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