Developing a Treatment for Post-Bariatric Hypoglycemia

December 9, 2016

Developing a Treatment for Post-Bariatric Hypoglycemia

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© 2016 Eiger Biopharmaceuticals, Inc., all rights reserved. Sarasar is a registered trademark of Merck Sharp & Dohme Corp. Bestatin is a trademark of Nippon Kayaku Co., Ltd. All other trademarks belong to their respective owners. 2

8:00 AM Welcome David Cory - Corporate Highlights and Pipeline - HDV program update / next steps

8:15 AM PBH: Defining the Problem Mary-Elizabeth Patti, MD

Joslin Diabetes Center

8:30 AM Pharmacologic Approaches to PBH Marzieh Salehi, MD Cedars-Sinai

8:45 AM Exendin 9-39 in PBH Colleen Craig, MD - Review of IV / SC Data Stanford / Eiger - Interim Results of MAD Study - Novel Liquid Formulation - Next Steps

9:05 PM Panel Discussion and Q&A All

Agenda

3

Post-Bariatric Hypoglycemia (PBH): A Challenging Clinical Syndrome

Mary-Elizabeth Patti, MD Investigator and Adult Endocrinologist Research Division Director, Hypoglycemia Clinic Joslin Diabetes Center Harvard Medical School

4

•  Bariatric surgery increasing worldwide - 193,000 bariatric procedures in the US in 2015 and growing*

•  Post-prandial hyperinsulinemia and hypoglycemia - Neuroglycopenia – seizures, loss of consciousness, and even death - Disability – impaired ability to work, drive, perform daily activities - Asymptomatic hypoglycemia is substantial

•  Impacts ~5-10% of gastric bypass patients: Orphan Disease

-  ~ 60,000 gastric bypass procedures in US in 2015 -  ~ Up to 3,000 new patients annually in US (estimated incidence)** -  ~ 30,000 current patients in US (estimated prevalence)**

•  No approved therapy; high unmet medical need

Post-Bariatric Hypoglycemia (PBH) Complication of Bariatric Surgery

* ASMBS 2015, **Market research estimates 5

Common Bariatric Procedures in US

Normal Anatomy

Adjustable Gastric Band

(AGB)

Roux-en-Y Gastric Bypass

(RYGB)

Vertical Sleeve Gastrectomy

(VSG)

ASMBS 2015: 193,000 procedures per year in US

10% 27% 52%

6

Gastric Bypass is Highly Effective for Sustained Weight Loss and Remission of Type 2 Diabetes

Sjostrom L et al. N Engl J Med 2007; 357:741-752

Banding C

hang

e in

Wei

ght (

%)

Years

0

-10

-20

-30

15 10 8 6 4 0 1 2 3

Control

Vertical-Banded Gastroplasty

Gastric Bypass

7

Healthy Range

70-100 mg/dL

Diabetes

> 126 mg/dL

Hypoglycemia (low blood glucose)

< 54 mg/dL

Blood Glucose Levels Are Tightly Regulated

8

Food Intake & Absorption or ↑ Glucose

Pancreas

Liver

Glucose Uptake into Muscle & Other TIssues

Glycogen Synthesis

Lowering of Blood Glucose

GLP1

Insulin Release

Blood Glucose Levels Are Tightly Regulated After Meals

Stomach

9

GLP1

Insulin Release

Glycogen Breakdown

Liver Glucagon

Low Blood Glucose

Raises Blood

Glucose

Counterregulatory hormones: cortisol, catecholamines, GH, neural input

Blood Glucose Levels Are Tightly Regulated

Pancreas

Stomach

10

Whipple’s triad required to diagnose hypoglycemia

•  Symptoms of hypoglycemia

•  Low plasma glucose at time of symptoms

(< 54 mg/dL*)

•  Relief of symptoms by raising glucose

Allen O. Whipple Surgeon

* ADA/EASD Hypo Study Group, Diabetes Care, Nov 2016

How Do We Diagnose Hypoglycemia?

11

Adrenergic Tremor Palpitations Anxiety

Cholinergic Sweating Hunger Paresthesias

•  These symptoms are often nonspecific! •  Overlap with “dumping syndrome”

- Occurring post-meals in bariatric patients

Neuroglycopenia Impaired cognition Seizures ↓ Consciousness

Hypoglycemia Symptoms

12

Adrenergic Tremor Palpitations Anxiety

Cholinergic Sweating Hunger Paresthesias

Neuroglycopenia Impaired cognition Seizures ↓ Consciousness

Hypoglycemia Symptoms

•  Brain requires glucose for normal functioning •  Hypoglycemia Unawareness: A Threat to Safety

- loss of adrenergic or cholinergic warning symptoms with repeated hypoglycemia - abrupt onset of neuroglycopenia - can result in serious falls, motor vehicle accidents, seizures, loss of consciousness

13

Post-Bariatric Hypoglycemia is Increasingly Recognized

•  Mainly after gastric bypass, but also sleeve gastrectomy •  PBH can be mild, moderate or severe

•  Mild / moderate can be managed with diet modification –  Avoid easily digested carbohydrates (simple carbohydrates) –  Focus on defined quantities of complex carbohydrates only –  Frequent small meals –  No liquids with meals –  Snack before activity –  Avoid alcohol –  Carry glucose tablets at all times

14

•  Low plasma glucose levels at time of neuroglycopenia –  with inappropriately high insulin levels

•  Symptoms resolve with glucose administration

•  Typical onset 2-3+ years after surgery

•  Usually 1-3 hours after meals

•  Normal glucose and insulin response to prolonged fasting

•  Loss of consciousness, seizures, strokes, falls, disability

•  Unresponsive to dietary management

Severe PBH Occurs in a Subset of Patients

15

Roller Coaster of Post-Bypass Glycemia Continuous Glucose Monitoring Reveals Spikes and Troughs

Patient Glucose Chart

16

Time (min) 0 20 40 60 80 100 120

Glu

cose

(mg/

dL)

60

80

100

120

140

160

180

200

OW MOb

GB + NG Post-bypass hypoglycemia patients with neuroglycopenia GB Post-bypass, NO symptoms of hypoglycemia OW Obese, matched to patients’ current BMI MOb Morbidly obese, matched to patients’ pre-op BMI

Goldfine & Patti, JCEM 2007

GB Alters Post-Prandial Glucose Patterns

17

Time (min) 0 20 40 60 80 100 120

Glu

cose

(mg/

dL)

60

80

100

120

140

160

180

200

GB OW MOb




18

Time (min) 0 20 40 60 80 100 120

Glu

cose

(mg/

dL)

60

80

100

120

140

160

180

200

GB+NG (PBH) GB OW MOb




19

Time (min) 0 20 40 60 80 100 120

Glucose (mg/dL)

60

80

100

120

140

160

180

200

Higher Levels of Insulin In Post-GB Patients with Neuroglycopenia

p (ANOVA) = 0.06

GB+NG GB OW MOb


0 20 40 60 80 100 120

Insulin (µU/mL)

0

50

100

150

200

250

300 GB+NG GB OW MOb

Time (min)

20

Time (min) 0 20 40 60 80 100 120

0

100

200

300 GLP-1

GLP-1 Levels are Increased in PBH


*

*

*

*

p (ANOVA) = 0.03 pm

ol /

L

GB+NG GB OW MOb

Food Intake & Absorption

GLP-1

Intestine

Pancreas

GLP1

Insulin 21

Food Intake in Post-Bariatric Patient

•  Accelerated Intestinal Delivery

•  Rapid ↑ Plasma Glucose

Chronic Intestinal & Neural Adaptation

•  Dysregulated Enteroendocrine Cell Secretion •  ↑ Secretion of incretin hormones e.g. GLP-1 •  Altered Gut Microbiota •  ↑ Bile Acids •  Altered Intestinal Metabolism •  β-Cell Trophic Hormones •  Insulin-independent glucose disposal

↑ Postprandial Insulin

Secretion

Severe Hypoglycemia

Patti & Goldfine, Lancet Diab & Endo, 2016 22

Method of Diagnosis Prevalence Hospitalization 0.1 - 1%a

Clinical recognition 0.4 - 6.6%b

Symptoms (survey) 33%c

OGTT glucose < 50 mg/dL 10 - 33%d

MMTT glucose < 55 mg/dL 29%e

CGMS (sensor glucose < 55 mg/dL) 75%e

Duration CGMS (sensor glucose < 60 mg/dL) 30 - 71 minf

Prevalence of PBH is Significant

aMarsk, Gribsholt, Sarwar, Lee; bKellogg, Gribsholt; cLee; dPigeyre, Goldfine, Papamargatis; eKefurt, fHalperin, Abrahamsson, Kefurt 23

PBH: A Debilitating Disorder Summary

•  Bariatric surgery is now recommended in treatment guidelines as an option for obesity and type 2 diabetes*

•  RYGB and VSG are most common bariatric surgeries •  Post-prandial hyperinsulinemia and hypoglycemia

- Impacts a significant % of RYGB patients - Neuroglycopenia, disability - Asymptomatic hypoglycemia is substantial

•  Prevalence of post-bariatric hypoglycemia is significant

•  Pharmacological treatment for PBH is needed *2016 Diabetes Surgery Summit (DSSI) guidelines

24

Joslin Allison Goldfine Ping Li Ali Bajwa CRC Nurses & Staff Christopher Mulla Rohit Kulkarni Susan Bonner-Weir Gordon Weir Franco Folli Stefano La Rosa Jonathan Dreyfuss Hui Pan Emmy Suhl Joanne Rizzotto Patients!

Thank you to…

Surgery Edward Mun Daniel Jones Ben Schneider Douglas Hanto Mark Callery David Lautz Jim Moser

Pathology Jeffrey Goldsmith Eric Yee Radiology Elisa Franquet Gerald Kolodny George Watts

External Colleagues Jens Holst University of Copenhagen

Jean-Claude Reubi University of Geneva

Clary Clish Broad Institute

Funding NIDDK-SBIR (with Xeris)

AZ/BMS/Amylin Medimmune

Harvard School of Engineering Eyal Dassau Alejandro Laguna Frank Doyle

25

Pharmacological Approaches to Hypoglycemia after Gastric Bypass

Surgery

Marzieh Salehi, MD Director of the Clinical & Translational Research Center Cedars-Sinai Medical Center

26

Adapted: McIntyre N, et al; Lancet 1964; 41:20-1

Blood glucose Plasma insulin

Time (min)

Blo

od G

luco

se (m

g/dL

)

Intravenous Intrajejunal

Plas

ma

Insu

lin (

pmol

/L)

-30 -15 0 15 30 45 60 75 90 105 120 135 -30 -15 0 15 30 45 60 75 90 105 120 135

300

250

200

150

100

50

0

300

250

200

150

100

50

0

Time (min)

incretin effect ü  GI hormones (GLP-1 / GIP) ü  Neural factors ü  Direct nutrient effect

Insulin Secretion is Greater With Oral Compared to IV Glucose

27

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0

3 .0

4 .5

6 .0

7 .5

9 .0

1 0 .5

T im e (m in )

Blo

od

glu

co

se

(m

mo

l/l)

A s y m p to m a tic -G B (2 9 )C o n tro ls (1 1 )

S y m p to m a tic -G B (3 6 )

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 00

4 0 0

8 0 0

1 2 0 0

1 6 0 0

T im e (m in )

Ins

uli

n (

pm

ol/

l)

Increased incretin effect after GB ü  Gut hormones (mainly GLP-1) ü  Neural factors ü  Direct nutrient stimuli

Postprandial insulin secretion after RYGB is exaggerated in post-RYGB hypoglycemia

Salehi, et al; JCEM 2014 28

•  Frequent meals low in glycemic index

•  Adding protein and fat to all meals and snacks

•  Modification of source of carbohydrate - fructose instead of glucose

•  Uncooked starch (Extend bar)

•  Not effective in all patients with post-RYGB hypoglycemia

•  Generally combined with other therapeutic options

Dietary Modification First Line Intervention

29

•  Pharmacological Treatments (approved for other indications) –  Acarbose –  Somatostatin analogues –  Diazoxide (symptom relief) –  Calcium Channel Blockers (symptom relief) –  GLP-1 receptor analogue (liraglutide)

•  Investigational Pharmacological Treatments –  XOMA 358 –  GLP-1 receptor antagonist (Exendin 9-39)

Pharmacological Approaches No FDA Approved Rx

30

N=8

Acarbose (alpha-glucosidase inhibitor) Insulin secretion is reduced as a result of lower carbohydrate absorption

Valderas, et al; Obes Surg 2012 31

Glucose Starch Sucrose Maltose

•  Differential effect of on carbohydrate absorption •  GI side effects (abdominal gas, bloating, and diarrhea)

Acarbose

Jenkins, et al; Diabetes 1981 32

0 60 120 180 240 300 0 60 120 180 240 300

•  Suppress insulin secretion both fasting and post-meal •  Reduce GLP-1 secretion •  Suppress glucagon and growth hormone (counter-regulatory hormones) •  Limited by GI side effects (diarrhea) and cost

Case report: Hypoglycemia after RYGB compared with non-surgical controls (n=8)

Octreotide (100mcg) or placebo Before oral glucose ingestion

Glu

cose

(pm

ol/L

)

Insu

lin (p

mol

/L)

Somatostatin Analogues

Myint, et al; Euro J Endocrinol 2012

Time (min) Time (min)

33

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0

3 .0

4 .5

6 .0

7 .5

9 .0

1 0 .5

T im e (m in )

Blo

od

glu

co

se

(m

mo

l/l)

A s y m p to m a tic -G B (2 9 )C o n tro ls (1 1 )

S y m p to m a tic -G B (3 6 )

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 00

4 0 0

8 0 0

1 2 0 0

1 6 0 0

T im e (m in )

Ins

uli

n (

pm

ol/

l)

Increased incretin effect after GB ü  Gut hormones (mainly GLP-1)

Post-prandial insulin secretion after RYGB is exaggerated in post-RYGB hypoglycemia

Salehi, et al; JCEM 2014 34

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 00

7 0

1 4 0

2 1 0

T im e (m in )

GL

P-1

(p

g/m

L)

N o n -s u rg ic a l c o n tro ls

A s y m p to m a tic -R Y G BH y p o g ly c e m ic -R Y G B

L-Cell (ileum)

Proglucagon

GLP-1 [7-37]

GLP-1 [7-36NH2]

Salehi, et al; JCEM 2014

Hypoglycemic patients have larger GLP-1 response compared to those without

GLP-1 levels post-meal are greater after RYGB compared to non-surgical controls

35

Accentuated GLP-1 action contributes to enhanced insulin

secretion after GB in general, and to a greater extent in

patients with hypoglycemia

36

0.5 pmol/kg/min exendin 9-39 500 pmol/kg/min exendin 9-39

Pla

sma

Insu

lin (p

mol

/L)

Pla

sma

Glu

cose

(pm

ol/L

)

Glucose Insulin

0.5 pmol/kg/min exendin 9-39 500 pmol/kg/min exendin 9-39

Exendin 9-39 is a Potent GLP-1r Antagonist GLP-1-induced insulin response is suppressed by Exendin 9-39

1:1000 dose ratio

Edwards et al; Diabetes 1999 37

Exendin 9-39: 500 pmol/kg/min IV

Insulin Glucose

Edwards et al; Diabetes 1999

Endogenous GLP-1 is important in regulation of glucose tolerance

GLP-1-induced insulin secretion is confounded by hyperglycemia

38

2 0

4 0

6 0

8 0(%

)

*

G L P -1 - in d u c e d IS R(p o s tp ra n d ia l)

G B C O N

Salehi, et al; Diabetes 2011

GLP-1-stimulated insulin response to meal ingestion is larger in GB subjects

MTT: Fixed glucose 240-250 mg/dL

39

3 0

5 5

8 0

1 0 5

1 3 0

1 5 5

1 8 0

In tra v e n o u s E x -9 o r s a lin e in fu s io n

M e a l

S a lin eE x -9

Blo

od

glu

co

se

(m

g/d

l) H yp o g ly c em ic -G B


M e a l

S a lin eE x -9

A s ym p tom a tic -G B

-120 -90 -60 -30 0 30 60 90 120 150 1800

300

600

900

1200

1500

1800

Time (min)

Insu

lin (p

mol

/l)

-120 -90 -60 -30 0 30 60 90 120 150 180Time (min)

-120 -90 -60 -30 0 30 60 90 120 150 180Time (min)

Blocking GLP-1r Corrected GB-related Hypoglycemia Through Reduction of Insulin Secretion


M e a l

S a lin eE x -9

C o n tro lsHypoglycemia-GB Asymptomatic-GB Controls

Blo

od g

luco

se (m

g/dL

) In

sulin

(pm

ol/L

)

Salehi, et al; Gastroenterology 2014 40

•  Medical nutrition therapy remains the first line of treatment

•  No approved pharmacological therapy for RYGB-related hypoglycemia •  Current treatments are suboptimal

•  Exendin 9-39 targets underlying pathogenic factor:

à  Increased GLP-1 contribution to insulin secretion

ü  Intravenous infusion of Exendin 9-39 has been shown to correct

hypoglycemia in meal studies

ü  Phase 2 studies with Exendin 9-39 in PBH underway (Eiger)

Summary

41

Exendin 9-39 in

Post-Bariatric Hypoglycemia

COL L E EN M. CRA I G , M .D .

Division of Endocrinology, Metabolism & Gerontology Stanford University School of Medicine

Director, Clinical Development

Eiger BioPharmaceuticals

42

Byetta (exenatide)

Bydureon (exenatide er) GLP-1 Agonist

Exendin 9-39 Well-characterized GLP-1 Antagonist

Exendin 9-39

GLP-1 Antagonist

31-amino-acid fragment of exenatide, a GLP-1 agonist

43

Exendin 9-39 Blocks the GLP-1 Receptor Prevents Dysregulated Secretion of Insulin

44

Study # Patients Duration of dosing Dose Status

Phase 1 Continuous IV infusion

8 Single dose 0.03 mg/kg bolus

+ 0.35 mg/kg

Complete In press: Diabetologia

Phase 2a SAD

SC injection 8 Single dose 0.1 – 0.3 mg/kg

Complete Oral presentation 2016 ADA

Manuscript in draft

Phase 2a MAD SC injection

11 (completed

to date)

Up to 3 days

BID dosing 0.05 - 0.4 mg/kg In progress

3 Clinical Studies of Exendin 9-39 at Stanford 27 Patients Dosed

Over 300 patients are reported to have received exendin 9-39 as an investigational agent worldwide.

45

Exendin 9-39: Phase 1b IV Infusion Study Crossover Design, Placebo-controlled Trial

46

Day 1 OGTT

Day 2 OGTT

Screening & Randomization

Washout 24 hr – 7 day

Ran

dom

izat

ion

Inclusion Criteria: 1) Whipple’s triad 2) Hyperinsulinemia (> 3 uU/mL)

Endpoints: 1°: Prevention of hypoglycemia (≤ 50 mg/dL) 2°: Improvement in symptom score

N = 8

Exendin 9-39: Phase 1b IV Infusion Study Crossover Design, Placebo-controlled Trial

OGTT = oral glucose tolerance test 47

0

50

100

150

200

250

0 30 60 90 120 150 180

Mea

n G

luco

se (m

g/dL

)

Time (minutes)

Placebo (n=8)

Hypoglycemia

Placebo IV Infusion All patients became hypoglycemic

Rapid decline

High peak

All subjects required rescue with IV dextrose

48

0

50

100

150

200

250

0 30 60 90 120 150 180

Mea

n G

luco

se (m

g/dL

)

Time (minutes)

IV Ex-9 (n=8)

Placebo (n=8)

* *

Hypoglycemia

Exendin 9-39: 100% Reversal of Hypoglycemia Phase 1b IV Infusion Study

Hypoglycemia prevented

* P < 0.01

Reduced rate of glucose decline

IV Exendin 9-39 (n=8)

Peak magnitude unchanged

In press: Diabetologia

No patients required rescue with IV dextrose

Dose = 0.38 mg/kg

49

Severity ranked 5-point scale: •  0=none •  5=severe ** **

Subjects surveyed every 30 min for presence of: •  Autonomic symptoms •  Neuroglycopenia •  Malaise

Composite Scores

** P < 0.001

Improved Symptoms of Hypoglycemia Exendin 9-39 Phase 1b IV Infusion Study

Edinburgh Hypoglycemia Symptom Scoring

)

50

Overall Glucose Rise Glucose Fall Placebo 26.5 8.1 24.0 IV Exendin (9-39 4.5 3.1 3.9

0

5

10

15

20

25

30

Sym

ptom

Sco

re

Exendin 9-39: Phase 2a SC SAD Study Single-Ascending Dose Study

51

SC Exendin 9-39 with OGTT Baseline OGTT

Ran

dom

izat

ion

Endpoints: 1°: Prevention of hypoglycemia (≤ 50 mg / dL) 2°: Improvement in hypoglycemia symptom score Pharmacokinetic profile Safety & Tolerability

N=8

Exendin 9-39: Phase 2a SC SAD Study

OGTT = oral glucose tolerance test 52

0

50

100

150

200

250

0 60 120 180

Mea

n G

luco

se (m

g/dL

)

Time (minutes)

Baseline (n=8)

Hypoglycemia

Baseline OGTT: All Patients Became Hypoglycemic Phase 2a SAD SC Exendin 9-39 Study

All subjects required rescue

Rapid decline

High peak

53

Exendin 9-39: All Doses Therapeutic Phase 2a SAD SC Study

0

50

100

150

200

250

0 60 120 180

Mea

n G

luco

se (m

g/dL

)

Time (minutes)

SC Ex-9 (n=8)

Baseline (n=8)

Hypoglycemia

**

* P < 0.05

*

** P < 0.01

Hypoglycemia prevented

Rate of glucose decline reduced

Peak statistically unchanged

Presented at 2016 ADA Manuscript in draft

No patients required rescue with IV dextrose

54


**

*

Exendin 9-39 Reduced Symptoms of Hypoglycemia Phase 2a SAD SC Study

Overall Glucose Rise Glucose Fall Baseline 21.6 11.4 17.5 SC Exendin (9-39) 14.6 12.3 4.0

0

5

10

15

20

25

Sym

ptom

Sco

re

* P < 0.01 ** P < 0.001

55

Exendin 9-39: Phase 2a SC MAD Study Multiple-Ascending Dose Study

56

OGTT = oral glucose tolerance test

N =

16

DAY 4 PK + Safety

Baseline

OGTT DAY 1 SC inj

DAY 2 SC inj

DAY 3 OGTT + SC inj

Purpose: •  To evaluate the efficacy, safety, and PK profile of multi-ascending doses of SC

exendin 9-39 after up to 3 days of treatment •  To determine the lowest effective dose

Exendin 9-39: Phase 2 SC MAD Study Multiple-Ascending Dose Study

0.4 mg/kg

0.3 mg/kg

0.2 mg/kg

0.1 mg/kg

0.05 mg/kg Bro

ader

spe

ctru

m o

f dos

es

57

Dose (mg/kg) 0.05 0.1 0.2 0.3 0.4

# Patients 3 3 1 2 2

% Increase Nadir 11 ± 18 4 ± 5 26 41 ± 17 31 ± 3

Mea

n %

Incr

ease

in

Glu

cose

Nad

ir

Therapeutic Increase in Glucose Nadir For Patients Dosed ≥ 0.2 mg/kg

0

10

20

30

40

0.05 mg/kg 0.1 mg/kg 0.2 mg/kg 0.3 mg/kg 0.4 mg/kg

All patients required rescue

All dose levels reduced magnitude of hypoglycemia

58

Exendin 9-39 Prevented Severe Hyperinsulinemia Fasting Insulin, Fasting Glucose Not Raised: a Targeted Therapeutic Approach

Insu

lin (µ

U/m

L)

Time (min) A

UC

insu

lin (µ

U/m

L m

in)

0

5000

10000

15000

20000

25000

30000

35000

Baseline SC Ex-9

51% reduction in peak insulin

0

50

100

150

200

250

300

350

400

0 30 60 90 120 150 180

baseline SC-ex

59

Exendin 9-39 Improved Symptoms of Hypoglycemia For Patients Dosed ≥ 0.2 mg/kg

Overall Glucose Rise Glucose Fall Baseline 16 12 13 SC-Ex-9 9 8 6

0

5

10

15

20

Sym

ptom

Sco

re


0 1 2 3 4 5 6 7 8

Autonomic Neuroglycopenic

Baseline

SC Ex-9

*

* P < 0.05

Sym

ptom

Sco

re

60

Dog

Pla

sma

of E

xend

in

9-39

(ng/

mL)

Time (h)

800

600

400

200

0 0 2 4 6 8 10 12 14 16 18 20 22 24

Novel Liquid Formulation: Improved Exposure Compared to Original Lyophilized Formulation

To be evaluated in planned Phase 1 PK study in healthy humans To be tested in remaining patients in ongoing MAD study

3x higher Cmax; potential opportunity for lower dosing

Data will inform dosing for planned Phase 2 study

Liquid formulation 0.72 mg/kg Lyophilized powder 0.72 mg/kg

0.72 mg/kg dose in dog = 0.38 mg/kg dose in human 61

Phase 2a SC Exendin 9-39 MAD Study Summary

•  Exendin 9-39 SC administered in doses ranging from 0.05 - 0.4 mg/kg

•  All doses administered were well-tolerated -  Headache and nausea were reported

•  All doses reduced the magnitude of post-prandial hypoglycemia

•  All doses reduced the presence and severity of symptoms of hypoglycemia •  Novel liquid formulation appears to increase Cmax by 3x

-  Potential opportunity for lower dosing

62

Exendin 9-39 Clinical and Regulatory Path to Registration

2015

N=8

N=8

SC Injection SAD

Study

SC SAD Oral Preso

IV Infusion Study

IV Manuscript in Press: Diabetologia

N=16

SC Injection MAD Study

Dosing Now

ADA June 2016

US & EU Orphan Designation

File Eiger IND

2016 2017

Phase 1 PK

Study

Phase 2 Study

Dosing with new liquid formulation planned

63

Acknowledgements

Stanford University McLaughlin Lab Tracey McLaughlin Li-fen Liu Dalia Perelman Marilyn Tan Cindy Lamendola Roger Luong Thi Nguyen Kathryn Weaver Elizabeth Colbert University of Copenhagen Carolyn Deacon Jens Holst Lene Albaek Washington University David Gibson

Eiger BioPharmaceuticals Stanford TRAM Pilot program Dean Felsher Joanna Lilienthal Stanford SPARK program Daria Mochly-Rosen Kevin Grimes KL2 Mentored Career Development Award NIH KL2 TR 001083

64

Q & A

Developing a Treatment for Post-Bariatric Hypoglycemia

Clinical Data and News Flow Phase 2 Results Across All Programs

2016

Lonafarnib: LOWR HDV – 2 Interim (EASL 2016)

Exendin 9-39: SC SAD Study Data (ADA 2016)

Lonafarnib: LOWR HDV EOT Data (AASLD 2016)

Exendin 9-39: SC MAD Interim Data

Lonafarnib: LOWR HDV EOF Data (EASL 2017)

Exendin 9-39: SC MAD Final Data

Lonafarnib: HDV Agency Meeting

Ubenimex: Lymphedema ULTRA Study

Ubenimex: PAH LIBERTY Study

2017

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Developing a Treatment for Post-Bariatric Hypoglycemia

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