Farmaci anti-HIV e anti-HCV: Dalla ricerca Farmacologica allaccesso - - PowerPoint PPT Presentation

Milano, 19 Novembre 2013

Burden of illness dell’epatite C, stato dell’arte della terapia

Farmaci anti-HIV e anti-HCV: Dalla ricerca Farmacologica all’accesso in clinica

Alessio Aghemo, MD, PhD U.O. Gastroenterologia ed Epatologia Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Università degli Studi di Milano

Current Prevalence of HCV Infection In Different European Countries

Esteban JI et al J Hepatol 2008;48:148-162

Northern Europe: Prevalence: 0.1%-1.0% Central Europe: Prevalence: 0.2%-1.2%

Epidemiology of Hepatitis C In Europe

Southern Europe (Italy, Spain, Greece, Southern France): Prevalence: 2.5% - 3.5% Spread of infection: 1) initial epidemic (> 50 years ago): iatrogenic nature 2) ongoing epidemic: IDU-related

Natural History of hepatitis C

Decompens.

, , steatosis, Fe.

Decompens. Liver cancer Death

(Modified by Lauer and Walker NEJM 2001;345:41-52)

The Burden of Hepatitis C in Italy

• The cause of death in at least 10,000 persons each year
• The single etiologic agent in half the patients with cirrhosis
• The single etiologic agent in more than half the patients with a liver cancer
• The indication for liver transplantation in half the patients with ESLD
• Each year 67,460 patients with cirrhosis or HCC hospitalized for 11 days
• n average, 50% HCV (SIS)
• Each year 220 million € spent to treat chronic infection with HCV

General Strategy of Hepatitis C Therapy

• Goal of therapy

To prevent complications of HCV infection, which is principally achieved by eradication of HCV.

• The optimal treatment

Peg-interferon alpha and Ribavirin, dose and duration of therapy depending on HCV genotype and early virological response.

• End-point of therapy

Infection is considered eradicated when there is a (Surrogate?) sustained virologic response (SVR) defined as the absence of HCV-RNA by a sensitive PCR assay at the end of treatment and 6 months later.

Strader DB et al, Hepatology. 2004;39:1147-71 AASLD Practice Guidelines

Mortality in Patients With Chronic Hepatitis C Infection: A Nationwide Cohort Study

Denmark: 5.4 million. 0.3% HCV;1996-2005:13,005 HCV identified; 6,292 included (37% cleared HCV) Liver related death in chronic HCV vs cleared HCV: SDHR: 2.42, 95% CI: 1.51-3.88

HCV HCV

Omland et al, J Hepatol 2010;53:36-42

HCV HCV

Survival Outcomes in Patients with Advanced Hepatic Fibrosis Due to HCV

Van der Meer JAMA 2012;308:2584-93

Rates of Cirrhosis Regression According to the METAVIR Scoring System

100 60 80

TIENTS (%)

15 F4 F3 F2

Metavir

40

PRE-TREATMENT POST-TREATMENT

NUMBER OF PAT

38 2 7 15 14 20

Cirrhosis Regression in 23 (61%) Patients

F2 F1 F0 D’Ambrosio R et al Hepatology 2012, 56(2):532-43

Extrahepatic Clinical Benefits of a SVR in Patients with Chronic Hepatitis C

Clinical Event Number/Total Patients Reference

SVR (+) SVR (-) Diabetes 26/1167 (2.2%) 117/1175 (9.9%) Arase et al 2009 Malignant lymphoma 0/2161 (0%) 25/1048 (12.6%) Kawamura et al 2007 Improved Neurocognitive Functions* 8/8 100% 0/6 0% Byrnes et al 2012 * Improved Brain Metabolism: basal ganglia Cho/Cr and ml/Cr ratios

Antiviral Treatment For HCV Is Associated With Improved Renal And Cardiovascular Outcomes In Diabetic Patients

End-stage renal disease (3 cohorts) Ischemic stroke (3 cohorts)

Hsu et al, Hepatology in press

SVR to IFN-α Is Associated with Improved Outcome in HCV Related Cirrhosis: A Retrospective Study in Italy

Strata

• No. Patients

Person-yrs

• No. Event

Rate/100 Person- yrs (95% CI) Rate Ratio (95% CI)

Liver-related complications Non-SVR SVR 759 124 5,703 1,061 107 1.88 (1.54-2.27) 0 (0-0.35) n.a. HCC non-SVR SVR 759 124 5,805 1,055 122 7 2.10 (1.75-2.51) 0.66 (0.27-1.87) 3.12 (1.42-6.86) Liver-related mortality non-SVR SVR 728 120 5,781 1,019 83 2 1.44 (0.14-1.78) 0.19 (0.02-0.71) 7.59 (1.84-31.29) Non liver-related mortality non-SVR SVR 759 124 6,004 1,077 31 4 0.52 (0.35-0.73) 0.37 (0.1-0.96) 1.28 (0.44-3.68) Bruno S et al Hepatology 2007;45:579-587

A Key Period For the Treatment of HCV

• 1. Binding and

internalisation

• 2. release and

uncoating

• 3. IRES mediated

translation

• 4. polyprotein

processing (+)RNA (-)RNA

• 6. replication

(+)RNA

• 7. assembly

and release

Aghemo A et al, Nat Rev Gastroenterol Hepatol 2010;7(9):485-94

Endoplasmic reticulum

• 5. membraneous

web formation

adapted from Moradpour et al., Nat Rev Microbiol 2007;5:453-63

The First Class of Protease Inhibitors

A B

NS3 NS4 NS5A NS5B C E1 E2 p7 NS2

The NS3 serine protease and a cofactor NS4A allow for post-translational cleavage and proteolysis of the polyprotein to release NS5A

Linear covalent peptidomimetic inhibitors of the NS3/4A complex

N HN O O O H N O H N O N H O N N

Telaprevir Boceprevir

N HN O O O NH2 O H N O H N

New DAAs for anti-HCV Treatment

NS3

1° wave

Resistance profile Pan-genotypic Can’t be used as monotherapy, require PegIFN and Rbv Effective only against HCV-1 genotype efficacy Efficacy Adverse events

Good Average Unfavorable

Low SVR rates in some patients groups Poor safety in patients with advanced disease

Anti Anti-

• HCV

HCV drug e.g. drug e.g. NS3/4A NS3/4A protease inhibitor protease inhibitor

When Overall Antiviral Activity is Inadequate Resistant Variants May Be Selected

Viral Load Viral Load Time Time

Virus sensitive to small molecule Virus sensitive to small molecule Virus resistant to protease inhibitor Virus resistant to protease inhibitor

HCV RNA V HCV RNA V

HCV RNA HCV RNA detection limit detection limit

Anti Anti-

• HCV

HCV drug e.g. drug e.g. NS3/4A NS3/4A protease inhibitor protease inhibitor

The Crucial Role of PegIFN and Rbv as The Backbone of DAAs

Viral Load Viral Load

PegIFNalfa PegIFNalfa Ribavirin Ribavirin

Time Time

Virus sensitive to small molecule Virus sensitive to small molecule Virus resistant to protease inhibitor Virus resistant to protease inhibitor

HCV RNA V HCV RNA V

HCV RNA HCV RNA detection limit detection limit

Patients Dual Triple

∆

Pts # SVR Pts # SVR

Chance for Cure in HCV 1: Dual vs. Triple Therapy A Systematic Review

Previously untreated 1545 39% 1634 68.5% <2-fold Relapsers/Partial Resp. 539 26% 719 73% 3-fold Nonresponders 255 7.5% 386 44% 6-fold

Jurchis AR et al. EASL 2012, Poster 1123 (S442)

78 62

60 80 100

(%)

Telaprevir Telaprevir

Telaprevir & Boceprevir in Cirrhotic Naïve Patients

Boceprevir Boceprevir

67 52 226/290 45/73

F0/F2 F3/F4

20 40

SVR ( Jacobson IM, et al. NEJM 2011,364:2405-16

F0/F2 F3/F4

22/42 211/313 Poordad F, et al. N Engl J Med 2011;364:1195–206

Relapsers

72%

SVR Rates in Treatment Experienced Patients According to Previous Response

Relapsers Partial Responders

86%

Partial Responders Telaprevir REALIZE Telaprevir REALIZE Boceprevir RESPOND-2 Boceprevir RESPOND-2

80 100 72% 46%

Null Responders Zeuzem S . et al. NEJM 2011;364:2417-28

57% 31%

SVR (%) Bacon BR et al. N Engl J Med 2011;364:1207–17

20 40 60

60 80 100

SVR by Fibrosis Stage and Prior Response to Peg-IFN/RBV

Prior relapsers Prior partial responders Prior null responders

86% 85% 72%

%)

20 40 F0/F2 F3/F4 F0/F2 F3/F4 F0/F2 F3/F4 25% 42% 41%

Zeuzem S, et al. J Hepatol 2011;54(Suppl. 1):S3 SVR (%

144/167 101/119 34/47 21/50 24/59 22/88

Anaemia & Rash Adverse Events: The Telaprevir EAP

e of patients (%)

Grade 1: Hb 10.0 – 10.9 g/dL; decrease 2.5 – 3.4 g/dL Grade 2: Hb 9.0 – 9.9 g/dL; decrease 3.5 – 4.4 g/dL Grade 3: Hb 7.0 – 8.9 g/dL; decrease >4.5 g/dL Grade 4: Hb <7.0 g/dL

59% 42% Percentage

Colombo M et al, Gut in press

Baseline characteristic, % TVR CUPIC1 N=292 REALIZE F42 N=169* BOC CUPIC1 N=205 RESPOND 23 (BOC44/PR48) F0–F4 N=161 Male 68 75 68 70 Mean/median age, years (range) 57.2 (27–83) 54 (24–68) 56.9 (34–81) 52.3 F4 100 100 100 14 HCV genotype 1 subtype

CUPIC baseline characteristics: F4 treatment-experienced patients

1a 1b 34 54 57 42 40 50 60 38 HCV RNA ≥800,000 IU/mL 62 89 131 (64) 88 Hb level, g/dL (range) 14.6 (9.0–19.7) 15.6 (12.3–18.9) 14.8 (9.7–18.4)

• Platelets, /mm3 (range)

152,000 (18,000–604,000) 167,000 (88,000–425,000) 146,000 (33,900–346,000) 88% >150,000 Serum albumin, g/L (range) 40.1 (20.7–52.0)

• 40.4 (27.0–50.3)
• Total bilirubin, µmol/L (range)

15.4 (4.0–73.5)

• 15.0 (4.0–78.0)
• Esophageal varices

33 excluded 40

• Exclusion criteria

REALIZE RESPOND 2 33 46

• 29

40

• *All arms (TVR arms + control arm)
• 1. Hézode C, et al. J Hepatol. 2013;59:434–41
• 2. Pol S, et al. AASLD 2011; Abstract 31
• 3. Bacon B, et al. N Engl J Med 2011;364:1207–17

CUPIC Week 60 analysis: safety overview

Outcomes, % TVR CUPIC N=299 BOC CUPIC N=205 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 EPO use 57.0 62.6 Transfusion 17.7 11.8 RBV dose reduction 27.8 23.6

Hézode C, et al. Unpublished data

CUPIC: SVR12 and the risk of occurrence of severe complications

Platelets count ≤100,000/mm3 Platelets count >100,000/mm3 Albumin <35 g/L N Complications, n (%) SVR12, n (%) 37 19 (51.4%) 8 (21.6%) 31 5 (16.1%) 8 (29.0%)

Efficacy and safety suboptimal in the most in need patients

SVR12, n (%) 8 (21.6%) 8 (29.0%) Albumin ≥35 g/L N Complications, n (%) SVR12, n (%) 74 9 (12.2%) 25 (33.8%) 306 19 (6.2%) 165 (53.9%)

Hézode C, et al. Unpublished data

PegIFN and Rbv the culprits

New DAAs for anti-HCV Treatment

NS3

1° wave

NS3

2° wave

NS5A nuc NS5B non-nuc NS5B

Resistance profile Pan-genotypic efficacy Efficacy Adverse events

Good Average Unfavorable

Future Horizons in the Treatment of HCV

2 3 1

NS5B NUC + PR IFN Free Regimens 2nd Wave PIs+ PR

Aghemo A & De Francesco R, Hepatology 2013

QUEST-2: Virologic Response to Simeprevir + P/R Treatment

91% of pts in SMV arm met RGT criteria SMV + P/R P/R 100 80 60 (%) 81 50 86

Manns M, et al. EASL 2013. Abstract 1413.

SMV Arm: Total Duration of RGT Overall 24 wks 48 wks 40 20 SVR12 50 32

209/257 67/134 202/235 7/22

65 82 80 82 51 53

QUEST-2: SVR12 by Subtype and Fibrosis

100 80 60 SMV + P/R P/R

11/ 17 6/ 15

40

123/ 150 41/ 77 86/ 107 26/ 57

46

189/ 231 61/ 119

51 53

Manns M, et al. EASL 2013. Abstract 1413.

GT 1a No Cirrhosis Cirrhosis 60 40 20 SVR12 (%) GT 1b

NEUTRINO Trial

• Phase III, single group, open-label, HCV 1,4,5-6 naive

W 12

HCV 1: 291 (89%) Cirrhosis: 54 (17%) HCV 4: 28 (9%) HCV 5/ 6: 7 (2%)

W 12

Lawitz E et al, NEJM 2013 SOF + PR

HCV 1,4,5,6

N= 327 SOF 400 mg once daily; PegIFN alfa2a 180mcg; Rbv 1000-1200 mg

60 80 100% 89* 96 100 100

NEUTRINO Trial

SVR 12 60 80 80 92 87 98 100% P 0.002 P 0.006 20 40 GT1 GT6 Lawitz E et al, NEJM 2013 GT4 GT5

*92% 1a, 82% 1b

6/6 1/1 27/28 261/292

20 40

93/95 202/232

CC Non-CC Cirr No Cirr

252/273 43/54

AVIATOR: rates of SVR achieved with ABT-333 + ABT-267 + ABT-450 ± RBV

Treatment-naïve patients Null responders 100 80 60 40 SVR24 (%)

92 91 89 94 95 94 98 94 91 89 93 93 91 95 94 97 97 96 93 100

100 80 60 40 SVR24 (%)

Comparable high response rates were seen among 247 patients administered with 12 or 24 weeks of treatment

Kowdley KV, et al. EASL 2013: Oral 3 20 S

N= 78 81 108 50 35 124 113 42 115 44 N= 55 33 55 33 22 66 41 45 85 3

20 S

The Lonestar Study: Sofosbuvir + Ledipasvir (NS5A)

Single center study of GT 1 patients Broad inclusion criteria

• No upper limit to age or BMI
• Platelets ≥50,000/mm3

Lawitz E et al, Lancet in press

SVR12 Results

Lawitz E et al, Lancet in press

Pretransplant Sofosbuvir + Ribavirin

• Patient population
• DDLT candidates with HCV and HCC meeting MILAN criteria
• MELD exception for HCC
• MELD exception for HCC
• CPT ≤7
• Enrollment at 16 sites
• 8 UNOS regions
• 2 international sites
• 61 patients enrolled
• Original protocol: until LT or up to 24 weeks of treatment
• Amendment: extend treatment duration to 48 weeks or LT

Curry MP et al, AASLD 2013

Results: Post-Transplant Virologic Response

*3 subjects were >LLOQ at transplant. †1 subject has not reached pTVR12, 1 subject LTFU at Week 8 post transplant. Curry MP et al, AASLD 2013

Days Continuously TND Prior to Transplant: No Recurrence vs Recurrence in GT 1–4

Curry MP et al, AASLD 2013

Conclusions

Chronic HCV infection is curable Sustained virological response impacts positively on the natural course of the disease Current treatment options provide good SVR rates, but careful assessment of patients before therapy is necessary Future therapies will be expensive, but efficacy rates are staggering!!