2 adrian goldis__optimisations boceprevir and telaprevir.pdf

Assoc. Prof. Adrian Goldis University of Medicine Timisoara,

Clinic of Gastroenterology and Hepatology

How to optimize triple therapy with 1st generation of protease inhibitors in genotype-1 patients

Deuffic-Burban.S et al. Gastroenterology 2012; 143:974-85

The launch of Boceprevir (BOC)and Telaprevir(TVR) dramatically improved SVR rates in genotype-1 patients

In phase III studies ,SVR rates improved by nearly 30%, reaching 63% with BOC+PEG-IFN+RBV and 75% with TLV+PEG-IFN+RBV in treatment naïve genotype-1 patients

Benefit higher:treatment-experienced patients-SVR increased by 60% in relapsers, 45% in partial responders and 25% in null responders

The side effects profiles(of BOC and TVR) + the costs per SVR patients with advanced hepatic fibrosis => they should ideally no longer be used in patients infected with HCV genotype 1

New HCV DAAs in the firts half of 2014 in the EU: 1. Sofosbuvir, 2. Simeprevir, 3. Daclatasavir

EASL:”The panel recognises the heterogenity of per capita incomes and health insurance systems across Europe and in the other regions, and therefore the possible necessity to continue to utilise current standards of care with pegylated IFN-alfa and ribavirin, with or without the first-generation protease inhibitors telaprevir and boceprevir”

99/180 6/32 58/107 6/22 1081/ 1638

122/436

SVR %

Vierling JM, et al. EASL 2013

96/180 48/100 65/73 28/96

SVR %

Vierling JM, et al. EASL 2013

Effect OR(95% CI) P Value

Relapser vs non-responder

2.6(1.3-5) 0.06

Effect OR(95% CI) P Value

HCV RNA level ≤400000 vs >400000

11.6 (1.5-87.8)

0,02

IL28B CC vs TT

2.6 (1.3-5.1) 0.006

IL28B CC vs CT

2.1(1.2-3.7) 0.01

Cirrhosis No vs Yes

4.3(1.6-11.9)

0.04

Genotype 1b vs 1a

2(1.2-1.4) 0.005

Non Black vs Balck

2(1.1-3.7) 0.03

HCV RNA at baseline

SVR(%)

≤1000000 UI/ml 78-83%

>1000000 UI/ml 57-68%

The good candidates: Naives Treatment-experienced

Poordad F et al. Gastroenterology 2012;143:608-618 Gordon SC et al. J Clin Gastroenterol 2013.

CUPIC (n=212): 2 baseline factors associated with the occurrence of death at cirrhotic patients:

1. Platelet count<100000/mmc 2. Seric albumin<35 g/dl; At these subgroup: Risk of SAE=51,4% vs 6,2% (platelet count

>100000/mmc+seric albumin>3,5 g/dl subgroup)

SVR12 =27% vs 54.9% (platelet count >100000/mmc+seric albumin>3,5 g/dl subgroup)

Marc Bourliere, et al.:How to optimize current therapy of HCV genotype 1 infection with Boceprevir, Paris 2014

Baseline Characteristics

Odds ratio Minimally Adjusted Estimates

P value

CrCl(ml/min) 0.99 0.03

Albumin (g/dl) 0.3 <0.1

HCV RNA (log UI/ml)

0.76 <0.1

Bilirubin (log mg/dl)

2.93 0.2

Risk factors for decompensation among cirrhotic patients during PI therapy

Afdhal N, et al. AASLD 2013.Abstract 1865

The patient who do not be treated:Null responder cirrhotic

P=0.014

P=0.032

P=0.0013

BOCEPREVIR -CUPIC

55/ 102 36/ 94 0/10

Fontaine H, France, AFEF 2013

Jacobson I et al. Hepatology 2012;56:567-575

BOC:New TW8 stopping rules in patients with cirrhosis

Early viral kinetics allows to stop or continue treatment

Vierling JM et al. EASL 2013, Abs. 1430

Boceprevir:New TW8 stopping rules in patients with cirrhosis-CUPIC

P<0.001

Fontaine H, France, AFEF 2013,

Marc Bourlier, Paris Hepatite Conference 2014

Treatment-naïve G1 patients (n=687) received BOC-based therapy.Overall, 500 patients developed anemia(Hb≤ 10g/dl or were expected to reach that nadir before next visit) and were randomized to have anemia managed with either EPO(40000 units/week SC), or RBV dose reduction(by 200-400 mg/day).Transfussion in patients with Hb ≤ 8,5 g/dl was allowed to prevent study discontinuation

Poordad F, et al. EASL 2012.Abstract 1419

Hezode C, et al. AASLD 2013

N=167 treatment-experienced patients (85,6 % relapsers) A week 8 model predicting lack of EVR was created:

Variable OR 95% CI for OR P value Baseline ALT (IU/L) 1.0116 1.0053 to 1.0180 0.0003

F4 METAVIR 2.4103 1.0515 to 5.5251 0.03

Hb level at 8 week(g/dl)

1.6357 1.2772 to 2.0948 0.0001

ALT at 8 week(IU/L) 1.0211 1.0089 to 1.0334 0.0007

>1 log HCV RNA decrease at week 4

0.1276 0.0407 to 0.3995 0.0004

>2log HCV RNA decrease at week 8

0.0985 0.0383 to 0.2531 <0.0001

Association between clinical/biological parameters and presence of a viral load >100 IU/ml at week 12

L Gheorghe et al. JGLD, March 2014 Vol 23 No 1:45-50

Patients with mild disease often achieve a rapid virological response

These patients only need 24 weeks therapy Side effects are manageable

F0-F1 F2 F3 F4

Marcellin P, et al. J Hepatol 2011;54:S183

∆ 4%

(2-sided 95% CI:2,11)

Sherman KE, et al. N Engl J Med 2011;365:1014-24

Prior relapsers Prior partial responders Prior null responders

Pol S. et al Hepatology 2011;54(Suppl.S1):37 4A

<1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase

Proportion of patients in each category with <1 log10 HCV RNA reduction

10% 40% 59%

≥1 log 10 HCV-RNA reduction after 4-week Peg-IFN/RBV lead-in phase

n/N = 8/13 10/18 6/41 106/113 16/27 15/28

Foster GR, et al. J Hepatol 2011;54(Suppl.1)S3

Patients (%) T12/PR (750 mg q8h) N=1346

Pbo/PR48 N=764

Leading to discontinuation of all study drugs(%)

Skin and subcutaneous tissue disorders

Pruritus(SSC) 52 26 0.6

Rash (SSC) 55 33 2.6

Gastrointestinal disorders

Nausea 39 29 <0.5

Diarrhea 26 19 <0.5

Hemorrhoids 12 3 <0.5

Anorectal discomfort 8 2 <0.5

Anal pruritus 6 1 <0.5

Blood and lymphatic system disorders

Anemia(SSC) 32 15 0.9

http://fda.gov/downloads/AdvisoryCommittees/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252563.pdf

Telaprevir Boceprevir

Rash(55%) vs 33% Severe 5%

Anemia x2 (50% vs 25%)

Anemia x 2 (32% vs 15%) Dysgeusia(37-45% vs 11-18%)

Anorectal symptoms (26% vs 6%) Neutropenia<750/mmc 20-24% vs 9-14%

McHutchinson J et al., N Eng J Med 2009;360:1827-1838;

Hezode C et al.,N Eng J Med 2009;360:1839-1850

Jacobson IM et al., N Eng J Med 2011;364:2405-16

Kwo P et al.,Lancet 2010;376:705-716;

Bacon BR., et al. N Eng J Med 2011;364:1207-1217

Real-world(cirrhotics only) Treatment experienced

Treatment-naïve

Treatment-experienced

n=299 N=212

Patie

nts

with

ser

ious

AEs

(%)

Patie

nts

with

ser

ious

AEs

(%)

Outcomes,% TVR CUPIC N=299

BOC CUPIC N=212

Serious adverse event 53.8 44.3 Premature discontinuations due to serious adverse events

23.8 17.5

Death, n(%) 8(2.7) 3(1.4) Infections (grade 3/4) 9.7 2.4 Hepatic decompensation 4.7 4.2 EPO use 56.5 56.1 Transfusion 17.7 11.8 RBV dose reduction 27.8 23.6

Hezode C, et al. Unpublished data

Updated 26 September

T(1125 mgBID)+PR

IL28 B CC non F4: •Naives

•Relapsers

0 4 12 24 weeks

Follow up

PR

Randomization 2:1 in patients with RVR who continued all study drugs through Week 12

Nelson DR et al. EASL 2013; Abstract 881

Buti M, et al. AASLD 2012:LB-8

Optimal patients selection is crucial to achieve high SVR rate with reasonable safety profile

Optimizing BOC treatment includes: o Optimizing treatment design according to

baseline characteristics o Following optimal stopping rules o Preventing and managing SAE

Marc Bourliere, et al.:How to optimize current therapy of HCV genotype 1 infection with Boceprevir, Paris 2014

Early futility rules and short duration therapy allow personalised, cost-effective therapy

For patients with more advanced disease drugs with fewer side effects may be preferable

For patients with mild disease-telaprevir is a highly cost effective choise

For patients with advanced disease-telaprevir is not ideal

Graham R Foster:Personalised treatment with Telaprevir in 2014,Paris 2014