ABT-450/R (Abbott) – GS-9451 (Gilead) • Second Generation (Pan-Genotype, High Barrier to Resistance) – MK-5172 (Merck) – ACH-2684 (Achillion)
Paris Hepatitis Conference
New Therapeutic Strategies Second Generation Protease inhibitors
David R Nelson MD Professor and Associate Dean Director, Clinical and Translational Science Institute University of Florida Gainesville, USA
Outline
• HCV protease structure and drug targeting • First generation PIs – Major step forward – Major limitations • PIs in development – Second wave – Second generation • Clinical trial data – IFN-containing PI regimens – IFN-free PI containing regimens • Timelines and treatment paradigms NS3 protease targeting
active site “catalytic triad” NS4A
TARGETING . Substrate- and product analogs . Tri-peptides . Serine-trap inhibitors subdomain . Ketoamides (boceprevir, telaprevir) boundary . Macrocyclic inhibitors (e.g. Simeprevir, Danoprevir, Vaniprevir, etc.) zinc-finger . NS4A inhibitors Lorenz et al., Nature 2006 Kronenberger et al., Clin Liver Dis 2008 Welsch et al. Gut in press A Major Step Forward: First Generation PIs
PegIFN/RBV BOC or TVR + pegIFN/RBV 100 69-83 80 63-75
40-59 60 38-44 29-40 SVR SVR (%) 40 24-29
20 7-15 5 0 Naive[1,2] Relapsers[3,4] Partial Null Responders[3,4] Responders[3,4]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 3. Bronowicki JP, et al. EASL 2012. Abstract 11. Limitations of First Generation PI-Based Therapy
• Efficacy – Very dependent on the IFN response – Limited to gen 1 (1b>1a) • Low genetic barrier to resistance • Tolerability – Additional AEs beyond pegIFN/RBV • Regimens – Complicated (lead-in, RGT)/pill burden – TID regimens (food required with TVR) • DDIs – Many with both agents to common drugs (CYP3A4)
Protease Inhibitors in Active Phase 2/3 Development
• Second Wave (better dosing, improved tolerability, broader genotype cverage) – Asunaprevir (BMS) – Faldaprevir (Boehringer) – Simeprevir (Janssen/Tibotec) – Sovaprevir, (Achillion) – Danoprevir/r (Roche) – Vaniprevir (Merck) – ABT-450/r (Abbott) – GS-9451 (Gilead) • Second generation (pan-genotype, high barrier to resistance) – MK-5172 (Merck) – ACH-2684 (Achillion)
Antiviral Activity of NS3 Protease-Inhibitors
Protease-Inhibitor Monotherapy Data for 3–14 days in HCV genotype 1 patients (no head-to-head studies)
6 5.4 5 4.6 4.6 4.5 4.4 4.2 4.2 4.3
3.9 IU/mL) 4 3.3 3.3 10 3.2 2.9 3 2.1 2 1.8
1
decline (log decline
0 Mean or median RNA HCV median or Mean
Adapted from Sarrazin et al., J Hepatol 2012 suppl Expanded genotype activity of next generation HCV protease inhibitors
1 2 3 4 5 6 Boceprevir + Telaprevir + + Simeprevir + + + + + Faldaprevir + + + + Asunaprevir + MK-5172 + + (+) + + + ACH-2684 + + + + + + Improved genetic barrier to resistance for next generation protease inhibitors
V36A T54S/ V55A Q80R/ R155K/ A156S A156T D168A/E/G/ V170A/ /M A K T/Q /V H/T/V/Y T Telaprevir ** Boceprevir
Faldaprevir
Simeprevir ** Asunaprevir*
GS-9451*
ABT450*
MK-5172*** ** ACH-2684 mutations associated with resistance in patients ** mutations associated with resistance in vitro *** no viral break-through during 7 days monotherapy Adapted from Sarrazin et al., J Hepatol 2012 suppl ACH-2684 Potency against GT 1-6 and Activity Against Common 1st-Gen PI Resistant Mutations
500
400
300
(nM)
50
200 IC
100
0 1a 1b 2a 3a 4a 5a 6a
Potency Against Resistant Mutations
Protease IC50 (nM) Inhibitor R155Q R155K A156S A156T D168A D168V Incivek 370 500 >1000 >1000 33 29
ACH-2684 1.6 2.1 0.21 1.6 2.4 7.5
Data on File, Achillion Pharmaceuticals, Inc. MK-5172 has activities against RAVs elicited by the 1st generation PIs
> 8000 MK-5172 7000
BMS-032
6000 TMC-435 (nM)
5000 GS-9551 90 4000 BOC TVR 3000 2000
Replicon EC Replicon 1000 TVR 0 BOC GS-9551 TMC-435 BMS-032 MK-5172 Summary: Protease Inhibitor Profiles
DAA NS31 NS32 NS33
Resistance profile
Pan-genotypic efficacy
Efficacy
Adverse events
Good profile Average profile Least favorable profile
1: 1st generation 2: 2nd wave 3: 2nd generation Investigational HCV Regimens with PIs in Phase III Clinical Trials
Regimens With 1 DAA Regimens With 2 DAAs IFN-Free Regimens + PegIFN alfa/RBV + PegIFN alfa/RBV . Faldaprevir (BI 201335) . Daclatasvir + Asunaprevir . Daclatasvir + asunaprevir . Simeprevir (TMC-435) . ABT-450/RTV + ABT-267 ± ABT-333 ± RBV . Vaniprevir (MK-7009) . Faldaprevir + BI 207127 + RBV
ClinicalTrials.gov. TMC 435 (PI) + PEG-IFN/RBV in Treatment Naïve and Experienced Patients
Treatment naive, G1 Treatment experienced, G1 100 85* P = .013 P < .001 75* 100 80 86
81 80
60 65 (%)
51* 60 37 40 40 SVR SVR (%) SVR 19 20 20 9
0 0 TMC435 TMC435 Pbo Relapsers Partial Null 150 mg 150 mg PR Responders Responders 12-Wk 24-Wk PR PR
* Represents pooled TMC duration at 150mg dose
Fried MW, et al. AASLD 2011. Abstract LB-5; Zeuzem S, et al. EASL 2012. Abstract 2; SVR 12 of MK-5172 for 12 Weeks in Combination With Pegylated Interferon Alfa-2b and Ribavirin for 24 Weeks in HCV Genotype 1 Treatment-Naïve, Noncirrhotic Patients (Vanguard Cohort Analysis)
96.2% 100 86.7% 87.0% 81.5%
75
54.2%
50
SVR 12 SVR Patients, % Patients, 25
25/26 26/30 20/23 22/27 13/24 0 MK-5172 100 MK-5172 200 MK-5172 400 MK-5172 800 BOC + PR RGT mg + PR mg + PR mg + PR mg + PR
Dose-dependent transaminase levels in 400 Marcellin, P et al. AASLD 2012 Poster # 766 mg and 800 mg dosing in the course of therapy Asunaprevir (PI) + Daclatasvir (NS5A)
Pts: Gen1b, non-cirrhotic Null IFN ineligible responder and intolerant 100 91
80 Null 64 Daclatasvir + Asunaprevir responder (%) 60
40 IFN SVR24 Daclatasvir + Asunaprevir intolerant 20 9/10 weeks 0 0 24 N=21 n=22
Among pts with breakthrough (7%) or relapse (9%), Suzuki F, et al. EASL 2012. Abstract 14 low plasma concentrations of DAC and ASU AVIATOR: SVR12 Rates With ABT-450/ RTV, ABT-267, ABT-333, and RBV
Treatment-Naive Patients Null Responders
100 100 100 100 100 100 96 98 Observed data 100 88 88 89 86 82 100 81 100 100 (above bar) 100 96 96 100 80 96 89 84 79 85 83 81 ITT (within bar) 60 40
SVR12 (%) SVR12 20 n = 56 24 29 12 52 27 52 25 54 25 26 18 28 17 0 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-450 ABT-450 ABT-450 ABT-450 ABT-450 ABT-450 ABT-450 ABT-267 ABT-267 ABT-267 ABT-333 ABT-267 ABT-267 ABT-267 ABT-333 ABT-333 ABT-333 RBV RBV ABT-333 RBV RBV RBV RBV 8 wks 12 wks 12 wks
ABT-450: Protease/RTV QD ABT-267: NS5A QD
Kowdley KV, et al. AASLD 2012. Abstract LB-1. ABT-333 NNI BID First All Oral HCV Regimens Likely Available In The US in 2014-2015
Options for PI-Based Regimens Nucleoside-based regimens • Sofosbuvir + RBV (G2/3, select G1) • Sofosbuvir + Daclatasvir (off-label) • Sofosbuvir + PI (TMC 435, TVR, BOC, etc) (off-label) • Sofosbuvir + GS-5885 + RBV (pan-genotype)
Other regimens • Asunaprevir + Daclatasvir (G1b) • ABT-450/r + ABT-333 + ABT-267 + RBV (G1) • Faldaprevir + BI-207127 + RBV (G1b)
Conclusions: Future therapy options for PI
The second wave of PIs Second generation of PIs • Better tolerability, safety • Higher efficacy profile • Pan-genotypic • Improved dosing • High barrier to resistance • Broader genotype coverage for some • Improved DDI profile