improving the lives of patients with liver diseases · pol boudes, md, chief medical officer. aasld...

Improving the Lives of Patients with Liver Diseases

PBCers conference May 2018

Pol Boudes, MD, Chief Medical Officer

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

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

Ch

an

ge

f

ro

m D

ay

1

(

%)

- 8 0

- 6 0

- 4 0

- 2 0

0

2 0

4 0p = 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. AASLD 2016 & Lancet GE&H 2017

New Phase 2 Seladelpar ‘Low Dose’ Study Open label, randomized, dose ranging

Seladelpar 10 mg qd (n = 12)


Seladelpar (5, 10 or 25 mg)


12 Week Interim

Analysis


18 weeks


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

Time (weeks)

% C

han

ge in

AP

fro

m B

aselin

e0 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%

AASLD 2017: Phase 2 Seladelpar ‘Low Dose’ Study 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

Hirschfield et al., AASLD 2017

AASLD 2017: Phase 2 Seladelpar ‘Low Dose’ Study Decreases in ALT Provide an Additional Indication of Efficacy

T i m e ( w e e k s )

Me

an

A

LT

(

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


ALT changes from baseline to Week 12

AASLD 2017: Phase 2 Seladelpar ‘Low Dose’ 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


▪ 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

EASL 2018: Phase 2 Seladelpar ‘Low Dose’ Study Dose response and clinical activity with robust decreases in AP

7

Mean percent AP change from baseline to Week 12

Hirschfield et al, EASL, International Liver congress 2018

AP

% C

ha

ng

e f

ro

m B

as

eli

ne 0 2 4 6 8 1 0 1 2

-5 0

-4 0

-3 0

-2 0

-1 0

0

5 m g , n = 2 5

1 0 m g , n = 2 2

-3 3 %

-4 5 %

2 m g , n = 6

-2 1 %

M e a n S E M

W e e k s

8

AP changes from baseline to Week 26

EASL 2018: Phase 2 Seladelpar ‘Low Dose’ Study Sustained activity to Week 26

AP

% C

ha

ng

e f

ro

m B

as

eli

ne

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6

-5 0

-4 0

-3 0

-2 0

-1 0

0

5 m g , n = 1 3 -4 5 %

1 0 m g , n = 1 9 -4 3 %

5 to 1 0 m g , n = 6 -4 3 %

T itra t io n a llo w e d

W e e k s


EASL 2018: Phase 2 Seladelpar ‘Low Dose’ Study AP responders from baseline to Week 26

9

At Week 26

n (%)

Seladelpar Titration

5 mg or 5 to 10 mg

n=19

Seladelpar

10 mg

n=19

Baseline AP (U/L) 348 272

Primary Composite Endpoint

Responder Rate 13 (68%) 15 (79%)

AP < 1.67 x ULN 13 (68%) 15 (79%)

AP decrease ≥ 15% 18 (95%) 17 (89%)

Total bilirubin ≤ ULN 18 (95%) 17 (89%)

AP Normalization

AP ≤ ULN at Week 26 5 (26%) 6 (32%)


Week 12 Cohort Week 26 Cohort

EASL 2018: Phase 2 Seladelpar Low Dose StudyRobust anti-inflammatory effects: ALT

T im e (w e e k s )

Me

dia

n A

LT

% C

ha

ng

e f

ro

m B

as

eli

ne

0 2 4 6 8 1 0 1 2

-5 0

-4 0

-3 0

-2 0

-1 0

0

5 m g , n = 2 5 -2 8 %

2 m g , n = 6 -9 %

1 0 m g , n = 2 2 -3 5 %

T im e (w e e k s )

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6

-5 0

-4 0

-3 0

-2 0

-1 0

0

1 0 m g , n = 1 9 -4 3 %

5 m g , n = 1 9 -4 0 %


Week 26 Cohort

EASL 2018: Phase 2 Seladelpar ‘Low Dose’ StudyChanges in self reported symptom scores: Pruritus

-5 0

-4 0

-3 0

-2 0

-1 0

0

VA

S M

ed

ian

% C

ha

ng

e

fro

m B

as

eli

ne

1 2 4 6 8 1 2 1 6 2 0 2 6 1 2 4 6 8 1 2 1 6 2 0 2 6 (W e e k s )

5 m g , n = 19

1 0 m g , n = 19

▪ Six SAEs, all deemed unrelated to seladelpar

▪ No transaminase safety signal

▪ No signal for drug-induced pruritus

▪ Two AEs leading to seladelpar discontinuation, both unrelated to seladelpar

▪ Most frequent AEs: Pruritus (24%); fatigue, nasopharyngitis, and urinary tract infection (all 11%)

Phase 2 Low Dose Study in PBCSafety summary

Seladelpar for PBCNext steps

13

New ‘Long Term Extension’ study Initiated

Objective: submit a New Drug Application

Low dose study continues to recruit

Preparing for Phase 3 start in 2018

Back-up slides

SeladelparOnce daily oral PPAR agonist for inflammatory liver diseases

15

Human PPAR EC50 = 2 nM

630-Fold Selective Over PPAR

Inactive Against PPAR

OHO

O

S O

O

CF3

Bile Acid Homeostasis

Cholesterol synthesis

Bile acid synthesis (C4)

Transport

Fibrosis

Connective Tissue Growth Factor

Stellate cell activation

Collagen deposition

Inflammation

NFB-dependent

gene activation

Inflammatory cytokines

hs-C-Reactive Protein

Metabolic Effects

Cholesterol/LDL-C

Lipogenesis

Fatty acid oxidation

Insulin sensitivity

RXRPPAR

Gene Activation

or Repression

Hepatocyte

Hepatocyte

Cholangiocyte

Kupffer Cell

Stellate Cell

Myocyte

Adipocyte

Enterocyte

Macrophage

▲First line therapy for PBC

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

▼Additional 5% are intolerant to therapy

▲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

Current Therapies for PBCLimited treatment alternatives

16

Ursodeoxycholic Acid (UDCA)

1st Line

Obeticholic Acid (Ocaliva)

2nd Line

Significant need remains for (1) improved efficacy and (2) better tolerability

Phase 2 Low Dose Study in PBCSafety, Week 12 and Week 26 cohorts

17

Subjects

(n)

Dose Through Week 12

2 mg 5 mg 10 mg

Safety Population 11 30 30

Week 12 Cohort 6 25 22

Subjects

(n)

Dose Week 12 Through Week 26

2 or 2 to 5 mg 5 mg 5 to 10 mg 10 mg

Week 26 Cohort 4 13 6 19

Phase 2 Low Dose Study in PBCBaseline characteristics

18

Safety population, Mean (SD), Baseline: mean of screening(s) and Day 1

CB8025-21629 StudySeladelpar

2 mg

Seladelpar

5 mg

Seladelpar

10 mg

N 11 30 30

Age, years 55 (10) 57 (8) 56 (9)

Female/Male 11/0 30/0 27/3

BMI, kg/m2 29 (7) 27 (7) 26 (5)

History of Pruritus 7 (65%) 19 (63%) 22 (73%)

AP, U/L 300 (121) 310 (152) 265 (83)

GGT, U/L 255 (143) 201 (141) 254 (185)

ALT, U/L 54 (25) 40 (22) 49 (25)

Total Bilirubin, mg/dL 0.60 (0.12) 0.68 (0.35) 0.84 (0.34)

Albumin, g/dL 4.1 (0.2) 4.0 (0.4) 4.1 (0.3)

UDCA Dose, mg/kg 14 (4) 15 (3) 17 (6)

Week 12 Cohort Week 26 Cohort

Phase 2 Low Dose Study in PBCTotal bilirubin

T im e (w e e k s )

Me

dia

n T

B C

ha

ng

e

fro

m B

as

eli

ne

(m

g/d

L)

0 2 4 6 8 1 0 1 2

-0 .3

-0 .2

-0 .1

0 .0

0 .1 5 m g , n = 2 5

1 0 m g , n = 2 2

T im e (w e e k s )

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6

-0 .3

-0 .2

-0 .1

0 .0

0 .1

5 m g , n = 1 9

1 0 m g , n = 1 9

Phase 2 Low Dose Study in PBCPercent change in other biochemical parameters of interest

20

Week 12 Cohort

Week 26 Cohort

EASL 2018: Phase 2 ‘Low Dose’ StudyChanges in self reported symptom scores: PBC-40 QoL

-1 5

-1 0

-5

0

T o ta l S c o re

Me

dia

n P

BC

-40

% C

ha

ng

e f

ro

m B

as

eli

ne

4 8 1 2 1 6 2 0 2 6 4 8 1 2 1 6 2 0 2 6

-1 5

-1 0

-5

0

F a tig u e

5 m g , n = 19

1 0 m g , n = 19

4 8 1 2 1 6 2 0 2 6 4 8 1 2 1 6 2 0 2 6 (W e e k s )


improving the lives of patients with liver diseases · pol boudes, md, chief medical officer. aasld...

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