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Management of /HIV Co- Infection: New Combinations and Concepts in DAA Therapies

Anita Kohli M.D., M.S. St. Joseph’s Hospital and Medical Center Creighton University Medical School Phoenix, AZ

Objectives

To understand new combinations of DAAs in development and how they will impact current treatment paradigms

To understand new strategies in the simplification of DAA treatment with a focus on short duration therapies

Disclosures

No conflict of interest to disclose Unlabeled/Unapproved Use

The following will be discussed: oral direct acting HCV drugs (not yet FDA approved) Overview

History of Treatment for Hepatitis C

Drugs in Development for Hepatitis C Treatment

Novel Concepts: Short Duration Therapies Overview

History of Treatment for Hepatitis C

Drugs in Development for Hepatitis C Treatment

Novel Concepts: Short Duration Therapies Evolution of Treatment for Hepatitis C Weekly injections + 12 pills/day

Consensus First Pegylated alfa Interferon description interferon alfa Addition of 2b used to used to of non A 2b with protease cure hepatitis cure non B used to cure inhibitors used C infection hepatitis C hepatitis hepatitis C with peg-IFN infection alfa and ribavirin

1975 1989 1990 1992 1997 1998 2001 2002 2011 2012

Proof of Interferon Pegylated Isolation Interferon alfa + principle that alfa 2a interferon and ribavirin used therapy with used to alfa 2a with cloning of to cure directly acting cure ribavirin hepatitis C hepatitis C antivirals only hepatitis C used to cure virus infection can cure infection hepatitis C hepatitis C

Daily injections Weekly injections + 6 pills/day 1-10 pills/day Daily injections + Kohli A. …Kottilil S. JAMA 2014 6 pills/day Changing Treatment Paradigms for HCV

DAAs only DAAs 2013 100 2011 PegIFN 90+

80 RBV 2001 Standard 70+ IFN 1998 60 55 1991 42 39 40 34

20 16 6 0 IFN IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/ DAA 6 mos 12 mos 6 mos 12 mos 12 mos RBV RBV/ ± RBV 12 mos DAA ± PegIFN

Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD and Clinical Care Options, http://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/HCV%20Keeping%20Up/Interactive%20Virtual%20Presentation/Slides.aspx, Accessed May 27, 2014 Continued Work in Development of of HCV DAAs IFN free HCV treatment IFN and RBV free HCV treatment

6 weeks of treatment Trials Trials

HCV 3 months of treatment 4 weeks of treatment 2010 2011 2012 2013 2014 2015

plan Community Awareness Increasing Test all Treat all Overview

History of Treatment for Hepatitis C

Drugs in Development for Hepatitis C Treatment

Novel Concepts: Short Duration Therapies Mechanism of HCV Clearance

Infection

Virions DAA Infected Target cell hepatocyte

Host Immunity

Death Clearance Death/loss Major HCV Drug Classes

NS3/4A NS5B Polymerase Inhibitors NS5A Cyclophilin A Protease Nucleos(t)ide Non- Inhibitors Inhibitors Inhibitors Analogue nucleos(t)ide . High . Mimic natural . Bind to several . NS5A has role . Supports HCV- efficacy substrates of the different in assembly of specific RNA polymerase allosteric replication replication, . Low genetic enzyme sites; complex protein . barrier to Incorporated into results in expression . resistance RNA chain conformational Mechanism of causing chain inhibition . Interacts with . change Macrocyclic termination under study NS2, NS5A, or linear . Resistance NS5B . . Broad genotypic more frequent Phase III: . Phase III: . coverage than nucs , May regulate , , polypeptide . High genetic . processing, barrier to viral assembly resistance . Phase III: . Phase II/III Alisporivir

Courtesy of Clinical care options DAA Targets

Paritaprevir Simeprevir ** Sofosbuvir Dasabuvir

Ledipasvir Daclatasvir Ombitasvir Elbasvir** ** not FDA approved C-EDGE TN: 12-Wk Grazoprevir/Elbasvir for Treatment-Naive Pts With GT1/4/6 HCV

• International, randomized, blinded, placebo-controlled, parallel-group phase III trial

Treatment Follow-up Follow-up Wk 12 Wk 4 Wk 16 Randomized period

Treatment-naive Grazoprevir/Elbasvir GT1, 4, or 6 (n = 316) Open-label period HCV–infected pts Placebo (N = 421) (n = 105) Grazoprevir/Elbasvir

Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily.

• Pts well matched at baseline: 91% infected with GT1a or 1b HCV, 68% HCV RNA > 800,000 IU/mL, 22% cirrhotic

• Fewer white pts in immediate vs deferred treatment arm (60% vs 70%, respectively)

Zeuzem Z, et al. EASL 2015. Abstract G07. C-EDGE TN: Efficacy Results

SVR12 With 12 Wks of Grazoprevir/Elbasvir According to Genotype

95 92 99 100 100 80

80 60 40 SVR12 (%) 20 299/ 144/ 129/ 18/ 8/ n/N = 316 157 131 18 10 0 All Pts GT1a GT1b GT4 GT6

Non-virologic 4 3 1 0 0 failure Breakthrough 1 1 0 0 0 Relapse 12 9 1 0 2 . Subgroup analysis: significantly lower SVR12 rates in pts with baseline HCV RNA > 800,000 IU/mL ‒ No differences according to race, IL28B status, presence of cirrhosis

. Lower SVR12 rates in pts having baseline NS5A RAVs associated with > 5-fold loss of susceptibility to elbasvir Zeuzem Z, et al. EASL 2015. Abstract G07. C-EDGE TN: Adverse Events

GZR/EBV Pbo • Grazoprevir/elbasvir generally well Parameter, % (n = 316) (n = 105) tolerated in cirrhotic, noncirrhotic Common AEs (> 5%) pts . Headache 17 18 – No serious treatment-related AEs . Fatigue 16 17 – 1% discontinued active drugs for AEs . Nausea 9 8 . Arthralgia 6 6 Late ALT or AST elevation Cirrhotic Pts . Noncirrhotic Pts > 2 to 5 x ULN 1.0 3.8 . Adverse > 5 x ULN 1.3 0 Events, % GZR/EBV Pbo GZR/EBV Pbo Total bilirubin elevation . (n = 246) (n = 83) (n = 70) (n = 22) > 2 to 5 x baseline 0.9 0 . > 5 x baseline 0.3 0 ≥ 1 AE 71 69 54 68 Decreased hemoglobin Drug-related . Grade 1/2 2.9 3.8 39 39 26 41 AE . Grade 3/4 0 0 SAE 3 4 3 0 Drug-related 0 0 0 0 SAE Discontinued 1 0 1 5 for AE Death < 1 0 1 0

Zeuzem Z, et al. EASL 2015. Abstract G07. Reproduced with permission. C-EDGE TE: Grazoprevir/Elbasvir ± RBV for Treatment-Experienced Pts

• International, randomized, open-label, parallel-group, phase III trial

Wk 12 Wk 16

Grazoprevir/Elbasvir (n = 105)

PegIFN/RBV- Grazoprevir/Elbasvir + RBV experienced pts (n = 104) with GT1, 4, or 6 HCV infection Grazoprevir/Elbasvir (N = 420) (n = 105)

Grazoprevir/Elbasvir + RBV (n = 106)

Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily; weight-based RBV

• Pts well matched at baseline: ~ 90% infected with GT1a or 1b HCV, ~ 35% cirrhotic • Fewer GT4 HCV–infected pts in 16-wk arms, no GT6 HCV–infected pts in 12-wk arms

Kwo P, et al. EASL 2015. Abstract P0886. C-EDGE TE: Efficacy Results

12 Wks 16 Wks

97 100 92 94 92

80 60 40

SVR12 (%) 20 97/ 98/ 97/ 103/ n/N = 105 104 105 106 0 GZR/EBV GZR/EBV + RBV GZR/EBV GZR/EBV + RBV

Breakthrough 0 0 1 0 Rebound 0 0 2 0 Relapse 6 6 4 0 LTFU/Early DC 2 0 1 3

. Subgroup analysis: 99% SVR12 in black pts and no evidence of reduced efficacy at high baseline HCV RNA (cutoff = 2 million IU/mL) • Among pts with GT1a HCV infection, previous response and cirrhosis status did not impact SVR12 rates • SVR12 rate reduced (52.4%) in GT1a HCV–infected pts with baseline NS5A variants associated with > 5-fold change in elbasvir susceptibility

Kwo P, et al. EASL 2015. Abstract P0886. Reproduced with permission.

SOF + GS-5816 ± RBV x 8 or 12 Wks in Tx- Naive Noncirrhotic Pts With GT1-6 HCV

Part A 12 wks

Tx-naive SOF + GS-5816 25 mg/day Pts noncirrhotic pts (n = 27) followed with GT1 HCV SOF + GS-5816 100 mg/day to Wk 24 (N = 55) (n = 28)

Tx-naive SOF + GS-5816 25 mg/day Pts noncirrhotic pts (n = 27) followed with GT3 HCV SOF + GS-5816 100 mg/day to Wk 24 (N = 54) (n = 27)

Tx-naive SOF + GS-5816 25 mg/day Pts noncirrhotic pts (n = 23) followed with GT2, 4, 5, 6 SOF + GS-5816 100 mg/day to Wk 24 HCV (n = 22) (N = 45)

Tran TT, et al. AASLD 2014. Abstract 80. SOF + GS-5816 ± RBV x 8 or 12 Wks in Tx- Naive Noncirrhotic Pts With GT1-6 HCV

Part B 8 wks SOF + GS-5816 25 mg/day (n = 30) Tx-naive SOF + GS-5816 25 mg/day + RBV Pts noncirrhotic pts (n = 30) followed with GT1 HCV SOF + GS-5816 100 mg/day to Wk 20 (N = 120) (n = 29) SOF + GS-5816 100 mg/day + RBV (n = 31)

SOF + GS-5816 25 mg/day (n = 26) Tx-naive SOF + GS-5816 25 mg/day + RBV Pts noncirrhotic pts (n = 25) followed with GT2 HCV SOF + GS-5816 100 mg/day to Wk 20 (N = 103) (n = 26) SOF + GS-5816 100 mg/day + RBV (n = 26)

Tran TT, et al. AASLD 2014. Abstract 80. SVR Rates Reduced With 8-Wk Regimen in GT1 & 2; 12 Wks Effective in GT1, 2 and 3 Part A: 12-Wk Duration Part B: 8-Wk Duration

SOF + GS-5816 25 mg SOF + GS-5816 25 mg + RBV SOF + GS-5816 100 mg SOF + GS-5816 100 mg + RBV

96 100 91 100 93 93 87 90 88 88 88 100 83 81 77

80

60

40 (%) SVR12

20 26/ 28/ 10/ 10/ 25/ 25/ 26/ 25/ 26/ 25/ 20/ 22/ 23/ 23/ 27 28 11 10 27 27 30 30 29 31 26 25 26 26 0 GT 1 GT 2 GT 3 GT1 GT2

Tran TT, et al. AASLD 2014. Abstract 80. 8-Wk Duration: Impact of Baseline NS5A RAVs on Efficacy

GT1 8-Wk Treatment GT2 8-Wk Treatment

76% 49% 51% with no 24% with no with NS5A with SVR NS5A NS5A SVR RAVs at NS5A 86% RAVs at RAVs 81% baseline: RAVs baseline: SVR 88% SVR 94%

• Response rate lower in GT2 pts with baseline NS5A RAVs

Tran TT, et al. AASLD 2014. Abstract 80. Overview

History of Treatment for Hepatitis C

Drugs in Development for Hepatitis C Treatment

Novel Concepts: Short Duration Therapies Why Shorten Duration

• Short durations and fewer pills associated with better adherence

• 200 million people infected worldwide – Concentrated in resource limited settings – Uncomplicated, well tolerated therapy required

• The optimal combination of DAA agents required to cure HCV in a short period of time has not been established Clinical Trials Evaluating Short Duration DAA Therapy

Duration # of Total # of (weeks) Studies Patients Enrolled 24 8 986 12 18 2,571 8 7 983 6 6 237 4 3 96 Short Duration DAA Tx: 8, 4, or 6 weeks of SOF/GS-5816 ± GS-9857 Short Duration DAA Tx: 8, 6 or 4 weeks of SOF/LDV ± GS-9669 ± GS-9451 Short Duration DAA Tx: 8, 6 or 4 weeks of SOF/Grazoprevir/Elbasvir Conclusions (1)

Novel DAA only regimens for HCV have dramatically improved cure rates of HCV Further simplification of treatment regimens is possible through the ongoing development of pan- genotypic regimens Development and approval of additional effective DAA regimens will hopefully lead to competitive pricing, improving access Conclusions (2)

Development and approval of additional DAAs may allow for additional options for patients who have failed initial DAA therapy- a growing population of patients. Regimens that multiple DAAs targeting various stages of the HCV lifecycle in combination can effectively reduce HCV treatment durations, the lower limit of which still needs to be determined Strategy for HCV Cure

Emerging HCV Therapy

High cure rate Reinfection All oral therapy Resistance Low pill burden Screening Shorter course Linkage to care Fewer side effects Economics

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