Treatment Efficacy and Safety of Low Dose Seladelpar a ......1 Treatment Efficacy and Safety of Low...

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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

    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

  • 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 )

    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

  • 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 )

    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 BaselineMean 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

  • 14

    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

  • 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 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

  • 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

    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

  • 19

    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

    Treatment Efficacy and Safety of Low Dose Seladelpar a Selective PPAR- Agonist, in Patients with Primary �Biliary Cholangitis: ��12-week Interim Analysis of an International, Randomized, Dose Ranging, Phase 2 StudyPBC is a Significant Cause of Chronic Liver InjuryCurrent Licensed Therapies for PBC Remain LimitedPatients Exhibit a Persistent Cycle of InjurySeladelpar: Once Daily Oral PPAR- Agonist for Inflammatory Liver DiseasesAASLD 2016: Proof-of-Concept in High Dose Study �Benefit/risk supported rationale for lower dose studyPhase 2 Low Dose Study in PBC�Open label, randomized, dose rangingBaseline Characteristics: High Risk Population5 mg and 10 mg Doses Both Result in Rapid and Robust Decreases in APComparable Substantial Decrease in Absolute AP at Both DosesAt 12 Weeks Notable Proportion of Patients with AP < 1.67 ULN or ≤ ULNAdditional Anti-cholestatic and Anti-inflammatory EffectsDecreases in ALT Provide an Additional Indication of EfficacySeladelpar Not Associated with Worsening PruritusInterim Safety: Seladelpar Appears Safe and Well ToleratedStudy Modified to Extend Duration and Expand DatabaseConfidence to Move to Phase 3ConclusionsSeladelpar Low Dose Study Group Investigators