targeting chronic inflammation driven by mast cells and
Post on 26-Feb-2022
1 Views
Preview:
TRANSCRIPT
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
*
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
SOURCE:Dellon ES, et al. N Engl J Med. 2020. In Press
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
25
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
SOURCE:Chehade M. EAACI 2019
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
EGD, esophagogastroduodenoscopy
SOURCE:Chehade M. EAACI 2019
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
EGD, esophagogastroduodenoscopy
SOURCE:Chehade M. EAACI 2019
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
All Patients Adults Adolescents Children
Subset of patients (N=1,569) who were not diagnosed on initial EGD
EGD, esophagogastroduodenoscopy
SOURCE:Chehade M. EAACI 2019
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
All Patients Adults Adolescents Children
SOURCE:Chehade M. EAACI 2019
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
All Patients Adults Adolescents Children
SOURCE:Chehade M. EAACI 2019
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)
SOURCE:Chehade M. EAACI 2019
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
top related