Etrasimod, a Novel, Oral, Selective Sphingosine 1

ACKNOWLEDGEMENTS AND DISCLOSURES: EGY has acted as a consultant for and received grants/honoraria from AbbVie; Anacor; Celgene; Celsus Therapeutics; Dermira; Galderma; Glenmark; Janssen Biotech; LEO Pharmaceuticals; MedImmune; Novartis; Pfizer; Regeneron Pharmaceuticals, Inc.; Sanofi; Stiefel/GlaxoSmithKline; Vitae; Mitsubishi Tanabe; Eli Lilly & Co; Asana Biosciences; and Kiowa Kirin; has acted as an investigator for Celgene; Glenmark; Leo Pharmaceuticals; MedImmune; Regeneron Pharmaceuticals, Inc; and Eli Lilly & Co; and has participated in advisory boards for Celgene; Celsus Therapeutics; Dermira; Galderma; Glenmark; MedImmune; Novartis; Pfizer; Regeneron Pharmaceuticals, Inc.; Sanofi; Stiefel/GlaxoSmithKline; Vitae; and Asana Biosciences. RB is a consultant with honoraria for AbbVie, Arena, Boehringer-Ingelheim, CARA Therapeutics, Kyowa Kirin, Pfizer and Respivant; an investigator with grants/research funding for AbbVie, Arcutis, Arena, Asana BioSciences, Bellus, Boehringer-Ingelheim, CARA Therapeutics, Eli Lilly, Incyte, Pfizer, RAPT and Sanofi Genzyme; an advisor with honoraria for Arena, Eli Lilly, Galderma, Incyte, LEO Pharma, Pfizer and RAPT. R Bissonnette is also an employee and shareholder of Innovaderm Research. LK reports personal fees as a speaker from Sanofi, grants from Arena and grants and personal fees as a consultant or speaker from AbbVie, Arcutis, Dermavant, Dermiera, Incyte, LEO Pharma, Lilly, Novartis, Ortho Dermatologies, Pfizer, and Regeneron. DM has received grants as investigator and honoraria as advisor for Galderma, Sanofi, Anacor, Pfizer, Menlo, Pierre Fabre, and GlaxoSmithKline and has also served as an investigator for Regeneron and Medimmune. GA, AS, and KL are full-time employees of Arena Pharmaceuticals, Inc. JS has acted as a consultant for and/or received grants/honoraria from AbbVie; AnaptysBio; Asana Biosciences; LLC; Eli Lilly & Co; Galderma Research & Development, LLC; GlaxoSmithKline, Glenmark Generics, Inc.; Kiniksa Pharmaceuticals, Ltd; Leo Pharma, Inc.; Medimmune; Menlo Therapeutics; Pfizer, Inc.; PuriCore, Inc.; Regeneron Pharmaceuticals, Inc.; and Sanofi.The study was supported by Arena Pharmaceuticals, Inc. The authors and Arena Pharmaceuticals were responsible for the analysis and decision to submit the abstract. All authors critically reviewed the abstract and approved the final version for submission. Medical writing and editorial support was provided by Ellen Mercado, PhD, Health Interactions, which was funded by Arena Pharmaceuticals, Inc.

Etrasimod, a Novel, Oral, Selective Sphingosine 1-Phosphate Receptor Modulator, Improves Patient- and Clinician- Reported Outcomes in Adults With Moderate-to-Severe Atopic Dermatitis in a Randomized, Double-Blind Placebo-Controlled Phase 2 Study (ADVISE)

Emma Guttman-Yassky,1 Robert Bissonnette,2 Leon Kircik,1,3 Dedee Murrell,4 Andrew Selfridge,5 Kris Liu,5 Gurpreet Ahluwalia,5 Jonathan Silverberg6

1Icahn School of Medicine at Mount Sinai, New York, New York; 2Innovaderm Research, Montreal, Quebec; 3Indiana University Medical Center, Indianapolis; Physicians Skin Care, Louisville, Kentucky; DermResearch, PLLC, Louisville; and Skin Sciences, PLLC, Louisville, USA; 4Department of Dermatology, St George Hospital, Faculty of Medicine, University of New South Wales, Sydney, Australia; 5Arena Pharmaceuticals, Inc., San Diego, CA; 6Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC

An electronic version of this poster may be obtained by scanning this QR code with your smartphone app.Presented at the Revolutionizing Atopic Dermatitis (RAD) Conference

June 13, 2021

BACKGROUNDFigure 1. S1P1 Modulation With Etrasimod May Interrupt Multiple Pathways That Mediate Acute and Chronic Disease Phases of AD

3

Acute Disease: Th2 Inflammation

Chronic Disease: Heterogeneous Th1/Th2/Th17 Inflammation

3

Etrasimod

Etrasimod

2

1 4

Etrasimod

Etrasimod Disrupts Immune Cell Trafficking(Based on Preclinical Data)1

Downstream Functional Outcomes(Based on Preclinical Data)1

Reduced circulating lymphocytes:S1P1 modulation selectively reduces migrationof lymphocytes from lymph nodes2,3 leading to fewer immune cells available to traffic to the skin, including T cells, B cells, and eosinophils

Reduced trafficking of dendritic cells from skin to lymph node:reduced activation of T cells in lymph node

By broadly limiting T cell trafficking, both Th2 and Th1 tissue cytokines were decreased, including IL-4 and IFN

Etrasimod potential overall disease outcome: May decrease inflammation and lower histological score

AD, atopic dermatitis; S1P1, sphingosine 1-phosphate receptor 1.

ETRASIMOD CLINICAL DEVELOPMENT y The Phase 2 ADVISE study4 of etrasimod was the first to evaluate S1P receptor modulation as a potential mechanism for

treatment of patients with moderate-to-severe atopic dermatitis – This study was designed to assess for clinical efficacy as well as tolerability, and provide dose support for moving to the next development phase

y Etrasimod is a once-daily, oral S1P1,4,5 modulator being evaluated in global Phase 3 trials in moderate-to-severe ulcerative colitis (UC)4 following demonstration of safety and efficacy in a Phase 2 trial in UC5

– Etrasimod is also under investigation for other immune-mediated inflammatory conditions, including alopecia areata,4 eosinophilic esophagitis,6 and Crohn’s disease4

S1P, sphingosine 1-phosphate; S1P1,4,5, S1P receptor 1,4,5.

Figure 2. Etrasimod Phase 2 Trial for ADA PHASE 2 PLACEBO-CONTROLLED, DOSE FINDING TRIAL TO ASSESS THE SAFETY AND EFFICACY OF ETRASIMOD IN PATIENTS WITH MODERATE-TO-SEVERE AD STUDY ENROLLED 140 PARTICIPANTS IN SITES ACROSS THE US, CANADA, AND AUSTRALIA

5

DAY 1 WEEK 16

Screening Period

12-Week Treatment Period

Follow-upPeriod

WEEK 12

4-WeekFollow-up visit

Etrasimod 2 mg

Etrasimod 1 mg

Placebo

≤ 4 Weeks

R

WEEK 68

52-Week Open-Label Extension Period (ongoing)

WEEK 72

Follow-upPeriod

4-WeekFollow-up visit

Etrasimod 2 mgCompleters

1:1:1

AD, atopic dermatitis; NRS, numerical rating score. Clinicaltrials.gov NCT04162769, Data on File.

INCLUSION CRITERIA y Male and female participants 18–70 years of age

y Eczema Area and Severity Index (EASI) ≥16 at baseline

y Validated Investigator Global Assessment (vIGA) ≥3

y Body Surface Area (BSA) ≥10%

PRIMARY ENDPOINT y Percent change in EASI from baseline to Week 12

KEY SECONDARY ENDPOINT y Proportion of participants with a vIGA of 0 or 1 and reduction from baseline of ≥2 points at Week 12

PATIENT-REPORTED OUTCOMES y Percent change in weekly peak pruritus NRS at Week 12

y Change in Dermatology Life Quality Index (DLQI) from Baseline to Week 12

y Change in Patient-Oriented Eczema Measure (POEM) from Baseline to Week 12

RESULTSTable 1. Demographics and Clinical CharacteristicsFULL ANALYSIS SET (N=140)

Placebo (n=46)

Etrasimod 1 mg (n=47)


All (N=140)

Age (years), mean (SD) 44.1 (16.2) 41.7 (13.3) 41.8 (14.8) 42.5 (14.7)

Sex, female, n (%) 27 (58.7) 30 (63.8) 29 (61.7) 86 (61.4)

Race, n (%)

White 31 (67.4) 27 (57.4) 26 (55.3) 84 (60.0)

Asian 2 (4.3) 2 (4.3) 3 (6.4) 7 (5.0)

Black or African American 11 (23.9) 15 (31.9) 18 (38.3) 44 (31.4)

Other Combined* 2 (4.4) 3 (6.4) 0 (0) 5 (3.5)

EASI, mean (SD) 25.7 (10.6) 25.6 (8.5) 25.5 (10.6) 25.6 (9.9)

vIGA, n (%)

3 = Moderate 39 (84.8) 38 (80.9) 39 (83.0) 116 (82.9)

4 = Severe 7 (15.2) 9 (19.1) 8 (17.0) 24 (17.1)

BSA AD Involvement (%), mean (SD) 30.9 (17.9) 38.8 (24.6) 33.2 (20.4) 34.3 (21.2)

Peak Pruritus NRS, mean (SD) 7.6 (2.0) 8.0 (2.2) 8.2 (1.8) 7.9 (2.0)

*Other Combined comprises American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and Other.AD, atopic dermatitis; BSA, body surface area; EASI, Eczema Area and Severity Index; NRS, numerical rating score; vIGA, validated Investigator Global Assessment.

Figure 3. Proportion of Participants Achieving vIGA Success Over Time and at Week 12vIGA 0 or 1 and Reduction From Baseline of ≥2 Points

40

30

Part

icip

ants

With

vIG

A 0

or 1

(%)

Placebo (n=46)1 mg etrasimod (n=47)2 mg etrasimod (n=47)

WeeksFAS, CMH, NRI

20

10

00 1 2 4 6

*

8 12

40

30

Part

icip

ants

With

vIG

A 0

or 1

(%)

Week 12FAS, CMH, NRI

2013.0%

Placebo Etrasimod 1 mg Etrasimod 2 mg

14.9%

*29.8%

10

0

* P<0.05 vs placebo.CMH, Cochran-Mantel-Haenszel; FAS, Full Analysis Set; NRI, non-responder imputation; vIGA, validated Investigator Global Assessment.

Figure 4. Improvement in Weekly Peak Pruritus NRSPercent Change in Weekly Peak Pruritus NRS

Achievement of ≥4-Point Improvement in Peak Pruritus NRS at Week 12

20

0

Perc

ent C

hang

e Fr

om B

asel

ine

in W

eekl

y PP

-NR

S (L

SM ±

SE)

WeeksFAS, MMRM

-20

-40

-600 1 2

*#

*# *

## #

4 6 8 12


50

40

30

Part

icip

ants

With

≥4-

Poin

tR

educ

tion

in W

eekl

y PP

-NR

S (%

)

Week 12FAS†, NRI

20

27.0%


32.5%

*42.1%

10

0

*P<0.05 etrasimod 2 mg vs placebo.#P<0.05 etrasimod 1 mg vs placebo.FAS, Full Analysis Set; LSM, least squares mean; MMRM, mixed model repeated measures; NRI, non-responder imputation; NRS, numeric rating scale; PP-NRS, peak pruritus NRS; SE, standard error. Peak pruritus NRS is the average for peak (worst) NRS over the previous 7 days from the participant’s diary. Baseline is the NRS value at baseline visit. †Among patients with baseline PP-NRS ≥4.

Figure 5. Improvement in DLQI

Change in DLQI Over Time

Achievement of ≥4-Point Improvement in DLQI at Week 12

0

-2

-4

Cha

nge

From

Bas

elin

ein

DLQ

I (LS

M ±

SE)

WeeksFAS, MMRM

-6

-8

-100 1 2 4 6 8 12

*


100

80

60

Part

icip

ants

With

≥4-

Poin

tR

educ

tion

in D

LQI (

%)


40

55.6%


64.4%

*69.8%

20

0

*P<0.05 etrasimod 2 mg vs placebo.CMH, Cochran-Mantel-Haenszel; DLQI, Dermatology Life Quality Life Index; FAS, Full Analysis Set; LSM, least squares mean; MMRM, mixed model repeated measures; NRI, non-responder imputation; SE, standard error.

Figure 6. Improvement in POEMChange in POEM Over Time

Achievement of ≥4-Point Improvement in POEM at Week 12

0

Cha

nge

From

Bas

elin

ein

PO

EM (L

SM ±

SE)

WeeksFAS, MMRM

-5

-100 1 2 4 6 8

##

**

##

*#

#

##

12


100

80

60

Part

icip

ants

With

≥4-

Poin

tR

educ

tion

in P

OEM

(%)


40 37.0%


##

61.7%*

58.7%

20

0

*P<0.05 etrasimod 2 mg vs placebo.**P<0.01 etrasimod 2 mg vs placebo.#P<0.05 etrasimod 1 mg vs placebo.##P<0.01 etrasimod 1 mg vs placebo.CMH, Cochran-Mantel-Haenszel; FAS, Full Analysis Set; LSM, least squares mean; MMRM, mixed model repeated measures; NRI, non-responder imputation; POEM, Patient-Oriented Eczema Measure; SE, standard error.

Table 2. Overall Summary of Adverse Events in ≥5% of Participants in any Treatment Group Placebo (n=46)



Participants with any TEAE* 22 (47.8) 19 (40.4) 28 (59.6)Treatment-emergent adverse events, n (%)

Nausea 2 (4.3) 1 (2.1) 3 (6.4)Constipation 0 (0) 0 (0) 3 (6.4)Urinary tract infection 3 (6.5) 0 (0) 3 (6.4)Back pain 1 (2.2) 0 (0) 3 (6.4)Dizziness 1 (2.2) 2 (4.3) 3 (6.4)Headache 4 (8.7) 1 (2.1) 0 (0)

Atopic dermatitis 4 (8.7) 0 (0) 2 (4.3)

≥1 serious adverse event, n (%) 0 (0) 0 (0) 0 (0)*There were 8 CTCAE Grade 1-3 TEAEs of lymphocyte decrease in the etrasimod groups: one in 1 mg and 7 in the 2 mg group which are not shown in the table. Lymphocyte count decrease is an on-target effect of etrasimod and the means by which the investigational drug potentially confers therapeutic benefit. Therefore, these lymphocyte-related AEs have not been included in the TEAE list. AE, adverse event; CTCAE , Common Terminology Criteria for Adverse Events; TEAE, treatment-emergent AE.

SUMMARY/CONCLUSIONS

Etrasimod 2 mg improved both patient- and clinician-assessed outcomes vs placebo over 12 weeks

Treatment with etrasimod 2 mg resulted in significantly greater proportions of participants achieving a vIGA score of 0 or 1 (clear or almost clear), DLQI, and POEM at Week 12 compared with placebo

Etrasimod was well tolerated in patients with atopic dermatitis and the safety profile was consistent with previous trials. There were no serious adverse events in the study

These results support the rationale of S1P1 modulation as a potential new mechanism of action and oral treatment for atopic dermatitis and warrants further investigation in Phase 3 clinical trialsDLQI, Dermatology Life Quality Index; POEM, Patient-Oriented Eczema Measure; S1P1, sphingosine 1-phosphate receptor 1; vIGA, validated Investigator Global Assessment.

REFERENCES: 1. Crosby C, et al. Br J Dermatol; 2020;183(4):e103; 2. Peyrin-Biroulet L et al. Autoimmune Rev. 2017;16:495-503; 3. Olivera P et al. Gut. 2017;66:199-209; Image adapted from: Leung DY, Guttman-Yassky E. J Allergy Clin Immunol. 2014;134(4):769-779. 4. Clinicaltrials.gov NCT03945188, NCT03996369, NCT03950232, NCT04173273, NCT04162769, NCT04556734. 5. Sandborn, et al. Gastroenterology. 2020;158:550-561. 6. https://www.arenapharm.com/pipeline (accessed Dec. 3, 2020).

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Etrasimod, a Novel, Oral, Selective Sphingosine 1