AASLD Talk - Hepatitis C

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Transcript AASLD Talk - Hepatitis C

Hepatitis C Choices in Care

HCV State of the Art Management for a Curable Disease

Robert G. Gish MD Robert G Gish Consultants LLC Member VHAC Founding member of CEVHAP Executive Committee (VP): NVHR Senior Medical Director: St Josephs Medical Center Phoenix Professor of Clinical Medicine University of Nevada Las Vegas

Complexity of Hepatitis C Patient Management

After HEPTIC EMR program Futur e

Why Treat Chronic Hepatitis C?

  The disease        Common, chronic, and potentially progressive Complications are becoming more common   Liver failure Hepatocellular carcinoma (HCC) Decrease transmission Improve quality of life Systemic disease Improve survival due to the linkage of HCV to (non liver) all cause mortality Decrease immediate and long-term health care costs The treatment    Viral cure, or sustained virologic response (SVR), is achievable SVR associated with histologic improvement and gradual regression of fibrosis 1 SVR leads to lower risk for liver failure and HCC, and improved survival 2,3 1. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 2. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 3. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.

Treatment starts NOW with behavior modification

 Alcohol abstinence  Weight loss of OW/Obese  No THC use  Stop IVDU

HCV as a Systemic Disease

  Association between chronic HCV infection and:  Diabetes/insulin resistance     Cardiovascular disease HCV and Brain: decreased cognitive function and QOL Cancer Renal impairment Effects of antiviral therapy and SVR on prognosis:  Clear mixed cryoglobulinemia     Decrease liver-related mortality Abrogate non-liver-related mortality Stop graft loss in renal and liver transplant patients Change outcomes in immune suppressed patients with HIV and other treatments or disease states

SVR Reduces Risk of Development of Diabetes in Patients with HCV

   Veterans Affairs Clinical Case Registry: 27,636 patients with HCV Followed for median 5 years Antiviral treatment initiated 1998-2007 HR = 0.77: 95% CI 0.71-0.84

Hyder S. and et al Digestive Disease week, 2013

Hyder S et al. DDW 2013; poster 608.

HCV+ individuals die 15 years sooner

Pinchoff J et al. IDWeek 2013; poster 1777.

CHeCS: Annual Rate of Length of Stay (days/year) by FIB4 score*, 2006-2010

10 7 6 9 8 5 2 1 4 3 0 2006 2007 2008 2009 2010

Year

*FIB4, calculated from ALT, AST, platelet count and patient age, increases with worsening fibrosis; values > 5.88 indicate cirrhosis and end-stage liver disease FIB4<=1.21

1.21

FIB4>5.88

HCV-infected persons in CHeCS: Mortality rates also increasing*

Year

2006 2007 2008 2009 2010

Mortality rate (per 100 py)

1.4

2.1

2.8

3.2

4.4

From:

R Mahajan et al, Abstract submitted to IDWeek 2013

The real impact of HCV mortality in the United States*

    Despite high death rates, only 19% of the 1600 confirmed chronic HCV patients in CHeCS had HCV infection noted on their death certificate; only 30% even of those dying with liver-related conditions 70% had pre-mortem ICD9 codes, liver biopsies, and FIB4 scores indicative of substantial liver damage This suggests that even if

all

HCV-infected patients are identified before death – clearly, not the case-- actual mortality in them exceeds 80 000/yr, most of it contributed to by underlying HCV related liver disease Whatever the listed cause of disease, HCV-infected persons died 15 years younger than everyone else * Reena Mahajan et al, ‘Rates and Causes of Mortality…”, Manuscript submitted; IDWeek 2013 abstr 1774

Current Treatment

The Evolution of HCV Therapy

100

1986 1998 2001 2002 2011-13

80 70-75 60 54-56 42 39 40 34 20 16 6 0

IFN 6 mo IFN 12 mo

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

IFN/RBV 6 mo IFN/RBV 12 mo PEG-IFN 12 mo PEG-IFN /RBV 12 mo PEG-IFN /RBV + PI 6-12 mo

2014+ 90+% +/ INF RIBA

Side Effects

           PEG IFN/RBV + new therapies results in increased SVR rates, this may be accompanied by a higher incidence of Anemia, often requiring erythropoietin and/or transfusion Rash Taste abnormalities (dysgeusia) Fatigue Flu-like symptoms Nausea Pruritus/dry skin Neutropenia/thrombocytopenia Fever Depression +++ Poordad F, et al.

N Engl J Med.

2011;364:1196-1206. Bacon BR, et al.

N Engl J Med

. 2011;364:1207-1217.

Sherman KE, et al. 61st AASLD; October 29-November 2, 2010; Boston, Mass. Abstract LB-2.

Telaprevir NDA 201-917. April 28, 2011. Available at: www.fda.gov.

INF + Riba +Telaprevir: SVR12 safety findings

Patients, n (% patients with at least one event)

Serious adverse events (SAEs)* Premature discontinuation / due to SAEs Death Infection (Grade 3/4) †

Telaprevir n = 295

535 in 160 patients (54.2%) 139 (47.1%) / 63 (21.3%) 7 (2.4 %) 27 (9.1 %) Hepatic decompensation (Grade 3/4) Rash (grade 3/SCAR) 15 (5.1 %) 16 (5.4 %) / 2 (0.6 %) Anemia (Grade 3/4 : Hb < 8 g/dL) 38 (12.9 %) EPO use / blood transfusion GCSF use 168 (57 %) / 53 (18 %) TPO use *SAEs in patients; SCAR: severe cutaneous adverse reaction † 3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection 8 (2.7 %) 6 (2 %)

INF + Riba + Boceprevir: SVR12 safety findings

Patients, n (% patients with at least one event)

Serious adverse events (SAEs)* Premature discontinuation / due to SAEs Death † Infection (Grade 3/4) Hepatic decompensation (Grade 3/4) Rash (grade 3/SCAR) Anemia (Grade 3/4: Hb < 8 g/dL) EPO use / blood transfusion GCSF use TPO use *SAEs in patients; SCAR: severe cutaneous adverse reaction † 1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia

Boceprevir n = 190

321 in 97 patients (51.0%) 80 (42.1%) / 27 (14.2%) 3 (1.6 %) 8 (4.2 %) 9 (4.7 %) 2 (1.0 %) 19 (10.0 %) 119 (62.6 %) / 26 (13.7 %) 13 (6.8 %) 3 (1.6 %)

HCV — The Revolution Has Begun

Antiviral activity in all HCV genotypes All-oral combination regimen QD (or BID) dosing No/less selection of resistance Short treatment duration 6-12 weeks Excellent safety and tolerability Less or no DDI Applicable in difficult-to-treat populations:

Transplant

Coinfection

End-stage renal disease, etc.

HCV Therapy —Past, Present, and Future IFN-free DAA Frequent combinations (G1) curability of Suppression of SVR 90-100% diverse HCV with DAA Ribavirin populations combination (PI + NI) without IFN Interferon Proof of concept for DAA (PI) Telaprevir and boceprevir Potential approval of other DAAs with IFN (eg faldaprevir) 1990 2000 2005 2010 2011 2012 2013 2014 2015 Pegylated interferons

Thank you to Dr Ira Jacobson

Curability of HCV without Interferon Target >90% SVR reached in Phase II and III trials Approval of simeprevir and sofosbuvir with IFN:G1, others?

First approved IFN-free therapy: SOF+RBV: G2, 3

Two New Protease Inhibitors are coming in combination with PEG IFN/RBV

 Simeprevir  NS3 protease Inhibitor  Q daily dosing  Improved side effect profile  No anemia  Fewer DDIs  Faldaprevir  NS Protease inhibitor  Q daily dosing  Improved side effect profile  No anemia 18

Simeprevir (TMC 435)

 HCV-specific NS3/4A protease inhibitor  Antiviral activity in patients infected with GT 1, 2, 4, 5, and 6  Oral, once-daily tablet  Limited drug-drug interactions as CYP 3A4 inhibitor only at level of intestine  Safe and well tolerated, n ~3800 patients

Simeprevir —Completed Phase III Studies

 QUEST-1 and QUEST-2  Same study design, but conducted independently of each other  Treatment naïve GT 1 patients  PROMISE  Same study design as QUEST-1 and QUEST-2  GT 1 prior relapsers Jacobson I, et al. EASL 2013, Abstract 1425. Manns M, et al. EASL 2013, Abstract 1413. Lawitz E, et al. DDW 2013, Abstract 869b.

Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment Naïve and Prior Relapsers

Simeprevir/PEG/RBV PEG/RBV 100 80 80* 81* 79* 60 50 50 37 40 20

210/ 264 65/ 130 209/ 257 67/ 134 206/ 260 49/ 133

0 QUEST-1 QUEST-2 PROMISE

*P

<0.001

Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013; Abstract 869b.

QUEST-1 —SVR by Subgroup

SIM+PR PR 100 90 94 80 83 70 71 78 76 65 60 60 52 49 42 40 28 24 20

152/ 183 54/90 54/77 11/40 105/ 147 36/74 105/ 117 29/56 72/77 29/37 114/ 150 32/76 24/37 4/17

0 F0-F2

Fibrosis

F3-F4 1a 1b/other

Genotype

CC CT

IL28B genotype

Q80K polymorphism affected SVR Jacobson I, et al. EASL 2013;Abstract 1425. TT

QUEST-2 —SVR by Stage of Fibrosis

Simeprevir/PEG/RBV + PR PEG/RBV 100

85

80

67 65

60

51 53 40

40 20 0

165/195 52/102

F0-F2

24/36

F3

9/17 11/17 6/15

F4 (Cirrhosis) Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013; Abstract 869b.

ASPIRE —Virologic Response to Simeprevir + PEG/RBV in Prior Partial and Null Responders

Placebo + PEG/RBV SMV 100 mg* + PEG/RBV SMV 150 mg* + PEG/RBV 100 85 85 80 75 60 57 51 46 40 37 19 20 9 n = 27 79 79 23 68 69 16 50 0 Relapsers Partial Responders Null Responders *For each dose, SVR for different treatment durations were similar so results were pooled.

Abbreviation: SMV, simeprevir.

51 Zeuzem S, et al. EASL 2012;Abstract 2.

QUEST-2 —Safety Profile

Patient % Adverse Events SMV/PR (n = 257) Placebo/PR (n = 134)

Grade 1 or 2 AE Grade 3 or 4 AE Serious AE AE leading to discontinuation of SMV * Most common AEs ( ≥25% in SMV arm) Headache Pyrexia Fatigue Influenza-like illness Other AEs of interest Rash (any type) Anemia   70.0

25.7

2.3

1.6

37.0

30.4

34.6

25.7

23.7

13.6

Pruritus 18.7

3.9

The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2 73.1

23.9

1.5

0.7

33.6

35.8

38.8

25.4

11.2

15.7

14.9

0.7

*Without regard to PEG IFN and RBV.

Abbreviations: AE, adverse event; PR, PEG IFN + ribavirin; SMV, simeprevir.

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

Simeprevir —Benefits

 Virtually all patients qualify for short-duration (24 weeks) therapy  Limited drug-drug interactions  Daily dosing

Simeprevir —Data Gaps

 GT 2 and 4 subtypes  Phase III data in prior PEG/RBV partial and null responders  Renal disease  Pre and post transplant

All Oral: Sofosbuvir plus Ribavirin Genotype 2 and 3*

100 80 60 81 87 97 98 100 100 73 50 40 20 0 2 Treatment Week 4 EOT SVR *Patients with previous non-response to IFN-based treatment Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.

Weeks of Treatment: 12 (N=100) 16 (N=95)

All Oral: Sofosbuvir plus Ribavirin Cirrhosis vs No Cirrhosis

96 100

100

78

80 60 40 20 0

60

25/ 26 23/ 23 6/ 10 No Cx Genotype 2 Cx 7/ 9

63 61 37

14/ 38 25/ 40

19

5/ 26 14/ 23 No Cx Cx Genotype 3 Weeks of Treatment: 12 (N=100) 16 (N=95) Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.

Sofosbuvir + RBV

VALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures

G2 G3 SOF+RBV (n=73) SOF+RBV (n=250) SVR12 =93%

Wk 24 Wk 0 100 80

SVR 12 (%)

60 93

Genotype 3

92 85 60 40 20 0 86/92 12/13 85/100 27/45 Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Naïve Treatment-experienced FDA Advisory Committee Meeting, Oct 25, 2013; Zeuzem S et al, AASLD 2013, #1085

Sofosbuvir/PegIFN/Ribavirin Genotype 1 (N=327)

99 99

100 80 60 40 20 0

91

2 4 Treatment Week Lawitz E, et al. N Engl J Med 2013;368:1878-87.

EOT

90

SVR

Cohort 1: Null responders (F0-2)

100 90 80 70 60 50 40 30 20 10 0

24 week treatment

100 14/14 SMV/SOF 24 wks 1/24 4/24 4,2 16,7 79 100 90 80 70 60 50 40 30 20 10 19/24 SMV/SOF/RBV 0 24 wks SVR12 (SMV/SOF) SVR12 (SMV/SOF/RBV) Non-virologic failure Relapse

9

2

12 week treatment

7,8 1/14 13/14 SMV/ SOF… 12 wks 3,7 96 26/27 1/27 SMV/ SOF/RBV… 12 wks

Cohort 2: Naïve and prior null responders (F3-4): Interim analysis, SVR4

100 90 80 70 60 50 40 30 20 10 0 100 96,3 1/27

12 week treatment

100 100 100 93.3

1/15 14/14 26/27 7/7 12/12 7/7 14/15 Total Naives Nulls 9 naïve and 9 null responders METAVIR F4 patients Only relapser was a F4 prior null responder SVR4 (SMV/SOF) SVR4 (SMV/SOF/RBV) Relapse

Conclusion

    Treatment with SMV + SOF ± RBV results in:   High SVR12 rates in HCV GT 1 null responder patients High SVR4 rates in naïve and null-responder patients with METAVIR F3-F4 These findings suggest that addition of RBV to SMV + SOF may not be necessary to achieve good virologic response in this patient population 12 weeks’ treatment may confer similar clinical benefit to 24 weeks’ treatment SMV + SOF ± RBV was generally well tolerated

IFN-free Summary Cross-company Studies

Daclatasvir + Sofosbuvir (N=41, GT-1) Simeprevir + Sofosbuvir COSMOS (N=80)

Weeks

12 12

SVR

100% 100% Sulkowski MS, et al. EASL 2013; abstract 1417.

Lawitz EM, et al. CROI 2013; abstract 155LB.

IFN-free Summary Phase 2 Study Results

ABT450/r + ABT267 + ABT333 + RBV (N=571) Sofosbuvir + ledipasvir + RBV (N=34) Faldaprevir + deleobuvir + RBV (GT1b, N=20) DCV + ASV + BMS-791325 (N=66)

Weeks

12 8-12 16 12-24

SVR

~90% 95-100% ~95% 88-94% Kowdley K, et al. EASL 2013; abstract 3.

Gane E, et al. CROI 2013; abstract 41LB.

Zeuzem S, et al., APASL 2013.

Everson GT, et al. IDSA 2013; abstract 1828.

Projected Timing for New Regimen Launches

2013 2014

BMS DCV/ASV/RBV* ---- GT1b Naïve/Tx-Exp/ IFN Intolerant COSMOS Study Off Label use SOF + SIM G-1 Sofosbuvir + RBV GT2/3 , Naïve/Tx EXP/ IFN Ineligible TX-Exp Daclatasvir Triple ---- Gt1. Naïve only Sofosbuvir + lepedisvir ---- GT1/2/3, Naïve/TX EXP/ IFN Ineligible Sofosbuvir Triple --- GT1, 4, 5, 6, Naive ABT 450/267/333/RBV --- GT1, Naïve/Tx-EXP Simeprevir Triple --- GT1, Naïve, Tx Exp Faldaprevir (BI201335) Triple --- GT1 Naïve, Tx-EXP

2015 2016

Triple IFN-Free

Q1 Q2 Q3 Q4 2013 Q1 Q2 Q3 Q4 2014 Q1 Q2 Q3 Q4 2015 Q1 Q2 Q3 Q4 2016

* Precise timing TBD

To Treat or not to Treat: A Constellation of Considerations Genotype virus Histologic stage

To Treat or not to Treat:

Q80K mutation or others 20%+ life time risk Of cirrhosis Duration of infection

A Constellation of Considerations

Personal plans (marriage, pregnancy) Age Family and other support Patient "mindset" Extrahepatic Features (Fatigue, EMC, PCT) COST HIV coinfection Occupation Contraindications & comorbidities Insulin Resistance