Narlaprevir is an effective component of affordable treatment regimens

Transcription

1 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

2 KEY QUESTIONS 1. Interferon (IFN)-based combinations in CHC treatment 2. Narlaprevir-based regimen is one more IFNbased therapy in CHC

3 WHO STRATEGY Most viral hepatitis deaths in 2015 were due to: chronic liver disease ( deaths); primary liver cancer ( deaths) In May 2016, the World Health Assembly endorsed the Global Health Sector Strategy (GHSS) on viral hepatitis 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/ , Global Hepatitis report 2017,

4 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, (2014)

5 HCV Epidemiology in Russia Total population size Anti-HCV Ab-positive CHC diagnosed (viremic) New cases /year AVT 9 227*/year AVT antiviral therapy; CHC chronic hepatitis C data, Saraswat V, Norris S, et al. J Viral Hepat ;22 Suppl 1:6-25; Yuschuk ND, Znoyko OO, et al. Epidemiol Vaccine Prevent ; *IMS Health data, 2016

6 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

7 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

8 SVR12 (%) QUEST-1: Simeprevir + PegIFN-a + ribavirin SVR12 by Fibrosis Level SMV + P/R /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:

9 SVR12 (%) Optimal group (QUEST-1 /QUEST-2): Simeprevir + PegIFNa + RBV SVR12 in treatment naïve patients ,4 All patients (1a+1b GT) 86,6 All European patients (1a+1b GT) 89,6 88,0 419/ / /276 75/ /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

10 SVR12 (%) The PROMISE trial (Simeprevir + PegIFN-a + RBV) SVR12 in patients who relapsed after previous IFN-based therapy ,2 All patients (1a+1b GT) 87,5 87,2 88,2 206/260 49/ /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

11 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

12 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 SVO / / /178 All GT 1a GT 1b Jensen, Donald et al. Journal of Hepatology, Volume 63, Issue 1, 30-37

13 KEY QUESTIONS 1. Interferon (IFN)-based combinations in CHC treatment 2. Narlaprevir is an effective component of affordable treatment regimens

14 Tong X et al. Antimicrob. Agents Chemother. 2010;54: Joep de Bruijne et al., HEPATOLOGY 2010;52: Бурневич Э.З., Тихонова Н.Ю., Щаницына С.Е. «Клиническая фармакология и терапия», 2014, 23, (5) V. Isakov et al. Antimicrob. Agents Chemother. December : Narlaprevir (SCH ) 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

15 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,

16 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):S

17 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,

18 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 < МЕ/мл 30/32 14/22 Baseline VL > МЕ/мл VL Viral Load Abdurakhmanov D.T. et. al.. // Abstract of the III All-Russian Scientific and Practical Conference with international participation, Sochi,

19 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):S

20 COST EFFECTIVENESS OF PROTEASE INHIBITORS IN HCV GT1 TREATMENT (NARLAPEVIR VS. SIMEPREVIR) Therapy cost, RU SIMEPREVIR SIMEPREVIR NARLAPREVIR < > 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, С

21 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

22 This information is provided as information and educational support for doctors. The opinions expressed on the slides and in the presentation reflect the speakers point of view which does not necessarily reflect JSC R-Pharm views. JSC R-Pharm does not recommend to take medications in ways other than the ones described in the patient information leaflet. Due to differences in the requirements of regulatory authorities in different countries, the registered drug indications and administration routes mentioned in this presentation may vary. Before prescribing any medications, please read the local instructions for medical use provided by manufacturing companies. Complete instructions for medical use are available on request. Information on disclosure of financial interest. The lecturer hereby confirms that he provides services in the field of scientific and educational activities (including, among other things, the preparation of scientific literature reviews, training and information materials, participation in clinical trials and advisory boards, etc.) of JSC "R-Pharm". This presentation is supported by the JSC «R-Pharm»