Eduardo B. Martins, MD, DPhil SVP, Liver and Infectious Diseases Drug Development

Eiger’s Approach for an HDV Cure

Boston, November 11, 2016

Hepatitis B Research and Development: Understanding the FDA Guidance and Novel Treatments for HBV Cure

•  Lonafarnib o  Prenylation inhibition for HDV o  Clinical trials o  Milestones

•  Pegylated interferon lambda

o  Scientific rationale o  Clinical trials o  Milestones

•  Perspective on HDV cure

Overview

2

Lonafarnib

3

The HDV Life Cycle

Uncoating of Virus

Transport to Nucleus

Replication

Assembly

prenylated LHDAg

HDV genome

prenylated LHDAg prenyl moiety

small HDAg

Release of Progeny

Cytoplasm

HBV surface antigen

large HDAg

small delta

antigen

large delta

antigen HDV

genome

HDV genome

large HDAg

HBsAg

Prenylation

4

Proof of Concept Virus Like Particle (VLP) Infectious Virus In Vivo Animal Model

l  Jeffrey  S.  Glenn   5

Prenylation Inhibitors as Antivirals HDV is a Genetically Validated Target  

Lonafarnib for HDV

•  Small molecule, oral, prenylation inhibitor

•  Well-characterized through Phase 3 -  >2,000 patients dosed in oncology program by Merck (Schering) -  Dose limiting toxicity is GI (class effect)

•  Prenylation is a host target; confers high barrier to resistance

•  Over 100 HDV patients dosed across international sites

•  Orphan Designation, Fast Track Granted

NO

NO

NH2N

Br

Br

Cl

Koh et al, Lancet Infect Dis, 2015. 6

Sarasar® (lonafarnib) Phase 2 HDV Program 111 HDV Infected Patients Dosed

•  Proof of Concept

–  Monotherapy N = 14

•  LOWR HDV – 1 –  Combinations +/- PEG IFN α N = 15

•  LOWR HDV – 2 –  Dose Finding +/- PEG IFN α N = 46

•  LOWR HDV – 3 –  QD N = 21

•  LOWR HDV – 4 –  Dose-Escalation N = 15

MHH Hannover Medical School

LOWR HDV = LOnafarnib With Ritonavir in HDV

Dosing

Last Patient Dosed

Last Patient Dosed

2015

2015

7  

HDV RNA Decline with 4 Weeks of Lonafarnib

Lonafarnib 100 mg BID Placebo 0.5

0

-0.5

-1

-1.5

-2

-2.5

Mean ∆ - 0.74 Log

Mean ∆ - 0.2 Log

N = 4 N = 6

Mea

n ch

ange

in L

og H

DV

RN

A

Lonafarnib 200 mg BID

Mean ∆ - 1.6 Log

N = 6

National Institutes of Health NIH POC (AASLD 2014)

Lonafarnib 100 mg BID

+ Ritonavir

100 mg QD

Mean ∆ - 2.4 Log

N = 3

Mean ∆ - 1.8 Log

Lonafarnib 100 mg BID

+ PEG IFN α

180 mcg QW

N = 3 N = 3

Lonafarnib 300 mg BID

Mean ∆ - 2.0 Log

Lonafarnib 200 mg BID

Mean ∆ - 1.6 Log

N = 3 N = 3

Lonafarnib 100 mg TID

Mean ∆ - 1.2 Log

Ankara University LOWR HDV -1 (EASL 2015)

8

High Dose

Months 4-6 Months 1-3

LNF 50 mg BID or LNF 25 mg BID

LNF ≥ 75 mg BID + RTV

LOWR HDV – 2: “Dose Finding” Study Tolerability, Longer Dosing, and Triple Combination

LNF 50 mg BID or LNF 25 mg BID

+ RTV 100 mg BID

+ RTV 100 mg BID + PEG IFN α 180 mcg QW

Lower Dose

Lower Dose: Triple Combination

N=19

N=15

N=12

N=46 9

LOWR HDV – 3: “QD” Study Dosing Completed

N=4

N=4

LNF 50 mg QD + RTV 100 mg QD

Placebo

N=4 LNF 75 mg QD + RTV 100 mg QD

LNF 100 mg QD + RTV 100 mg QD

N=21

Placebo

Placebo LNF 50 mg QD + RTV 100 mg QD

LNF 75 mg QD + RTV 100 mg QD

LNF 100 mg QD + RTV 100 mg QD

N=3

N=3

N=3

Weeks 13-24 Weeks 1-12

10

EOT

LNF 50 mg BID +

RTV 100 mg BID

≥ 4 Weeks

N=15

≥ 2 Weeks 18 Weeks

LNF 50 mg BID +

RTV 100 mg BID

LNF 75 mg BID +

RTV 100 mg BID

LNF 75 mg BID +

RTV 100 mg BID

LNF 100 mg BID +

RTV 100 mg BID

11

MHH Hannover Medical School

LOWR HDV – 4: “Dose-Escalation” Study Dosing Completed

EOT

24 Weeks

12 * Yurdaydin, C. et al, AASLD Abstract #1845; ** Koh, C. et al, 12th HDIN Meeting; *** Wedemeyer, C. et al, AASLD Abstract #230.

LOWR HDV – 2* •  Dose optimization study to identify optimal LNF-RTV combinations +/- PEG IFN

LOWR HDV – 4*** •  Is rapid dose-escalation possible?

LOWR HDV – 3 “QD” Study

N = 21

LOWR HDV – 4 “Dose-Escalation” Study

N = 15

LOWR HDV – 2 “Dose-Finding” Study

N = 46

LOWR HDV – 3** •  Is once-daily dosing sufficient?

LOWR HDV Program Identifying Dose and Regimen for Registration Program

Phase 2 LOWR HDV – 2

Phase 2 LOWR HDV – 3

Interim Data

2015 2016 2017

Data

Phase 2 LOWR HDV – 4 Data

2016

2016

Data

2016

Post TRx Data

Post TRx Data

2017

2017

N = 46

N = 21

N = 15

13

LOWR HDV Program Data Presentations

Post TRx Data

2017

Pegylated Interferon Lambda 1-a

3

Cum

ulat

ive

Eve

nt F

ree

Sur

viva

l

20 15 10 5 0

1.0

0.8

0.6

0.4

0.2

0 NUCs No therapy

IFN αp < 0.01 vs NUCs

p = 0.02 vs NUCs

p = 0.05 vs no therapy

Years

Fewer Clinical Events with IFN Alfa Decompensation, HCC, Transplant, Death

15 Wranke, A. et al. EASL 2016. J Hepatol, accepted manuscript

•  A novel, first in class Type III interferon

- Lambda secreted in response to viral infections

•  Binds to a unique receptor versus Type I interferons

- Highly expressed on hepatocytes

- Limited expression on hematopoietic cells and CNS cells

•  Similar downstream signaling pathway as Type I interferons

•  Greater than 3,000 patients in 17 clinical trials

•  HCV antiviral activity with less of the typical IFN alfa related side effects

•  Anti-HDV activity in humanized liver mouse model

PEG IFN Lambda A targeted interferon for HDV

16

Lambda associated with fewer systemic adverse events, such as myalgia, arthralgias, pyrexia and chills, as compared with alfa

17  

AEs, % (≥ 20% in any arm)

Lambda 180 µg

(N = 102)

Alfa 180 µg

(N = 103) Fatigue 46.1 42.7

Headache 27.5 41.7 Myalgia 5.9 33.0 Pyrexia 7.8 33.0 Nausea 21.6 30.1 Pruritus 17.6 29.1

Insomnia 17.6 25.2 Rash 14.7 24.3 Chills 3.9 21.4

Arthralgia 5.9 20.4 GT1,4 through 48 week treatment* * GT2,3 patients on 24 week treatment showed similar safety profile

Zeuzem S, et al. 47th EASL; Apr 18-22, 2012; Barcelona, Spain. Oral 1435. Muir AJ, et al. 63rd AASLD; Nov 9-13, 2012; Boston, MA, USA. Oral 214.

PEG IFN Lambda Safety vs PEG IFN Alfa Results in HCV-Infected Patients: EMERGE 2b Study

PEG IFN Lambda Suppression of HDV RNA Induction of Innate Immune Response in Human Hepatocytes

HDV Viremia Experimental Design

ISG15 = 6.2 Fold STAT2 = 11.2 Fold

Dandri et al, EASL 2013 Monothematic Conference, Poster

Rig-I = 1.9 Fold STAT1 = 6.2 Fold

18

LMD 180 mcg QW Rx-free follow-up

Arm 1 N = 15

Arm 2 N = 15

LMD 120 mcg QW Rx-free follow-up

EOT* EOFU* 48 Weeks 24 Weeks

19  

HDV-RNA ALT

Safety / Tolerability HDV-RNA Negativity

ALT Change

Lambda Proof of Concept in HDV

* HDV-RNA negative at EOT and 3-6 months post cessation of therapy

LIMT HDV Phase 2 Study Lambda Interferon MonoTherapy Study in HDV

HDV Cure

3

21  

6 16

34 42 39

55

70

90

0

20

40

60

80

100

IFN 6m

IFN 12m

IFN + RBV 6m

IFN + RBV 12m

PEG 12m

PEG + RBV 12m

PEG + RBV + PI

6-12m

Multiple DAAs

3m

Sust

aine

d Vi

rolo

gic

Res

pons

e (%

)

1986 1998 2001 2002 2011 2014

IFN 6 months

IFN 12 months

IFN +

RBV 6 months

IFN +

RBV 12 months

PEG IFN 12 months

PEG IFN +

RBV 12 months

PEG IFN +

RBV + PI 6-12 months

Multiple DAA’s

3 months

%  %  

%  %   %  

%  

%  

%  Evolution of Therapy for HCV

* Frost and Sullivan HCV Reports, Manns et al Nat Rev Drug Dis 12 (2013), Spach HIV, HCV, and HBV Update

Over 25 Years to Optimally Cure HCV Response Rates Increased Over Time  

Patterns of HCV Response Lessons for HDV Cure

Nonresponder

Time

Relapser

Partial responder

HCV RNA Undetectable

HC

V R

NA

Breakthrough

LLOD Sustained responder

(cure)

Post-Treatment 3 Months Treatment

HDV Cure Lessons from HCV

Time

HDV RNA Undetectable

HD

V R

NA

LLOD Sustained responder

(cure)

Post-Treatment 3 Months Treatment

•  Lonafarnib

-  POC data published The Lancet ID 2015

-  LOWR HDV – 2, – 3, – 4 EOT data at AASLD 2016

-  LOWR HDV – 2, – 3, – 4 EOFU data at EASL 2017

•  Pegylated Interferon Lambda

-  SVR induction in HCV equivalent to pegylated interferon alfa

-  Better tolerability profile

-  Supportive in vivo data

-  Phase 2 study enrolling

•  HDV Cure

- SVR 12: HDV-RNA undetectable 12 weeks EOT

Eiger’s Approach For HDV Cure Summary

24

Thank You!

Eiger’s Approach for an HDV Cure

Boston, November 11, 2016