PI Narlaprevir in Russian Patients with Genotype 1 Chronic Hepatitis C
The «second wave» PI Narlaprevir in Russian patients with genotype 1 chronic hepatitis C
Professor Igor Bakulin Moscow Clinical Scientific Center
June 5, 2015 Key points
Background
Narlaprevir in clinical trials
Interim results of Phase III Russian PIONEER study
Conclusions
11.06.2015 2 HCV Epidemiology in Russia
Total population size1 143 000 000
Anti-HCV Ab-positive1 5 861 000
CHC diagnosed (viremic)1 1 789 500
New cases2 55 900/year
AVT3 5 500*/year
AVT – antiviral therapy; CHC – chronic hepatitis C 1 2010 data, Saraswat V, Norris S, et al. J Viral Hepat. 2015 ;22 Suppl 1:6-25; 2 Yuschuk ND, Znoyko OO, et al. Epidemiol Vaccine Prevent. 2013; 3 11.06.2015 Regional registries data, 2011 in Saraswat V, Norris S, et al. J Viral Hepat. 2015 ;22 Suppl3 1:6-25 *8 000/year according to IMS Health data calculated on the basis of PegIFN sales for all genotypes in 2014 Access to Direct Acting Antivirals in 2015
SMV SOF
SMV No access to PR federal budget
SOF
SOF LDV Access to new DAA in DCV Russia and some other European countries is limited 3D/r EASL Monothematic Conference on “Liver Disease in Resource Limited Settings”, 2015 11.06.2015 4 EASL Recommendations 2015
IFN-free regimens Genotype Sofosbuvir + RBV 2, 3 Sofosbuvir/Ledipasvir (+/- RBV) 1, 4, 5, 6 Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (+/- RBV) 1 Sofosbuvir + Simeprevir (+/- RBV) 1, 4 Sofosbuvir + Daclatasvir (+/- RBV) All Ombitasvir/Paritaprevir/Ritonavir (+/- RBV) 4
For countries with limited resources IFN-containing regimens are still relevant PegIFN-α + RBV + Sofosbuvir All PegIFN-α + RBV + Simeprevir 1, 4
11.06.2015 5 HCV Protease Inhibitors Value in Russia
Protease inhibitors - a promising DAA group for the treatment of HCV 1b GT, the most prevalent genotype in Russia
HCV Genotypes
Protease inhibitors
Asunaprevir Boceprevir Narlaprevir/r Paritaprevir/r Simeprevir
Saraswat V, Norris S, de Knegt RJ, et al. J Viral Hepat. 2015;22 Suppl 1:6-25. Russian MoH Guidelines on HCV Diagnostics and Treatment in Adults. 2014. 11.06.2015 6 Key points
Background
Narlaprevir in clinical trials
Preliminary results of Phase 3 first Russian PIONEER study
Conclusions
11.06.2015 7 Narlaprevir – a new “second wave” PI
• Oral HCV NS3 serine protease inhibitor (PI) • Reversible covalent binding with active NS3-protease site with ketoamid functional group • Ki = 7 ± 1 nМ, EC50 = 20 nМ, EC90 = 40 nМ • Mild cross-reactivity exists just with human cathepsin and neutrophyl elastase • No cross-reactivity with HIV-proteases
Tong X et al. Antimicrob. Agents Chemother. 2010;54:2365-2370 11.06.2015 8 Extensive Clinical Program was Conducted by Merck/Schering-Plough
Nearly 500 healthy volunteers and HCV-infected patients received at least one dose of Narlaprevir in completed clinical trials to date
9 Phase I Studies
• 360 healthy volunteers and 32 chronic hepatitis C patients were exposed to at least one dose of Narlaprevir
Phase IIa Study (NEXT-1)
• 93 chronic hepatitis C patients were on Narlaprevir
11.06.2015 9 Increase in Narlaprevir Exposure after Standard Meal
TabletTablet formulationFormulation
) 350 FastedFasted
ng/mL FedFed
( 300
250
200
(ng/mL) 150
100 plasma concentration
50 SCH900518PlasmaConcentration 0
0 2 4 6 8 10 12 14 16 18 20 22 24
Narlaprevir TimeTime (hours (hr) )
Narlaprevir administration under fed condition leads to increase in mean AUC(I) by 1,8 and Cmax by 2,8 compared to fasted state
Reesink H.W., Bergmann J.F., et al., 2009, 50 (Suppl. 1), S35-S36. 11.06.2015 10 Low Doses of Ritonavir Significantly Increased
Narlaprevir Exposure after Single Dosing
mL)
/ Narlaprevir 400 mg alone ng
( Narlaprevir 400 mg with Ritonavir
plasma concentration plasma concentration
Narlaprevir Time (hours)
Single Narlaprevir dosing in combination with Ritonavir leads to Narlaprevir AUC(I) and Cmax increase by 10 and 4 times, respectively, compared to single Narlaprevir dosing alone
Reesink H.W., Bergmann J.F., et al., 2009, 50 (Suppl. 1), S35-S36. 11.06.2015 11 Phase 2а Study NEXT-1 Design
HCV RNA NVR/r – Narlaprevir + Ritonavir 12 weeks LOD – Low limit of detection Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 12 Phase 2а Study NEXT-1 Baseline Patients Characteristics Most of patients were with genotype 1a and high viral load in all treatment groups Group 2 Group 3 Group 4 Group 5 Group 6 Group 1 NVR 200mg NVR 400mg LI + NVR LI + NVR NVR 100mg Control QD QD 200mg QD 400mg QD BID N=18 N=20 N=19 N=17 N=20 N=17 Male, % (n) 56 (10) 55 (11) 74 (14) 59 (10) 50 (10) 53 (9) White, % (n) 72 (13) 100 (20) 79 (15) 88 (15) 80 (16) 88 (15) Age (SD), years 46 (7) 43 (9) 45 (11) 45 (10) 46 (9) 46 (9) Weight (SD), kg 81 (20) 80 (11) 85 (10) 76 (17) 82 (18) 80 (18) BMI (SD), kg/m2 28 (6) 29 (4) 28 (2) 26 (5) 28 (4) 27 (5) Genotype 1а, % (n) 72 (13) 80 (16) 74 (14) 76 (13) 80 (16) 82 (14) Viral load 83 (15) 65 (13) 84 (16) 82 (14) 85 (17) 94 (16) >600 000 IU/mL, % (n) BMI – body mass index, LI – lead-in, NVR – narlaprevir, SD – standard deviation Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 13 Phase 2а Study NEXT-1 High Antiviral Activity Mean HCV RNA decrease after 2 weeks of therapy exceeded 5 log10 IU/mL Narlaprevir was administered with Ritonavir 100 mg in all dosage groups * Including detected and non-detected HCV RNA < 25 IU/mL LLQ – low limit of quantification; NVR – narlaprevir; PegIFN – pegylated interferon alfa, RBV - ribavirin 11.06.2015 Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract14 LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. Phase 2а Study NEXT-1 Pharmacokinetics Narlaprevir* 200 mg QD Narlaprevir 400 mg QD Narlaprevir 100 mg BID Twice daily dosing and increased 400 mg dose didn’t give significant benefits for therapeutic concentration achievement compared to dose 200 mg once daily Time, hours * Narlaprevir was administered with Ritonavir 100 mg in all dosage groups Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 15 Phase 2а Study NEXT-1 Sustained Virological Response 200 mg once daily without lead-in period group had the optimal SVR rate , % % , Patients * Narlaprevir was administered with Ritonavir 100 mg in all dosage groups LI – 4-week lead-in period; NVR – narlaprevir; PegIFN – pegylated interferon alfa; RBV – ribavirin; SVR – sustained virological response Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 16 Phase 2а Study NEXT-1 Baseline Patients Characteristics Dosage groups with 200 mg Narlaprevir will be present on the next slide Group 2 Group 3 Group 4 Group 5 Group 6 Group 1 NVR NVR LI + NVR LI + NVR NVR Control 200mg QD 400mg QD 200mg QD 400mg QD 100mg BID N=18 N=20 N=19 N=17 N=20 N=17 Men, % (n) 56 (10) 55 (11) 74 (14) 59 (10) 50 (10) 53 (9) White, % (n) 72 (13) 100 (20) 79 (15) 88 (15) 80 (16) 88 (15) Age (SD), years 46 (7) 43 (9) 45 (11) 45 (10) 46 (9) 46 (9) Weight (SD), kg 81 (20) 80 (11) 85 (10) 76 (17) 82 (18) 80 (18) BMI (SD), kg/m2 28 (6) 29 (4) 28 (2) 26 (5) 28 (4) 27 (5) Genotype 1а, % (n) 72 (13) 80 (16) 74 (14) 76 (13) 80 (16) 82 (14) Viral load 83 (15) 65 (13) 84 (16) 82 (14) 85 (17) 94 (16) >600 000 IU/mL, % (n) BMI – body mass index, LI – lead-in, NVR – narlaprevir, SD – standard deviation Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 17 Phase 2а Study NEXT-1 Safety Profile All adverse event rates were comparable to control PegIFN/RBV group Control Groups 2 + 4 Adverse events, % (n) PegIFN/RBV NVR 200 mg QD N=18 N=37 Fatigue 56 (10) 32 (12) Nausea 50 (9) 43 (16) Flu-like illness 44 (8) 16 (6) Headache 39 (7) 22 (8) Insomnia 39 (7) 30 (11) Anaemia 6 (1) 27 (10) Arthralgia 28 (5) 16 (6) Diarrhoea 17 (3) 14 (5) Pyrexia 17 (3) 14 (5) Irritability 28 (5) 19 (7) Pruritus 33 (6) 11 (4) Rash 11 (2) 3 (1) NVR – narlaprevir, PegIFN – pegylated interferon alfa; QD – once daily; RBV – ribavirin 11.06.2015 Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract18 LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. Key Learnings from NEXT-1 Narlaprevir 200 mg with Ritonavir 100 mg once daily was the optimal regimen in combination with PegIFN/RBV SVR rate 85% was achieved There is no need in lead-in period Safety profile was comparable to PegIFN/RBV 24 weeks double therapy (12w triple + 12w double) Vierling J., Poordad F., et al. AASLD 2009. Boston. Oct 30-Nov 1, 2009. Abstract LB4. Vierling J., Poordad F., et al. Hepatology, 2011, 54, 1439A. 11.06.2015 19 Key points Background Narlaprevir in clinical trials Preliminary results of Phase 3 first Russian PIONEER study Conclusions 11.06.2015 20 Phase III Study PIONEER Design • International multicenter randomized placebo-controlled double-blind study • 420 non-cirrhotic naïve and treatment-experienced patients with GT1 • PegIFN choise: PegIntron/ Pegasys 50 / 50 • Randomization 2:1 to Narlaprevir/Ritonavir and placebo (280 patients on Narlaprevir) Narlaprevir/r PegIFN/RBV Follow-up + PegIFN/RBV 270 Naives PegIFN/RBV + PegIFN/RBV Follow-up Placebo Narlaprevir/r PegIFN/RBV Follow-up 150 PegIFN/RBV + PegIFN/RBV failurers PegIFN/RBV + PegIFN/RBV Follow-up Placebo Weeks 0 4 12 24 36 48 60 72 Unblinding SVR 24 SVR 24 Interim analysis In active-treatment group In placebo group 11.06.2015 21 Phase III Study PIONEER Baseline Patients Characteristics Narlaprevir/r + Placebo PegIFN/RBV PegIFN/RBV All N=282 N=138 N=420 Genotype HCV 1b, % (n) 91,5% (258) 94,2% (130) 92,4% (388) Naives 64,5% (182) 63,8% (88) 64,3% (270) Previously treated 35,5% (100) 36,2% (50) 35,7% (150) Previous treatment Null-responders 14,5% (41) 13,8% (19) 14,3% (60) status, % (n) Partial responders or 19,9% (56) 21,7% (30) 20,5% (86) relapsers Mean baseline viral IU/mL 2,1 x 106 2,6 x 106 2,3 x 106 load log10 IU/mL 6,3 6,4 6,4 11.06.2015 22 Phase III Study PIONEER Viral Load Dynamics HCV RNA level decreased by a mean of 5,2 log10 after 2 weeks of treatment on Narlaprevir and by a mean of 5,8 log10 after 4 weeks 7 6 ) Narlaprevir Placebo 5 IU/mL 4 Log10 Log10 ( 3 >5 Log10 IU/mL 2 HCV RNA level RNA HCV 1 0 Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 16 Week 20 Week 24 11.06.2015 23 Phase III Study PIONEER 12 Week Response (ITT analysis) * LOD = LLOQ <15 IU/mL 11.06.2015 24 Narlaprevir vs. Simeprevir in Naïve Patients (ITT analysis for both) Week 12 on treatment response rate is comparable with Simeprevir 1 HCV RNA <15 IU/mL 2 HCV RNA < 25 IU/mL *TMC435 in Combination with Peginterferon and Ribavirin in Treatment-naïve HCV Genotype 1 Patients: Final Analysis of the PILLAR Phase IIb Study (TMC435-C205). AASLD 2011, San Francisco. Only results in Simeprevir 150 mg treatment groups are presented 11.06.2015 25 Phase III Study PIONEER Most Common Adverse Event Hematological adverse events rates were comparable with PegIFN/RBV group Narlaprevir/r + Placebo + Adverse events, % (n) PegIFN/RBV PegIFN/RBV N=282 N=138 Neutropenia 44,7 (126) 51,5 (71) Leukopenia 31,6 (89) 34,1 (47) Flu-like illness 29,1 (82) 31,9 (44) Asthenia 26,2 (74) 24,6 (34) Pyrexia 23,4 (66) 21,0 (29) Hemoglobin level decrease 22,0 (62) 21,0 (29) Anaemia 20,2 (57) 14,5 (20) Thrombocytopenia 17,4 (49) 18,8 (26) Headache 12,1 (34) 10,9 (15) Weight decrease 9,9 (28) 11,6 (16) Cough 8,2 (23) 11,5 (16) Аlopecia 10,6 (30) 5,1 (7) Pruritus 7,1 (20) 5,8 (8) Appetite decrease 6,0 (17) 6,5 (9) Nausea 5,3 (15) 8,1 (11) Fatigue 5,3 (15) 7,2 (10) 11.06.2015 26 Key Learnings from Phase III Study PIONEER 12 Weeks Results Safety profile after Viral load dynamic 12 weeks of triple shows high Narlaprevir therapy is comparable to antiviral activity PegIFN/RBV Triple therapy is significantly more effective than double therapy in naive and in previously treated patients 11.06.2015 27 Perspectives for Narlaprevir Development IFN-free regimens Shorter HIV/HCV - treatment NARLAPREVIR coinfection duration Cirrhosis 11.06.2015 28 Conclusions IFN-containing regimens in Russia are currently relevant and supposed to be important in the near future Protease inhibitors - a promising DAA group for the treatment of HCV 1b GT, the most prevalent genotype in Russia Interim data of phase III PIONEER study show a high antiviral activity and a good safety profile of Narlaprevir Triple therapy with Narlaprevir will be an appropriate regimen among DAA-based treatment options for chronic hepatitis C 11.06.2015 29 Thank you for your attention! 11.06.2015 30