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Treatment Efficacy and Safety of Low Dose Seladelpar a Selective PPAR-δ Agonist, in Patients with Primary Biliary Cholangitis:

12-week Interim Analysis of an International, Randomized, Dose Ranging, Phase 2 Study

Hirschfield G., Bowlus C., Harrison S., Galambos M., Borg B., Gordon S., Gitlin N., Hassanein T., Odin J., Bacon B., Bernstein D., Vierling J., Steinberg A., Choi Y.-J., Varga M., Martin R., McWherter C., Boudes P., Jones D., for the Seladelpar Low Dose Study Group Investigators.

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Chronic non-suppurative destructive cholangitis

1 in 1000 women over the age of 40 are estimated to have PBC

PBC is a Significant Cause of Chronic Liver Injury

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Significant need for:(1) Rational, targeted next-generation therapy(2) Improved efficacy(3) Better tolerance

▲First line therapy for PBC

▼~40% inadequate responders: AP >1.67x ULN

▼Additional 5% are intolerant to therapy

▼Lacks defined mechanism (dosed in grams)

▲Combination therapy for UDCA inadequate responders

▲Monotherapy for UDCA intolerant patients

▲Established AP/bilirubin as biomarker for accelerated approval

▼~50% inadequate responders

▼Can cause or worsen pruritus

▼Dose adjustment in hepatic impairment

Current Licensed Therapies for PBC Remain Limited

Ursodeoxycholic Acid (UDCA) 1st Line

Obeticholic Acid (Ocaliva)2nd Line

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Fibrosis

Immune Response

Cholestasis

Patients Exhibit a Persistent Cycle of Injury

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Bile acid homeostasis cholesterol synthesis

bile acid synthesis (C4)

transport

Fibrosis Connective Tissue Growth

Factor (CTGF)

stellate cell activation

collagen deposition

Inflammation NFκB-depend. gene activation

inflammatory cytokines

hs-C-Reactive Protein (CRP)

Metabolic Benefits LDL-C

cholesterol

lipids and increase in insulin sensitivity

Seladelpar: Once Daily Oral PPAR-δ Agonist for Inflammatory Liver Diseases

RXRPPAR-δ

Gene Activationor Repression

S

Hepatocyte

Hepatocyte

Kupffer cell

Stellate cell

Cholangiocyte

Human PPAR-δ EC50 = 2 nM600-fold selective over PPAR-α

Inactive against PPAR-γ

OHO

O

S OO

CF3

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AASLD 2016: Proof-of-Concept in High Dose Study Benefit/risk supported rationale for lower dose study

T i m e ( m o n t h s )

Me

an

AP

(U

/L)

0

1 0 0

2 0 0

3 0 0

1 . 6 7 x U L N

U L N

L L N

0 1 2 3

Efficacy: Alkaline Phosphatase

Ch

an

ge

fr

om

Da

y 1

(%

)

- 8 0

- 6 0

- 4 0

- 2 0

0

2 0

4 0 p = 0 . 0 0 6 0

p = 0 . 0 0 2 2

N S

Mechanism: Bile Acid Synthesis (C4)

Safety: Study stopped after 3 reversible asymptomatic transaminase elevations

Placebo50 mg200 mg

Jones et al. (2017) Lancet GE&H

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Phase 2 Low Dose Study in PBCOpen label, randomized, dose ranging

Seladelpar 10 mg qd (n = 12)

Seladelpar 5 mg qd (n = 12)

Seladelpar (5, 10 or 25 mg)

Seladelpar 25 mg qd (n = 12)

12 Week InterimAnalysis

Seladelpar (5, 10 or 25 mg)

18 weeks

Seladelpar (5, 10 or 25 mg)

Main

Main Extension (Option for Dose Adjustment)

Extension (Option for Dose Adjustment)

18 weeks

AP ≥ 1.67 x ULN; ALT/AST ≤ 3 x ULN; Total Bilirubin ≤ 2 x ULN *

* UDCA therapy for prior 12 months

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Baseline Characteristics: High Risk Population

Parameters (normal range) Seladelpar 5 mg Seladelpar 10 mg

n 12 12

Age 58 (9) 54 (10)

Sex F/M 12/0 11/1

UDCA inadequate/intolerant 11/1 11/1

AP (37 - 116 U/L) 356 (180) 260 (60)

GGT (7 - 38 U/L) 220 (144) 257 (158)

ALT (6 - 41 U/L) 39 (19) 52 (27)

Total bilirubin (0.1 - 1.1 mg/dL) 0.65 (0.11) 0.84 (0.35)

Albumin (3.5 - 5.5 g/dL) 3.9 (0.4) 4.1 (0.4)

Platelets (140 – 400 x 103/µL) 211 (78) 222 (65)

LDL-C (50 - 130 mg/dL) 139 (26) 153 (44)

Safety population, Mean (SD), Baseline: mean of screening(s) and Day 1 Phase 2 Low Dose Study in PBC

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Time (weeks)%

Cha

nge

in A

P fro

m B

asel

ine

0 2 4 6 8 10 12

-50

-40

-30

-20

-10

0

5 mg, n=12 (except Week 12, n = 11)10 mg, n=11 (except Week 1, n = 10)

-39%

-45%

5 mg and 10 mg Doses Both Result in Rapid and Robust Decreases in AP

Mean percent AP change from baseline to Week 12

Mean ± SE

Phase 2 Low Dose Study in PBC

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Comparable Substantial Decrease in Absolute AP at Both Doses

Mean absolute AP changes from baseline to Week 12

T i m e ( M o n t h s )

LS

Me

an

Ch

an

ge

in

AP

(U

/L)

- 1 5 0

- 1 0 0

- 5 0

0

1 2 3 1 2 3

5 m g 1 0 m g

5 mg n = 12 (except for Month 3, n = 11)10 mg n = 11 LS Mean ± SELS = Least Squares

No statistical differences between dosegroups

Phase 2 Low Dose Study in PBC

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At 12 Weeks Notable Proportion of Patients with AP < 1.67 ULN or ≤ ULN

45% of patients on 5 mg < 1.67 x ULN 82% of patients on 10 mg < 1.67 x ULN Nearly half of patients on 10 mg had normal AP at Week 12

n = 12 each for mean AP at baseline

Seladelpar Mean AP Baseline

Mean AP Change

Week 12AP < 1.67 x ULN AP ≤ ULN

5 mg (n = 11) 356 U/L -39% 45% 18%

10 mg (n = 11) 260 U/L -45% 82% 45%

Phase 2 Low Dose Study in PBC

AP responders from baseline to Week 12

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Additional Anti-cholestatic and Anti-inflammatory Effects

ParameterPercent change from baseline*

5 mg (n = 11) 10 mg (n = 11)

GGT -28 (28) -39 (25)

Total Bilirubin -3 [-24,2] -8 [-15,7]

ALT -11 (42) -35 (20)

LDL-C -14 (11) -14 (9)

hs-CRP -14 [-43,17] -27 [-46,22]

Reduces cholestasis

Decreases transaminases

Decreases LDL-cholesterol

Reduces inflammation

* Mean (SD), except Median [inter-quartile range] for Total Bilirubin and hs-CRP Phase 2 Low Dose Study in PBC

Changes in other biochemical from baseline to Week 12

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Decreases in ALT Provide an Additional Indication of Efficacy

T i m e ( w e e k s )

Me

an

AL

T (

U/L

)

0 2 4 6 8 1 0 1 2

0

2 0

4 0

6 0

8 0

U L N

L L N

5 m g

1 0 m g

Mean ± SD

Phase 2 Low Dose Study in PBC

ALT changes from baseline to Week 12

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Seladelpar Not Associated with Worsening Pruritus

No itching Worst possible itching

Phase 2 Low Dose Study in PBC

Pruritus Visual Analog Scale (VAS)

VAS5 mg (n = 11) 10 mg (n = 11)

Median Range Median Range

Baseline 8 0 - 63 25 0 - 80

Week 12 3 0 - 47 6 0 - 75

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o No Serious Adverse Events• No grade 2 or grade 3 increase in transaminase activities*• No signal for drug-induced pruritus

o Other events• One asymptomatic myocardial infarction not related to seladelpar:

Patient enrolled with high LDL-C and poorly controlled diabetes, continues on treatment

• One discontinuation for pruritus: Patient entered the study with intense pruritus and discontinued after 5 days for increased pruritus, deemed possibly related to PBC

Interim Safety: Seladelpar Appears Safe and Well Tolerated

* Grade 2: >3.0 - 5.0 x ULN; Grade 3: >5.0 - 20.0 x ULN Phase 2 Low Dose Study in PBC

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Study Modified to Extend Duration and Expand Database

Seladelpar 10 mg (n = 49) Seladelpar (5 mg, 10 mg)

Seladelpar 5 mg (n = 49) Seladelpar (5 mg, 10 mg)

Seladelpar 2 mg (n = 18) Seladelpar (2 mg, 5 mg, 10 mg)

Main Extension (Option for Dose Adjustment)

52 weeksPhase 2 Low Dose Study in PBC

Extended to 52 weeks Increased 5 mg and 10 mg groups to 49 patients each Dosing above 10 mg not planned To assess minimally effective dose, added a 2 mg arm

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Confidence to Move to Phase 3

Seladelpar OCA*

-60

-50

-40

-30

-20

-10

0

NS

5 mg 10 mg

-60

-50

-40

-30

-20

-10

0

p < 0.0001 p < 0.0001 p < 0.0001

Placebo 10 mg 25 mg 50 mg

Mean ± SEM

Data highlighted on this slide are from two separate studies and do not represent a head-to-head comparison.* Adapted from Hirschfield G. et al. Gastroenterology 2015;148(4): 751-61 Phase 2 Low Dose Study in PBC

Mean percent change in AP from baseline to Week 12

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o Seladelpar retains potent, clinically significant, anti-cholestatic and anti-inflammatory activity, both at 5 mg and 10 mg / day

o Seladelpar appeared safe and well tolerated• At low doses, the transaminase activity safety signal was replaced with

an efficacy signal (decreased transaminase activity) • No evidence of drug-induced pruritus • Both 5 mg and/or 10 mg are candidate doses for phase 3

Conclusions

Phase 3 starts in 2018

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Seladelpar Low Dose Study Group Investigators

CanadaMark Swain, M.D. Calgary

GermanyChristoph Berg, M.D. TübingenPeter Buggisch, M.D. HamburgYvonne Doerffel, M.D. BerlinAndreas Kremer, M.D., Ph.D. ErlangenMarkus-Alexander Wörns, M.D. Mainz

United KingdomRichard Aspinall, M.D., Ph.D. PortsmouthLindsey Corless, M.D. HullGideon Hirschfield, FRCP, Ph.D. BirminghamDavid Jones, M.D., Ph.D. Newcastle upon TyneDavid Sheridan, M.D., Ph.D. PlymouthDouglas Thorburn, M.D. London

United StatesBruce Bacon, M.D. Saint LouisDavid Bernstein, M.D. Lake SuccessBrian Borg, M.D. JacksonChristopher Bowlus, M.D. SacramentoMichael Galambos, M.D. AtlantaNorman Gitlin, M.D. AtlantaStuart Gordon, M.D. DetroitStephen Harrison, M.D. Live OakTarek Hassanein, M.D. CoronadoCynthia Levy, M.D. MiamiMarlyn Mayo, M.D. DallasJoseph Odin, M.D. New YorkMitchell Shiffman, M.D. RichmondPaul Thuluvath, M.D. BaltimoreJohn M Vierling, M.D. Houston