Targeting Chronic Inflammation Driven by Mast Cells and

Targeting Chronic Inflammation Driven by Mast Cells and Eosinophils with Lirentelimab (AK002)

Lirentelimab (AK002) Clinical Summary

• Lirentelimab, an anti-Siglec-8 mAb, has demonstrated activity in several inflammatory diseases– Eosinophilic Gastrointestinal Disorders: Eosinophilic gastritis (EG), duodenitis (EoD), esophagitis (EoE)– Mast Cell Gastrointestinal Diseases (MGIDs)– Chronic urticaria– Indolent systemic mastocytosis– Severe allergic conjunctivitis/atopic diseases

• Strong scientific rationale for development of AK002 in additional indications– Asthma, atopic dermatitis, ulcerative colitis, and other diseases

• Studies initiated in 2020– Phase 3 study in eosinophilic gastritis and/or duodenitis– Phase 2/3 study in eosinophilic esophagitis– EGID/MGID prevalence study– AK002 subcutaneous PK/PD/safety study

2

Lirentelimab (AK002) Targets Siglec-8 on Mast Cells and Eosinophils3

Confidential

Mast Cells and Eosinophils Are Key Drivers of Inflammatory Disease4

Tissue damage, fibrosisBronchoconstriction, increased GI motility, pain, itch

T Cell B Cell

ActivatedB Cell

IgE

ACTIVATION AND RECRUITMENT OF OTHERIMMUNE CELLS AND TISSUE INFLAMMATION

Smooth Muscle

Histamine, LTC4, PGD2 and proteases

IL- 4 IL-13

IL- 4 IL-13

HistamineNGF, Histamine

MacrophageEosinophil Neutrophil

IL-5 IL-8 IL-6, TNFa

Allergens

Epithelium

Mast CellNeuron

Sub P

IL-33 TSLP

ECP, MBP, elastase, MMP, TNFa , IL-1b, TGFb

ACUTE AND CHRONIC INFLAMMATIONSENSITIZATION ACUTE AND CHRONIC INFLAMMATIONSENSITIZATION

Sub P

Mast Cells and Eosinophils Contribute to Allergic and Non-Allergic Inflammation

5

ALLERGEN-MEDIATED NON-ALLERGEN-MEDIATED

Eosinophilic Gastrointestinal Diseases (EoE, EG, EoD, EC)

Atopic Dermatitis

Severe Allergic Conjunctivitis (AKC)

Asthma

Severe Allergic Conjunctivitis (PAC, VKC)

Chronic Urticaria

IBD

Indolent Systemic Mastocytosis

IBS

Idiopathic MCAS

IPF

Eosinophil

Mast Cell

MIXED

Clinical Program Highlights MOA and MC / Eosinophil role in Disease6

Key Findings

Eosinophilic Gastrointestinal

Diseases• Positive Phase 2 EG/EoD study: significant histological and clinical improvements• Strong EoE signal

Chronic Urticaria • High response rates in multiple forms of antihistamine-resistant chronic urticaria, including omalizumab-refractory and inducible urticaria

Indolent Systemic Mastocytosis • Substantial symptom and quality of life improvement

Severe Allergic Conjunctivitis

• Substantial reduction of patient reported ocular symptoms and physician assessed signs and symptoms

• Improvements observed in comorbid atopic dermatitis, asthma and rhinitis

Healthy Volunteers• Rapid depletion of eosinophils• Dose-dependent duration of eosinophil depletion

Characterizing Eosinophilic Gastrointestinal Disorders (EGIDs)

7

Eosinophilic Gastrointestinal Disorders (EGIDs)8

EOSINOPHIL THRESHOLD1

Eosinophilic Esophagitis (EoE) ≥15 / hpf

Eosinophilic Gastritis (EG) ≥30 / hpf

Eosinophilic Duodenitis (EoD) ≥30 / hpf

1. Collins et al., 2014. 43(1):257-268 and FDA-accepted diagnostic thresholds defined as number of eosinophils (eos) per high powered field (hpf); 2. Jensen et al., 2016; 62(1):36-42; 3. Dellon and Hirano 2018; 154(2):319-332; 4. Chehade et al., 2018; 6(5):1534-1544; 5. Pineton de Chambrun, et al., 2011; 9(11):950-956

Many patients with EGIDs remain undiagnosed for years4,5, suggesting a high underdiagnosis rate

EG/EoD Patients Endure a Tortuous Path to Diagnosis9

53.6

36.8

36.8

47.2

0 20 40 60

Adults

Adolescents

Children

All patients

Months

(3.9 years)

0%

10%

20%

30%

40%

50%

Unspecifiednon-infectiousgastroenteritis

and colitis

Gastric/pepticulcer

Functionaldyspepsia

Irritable bowelsyndrome

Prop

ortio

n of

pat

ient

sAll patients Children Adolescents Adults

* (3.1 years)

* (3.1 years)

(4.5 years)

Average time from presentation to EG/EoD diagnosis

Common alternative diagnoses prior to confirmed EG/EoD diagnosis

Source: Chehade et al., EAACI 2019 and data on file; *P < 0.01 comparing children or adolescents vs adults

*

** *

*

Factors contributing to diagnostic delay:• Delayed GI referral and endoscopy• Failure to diagnose on first endoscopy• Lack of histopathology evaluation of biopsy samples

Mast Cell and Eosinophil Numbers are Elevated in EGIDs10

AllergenEosinophilMast Cell

SOURCE:Youngblood BA, et al. JCI Insights 2019; Collins MH, et al. Frontiers in Medicine. 2018; Dellon ES, et al. DDW 2019.

HEALTHY

Lumen

Mucosa

Sub-mucosa

BloodVessel

EGIDs

EGID Biopsies Have Elevated Eosinophils & Mast Cells11

Source: Butuci M, et al. DDW 2020.

** p<0.01; *** p<0.001

5

10

15

% o

f CD

45+

Viab

leC

ells

5

10

15** ***

0 0Normal EoE Normal EoE

Esophageal TissueEosinophils Mast Cells

Gastric Tissue

0

4

8

12***

0

5

10

15

20

% o

f CD

45+

Viab

leC

ells

Eosinophils**

Normal EG/EoD Normal EG/EoD

Increased numbers of eosinophils and mast cells are found across EGIDs

Mast Cells

Eos and Mast Cells Are Activated in EGID Biopsies12

CD633000

2000

1000

0

150000

100000

50000

0

IgE8000

4000

2000

0

6000

CD49d60000

40000

20000

0

CD11b

Eosinophils Mast Cells

Normal EG Normal EGNormal EG Normal EG

Source: Youngblood B, et al. JCI Insights. 2019

*p<0.05

Eosinophils and mast cells both appear to play a pathogenic role

Expr

essi

on (M

FI)

ENIGMA Study: AK002 in Eosinophilic Gastritis and/or Eosinophilic Duodenitis

13

ENIGMA Phase 2 Study14

Study Design• Randomized, double-blind, placebo-controlled study in EG/EoD with 4 monthly infusions of

AK002 or placebo• Active moderate to severe symptoms• Biopsy confirmed EG/EoD

– Stomach: ≥30 eos/high powered field (hpf) in 5 hpfs– Duodenum: ≥30 eos/hpf in 3 hpfs

• 65 Patients – 3 arms– 22 patients 0.3, 1.0, 1.0, 1.0 mg/kg AK002– 21 patients 0.3, 1.0, 3.0, 3.0 mg/kg AK002– 22 patients placebo

• 4 monthly doses• Endpoints assessed two weeks after last dose

SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press

Symptoms Assessed Using Validated Patient-Reported Outcome (PRO)

15

- Abdominal pain - Nausea - Vomiting - Early satiety

- Loss of appetite - Abdominal cramping - Bloating- Diarrhea

• Developed in accordance with FDA guidance on PRO development• Captures the symptoms of EG/EoD patients on a daily basis• Measures 8 symptoms each on a scale of 0-10 (Total Symptom Score 80 points):

EG/EoD Questionnaire©

This is the only validated PRO tool for Eosinophilic Gastritis and Eosinophilic Duodenitis


Prespecified Hierarchical Analysis Per Protocol16

Primary Endpoint • Mean percent change in gastrointestinal eosinophil counts from baseline

Responder Secondary Endpoint• Proportion of patients who have:

- >75% decrease in tissue eosinophils AND >30% benefit in Total Symptom Score (TSS)

Symptoms Secondary Endpoint• Mean percent change in TSS from baseline

Endpoints designed to show (1) tissue eosinophil depletion, (2) symptom improvement, and (3) that these effects occur in the same individuals


Primary Endpoint Met for All AK002 Groups17

Treatment Arm

Baseline Eosinophil

Counts / hpf

Mean %∆ in Eosinophil

Countsp - value

High Dose AK002 (n=20) 76 -97% <0.0001

Low Dose AK002 (n=19) 80 -92% <0.0001

Combined AK002 (n=39) 78 -95% <0.0001

Placebo (n=20) 75 +10% -

Confidential


37 of 39 AK002 patients had ≤6 eos/hpf & 31 of 39 patients had 0 eos/hpfNo placebo patients had ≤6 eos/hpf

Stomach/Duodenal Eos ≤ 6/HPF

95%

0%

0%

25%

50%

75%

100%

AK002 Demonstrates Potent Tissue Eosinophil Depletion18

% o

f Pat

ient

s

AK002 Placebo

(0/20)

(37/39)

Confidential

* p <0.0001

*


AK002 Met Treatment Responder Secondary Endpoint19

Treatment ArmTreatment

Responders*p - value

High Dose AK002 (n=20) 70% 0.0009

Low Dose AK002 (n=19) 68% 0.0019

Combined AK002 (n=39) 69% 0.0008

Placebo (n=20) 5% -

*Treatment responder defined as: >75% reduction in tissue eosinophil counts AND >30% reduction in symptoms (TSS)

Confidential


AK002 Met Patient Reported Symptoms Secondary Endpoint20

Treatment Arm

BaselineTotal Symptom

Score (TSS)

Mean % Change in

TSSp - value

High Dose AK002 (n=20) 34 -58% 0.0012

Low Dose AK002 (n=19) 35 -49% 0.0150

Combined AK002 (n=39) 34 -53% 0.0012

Placebo (n=20) 30 -24% -

Confidential


Improvement Across All Symptoms Measured on AK00221

EG/EoD-PRO Symptom ScoresAK002 (n=39)

-1

0

1

2

3

4

5

6

7

AbdominalPain

Nausea Vomiting EarlySatiety

Loss ofAppetite

AbdominalCramping

Bloating Diarrhea

Med

ian

Scor

e

-59%-79%

-100%

-65%-61% -57%

-47%

-55%

BaselineEnd of Tx

Confidential


Response in Concomitant EoE122

Severity of Dysphagia3Esophageal Eos ≤ 6/hpf2

93%

11%

0%

25%

50%

75%

100%

% o

f Pat

ient

s

AK002 Placebo * p <0.001†

*

(1/9)

(13/14)

-53%

-17%

-75%

-50%

-25%

0%

Mea

n %

∆ fr

om B

L

AK002(n=12)

Placebo(n=8)

1 25 patients with concomitant EoE (≥15 eos/hpf or history of EoE) and baseline dysphagia2 Excludes patients with eos < 6/hpf at baseline. At end of treatment, 10/14 AK002 patients had 0 eos/hpf; 2/14 AK002 patients had 1 eos/hpf;

1/14 AK002 patients had 3 eos/hpf; 1/14 AK002 patients had 105 eos/hpf (biopsy occurred 6 weeks post last dose instead of 2 weeks per protocol); 1/9 placebo patients had 2 eos/hpf; 8/9 placebo patients had 19 – 200 eos/hpf

3 All EoE patients with end of treatment dysphagia scores† p = 0.00015


Safety Summary23

Treatment-Emergent AEs in ≥5% of Patients

% of Patients, (n) AK002(n=43)

Placebo(n=22)

Infusion related reaction 60% (26) 23% (5)Headache 9% (4) 9% (2)

Upper respiratory tract infection 9% (4) 9% (2)Urinary tract infection 9% (4) 5% (1)

Nausea 7% (3) 14% (3)Fatigue 7% (3) 9% (2)

Diarrhea 5% (2) 9% (2)Nasopharyngitis 5% (2) 9% (2)Abdominal pain 2% (1) 9% (2)

Dehydration 2% (1) 9% (2)Gastroenteritis viral 2% (1) 9% (2)

Pyrexia 2% (1) 9% (2)Sinusitis 2% (1) 9% (2)

Cough 0% (0) 9% (2)Influenza 0% (0) 9% (2)

White blood cell count increased 0% (0) 9% (2)

• Generally well tolerated • Most common Adverse Event (AE) was

mild to moderate infusion related reactions (IRR)– 93% mild to moderate (flushing, feeling of

warmth, headache, nausea, dizziness)– Mostly on first infusion, greatly reduced or

does not occur on subsequent infusions– 1 drug-related serious adverse event, an IRR

which recovered within 24 hours with no further sequelae

• Treatment-emergent serious AEs: 9% on AK002, 14% on Placebo

• No other significant AEs


ENIGMA Summary24

• This was the first randomized study in eosinophilic gastritis and duodenitis• Study met all primary and secondary endpoints, demonstrating significant

histologic and symptom improvements in EG/EoD• Strong histologic and symptom improvement in EoE• Generally well-tolerated• These results build on clinical activity of AK002 observed in chronic

urticaria, severe allergic conjunctivitis, asthma, atopic dermatitis, and indolent systemic mastocytosis

Patients with EG/EoD Endure a Tortuous Path to Diagnosis

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Steps Required for Diagnosis of EG/EoDConfidential

26

Presentation Endoscopy with biopsies

Histopathologicevaluation

Diagnosis of EG/EoD

• Nonspecific symptoms and signs

• History of EoE, allergic disease, and/or peripheral eosinophilia increase clinical suspicion

• EGD• Multiple biopsies

from stomach and duodenum

• Standard H&E• Quantification of

eosinophils

• ≥30 eosinophils per hpf

• Rule out other causes of tissue eosinophilia (e.g. parasitic infection)

Unlike for EoE, there are no standardized diagnostic guidelines for eosinophilic gastritis (EG) or eosinophilic duodenitis (EoD)

EG/EoD Patients Endured a Diagnostic Delay of ~4 YearsConfidential

27

36.4

33.9

48.6

43.7

0 12 24 36 48 60

Children

Adolescents

Adults

All Patients

Mean months

Diagnosis

(3.7 years)

(4.1 years)

Presentation

(3.0 years)

(2.8 years)

SOURCE:Chehade M. EAACI 2019

Substantial Delay Between Required Diagnostic StepsConfidential

28

6.0

4.8

9.5

8.1

13.3

11.9

12.8

12.9

17.1

17.1

26.3

22.8

36.4

33.9

48.6

43.7

0 12 24 36 48 60

Children

Adolescents

Adults

All Patients

Mean months

Gastroenterologist

Index EGD

Diagnosis

(3.7 years)

(4.1 years)

Presentation

(3.0 years)

(2.8 years)

EGD, esophagogastroduodenoscopy


About 40% of Patients Were Not Diagnosed on Index EGDConfidential

29

62% 62% 64% 62%

38% 38% 36% 38%

0%

10%

20%

30%

40%

50%

60%

70%

80%

All patients Adults Adolescents Children

Perc

enta

ge o

f Pat

ient

s

Diagnosed on index EGD Diagnosed on repeat EGD



Patients Requiring Repeat EGD Endured Longer Dx DelayConfidential

30

3.0 3.42.3 2.4

4.6 5.1

3.7 4.0

0

1

2

3

4

5

6

All Patients Adults Adolescents Children

Mea

n ye

ars

Diagnosed on index EGD Diagnosed on repeat EGD

+1.6+1.7

+1.4+1.6



Patients Do Not Always Undergo Biopsy and HistopathologyConfidential

31

92%74%

88%

64%

97%86%

98%89%

0%

20%

40%

60%

80%

100%

Biopsy Histopathology

Perc

enta

ge o

f Pat

ient

s


Subset of patients (N=1,569) who were not diagnosed on initial EGD



EG/EoD Patients Present With Nonspecific GI SymptomsConfidential

32

0%10%20%30%40%50%60%70%80%90%

100%

Abdominal Pain Vomiting Diarrhea Nausea WeightLoss/Failure to

Thrive

GastrointestinalBleeding

Gas/Bloating

Perc

enta

ge o

f Pat

ient

s



About Half of Patients Received Alternative Diagnoses Prior to Diagnosis of EG/EoD

Confidential

33

0%

10%

20%

30%

40%

50%

60%

Any AlternativeDiagnosis

OtherGastroenteritis

FunctionalDyspepsia

Peptic Ulcer Irritable BowelSyndrome

Perc

enta

ge o

f Pat

ient

s



This Study Identified Several Reasons for Diagnostic Delay and Provides Tools to Aid in Prompt Diagnosis

Confidential

34

Presentation Endoscopy with biopsies

Histopathologicevaluation

Diagnosis of EG/EoD

• Delayed referral to gastroenterologist

• Lack of thorough diagnostic workup

• Colonoscopy only

• Non-specific symptoms and signs

• History of EoE, allergic disease, and/or peripheral eosinophilia increase clinical suspicion

• EGD• Multiple biopsies

from stomach and duodenum

• Standard H&E• Quantification of

eosinophils

• No collection of biopsies

• Biopsy samples not sent to pathology lab

• No quantification of eosinophils• Number and location of biopsies

insufficient to capture elevated eosinophilic infiltration due to patchy nature

X X X

• ≥30 eosinophils per hpf

• Rule out other causes of tissue eosinophilia (e.g. parasitic infection)


Conclusions35

• The journey to diagnosis for EG/EoD patients is long and tortuous

• Factors leading to delay in diagnosis– Lack of diagnostic criteria– Delay in referral to a gastroenterologist– Failure to diagnose on first endoscopy– Lack of routine histopathology evaluation

• Heightened disease awareness and standardized EG/EoD diagnostic criteria are needed

Allakos is conducting two clinical studies to test the safety and efficacy of experimental drug AK002 for eosinophilic gastrointestinal diseases (EGIDs)

EOSINOPHILIC GASTRITIS AND/OR EOSINOPHILIC DUODENITIS (EG/EOD)Eosinophilic gastritis (EG) and/or eosinophilic duodenitis (EoD), sometimes referred to as eosinophilic gastroenteritis or EGE, are chronic, inflammatory diseases characterized by high levels of mast cells and eosinophils (two types of immune system cells) in the stomach (gastritis) and/or the upper part of the small intestines known as the duodenum (duodenitis). This study will test whether AK002 can reduce eosinophils in the blood and the tissue of the stomach and/or duodenum and help improve symptoms. If you have been diagnosed with, or think you may have EG and/or EoD, you may be eligible for this study.

If you experience persistent gastrointestinal symptomslike:

Abdominal pain Nausea/Vomiting

DiarrheaEarly fullness when eating

Cramping

Bloating

Loss of appetite

You may have Eosinophilic Gastritis and/or EosinophilicDuodenitis

(EG and/or EoD)

WHO ISELIGIBLE

Females and males, age 18 to 80 years old who have a confirmed diagnosis of EG and/or EoD AND/OR have ongoing gastrointestinal symptoms

PARTICIPATIONDETAILS

• There is no cost to participate• Qualified participants will receive drugs, lab tests and medical care related to

the study at nocost• Participants are eligible for compensation to cover the cost of timeand travel• Learn more at www.clinicaltrials.gov –NCT#04322604

If youexperience symptomslike:

Difficulty swallowing Painful swallowing

Feeling like food isstuck after swallowingYou may have

Eosinophilic Esophagitis (EoE)

TO LEARN MORE ABOUT THESE STUDIES, OR TO LOCATE YOUR NEAREST STUDY CENTER, CALL: 1.833.209.8331

EOSINOPHILIC ESOPHAGITIS(EoE)Eosinophilic esophagitis (EoE) is a chronic, inflammatory disease characterized by high levelsof mast cells and eosinophils (two types of immune system cells) in the esophagus(muscular tube

connecting the mouth to the stomach).This study will test whetherAK002 can reduceeosinophils in the blood and the tissue of the esophagus and help improve symptoms. If youhave been

diagnosed with, or think you may have EoE, you may be eligible for this study.

WHO IS ELIGIBLE

Females and males, age 12 to 80 years old who have a confirmed diagnosis of EoE AND/OR have difficulty swallowing or discomfort when swallowing

PARTICIPATIONDETAILS

• There is no cost to participate• Qualified participants will receive drugs, lab tests and medical care related to

the study at nocost• Participants are eligible for compensation to cover the cost of timeand travel• Learn more at www.clinicaltrials.gov –NCT#04322708

AK002_0002_V1_20200617

http://www.clinicaltrials.gov/

http://www.clinicaltrials.gov/

Documents

Targeting Chronic Inflammation Driven by Mast Cells and