naïve 100% SVR G1 cirrhotics G2/3 null
Do you think that HCV therapy will be all oral in the next 5 years? 1. Yes for all patients 2. Yes for most patients 3. Yes for a few patients 4. No - not for any patients
Do you think that HCV will be treated by primary care physicians in the next 5 years? 1. Yes for nearly all patients 2. Yes for most patients 3. Yes for rare patients 4. No PCPs will not treat HCV
Interferon-free Oral Therapy Several oral regimens have emerged from phase 2 clinical trials with high SVR rates in naïve and null Data in cirrhotic patients limited No pan genotypic option yet Expect 2014-2015 will be the time frame for initial approvals for G1 all oral regimens Several regimens by 2016 Expect next generation drugs beyond this first wave Genotype 3 may now be the hardest strain to cure
% of Patients The Future (as I see it) 0 10 20 30 40 50 60 70 80 90 PEG/RBV PI+PEG+RBV PI 2 +PEG+RBV NUC+PEG+RBV DAA 1 + DAA 2 + RBV (or) DAA1 + DAA2 + DAA3 + RBV 100 2011 2012 2013 2014 2015 2016 2017 2018 2019
All Oral May Allow Increased Access to Care Difficulties currently Low screening rate Low specialist referral rate Limited specialist availability and numbers High cost of meds plus care delivery Ideal care system Expanded screening PCP care delivery Less toxic drugs = less monitoring Greater volume + less monitoring may lower overall costs
Proposed Provocative Paradigm Known cirrhosis Prior treatment failures Complicated co-morbidities Complicated cases Referred cases Specialist treated cases All HCV cases Identified naïve HCV cases PCP treatable cases Treatment failures SVR EMR linked HCV screening and high reported success rate Simple tool: HCV RNA + Plts >150K Retest HCV RNA at EOT and/or 12 wks post-eot
Thank you