1392GR1700862-01 3/2017

1392GR1700862-01 3/2017

DACLATASVIR: Update on new data from the real

world over the past year

Dr M. MELA

EVANGELISMOS GENERAL HOSPITAL

9th International Congress of Internal MedicineAthens, 9-11 March 2017

1392GR1700862-01 3/2017

Disclosures

Speaker BMS, MSD

Outline

• Introduction

• Clinical Trials

• Real world data

– German experience

– Greek experience

Life cycle of the hepatitis C virus

Manns MP, et al. Nat Rev Drug Discov. 2007

Fusion and

uncoating

(+) RNA

Translation and

polyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

NS5A* inhibitors

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

EASL Recommendations on Treatment of Hepatitis C 2016

Clinical Trials

ALLY Phase 3 Program

• Patients with cirrhosis or post-liver transplant

• GT 1 to 6

• DCV + SOF + RBV, 12 weeks

ALLY-1N = 113

• Patients with HIV coinfection

• GT 1 to 6

• DCV + SOF, 8 or 12 weeks

ALLY-2N = 203

• Patients with GT 3 infection

• Treatment-naive or treatment-experienced

• DCV + SOF, 12 weeks

ALLY-3N = 152

All-Oral DCV + SOF

ALLY-3+N = 50

• Patients with GT 3 infection

• Advanced liver disease

• DCV + SOF + RBV, 12 or 16 weeks

Daclatasvir + Sofosbuvir for HCV GT 1-4 and HIV Coinfection ALLY-2 Trial: SVR12 by HCV Genotype: 12-Week Groups

Wyles DL et al. N Engl J Med. 2015

n=101 n=52

cirrhosis8.9% in naïve28.8% in tx-experienced

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

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 2000Probst A et al. J Viral Hepatol 2011

Gondeau C et al. World J Gastroenterol 2015

Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Design

Nelson DR et al. Hepatology 2015Cirrhosisnaive: 19 (19%) treatment experienced: 13 (25%)

Daclatasvir + Sofosbuvir for HCV GT 3ALLY-3 Trial: Results

Nelson DR et al. Hepatology 2015

• Open-label, randomized phase IIIb study

– Primary endpoint: SVR12

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

Wk 12 Wk 16Stratified by F3/F4

fibrosis stage

Daclatasvir + Sofosbuvir + Ribavirin for HCV GT 3 and Advanced Liver Disease

ALLY-3+Trial: Design

Leroy V et al. Hepatology 2016

IFN-experienced: 31 patientsSOF-experienced: 6 patients

• No virologic failures or AE-related discontinuations

Daclatasvir + Sofosbuvir + Ribavirin for HCV GT 3 and Advanced Liver Disease

ALLY-3+Trial: Results

All Pts Advanced

Fibrosis

(F3)

Cirrhosis +

Treatment

Experienced

SV

R1

2 (

%)

12-wk DCV + SOF + RBV 16-wk DCV + SOF + RBV

Cirrhosis

88 92 100 100 83 89 88 86

21/

24

24/

26

6/

6

8/

8

15/

18

16/

18

14/

16

12/

14

80

100

60

40

20

0

n/N =

Leroy V et al. Hepatology 2016

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 94 96 92

Serious AEs 10 8 12

Death 2 4 0

Discontinuation for AEs 0 0 0

RBV dose reduction 12 8 15

AEs in ≥ 20% pts in any arm

Insomnia

Fatigue

Headache

Irritability

30

26

24

14

33

25

29

21

27

27

19

8

Grade 3 lab abnormalities

Hemoglobin < 9.0 g/dL

or decrease ≥ 4.5 g/dL

TBI > 2.5 x ULN

2

4

0

4

4

4

Leroy V et al. Hepatology 2016

Real World Data

Cornberg M et al, AASLD 2016

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

864 patients with GT3 German Hepatitis C Registry - 02/2014 to 05/2015

Cornberg M et al, AASLD 2016

Real World Efficacy of Antiviral Treatment in Chronic Hepatitis C Genotype 3 Infection: Data from the German Hepatitis C-Registry (DHC-R)

34.7% tx-experienced, 33.2% with liver cirrhosis

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 SVR12/24SVR12/24, n/N (%)

Subpopulations (n)

DCV + SOF 12 weeks

DCV + SOF + RBV

12 weeks

DCV + SOF 24 weeks

DCV + SOF + RBV

24 weeks

DCV + SOF ±RBVAll

treatmentdurations*

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)

Non-cirrhotic (n = 100)

63/66 (95.5) 17/17 (100) 1/1 7/8 92/100 (92.0)

Cirrhosis(n = 68)

5/7 8/8 12/13 (92.3) 27/28 (96.4) 45/68 (91.8)

Decompensated cirrhosis (n = 19)

4/5 1/1 4/4 4/5 15/19 (78.9)

Mauss S et al. Abstract 932, AASLD 2016

Discontinuation oftherapy occurred in 14 patients

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. Papatheodoridis1, Andreas Kapatais2, loannis Gou- lis3,

loannis S. Elefsiniotis4, Jiannis Vlachogiannakos^, Spilios

Manolakopoulos5, George N. Dalekos6, John Koskinas5, Stylianos

Karatapanis7, loannis Ketikoglou5, Melanie Deutsch5, Emanuel K.

Manesis8, Vassilios A. Sevastianos9, Maria J. Schina10, Christos K.

Triantos11, Evangelos Cholongitas3, Maria-Vasiliki Papageorgiou1,

Emmanouil Sinakos3, Theofanie Karaoulani2, Argyro Koukou- fiki3,

Eftychia Evangelidou4, Dimitrios Karagiannakis1, Anastasia Kourikou5,

Eirini I. Rigopouiou6, Maria Tampaki5, Georgios Ntets- kas7, Theodoros

Voulgaris9, Chrysostomos Tsolias11, Panagiota loannidou1, Evangelos

Akriviadis3;

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]

Patient characteristics: n=603

Age, years

patients >70 years

57±11105 (17%)

males 351 (58%)

ALT, IU/L 59 (53)

Hb 13.3±2.5

PLT, /mm3

PLT <100,000/mm3

172,789±128,230140/591 (24%)

BMI, kg/m2 27±5

Source of infectionIVDUTransfusionIatrog./Egypt/SexualUknown

132 (22%)204 (34%)

32 ( 5%)235 (39%)

Previous therapy(Peg)IFNa±RBVPeg-IFNa+RBV+BOC/TPV Regimens with SOF

403 (67%)72%15% 13%

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

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%

DAAs regimens according to genotype

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.

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

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) 2nd 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

0

20

40

60

80

100

G1a G1b G3 G4 Overall

SVR-12 rates (%) according to HCV genotype

SVR-12

%

100

90 9287 89

84/946/6 18/20 48/55 12/13

DCV/SOF±RBV (12w): 87% (67/77)DCV/SOF±RBV (24w): 100% (17/17)

p=0.20, NS

94 / 146 SVR-12

Daclatasvir (DCV) Plus Sofosbuvir (SOF)

10088,9 88,6

77,887,3

0

20

40

60

80

100

SVR-12 rates (%) σε G3 ασθενείς ανάλογα με τη βαρύτητα της ηπατικής νόσου

SVR-12

%

48/552/2 8/9 31/35 7/9

Daclatasvir (DCV) Plus Sofosbuvir (SOF)

SVR 12

114 patientsSVR in 92% (71/77)

Metabolism of DAAs

Smolders EJ et al. Drug safety 2016

Selected Potential Drug–Drug Interactions

Concomitant Medication SOF SIM LDV PTV/RTV/OBV + DSV

DCV GZR/EBV

Acid-reducing agents* X X

Amiodarone X X X X X X

Anticonvulsants X X X X X X

Digoxin X X X X

Ethinyl estradiol–containing products

X

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

*eg, proton pump inhibitors such as omeprazole. †Inhaled, intranasal.

AASLD/IDSA Guidelines. February 2016

Table. Patients with contraindications due to DDIs or

potential DDIs to HCV DAAs

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)

– 95-100% in naïve or treatment experienced

• REAL WORLD DATA CONFIRM THE SAFETY AND HIGH RATES OF RESPONSE