Feeling right at home Getting to Cure From Cure to Eradication - PowerPoint PPT Presentation

Feeling right at home

Getting to Cure From Cure to Eradication Jordan J. Feld MD MPH Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto

Dramatic Improvements DAAs 2014 PR + NI 95-99% 2013 100% PR + PI Peginterferon 90% 2011 Ribavirin 2002 80% Standard 75% 2001 Interferon 1998 55% SVR 60% 1995 42% 39% 1991 34% 40% 16% 20% 6% 0% PR/PI PR/SOF DAAs IFN IFN IFN/R IFN/R PegIFN PegIFN/R 6-12 mo 3 mo 3 mo 12 mo 6 mo 12 mo 6 mo 12 mo 12 mo

17 HCV Trials in NEJM since 2012

Very Rapid Progress 1 pill, OD, Perfectovir No AEs, ~100% SVR IFN-Free DAA Combos Efficacy Peg/RBV Peg/RBV + 2 nd gen DAA + BOC/TVR Peg/RBV Tolerability/Safety

Very Rapid Progress Efficacy Peg/RBV + BOC/TVR Peg/RBV Tolerability/Safety

A Major Advance: G1 Treatment- Naive and Treatment Failures PegIFN + RBV 100 100 BOC or TVR + PegIFN + RBV 69-83 80 80 63-75 40-59 60 60 SVR (%) SVR (%) 38-44 29-40 40 40 24-29 20 7-15 20 5 0 0 Null Relapsers Partial Responders PegIFN/RBV BOC or TVR + Responders PegIFN/RBV Poordad et al NEJM 2011 Jacobson et al NEJM 2011

Response to PIs depends on response to IFN Prior Prior partial Prior null relapsers responders responders 100 Pooled T12/PR48 86 85 84 Pbo/PR48 80 72 SVR (%) 56 60 41 39 40 34 32 20 18 20 14 13 13 10 6 0 0 0 n/N= 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10 No, minimal Bridging Cirrhosis No, minimal Bridging Cirrhosis No, minimal Bridging Cirrhosis Stage or portal fibrosis or portal fibrosis or portal fibrosis fibrosis fibrosis fibrosis Zeuzem EASL 2011

No free lunch Treatment is more effective but much more difficult

Other issues with PI-based therapy Pill Burden Food Requirement Resistance TVR = 12/d BOC = 18/d Drug-Drug Interactions CYP3A4 Metabolites PI

Very Rapid Progress Efficacy Protease Inhibitor Peg/RBV Peg/RBV + 2 nd gen DAA + BOC/TVR Nuc Polymerase Inhibitor Peg/RBV Tolerability/Safety

Sofosbuvir + PR G1, 4-6 Naïve (NEUTRINO) SOF 400 mg OD + Peg/RBV x 12 wks 100 100 96 92 100 90 82 80 SVR12 (%) 60 SVR12 (%) 40 20 295/ 206/ 54/ 27/ 1/ 6/ 327 225 66 28 1 6 0 All G1a G1b G4 G5* G6* AEs similar to Peg/RBV  no control arm *not in label Lawitz E, et al. NEJM 2013

A major advance for patients with cirrhosis No cirrhosis Cirrhosis 99 100 100 96 93 92 100 91 80 HCV RNA <LLOQ (%) 80 60 40 20 249/273 50/54 269/271 52/54 267/267 53/53 252/273 43/54 0 Week 2 Week 4 Week 12 Week 12 On treatment Post-treatment Lawitz E, et al. NEJM 2013

Summary on Sofosbuvir Pros • Once daily Nuc Polymerase Inhibitor • Very well tolerated • Given for only 12 weeks in ALL patients (no RGT) • High SVR even in cirrhosis (80%) • Some data in non-G1 • High barrier to resistance - no breakthrough  only relapse • About to be reimbursed (we hope!) Cons • Would have been nice to have a control group! • No data in treatment experienced – naïve only

The (many) billion dollar question? Can we get rid of IFN?

How many DAAs do we need? Assumptions: 1) Production of new virions = ~10 12 /day 2) HCV genome length = ~9600 nucleotides 3) Error rate = ~10 -5 /per nucleotide copied Therefore… Average number of changes/genome = 0.096/replication cycle # of nt Probability # of virions/d # of all % of all changes possible possible mutants mutants/d 9.1 x 10 11 0 0.91 8.7 x 10 10 2.9 x 10 4 1 0.087 100 4.2 x 10 9 4.1 x 10 8 2 0.0042 100 1.3 x 10 8 1.0 x 10 12 3.4x10 -3 3 0.00013 If the theory is right – should need 3 DAAs Rong et al Sci Trans Med 2011

Not all DAAs are created equal • Modeling predicts existence of RAVS, not success of RAVS • Genetic barrier – Some RAVS less likely to emerge  multiple substitutions (eg. 1a vs 1b for PIs/NS5A/NNI) • Fitness – Not all RAVS created equal  S282T for nucs very unfit

Fitness Affects Resistance Drug B – PI Drug A - Nuc HCV Resistant mutant…not so fit Resistant mutant… (like S282T – resistant but unfit) (like R155K - ?slower but still fit)

Fitness of Polymerase Inhibitor Mutants Non Nuc Nuc Le Pogam et al JVI 2006 Le Pogam et al JID 2010

The HCV Toolbox High barrier Nuc Nuc Nuc to resistance RBV NS5A NS5A IFN NNI NNI Modest barrier Low barrier PI PI PI to resistance to resistance (esp to G1a) (esp to G1a) Treatment Duration Challenges Genotype Subtype Cirrhosis Prior Trt/ Ethnicity BMI HCV RNA IL28B

The HCV Toolbox High barrier Nuc Nuc Nuc to resistance RBV NS5A NS5A IFN NNI NNI Modest barrier Low barrier PI PI PI to resistance to resistance (esp to G1a) (esp to G1a) Treatment Duration Challenges Genotype Subtype Cirrhosis Prior Trt/ Ethnicity BMI HCV RNA IL28B

The HCV Toolbox: Mix & Match Nuc Nuc Nuc RBV RBV RBV NS5A NS5A NS5A NNI NNI PI PI PI Treatment Duration Challenges Genotype Subtype Cirrhosis

Can we get rid of IFN? NS5A PI

PI + NS5A in prior null responders Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free) Japan [2] US [1] 100 90 US Study 80 9/11 G1a SVR24 (%) 60 Japanese Study 36 40 10/10 G1b 20 4/11 9/10 0 • Great for G1b…not adequate for G1a 1. Lok et al NEJM 2012;366:216-24, 2. Chayama et al, AASLD 2011, oral (LB-4)

PI + NS5A for G1b – relevant for HK Daclatasvir (NS5A) + Asunaprevir (PI) x 24 wks (IFN-Free) in G1b Null/ IFN Naive Partial Ineligible 100 90 90 Cirrhosis 82 82 80 73 SVR12 (%) 60  40 20 168/ 192/ 50/ 182/ 205 203 235 68 9/10 0 • Simple, cheap  good for areas with 1b  Asia • Major caveat: 12% NS5A resistance  SVR 40% • Reasonable option….but 24 wks … 1. Chayama AASLD 2011, Manns EASL 2014 Abst 0166

The HCV Toolbox: The near future If 2 are good, would 3 be better? RBV NS5A PI NNI

SAPPHIRE I (naïve) & II (PR failure) 3D + RBV : Co-formulated Paritaprevir(PI)/r/Ombitasvir(NS5A) + Dasabuvir (NNI) = 2 pill OD, 1 pill BID + RBV Week 0 Week 12 Week 24 Week 60 Week 72 Primary Double-blind Analysis: SVR 12 Treatment Period 48 weeks post-treatment follow-up N=473 (I) 3D+RBV N=297 (II) 48 weeks post-treatment follow-up N=158 (1) 3D+RBV Placebo N=97 (II) Open-label Treatment Period • No cirrhotics • Placebo controlled  real assessment of safety

PI + NS5A + NNI + RBV 3D + RBV: Paritaprevir/r (PI) + Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV x 12 wks Naive Treatment Failures (49% nulls) 98 96 96 97 100 100 96 95 80 80 SVR12 (%) SVR12 (%) 60 60 40 40 20 20 286/ 455/ 166/ 119/ 307/ 148/ 297 473 173 123 322 151 0 0 All G1a G1b All G1a G1b • 5 drugs (3 pills) BUT 12 wks, 1 size fits all • Very well tolerated (vs. placebo), few virologic failures Feld J NEJM 2014 Zeuzem S NEJM 2014

When everyone responds… 95.2 97.5 96.4 96.2 97.0 91.5 96.5 96.0 98.1 95.7 93.5 96.4 100 SVR12, % Patients 75 50 25 271 202 28 445 402 71 144 329 104 369 31 442 N 0 Gender Race BMI IL28B Baseline RBV (kg/m 2 ) Genotype HCV RNA Modification Feld J EASL 2014 Abst 060, NEJM 2014

Adverse Events 3D + RBV Placebo AE, (%) P Value (N=473) (N=158) Any AE 87.5* 73.4 <0.05 Fatigue 34.7 28.5 NS Headache 33.0 26.6 NS Nausea 23.7* 13.3 <0.05 Pruritus 16.9* 3.8 <0.05 Hb<10 g/dL 7* 0 <0.05 Bilirubin>3x ULN 5* 0.5 <0.05  DDIs: Similar to first-generation PIs (CYP3A)  check the label and other resources (eg, University of Liverpool Web site) Feld J NEJM 2014 Zeuzem S NEJM 2014

Is RBV necessary?

Ribavirin-Free Therapy in GT1b Wk 12 SVR12, % PEARL-II [1] 100 3 DAAs (n = 95) GT1b Tx Experienced 97 3 DAAs + RBV (n = 91) PEARL-III [2] 99 3 DAAs (n = 209) GT1b Tx Naive 99 3 DAAs + RBV (n = 210) PEARL-IV [2] 3 DAAs (n = 205) 90 GT1a Tx Naive 97 3 DAAs + RBV (n = 100)  RBV needed for GT1a, not necessary for GT1b noncirrhotics 1. Andreone P, Gastroenterology. 2014 2. Ferenci P, NEJM 2014

TURQUOISE • Largest trial of cirrhotics in HCV – n=380! • Mixed naïve and treatment failures Poordad NEJM 2014

3D + RBV in Cirrhosis by G1 Subtype 100 99 94 100 89 12 wks 80 24 wks SVR12 (%) 60 40 20 67/ 51/ 120/ 114/ 68 51 140 121 0 G1a G1b • 12 weeks clearly adequate for G1b • What about G1a? Poordad EASL 2014, LB, NEJM 2014

G1a null cirrhotics need 24 weeks… 100 100 100 12 wks 100 93 93 93 93 80 24 wks 80 SVR12 (%) 60 40 20 40/ 59/ 14/ 11/ 52/ 13/ 10/ 39/ 50 64 15 11 56 13 10 42 0 Naive Nulls Relapsers Partials • Suggests that 24 wks optimal for G1a null cirrhotics • 12 wks adequate for all others Poordad EASL 2014, LB, NEJM 2014

Summary 3D + RBV • Highly effective 12 week regimen – SVR 96% naïve/experienced – Similar G1a (95%) and G1b (98%) • Large cirrhotic trial – Similar efficacy & safety – 12 weeks adequate for all but G1a nulls  24 wks • Safety – Placebo controlled – minimal toxicity – Mostly to do with RBV – not needed for G1b • Resistance – Very few breakthroughs – 5 in all 3 trials! – Relapsers 2 or 3D resistance

The HCV Toolbox: The near future Nuc NS5A