Narlaprevir is an effective component of affordable treatment regimens Igor Bakulin Prof., MD, PhD North-Western State Medical University n.a. I.I. Mechnikov Saint Petersburg 9 June 2017
KEY QUESTIONS 1. Interferon (IFN)-based combinations in CHC treatment 2. Narlaprevir-based regimen is one more IFNbased therapy in CHC
WHO STRATEGY Most viral hepatitis deaths in 2015 were due to: chronic liver disease (720 000 deaths); primary liver cancer (470 000 deaths) In May 2016, the World Health Assembly endorsed the Global Health Sector Strategy (GHSS) on viral hepatitis 2016 2021 The GHSS calls for the elimination of viral hepatitis as a public health threat by 2030 (reducing new infections by 90% and mortality by 65%) WHO/HIV/2017.06, Global Hepatitis report 2017, http://www.who.int/hepatitis
The role of IFN in the new era. «In a utopian society, all patients would receive optimal medications; those with the highest efficacy and the least adverse effects regardless of cost. In reality, treating many diseases involves balancing efficacy, adverse events and cost. Understanding the mechanism by which IFN acts to cure HCV will enable the physician, patient and payer the ability to make these decisions.» Parth J Parekh & Mitchell L Shiffman Expert Review of Gastroenterology & Hepatology, 8:6, 649-656 (2014)
HCV Epidemiology in Russia Total population size 1 143 000 000 Anti-HCV Ab-positive 1 5 861 000 CHC diagnosed (viremic) 1 1 789 500 New cases 2 55 900/year AVT 9 227*/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 14.06.2017 Yuschuk ND, Znoyko OO, et al. Epidemiol Vaccine Prevent. 5 2013; *IMS Health data, 2016
Interferon-free: Interferoncontaining: CHC GT 1 therapy combinations registered in RU ribavirin PegIFN-alpha + ribavirin + simeprevir PegIFN-alpha + ribavirin + daclatasvir + asunaprevir PegIFN-alpha + ribavirin + narlaprevir/ritonavir PegIFN-alpha + ribavirin + sofosbuvir 3D (ombitasvir/paritaprevir/ritonavir + dasabuvir ) DUAL (daclatasvir + asunaprevir) sofosbuvir + ribavirin sofosbuvir + simeprevir sofosbuvir + daclatasvir
Пэг-ИНФ- + CHC GT 1 therapy combinations registered in RU рибавирин Simeprevir рибавирин + симепревир + PegIFN-alpha + ribavirin рибавирин + даклатасвир + асунапревир рибавирин + нарлапревир/ритонавир рибавирин + софосбувир
SVR12 (%) QUEST-1: Simeprevir + PegIFN-a + ribavirin SVR12 by Fibrosis Level 90 80 70 60 50 40 30 20 10 0 SMV + P/R 83 78 70 58 152/183 54/77 36/46 18/31 F0-F2 F3-F4 F3 F4 Baseline characteristics SMV + P/R (n=264) 1а 147 (56%) 1b 117 (44%) F0-F1* 118 (45%) F2* 65 (25%) F3* 46 (17%) F4* 31 (12%) * METAVIR score LOD = LLOQ <25 IU/mL Jacobson I, et al. Lancet 2014; 384: 403 13
SVR12 (%) Optimal group (QUEST-1 /QUEST-2): Simeprevir + PegIFNa + RBV SVR12 in treatment naïve patients 100 90 80 70 60 50 40 30 20 10 0 80,4 All patients (1a+1b GT) 86,6 All European patients (1a+1b GT) 89,6 88,0 419/521 132/264 239/276 75/142 172/192 52/95 191/217 64/110 LOD = LLOQ <25 IU/mL GT1b METAVIR score F0 F2 SMR/PR PBO/PR Foster GR., et al. Journal of Hepatology 2014 vol. 60, S456
SVR12 (%) The PROMISE trial (Simeprevir + PegIFN-a + RBV) SVR12 in patients who relapsed after previous IFN-based therapy 100 90 80 70 60 50 40 30 20 10 0 79,2 All patients (1a+1b GT) 87,5 87,2 88,2 206/260 49/133 161/184 40/90 109/125 32/68 105/119 34/70 All European patients (1a+1b GT) GT 1b METAVIR score F0 F2 SMR/PR PBO/PR Нижний порог выявления = Нижний порог количественного определения < 25 МЕ/мл Forns Х., et al. Journal of Hepatology 2014 vol. 60, S6
Пэг-ИНФ- + CHC GT 1 therapy combinations registered in RU рибавирин рибавирин + симепревир рибавирин + даклатасвир + асунапревир Daclatasvir + Asunaprevir + PegIFN-alpha + ribavirin рибавирин + нарлапревир/ритонавир рибавирин + софосбувир
SVR 12, % (95% CI) HALLMARK QUAD: Daclatasvir + asunaprevir + peginterferon alfa + ribavirin in HCV genotype 1 or 4 non-responders HALLMARK QUAD Study Design N=398 (Prior non-responders to PegINF/RBV Primary Endpoint: SVR12 in GT 1 infected patients 0 Daclatasvir+Asunaprevir+ PegINF/RBV Follow-up 24 48 SVO 12 100 99 95 93 90 87 85 80 329/354 153/176 176/178 All GT 1a GT 1b Jensen, Donald et al. Journal of Hepatology, Volume 63, Issue 1, 30-37
KEY QUESTIONS 1. Interferon (IFN)-based combinations in CHC treatment 2. Narlaprevir is an effective component of affordable treatment regimens
Tong X et al. Antimicrob. Agents Chemother. 2010;54:2365-2370 Joep de Bruijne et al., HEPATOLOGY 2010;52:1590-1599 Бурневич Э.З., Тихонова Н.Ю., Щаницына С.Е. «Клиническая фармакология и терапия», 2014, 23, (5) V. Isakov et al. Antimicrob. Agents Chemother. December 2016 60:7098-7104. Narlaprevir (SCH 900518) is a direct-acting antiviral agent Narlaprevir (NVR) is a HCV protease inhibitor developed in Russia, suppressing viral replication in infected host cells Narlaprevir is co-administered with ritonavir, CYP3A4 inhibitor Ritonavir boosts Narlapveir concentrations enabling an easy to use QD dosing schedule Narlaprevir Single Narlaprevir dose, both alone and in combination with ritonavir, was well tolerated both by healthy subjects and by cirrhotic patients! Narlaprevir has been approved for the treatment of naive and treatmentexperienced patients with CHC genotype 1 in combination with RTV, PEG-IFN and RBV
Patients, SVR (24 %) OPTIMAL GROUP OF PATIENTS WITH 1 GT HCV TO TRIPLE THERAPY WITH NARLAPREVIR BASED ON PREVIOUS TREATMENT STATUS Optimal group Baseline characteristics 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 89,1% Treatment naïve 69,7% Previously treated 86,5% 163/183 69/99 32/37 Relapse NVR + P/R (n=282) 1b 258 (91,5%) Treatment naive Previously treated 183 (64,9%) 99 (35,1%) Relapse 40 (14,2%) Partial response 16 (5,7%) Null response 42 (14,9%) LOD = LLOQ <15 IU/mL Абдурахманов Д.Т. и соавт. Эффективность нового отечественного ингибитора протеазы нарлапревира у первичных и ранее леченных больных хроническим гепатитом С 1 генотипа без цирроза печени (исследование 3 фазы, PONEER). // Сборник тезисов III Всероссийской научно-практической конференции с международным участием, Сочи, 01-04.11.2016.
SVR 24 (%) PIONEER: Narlaprevir/r + PegIFN-a + RBV SVR 24 by Fibrosis Level 100% 90% 80% 70% Treatment - naïve Relapse Partial responders and null responders 91,8% 93,3% 93,8% 92,3% 85,7% 80,0% 75,0% 66,7% 68,4% 66,7% 60% 50% 40% 30% 20% 41,7% 33,3% 10% 0% 56/61 56/60 36/42 15/20 15/16 12/13 4/6 4/5 5/12 13/19 12/18 3/9 F0 F1 F2 F3 F0 F1 F2 F3 F0 F1 F2 F3 LOD = LLOQ <15 IU/mL Abdurakhmanov D.T. et al. Hepatol Int (2017) 11 (Suppl 1):S305 306.
Patients with SVR 24 (%) PIONEER: Narlaprevir/r + PegIFN-a + RBV SVR 24 by Fibrosis Level (preferable patient s groups) Treatment naive Previously treated patients 100% 90% 80% 70% 60% 50% 90,8 88,6 Baseline characteristics NVR + P/R (n=282) F0 89 (31.6%) F1 92 (32.6%) 40% 30% 20% 10% 0% 148/163 31/35 F0-F2 F0-F2 with relapse F2 66 (23.4%) F3 35 (12.4%) F0 89 (31.6%) * METAVIR score LOD = LLOQ <15 IU/mL Абдурахманов Д.Т. и соавт. Эффективность нового отечественного ингибитора протеазы нарлапревира у первичных и ранее леченных больных хроническим гепатитом С 1 генотипа без цирроза печени (исследование 3 фазы, PONEER). // Сборник тезисов III Всероссийской научнопрактической конференции с международным участием, Сочи, 01-04.11.2016.
Patients with SVR 24 (%) Key learnings from Phase III Study PIONEER: SVR-24 by fibrosis and baseline viral load in treatment - naive patients 100% 90% 92,2% 93,8% 92,1% F0-1 F2-3 80% 70% 60% 63,6% 50% 40% 30% 20% 10% 0% 83/90 35/38 Baseline VL <2 000 000 МЕ/мл 30/32 14/22 Baseline VL > 2 000 000 МЕ/мл VL Viral Load Abdurakhmanov D.T. et. al.. // Abstract of the III All-Russian Scientific and Practical Conference with international participation, Sochi, 01-04.11.2016
SAFETY DATA: No unique or treatment-limiting adverse events were observed during therapy with NVR Adverse events, % (n) Narlaprevir/r + PegIFN/RBV N=282 Placebo + PegIFN/RBV N=138 Severe adverse events* 1,8% (5) 0% (0) At least one of any adverse event 92,9% (262) 94,2% (130) Most common adverse events list (>10% of cases) Neutropenia 48,9% (138) 56,5% (78) Leukopenia 35,5% (100) 39,9% (55) Influenza-like illness 29,4% (83) 31,9% (44) Asthenia 27,3% (77) 26,1% (36) Hemoglobin decrease 23,4% (66) 23,2% (32) Pyrexia 23,4% (66) 21,7% (30) Anaemia 24,8% (70) 25,4% (35) Thrombocytopenia 19,5% (55) 22,5% (31) Weight decrease 16,3% (46) 20,3% (28) Alopecia 15,2% (43) 9,4% (13) * Road traffic accident (death); vertebrobasilar insufficiency; psychotic disorder; acute psychosis; thyroiditis Abdurakhmanov D.T. et al. Hepatol Int (2017) 11 (Suppl 1):S305 306.
COST EFFECTIVENESS OF PROTEASE INHIBITORS IN HCV GT1 TREATMENT (NARLAPEVIR VS. SIMEPREVIR) Therapy cost, 100 000 RU 1 039 859 SIMEPREVIR SIMEPREVIR 913 754 640 553 NARLAPREVIR 1000 800 600 400 200 0 0 200 400 600 800 1000 < > BASE ( COST OF REGISTRATION) NARLAPREVIR ANLYSIS OF SENSITIVITY (BUYER'S PRICE 2016 ) Cost effectiveness of Narlaprevir therapy: - 38,4% vs. antiviral therapy with SMV А.В. Рудакова, Д.А. Гусев и соавт. Ингибитор протеазы нарлапревир в терапии хронического гепатита С 1 генотипа у пациентов, ранее не получавших противовирусную терапию, без цирроза: фармакоэкономические аспекты. Журнал инфектологии. Том 9, 1, 2017. С. 100-103.
Narlaprevir clinical development plan FUTURE DRUG INTERACTION STUDY WITH ANTIRETROVIRAL THERAPY INF-FREE ORAL COMBINATION RESEARCH (SOF, DAC) PREVIOUSLY COMBINATION OF Narlaprevir + Peg INF + RBV IN CLINICAL PRACTICE PHASE III DOUBLE-BLIND PIONEER STUDY (the PIONEER study) PHARMACOKINETICS STUDY IN COMPENSATED CIRRHOSIS
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