ENHANCE: Safety and Efficacy of Seladelpar in Patients With … · 2020. 12. 18. · Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay

Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay Therapeutics and AASLD for reuse.Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay Therapeutics and AASLD for reuse.

ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis Gideon Hirschfield, FRCP, PhDToronto Centre for Liver Disease, University of Toronto@autoimmuneliver

Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay Therapeutics and AASLD for reuse.

Disclosures

Gideon Hirschfield, FRCP, PhD

I disclose the following financial relationship(s) with a commercial interest: • CymaBay Therapeutics• Falk Pharma • Genfit• GSK• Intercept• Morphic Therapeutic• Mirum• Pliant• Roche

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ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis

A PHASE 3 INTERNATIONAL, RANDOMIZED, PLACEBO-CONTROLLED STUDY

Hirschfield GM, Kowdley KV, Shiffman ML, Khazanchi A, Zigmond E, Lawitz EJ, Pratt D, Aspinall R, Forman L, Gordon SC, Gulamhusein AF, Ladron-De-Guevara AL, Levy C, Ryder SD, Stanca CM, Bresky Ruiz C, Gonzalez Huezo MS, Heo J, Leggett BA, Minuk GY, Pagadala MR, Pound D, Raikelson K, Silveira MG, Swain MG, Yimam KK, Younes ZH, Zuckerman E, Corpechot C, Harrison SA, Invernizzi P, Nevens F, Thorburn D, Bowlus C, Dalekos G, Jones D, Kremer AE, Pares A, Vierling JM, Boudes P, Varga M, Choi YJ, McWherter C, Steinberg A, Mayo M

Sponsor: CymaBay Therapeutics, Inc

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Bile duct injury, portal inflammation, cholestasis, progressive liver fibrosis

Chronic, destructive, autoimmune,

cholestatic liver disease

Elevated serum markers of biliary injury:

Alkaline phosphatase (ALP)Total bilirubin

Symptoms including fatigue

and pruritus

Healthy liver

Inflammation Progressive Biliary Fibrosis Cirrhosis

CholestasisEND STAGE

LIVER DISEASE

4

Impaired quality and quantity of life Portal hypertensionLiver failure

Hepatocellular carcinoma

Liver transplantation

Death

1 in 1000 women over 40 years of age live with PBC

Primary Biliary Cholangitis (PBC)


Primary Biliary Cholangitis (PBC)

5

1 in 1000 women over 40 years of age live with PBC

Murillo Perez CF, et al. Am J Gastroenterol. 2020;115(7):1066-1074.

Chronic, destructive, autoimmune,

cholestatic liver disease

Symptoms including fatigue

and pruritus

Bile duct injury, portal inflammation, cholestasis, progressive liver fibrosis

Elevated serum markers of biliary injury:

Alkaline phosphatase (ALP)Total bilirubin

Healthy liver

Inflammation Progressive Biliary Fibrosis Cirrhosis

CholestasisEND STAGE

LIVER DISEASE

Portal hypertensionLiver failure

Hepatocellular carcinoma

Liver transplantation

Death

Impaired quality and quantity of lifeALP and total bilirubin are biochemical surrogates of disease activity that

highlight an individual’s risk of disease progressionTreatment goals recognize the importance of normalizing ALP and total bilirubin

Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay Therapeutics and AASLD for reuse.6

Lindor KD, et al. Hepatology. 2019;69(1):394-419.

Unmet Need Remains Despite Existing TreatmentsOpportunity for new therapy addressing disease activity and symptom burden

UrsodeoxycholicAcid (UDCA)

• 1st-line therapy for PBC

• ~40% are inadequate responders with ALP ≥1.67x ULN

• Additional ~5% are intolerant to therapy

• UDCA therapy does not improve pruritus or other symptoms associated with PBC

1STLINE

Seladelpar is a potentially improved 2nd-line treatment for PBC

Obeticholic Acid(Ocaliva®)

• Add-on therapy for UDCA inadequate responders

• Monotherapy for patients intolerant to UDCA

• ALP/bilirubin as biomarkers for accelerated approval

• ~50% are inadequate responders• Pruritus can worsen or be caused

2ND

LINE


SeladelparThe only potent and selective PPARδ agonist in development for liver disease

Targets all important cell types in liver disease

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Decrease Bile Acids1

Cholesterol synthesis

Bile acid synthesis (C4)

Transport

Anti-fibrotic2

Profibrotic genes

Stellate cell activation

Collagen synthesis/ deposition

Anti-inflammatory1

NFκB-dependent gene activation

Inflammatory cytokines

hs-C-reactive protein

Increase Lipid Metabolism3

Cholesterol/LDL-C

Fatty acid oxidation

Insulin sensitivity

Hepatocyte

Cholangiocyte

Stellate Cell

Kupffer Cell

Macrophage

Hepatocyte

Myocyte

Adipocyte

Enterocyte

PPARδ RXR

Gene Activation or Repression

CH3OHOOC

SO

O

CF3

CH3

Seladelpar

PPARδ, peroxisome proliferator-activated receptor delta.1. Jones D, et al. Lancet Gastroenterol Hepatol. 2017;2(10):716-726. 2. Harrison SA, et al. Poster presented at The Liver Meeting Digital ExperienceTM (TLMdX), American Association for the Study of Liver Diseases; November 13-16, 2020. Poster 1710. 3. Bays HE, et al. J Clin Endocrinol Metab. 2011;96(9):2889-2897.


Placebo

(n=80)

(n=80)

(n=80)

Day 1 Week 52

Long-term Safety Study

ENHANCE Phase 3 Study (Original Design)

Seladelpar 5 mgSeladelpar 10 mg

Seladelpar 5 mg

Seladelpar 10 mg

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ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; ELISA, enzyme-linked immunosorbent assay; ULN, upper limit of normal.Seladelpar was administered orally once daily. Seladelpar or placebo was administered as an add-on to UDCA therapy for patients who tolerated UDCA; for patients with UDCA intolerance, the study drug was administered as a monotherapy.The study was discontinued because of unexpected histological findings that were later determined to be pre-existing in the nonalcoholic steatohepatitis seladelpar program.

• 18 to 75 years old, male or female with a diagnosis of PBC based on any 2 of the following criteria:• History of ALP above 1.0x ULN for at least 6 months• Positive AMA titer (>1:40 on immunofluorescence or M2 positive by ELISA) or positive PBC-specific ANA• Documented liver biopsy results consistent with PBC

• UDCA for the past 12 months (stable dose) OR intolerant to UDCA• ALP ≥1.67x ULN; ALT/AST ≤3x ULN; total bilirubin ≤2x ULN

Key Inclusion Criteria

Week 26


• Intolerance or inadequate response to UDCA• ALP ≥1.67x ULN, bilirubin ≤ 2x ULN• Includes patients with severe pruritus

• Seladelpar 10 mg and 5/10 mg titration vs placebo (1:1:1 randomization)• Stratified by ALP value (<350 U/L vs ≥350 U/L) and pruritus Numerical Rating Scale (NRS) (<4 vs ≥4)

End Points

Design

Enrolled Patients

Placebo Seladelpar 5 mg Seladelpar 10 mgSafety/mITT Population 87 89 89

Month 3 56 56 55

Month 6 23 26 20

Study Population

Primary Endpoint:• Composite responder

rate at Month 3

Secondary Endpoints: • Proportion of patients with ALP ≤ 1.0 x ULN at 6 and 12 months• Change from baseline in pruritus NRS using e-diary at 6 months

Original placebo-controlled, double-blind 52-week study designPrimary Endpoint:• Composite responder

rate at Month 3*

Key Secondary Endpoints: • ALP normalization at Month 3• Change from baseline in pruritus NRS at Month 3

(patients with baseline NRS ≥4)

Other Secondary Endpoints:• Previous 3 endpoints at Month 6Endpoints

9

Blinded analysis after early termination. The safety analysis set included any patient who received at least 1 dose of study drug. The mITT analysis set included any patient randomized and dosed.

ENHANCE Design and Analysis Plan

*Composite responder: ALP <1.67x ULN, ≥15% decrease in ALP, total bilirubin ≤ULN.

Amended Endpoints (No dose titration prior to Month 6)

mITT, modified intention-to-treat.


Female, n (%) 85 (98%) 82 (92%) 83 (93%)Age, years 56 (8) 55 (10) 56 (9)Caucasian, n (%) 80 (92%) 83 (93%) 77 (87%)Duration of PBC, years 8 (6) 8 (6) 8 (6)History of Pruritus, n (%) 57 (66%) 66 (74%) 65 (73%)Pruritus NRS ≥4 27 (31%) 27 (30%) 27 (30%)UDCA Dose, mg/kg/day 15 (3) 16 (4) 15 (4)UDCA Intolerant, n (%) 2 (2%) 6 (7%) 8 (9%)ALP ULN: 116 U/L 293 (106) 290 (104) 291 (109)ALT ULN: 41 U/L 44 (21) 48 (21) 47 (21)AST ULN: 34 U/L 37 (17) 40 (14) 40 (15)GGT ULN: 38 U/L 229 (193) 231 (212) 243 (228)Total bilirubin ULN: 1.1 mg/dL 0.71 (0.32) 0.76 (0.35) 0.72 (0.32)Immunoglobulin M ULN: 230 mg/dL 358 (264) 332 (202) 316 (181)

Seladelpar 10 mg (n=89)


Demographic and Baseline CharacteristicsmITT population

Placebo (n=87)

10

GGT, gamma-glutamyl transferase.Mean (SD) unless otherwise specified.


10.3

47.5

64.6

0

20

40

60

80

100

Month 1

Prop

ortio

n of

Pat

ient

s (%

)

P<0.0001

P<0.0001

P<0.05

(n=78) (n=80) (n=79)

5 mgPlacebo 10 mg

12.5

57.1

78.2

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

P<0.0001

P<0.0001

P<0.05

Month 3

(n=56) (n=55)(n=56)

Month 6

21.7

61.570.0

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

P=0.0006

P=0.002

ns

(n=26) (n=20)(n=23)

78% of patients on seladelpar 10 mg achieved the primary composite endpoint with high statistical significance at 3 months

ALP <1.67x ULN, ≥15% decrease in ALP, total bilirubin ≤ULNPrimary Composite Endpoint Achieved at 3 months

ns, not significant.P values by Cochran-Mantel-Haenszel (CMH) test.CymaBay, Data on File 2020.

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ALP ≤1x ULNKey Secondary Endpoint Achieved: ALP Normalization Rate

05.0

12.7

0

10

20

30

40

50

Prop

ortio

n of

Pat

ient

s (%

)

P=0.0441

P=0.0013

ns

Month 1

(n=78) (n=80) (n=79)

0

11.5

30.0

0

10

20

30

40

50

Prop

ortio

n of

Pat

ient

s (%

)

ns

P=0.0023

ns

Month 6

(n=26) (n=20)(n=23)

27% of patients on seladelpar 10 mgnormalized ALP by 3 monthsP values by CMH test.

CymaBay, Data on File 2020.12

5 mgPlacebo 10 mg

Month 3

Prop

ortio

n of

Pat

ient

s (%

)

ns

P<0.0001

P<0.01

05.4

27.3

0

10

20

30

40

50

(n=56) (n=55)(n=56)

P<0.01


ALP Relative and Absolute Change at Month 3

LS Mean and P values by analysis of covariance (ANCOVA).CymaBay, Data on File 2020.

-3.7

-35.7

-44.2-50

-40

-30

-20

-10

0

LS M

ean

Cha

nge

in A

LP (%

)

P<0.0001

P<0.0001

P=0.0013

(n=56) (n=54) (n=53)

ALP Absolute ChangeALP Relative Change

-2.3

-101

-122-140

-120

-100

-80

-60

-40

-20

0

LS M

ean

Cha

nge

in A

LP (U

/L)

P<0.0001

P<0.0001

P=0.0286

(n=56) (n=54) (n=53)

5 mgPlacebo 10 mg

Significantdose-dependent relative and absolute reductions

in ALP were observedat 3 months

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Patients with baseline ALT >ULNALT Normalization at Month 3

P values by CMH test.CymaBay, Data on File 2020.

17.9

51.7 50.0

0

20

40

60

80

100Pr

opor

tion

of P

atie

nts

(%)

P=0.0102

P=0.0201

ns

Month 3

(n=29) (n=28)(n=28)

5 mgPlacebo 10 mg

In patients with elevated baseline ALTon seladelpar 10 mg

50% normalized ALT by 3 months

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mITT populationMonth 1(n=78)

Month 3(n=56)

Month 6(n=23)

Month 1(n=78)

Month 3(n=54)

Month 6(n=24)

Month 1(n=78)

Month 3(n=53)

Month 6(n=18)

ALT % Change -2.0% -4.0% 2.4% -14% -23% -23% -6% -17% -35%

GGT % Change -6.7% -6.5% 0.1% -28% -30% -24% -34% -36% -37%

AST % Change 1.3% -0.2% 1.4% -6.6% -8.5% -15% 3.8% -4.8% -17%

Total bilirubin % Change -1.3% 0.9% 1.7% -2.8% -6.1% -3.1% -9.9% -4.0% -15%

IgM % Change -2.6% -5.7% -3.4% -5.7% -10% -8.7% -7.3% -12% -12%

Seladelpar 10 mgSeladelpar 5 mgPlacebo

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Month 1, 3, and 6 treatment effects in mITT populationImprovement in Other Serum Liver Tests

Seladelpar demonstrated broad anti-cholestaticand anti-inflammatory effects

IgM, immunoglobulin M.


Patients with baseline NRS ≥4Key Secondary Endpoint Achieved: Treatment Improvement in Pruritus

LS Mean and P values by ANCOVA.CymaBay, Data on File 2020.

-1.14 -1.22

-2.38

-5

-4

-3

-2

-1

0

LS M

ean

Cha

nge

in N

RS

P=0.0111

ns

P=0.0170

(n=26) (n=26) (n=27)

Month 1

-2.47 -2.46

-4.24-5

-4

-3

-2

-1

0

LS M

ean

Cha

nge

in N

RS

ns

ns

ns

Month 6(n=6) (n=9) (n=7)

In patients with moderate and severe pruritus (baseline NRS of 6.2), significant improvements in pruritus were seen with seladelpar 10 mg at 3 months

16

-1.55-2.01

-3.14

-5

-4

-3

-2

-1

0

P=0.0164

ns

ns

Month 3(n=18) (n=17) (n=18)

LS M

ean

Cha

nge

in N

RS

5 mgPlacebo 10 mg


16.7

38.9 42.1

0

20

40

60

80

100

≥4-point Reduction

5.6

22.2

36.8

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

P=0.0183


33.3

50.0

68.4

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

) P=0.0361


Dose-Ordered Reductions in Pruritus NRS Observed at Month 3

Prop

ortio

n of

Pat

ient

s (%

)

P values by CMH test. Non-significant P values not shown.CymaBay, Data on File 2020.

Dose-ordered reductions in NRS were seen at 3 monthsin patients with moderate and severe pruritus

(n=18) (n=18) (n=19) (n=18) (n=19)(n=18) (n=18) (n=19)(n=18)

17

5 mgPlacebo 10 mg

Patients with baseline NRS ≥4


Safety Population, n (%)

Patients with at least 1 AE 64 (73.6) 56 (62.9) 58 (65.2)

Any treatment-related AE 16 (18.4) 25 (28.1) 15 (16.9)

Any treatment-related AE ≥ Grade 3 (CTCAE)* 0 0 0

Any AE with outcome of death 0 0 0

Any SAE 3 (3.4) 3 (3.4) 1 (1.1)

Any treatment-related SAE 0 0 0

Any AE leading to study drug discontinuation 2 (2.3) 2 (2.2) 2 (2.2)

Safety Overview

Placebo (n=87)



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Summary of treatment-emergent adverse events

*No Grade 3 ALT/AST elevations.

AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; SAE, serious adverse event.


Safety Population, n (%)

Abdominal pain upper 3 (3.4) 8 (9.0) 6 (6.7) 14 (7.9)Pruritus 11 (12.6) 3 (3.4) 10 (11.2) 13 (7.3)Nausea 4 (4.6) 5 (5.6) 7 (7.9) 12 (6.7)Headache 1 (1.1) 5 (5.6) 7 (7.9) 12 (6.7)Upper respiratory tract infection 2 (2.3) 6 (6.7) 4 (4.5) 10 (5.6)

Arthralgia 5 (5.7) 5 (5.6) 4 (4.5) 9 (5.1)Constipation 2 (2.3) 5 (5.6) 3 (3.4) 8 (4.5)Urinary tract infection 0 2 (2.2) 5 (5.6) 7 (3.9)Fatigue 8 (9.2) 2 (2.2) 4 (4.5) 6 (3.4)Dry mouth 0 5 (5.6) 1 (1.1) 6 (3.4)Sinusitis 5 (5.7) 2 (2.2) 1 (1.1) 3 (1.7)

Treatment-Emergent Adverse EventsOccurring in ≥5% of patients in any randomized treatment

Placebo (n=87)



Seladelpar Total (n=178)

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Treatment-Emergent Serious Adverse Events

Safety Population, n (%)Patients with at least one serious TEAE 3 (3.4) 3 (3.4) 1 (1.1) 4 (2.2)

Any treatment-related SAE 0 0 0 0List of SAEs by preferred term

Cellulitis 0 0 1 (1.1) 1 (0.6)Pyelonephritis acute 1 (1.1) 0 0 0Cognitive disorder 0 1 (1.1) 0 1 (0.6)Partial seizures 1 (1.1) 0 0 0Leukocytosis 0 1 (1.1) 0 1 (0.6)Adenoid cystic carcinoma 0 1 (1.1) 0 1 (0.6)Rectal polyp 1 (1.1) 0 0 0

Placebo (n=87)



Seladelpar Total (n=178)

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A 52-week Phase 3 global registration study(RESPONSE) to begin enrolling patients in Q1 2021

Safety and Efficacy of Seladelpar in Patients With PBC

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• 78% of patients achieved primary endpoint with 10 mg dose• Seladelpar 10 mg had a statistically significant effect on ALP normalization• Seladelpar 10 mg had a statistically significant reduction in pruritus• 10 mg dose is optimal with consistently greater effects on all endpoints• Overall, seladelpar was generally safe and well tolerated


Argentina Australia AustriaBelgiumCanadaChileFranceGermanyGreeceHungaryIsrael

We gratefully acknowledge the study patients, investigators, site staff, and the ENHANCE team!Acknowledgements

ItalyKoreaMexico Netherlands New Zealand Poland Romania Russia Spain UKUSA

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Thank You

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Documents

ENHANCE: Safety and Efficacy of Seladelpar in Patients With … · 2020. 12. 18. · Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay