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.
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Treatment Efficacy and Safety of Low Dose Seladelpar a ......1 Treatment Efficacy and Safety of Low Dose Seladelpar a Selective PPAR-δAgonist, in Patients with Primary Biliary Cholangitis:
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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
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
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