DACLATASVIR: Update on new data from the real world over the past year. Dr M. MELA EVANGELISMOS GENERAL HOSPITAL

Transcription

1 1392GR /2017

2 1392GR /2017

3 DACLATASVIR: Update on new data from the real world over the past year Dr M. MELA EVANGELISMOS GENERAL HOSPITAL 9 th International Congress of Internal Medicine Athens, 9-11 March GR /2017

4 Speaker BMS, MSD Disclosures

5 Outline Introduction Clinical Trials Real world data German experience Greek experience

6 Life cycle of the hepatitis C virus Fusion and uncoati ng (+) RNA LD NS5A* inhibitors ER lumen Virion LD assembly Translation NS3/4 and protease polyprotein inhibitors processing Membranous web ER lumen LD NS5B polymerase RNA replication inhibitors Manns MP, et al. Nat Rev Drug Discov. 2007

7 Daclatasvir (DCV) Approval Status: NS5A inhibitor, 2014 Indications and Usage - Indicated with sofosbuvir, with or without ribavirin for the treatment of chronic HCV genotype 1 and 3 in adults Dosing Preparations and Adjustments - Daclatasvir 60 mg and 30 mg tablets - No dosage adjustment with any degree of renal impairment - No dosage adjustment with mild, moderate, or severe hepatic impairment Most Common Adverse Effects - Headache, fatigue, nausea, diarrhea

8 EASL Recommendations on Treatment of Hepatitis C 2016

9 Clinical Trials

10 ALLY Phase 3 Program All-Oral DCV + SOF ALLY-1 N = 113 ALLY-2 N = 203 Patients with cirrhosis or post-liver transplant GT 1 to 6 DCV + SOF + RBV, 12 weeks Patients with HIV coinfection GT 1 to 6 DCV + SOF, 8 or 12 weeks ALLY-3 N = 152 ALLY-3+ N = 50 Patients with GT 3 infection Treatment-naive or treatment-experienced DCV + SOF, 12 weeks Patients with GT 3 infection Advanced liver disease DCV + SOF + RBV, 12 or 16 weeks

11 Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV Coinfection ALLY-2 Trial: SVR12 by HCV Genotype: 12-Week Groups cirrhosis 8.9% in naïve 28.8% in tx-experienced n=101 n=52 Drug Dosing Daclatasvir: 60 mg once daily; with efavirenz and nevirapine the dose was increased to 90 mg once daily and with ritonavir-boosted protease inhibitors the dose was decreased to 30 mg once daily Sofosbuvir: 400 mg once daily Wyles DL et al. N Engl J Med. 2015

12 Genotype 3 the most treatment-resistant patients progress more rapidly to fibrosis and cirrhosis a higher prevalence of severe steatosis a higher incidence of hepatocellular carcinoma GT-1 is the most prevalent worldwide (46%), followed by GT-3 (22%). In Asia GT-3 in 40%. The most frequent genotype among HCV-positive IVDUs few therapeutic options are effective for HCV GT-3 Rubbia-Brandt L et al. J Hepatol 2000 Probst A et al. J Viral Hepatol 2011 Gondeau C et al. World J Gastroenterol 2015

13 Daclatasvir + Sofosbuvir for HCV GT 3 ALLY-3 Trial: Design Cirrhosis naive: 19 (19%) treatment experienced: 13 (25%) Nelson DR et al. Hepatology 2015

14 Daclatasvir + Sofosbuvir for HCV GT 3 ALLY-3 Trial: Results Nelson DR et al. Hepatology 2015

15 Daclatasvir + Sofosbuvir + Ribavirin for HCV GT 3 and Advanced Liver Disease ALLY-3+Trial: Design Open-label, randomized phase IIIb study Primary endpoint: SVR12 Stratified by F3/F4 fibrosis stage Wk 12 Wk 16 Pts with GT3 HCV and F3/F4 liver disease (N = 50) DCV 60 mg/day + SOF 400 mg/day + RBV (n = 24) DCV 60 mg/day + SOF 400 mg/day + RBV (n = 26) All pts followed for SVR12 IFN-experienced: 31 patients SOF-experienced: 6 patients Leroy V et al. Hepatology 2016

16 SVR12 (%) Daclatasvir + Sofosbuvir + Ribavirin for HCV GT 3 and Advanced Liver Disease ALLY-3+Trial: Results No virologic failures or AE-related discontinuations 12-wk DCV + SOF + RBV 16-wk DCV + SOF + RBV n/n = 0 21/ 24 All Pts 24/ 26 6/ 6 8/ 8 Advanced Fibrosis (F3) 15/ 18 16/ 18 Cirrhosis 14/ 16 12/ 14 Cirrhosis + Treatment Experienced Leroy V et al. Hepatology 2016

17 Daclatasvir + Sofosbuvir + Ribavirin for HCV GT 3 and Advanced Liver Disease ALLY-3+Trial: Safety No discontinuations or deaths deemed Tx-related Safety Outcome, % DCV + SOF + RBV Overall (N = 50) DCV + SOF + RBV 12 Wks (n = 24) DCV + SOF + RBV 16 Wks (n = 26) Any AE Serious AEs Death Discontinuation for AEs RBV dose reduction AEs in 20% pts in any arm Insomnia Fatigue Headache Irritability Grade 3 lab abnormalities Hemoglobin < 9.0 g/dl or decrease 4.5 g/dl TBI > 2.5 x ULN Leroy V et al. Hepatology 2016

18 Real World Data

19 Real World Efficacy of Antiviral Treatment in Chronic Hepatitis C Genotype 3 Infection: Data from the German Hepatitis C-Registry (DHC-R) Proportion of treatment regimens during the 20 month study period Cornberg M et al, AASLD 2016

20 Real World Efficacy of Antiviral Treatment in Chronic Hepatitis C Genotype 3 Infection: Data from the German Hepatitis C-Registry (DHC-R) 864 patients with GT3 German Hepatitis C Registry - 02/2014 to 05/ % tx-experienced, 33.2% with liver cirrhosis Cornberg M et al, AASLD 2016

21 Real-world data of DCV + SOF in GT-3 patients from the German Hepatitis C Registry (DHC-R) GT-3 patients enrolled between 2/2014 and 2/2016 N = 1074, treatment with DCV + SOF ± RBV initiated in 383 patients 137/383 (36%) TE, 127/383 (33%) cirrhotic 168 patients have reached at least 12 W of post treatment f/up 152 patients achieved SVR12/24 Subpopulati ons (n) DCV + SOF 12 weeks DCV + SOF + RBV 12 weeks SVR12/24, n/n (%) DCV + SOF 24 weeks DCV + SOF + RBV 24 weeks DCV + SOF ± RBV All treatment durations* Discontinuation of therapy occurred in 14 patients TN (n = 95) 46/57 (90.2) 13/13 (100) 3/4 14/14 (100) 83/95 (87.4) TE (n = 73) 22/22 (100) 12/12 (100) 10/10 (100) 20/22 (90.9) 69/73 (94.5) Noncirrhotic (n = 100) Cirrhosis (n = 68) Decompensa ted cirrhosis (n = 19) 63/66 (95.5) 17/17 (100) 1/1 7/8 92/100 (92.0) 5/7 8/8 12/13 (92.3) 27/28 (96.4) 45/68 (91.8) 4/5 1/1 4/4 4/5 15/19 (78.9) Mauss S et al. Abstract 932, AASLD 2016

22 Efficacy and safety of the currently recommended regimens with direct acting antiviral(s) (DAA) in the treatment of chronic hepatitis C (CHC) patients in clinical practice. A Greek multicenter real-life cohort study George V. Papatheodoridis 1, Andreas Kapatais 2, loannis Gou- lis 3, loannis S. Elefsiniotis 4, Jiannis Vlachogiannakos^, Spilios Manolakopoulos 5, George N. Dalekos 6, John Koskinas 5, Stylianos Karatapanis 7, loannis Ketikoglou 5, Melanie Deutsch 5, Emanuel K. Manesis 8, Vassilios A. Sevastianos 9, Maria J. Schina 10, Christos K. Triantos 11, Evangelos Cholongitas 3, Maria-Vasiliki Papageorgiou 1, Emmanouil Sinakos 3, Theofanie Karaoulani 2, Argyro Koukou- fiki 3, Eftychia Evangelidou 4, Dimitrios Karagiannakis 1, Anastasia Kourikou 5, Eirini I. Rigopouiou 6, Maria Tampaki 5, Georgios Ntets- kas 7, Theodoros Voulgaris 9, Chrysostomos Tsolias 11, Panagiota loannidou 1, Evangelos Akriviadis 3 ;

23 Study design 11 liver centres throughout Greece Received treatment between 06/2014 and 04/2016 Patient fulfilled the national criteria for treatment reimbursement with DAA [F3 experienced, F4, decompensated cirrhosis (Ci), liver transplantation, severe extrahepatic manifestation]

24 Patient characteristics: n=603 Age, years patients >70 years 57± (17%) males 351 (58%) ALT, IU/L 59 (53) Hb 13.3±2.5 PLT, /mm 3 172,789±128,230 PLT <100,000/mm 3 140/591 (24%) BMI, kg/m 2 27±5 Source of infection IVDU Transfusion Iatrog./Egypt/Sexual Uknown Previous therapy (Peg)IFNa±RBV Peg-IFNa+RBV+BOC/TPV Regimens with SOF 132 (22%) 204 (34%) 32 ( 5%) 235 (39%) 403 (67%) 72% 15% 13% F0-F2 in 5%, F3 in 21% F4 in 64%, decompensated Ci in 10% GT1a: 11%, GT1b: 35% GT2: 5% GT3: 24% GT4: 24% GT5: 1% special groups: 58 (9.6%) CRF: 8 Kidey transplant: 3 OLT: 8 b-thalassemia: 5 Hemophilia: 10 HIV+: 5 (4 +hemophilia) autoimmune: 8 HCC: 3 CHB: 3 alcoholism: 5

25 DAAs regimens according to genotype

26 Greek experience: SVR12 SVR12 data were available for 410 (68%) pts SVR was achieved in 362 (88%) pts n/n (%) GT3 70/79 (79%) non GT3 292/321 (91%) F0-F3 96/104 (92%) F4 232/261 (89%) decompensated cirrhosis 34/45 (76%) SAEs of any type were observed more frequently with pegifna+rbv+sof (14%) and in pts with decompensated Ci (15%) than in those with F0-F4 CHC treated with IFNa free regimens (3.5%) (P<0.001). DAA therapy was discontinued early in 1.6% of pts.

27 149 patients 87 (58.4%) were treatment experienced of whom 9(10%)were DAA failures 119 (80%) F4 or decompensated

28 Daclatasvir (DCV) Plus Sofosbuvir (SOF) regimens in chronic hepatitis C virus (HCV) infected patients with advanced fibrosis or cirrhosis. A HEllenic multicenter ReAl life CLInical Study (HERACLIS) Ioannis S. Elefsiniotis (1), George Dalekos (2), John Koskinas (3), Panagiota Ioannidou (4), Evangelos Cholongitas (5), Spilios Manolakopoulos (3), John Goulis (5), John Vlachogiannakos (4), Melani Deutsch (3), Christos Triantos (6), Andreas Kapatais (7), Vassilios A. Sevastianos (8), Maria Schina (8), Stylianos Karatapanis (9), Ioannis Ketikoglou (3), Emmanuel Manesis (3), Maria-Vasiliki Papageorgiou (4), Emmanuel Sinakos (5), Nikolaos K Gatselis (2), Dimitrios Karagiannakis (4), Athanasia Tasovasili (1), Argyro Koukoufiki (5), Theodoros A. Voulgaris (8), Chrysostomos Tsolias (6), Evangelos Akriviadis (5), George V. Papatheodoridis (4) (1) University Department of Internal Medicine-Hepatogastroenterology Unit, National & Kapodistrian University of Athens,General and Oncology Hospital of Kifisia Agioi Anargyroi, (2) Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece, (3) 2 nd Department of Internal Medicine, National & Kapodistrian University of Athens, Hippokratio General Hospital of Athens, (4) Department of Gastroenterology, National & Kapodistrian University of Athens, Laiko General Hospital, Athens, (5) 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, (6) Gastroenterology Department, University Hospital of Patras, (7) General Hospital of Nikaia-Piraeus Agios Panteleimon, General Hospital of Western Attica Agia Varvara, Greece, (8) Evangelismos General Hospital, Athens, Greece, (9) General Hospital of Rhodes, Rhodes, Greece

29 Daclatasvir (DCV) Plus Sofosbuvir (SOF) 94 / 146 SVR % SVR-12 rates (%) according to HCV genotype SVR /6 18/20 48/55 12/13 G1a G1b G3 G4 Overall 84/94 DCV/SOF±RBV (12w): 87% (67/77) DCV/SOF±RBV (24w): 100% (17/17) p=0.20, NS

30 Daclatasvir (DCV) Plus Sofosbuvir (SOF) % SVR-12 rates (%) σε G3 ασθενείς ανάλογα με τη βαρύτητα της ηπατικής νόσου ,9 88,6 87,3 77,8 SVR-12 2/2 8/9 31/35 7/9 48/55

31 114 patients SVR in 92% (71/77) SVR 12

32 Metabolism of DAAs Smolders EJ et al. Drug safety 2016

33 AASLD/IDSA Guidelines. February 2016 Selected Potential Drug Drug Interactions Concomitant Medication SOF SIM LDV PTV/RTV/O BV + DSV Acid-reducing agents* X X DCV GZR/EBV Amiodarone X X X X X X Anticonvulsants X X X X X X Digoxin X X X X Ethinyl estradiol containing products Glucocorticoids X X X X PDE5 inhibitors X X X Rifamycin antimicrobials X X X X X X Sedatives X X X St John s wort X X X X X X Statins X X X X X X *eg, proton pump inhibitors such as omeprazole. Inhaled, intranasal.

34 Table. Patients with contraindications due to DDIs or potential DDIs to HCV DAAs

35 Conclusions Daclatasvir is: well tolerated, safe, with no major DDIs renal or hepatic impairment is no contraindication SVR 12 in GT3 (DCV+SOF) for 12 weeks 90% naïve 86% treatment experienced 96% non cirrhotics SVR 12 in GT3 (DCV+SOF+RBV) for 12weeks 85-89% in advanced fibrosis/cirrhosis SVR 12 in GT1 (DCV+SOF) % in naïve or treatment experienced REAL WORLD DATA CONFIRM THE SAFETY AND HIGH RATES OF RESPONSE