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  • 1

    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.

  • 2

    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

  • 3

    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

  • 4

    Fibrosis

    Immune Response

    Cholestasis

    Patients Exhibit a Persistent Cycle of Injury

  • 5

    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

    RXR PPAR-δ

    Gene Activation or Repression

    S

    Hepatocyte

    Hepatocyte

    Kupffer cell

    Stellate cell

    Cholangiocyte

    Human PPAR-δ EC50 = 2 nM 600-fold selective over PPAR-α

    Inactive against PPAR-γ

    O HO

    O

    S O O

    CF3

  • 6

    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 )

    M e

    a n

    A P

    ( 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

    C h

    a n

    g e

    f r

    o m

    D a

    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

    Placebo 50 mg 200 mg

    Jones et al. (2017) Lancet GE&H

  • 7

    Phase 2 Low Dose Study in PBC Open 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 Interim Analysis

    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

  • 8

    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

  • 9

    Time (weeks) %

    C ha

    ng e

    in A

    P fro

    m B

    as el

    in e

    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

  • 10

    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 )

    L S

    M e

    a n

    C h

    a n

    g e

    i n

    A P

    ( 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 ± SE LS = Least Squares

    No statistical differences between dose groups

    Phase 2 Low Dose Study in PBC

  • 11

    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 12 AP < 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

  • 12

    Additional Anti-cholestatic and Anti-inflammatory Effects

    Parameter Percent 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

  • 13

    Decreases in ALT Provide an Additional Indication of Efficacy

    T i m e ( w e e k s )

    M e

    a n

    A L

    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

  • 14

    Seladelpar Not Associated with Worsening Pruritus

    No itching Worst possible itching

    Phase 2 Low Dose Study in PBC

    Pruritus Visual Analog Scale (VAS)

    VAS 5 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

  • 15

    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

  • 16

    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 weeks Phase 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

  • 17

    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