enhance: safety and efficacy of seladelpar in patients with … · 2020. 12. 18. · slides are the...
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Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay Therapeutics and AASLD for reuse.Slides are the property of CymaBay Therapeutics and AASLD. Permission is required from both CymaBay Therapeutics and AASLD for reuse.
ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis Gideon Hirschfield, FRCP, PhDToronto Centre for Liver Disease, University of Toronto@autoimmuneliver
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Disclosures
Gideon Hirschfield, FRCP, PhD
I disclose the following financial relationship(s) with a commercial interest: • CymaBay Therapeutics• Falk Pharma • Genfit• GSK• Intercept• Morphic Therapeutic• Mirum• Pliant• Roche
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ENHANCE: Safety and Efficacy of Seladelpar in Patients With Primary Biliary Cholangitis
A PHASE 3 INTERNATIONAL, RANDOMIZED, PLACEBO-CONTROLLED STUDY
Hirschfield GM, Kowdley KV, Shiffman ML, Khazanchi A, Zigmond E, Lawitz EJ, Pratt D, Aspinall R, Forman L, Gordon SC, Gulamhusein AF, Ladron-De-Guevara AL, Levy C, Ryder SD, Stanca CM, Bresky Ruiz C, Gonzalez Huezo MS, Heo J, Leggett BA, Minuk GY, Pagadala MR, Pound D, Raikelson K, Silveira MG, Swain MG, Yimam KK, Younes ZH, Zuckerman E, Corpechot C, Harrison SA, Invernizzi P, Nevens F, Thorburn D, Bowlus C, Dalekos G, Jones D, Kremer AE, Pares A, Vierling JM, Boudes P, Varga M, Choi YJ, McWherter C, Steinberg A, Mayo M
Sponsor: CymaBay Therapeutics, Inc
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Bile duct injury, portal inflammation, cholestasis, progressive liver fibrosis
Chronic, destructive, autoimmune,
cholestatic liver disease
Elevated serum markers of biliary injury:
Alkaline phosphatase (ALP)Total bilirubin
Symptoms including fatigue
and pruritus
Healthy liver
Inflammation Progressive Biliary Fibrosis Cirrhosis
CholestasisEND STAGE
LIVER DISEASE
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Impaired quality and quantity of life Portal hypertensionLiver failure
Hepatocellular carcinoma
Liver transplantation
Death
1 in 1000 women over 40 years of age live with PBC
Primary Biliary Cholangitis (PBC)
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Primary Biliary Cholangitis (PBC)
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1 in 1000 women over 40 years of age live with PBC
Murillo Perez CF, et al. Am J Gastroenterol. 2020;115(7):1066-1074.
Chronic, destructive, autoimmune,
cholestatic liver disease
Symptoms including fatigue
and pruritus
Bile duct injury, portal inflammation, cholestasis, progressive liver fibrosis
Elevated serum markers of biliary injury:
Alkaline phosphatase (ALP)Total bilirubin
Healthy liver
Inflammation Progressive Biliary Fibrosis Cirrhosis
CholestasisEND STAGE
LIVER DISEASE
Portal hypertensionLiver failure
Hepatocellular carcinoma
Liver transplantation
Death
Impaired quality and quantity of lifeALP and total bilirubin are biochemical surrogates of disease activity that
highlight an individual’s risk of disease progressionTreatment goals recognize the importance of normalizing ALP and total bilirubin
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Lindor KD, et al. Hepatology. 2019;69(1):394-419.
Unmet Need Remains Despite Existing TreatmentsOpportunity for new therapy addressing disease activity and symptom burden
UrsodeoxycholicAcid (UDCA)
• 1st-line therapy for PBC
• ~40% are inadequate responders with ALP ≥1.67x ULN
• Additional ~5% are intolerant to therapy
• UDCA therapy does not improve pruritus or other symptoms associated with PBC
1STLINE
Seladelpar is a potentially improved 2nd-line treatment for PBC
Obeticholic Acid(Ocaliva®)
• Add-on therapy for UDCA inadequate responders
• Monotherapy for patients intolerant to UDCA
• ALP/bilirubin as biomarkers for accelerated approval
• ~50% are inadequate responders• Pruritus can worsen or be caused
2ND
LINE
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SeladelparThe only potent and selective PPARδ agonist in development for liver disease
Targets all important cell types in liver disease
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Decrease Bile Acids1
Cholesterol synthesis
Bile acid synthesis (C4)
Transport
Anti-fibrotic2
Profibrotic genes
Stellate cell activation
Collagen synthesis/ deposition
Anti-inflammatory1
NFκB-dependent gene activation
Inflammatory cytokines
hs-C-reactive protein
Increase Lipid Metabolism3
Cholesterol/LDL-C
Fatty acid oxidation
Insulin sensitivity
Hepatocyte
Cholangiocyte
Stellate Cell
Kupffer Cell
Macrophage
Hepatocyte
Myocyte
Adipocyte
Enterocyte
PPARδ RXR
Gene Activation or Repression
CH3OHOOC
SO
O
CF3
CH3
Seladelpar
PPARδ, peroxisome proliferator-activated receptor delta.1. Jones D, et al. Lancet Gastroenterol Hepatol. 2017;2(10):716-726. 2. Harrison SA, et al. Poster presented at The Liver Meeting Digital ExperienceTM (TLMdX), American Association for the Study of Liver Diseases; November 13-16, 2020. Poster 1710. 3. Bays HE, et al. J Clin Endocrinol Metab. 2011;96(9):2889-2897.
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Placebo
(n=80)
(n=80)
(n=80)
Day 1 Week 52
Long-term Safety Study
ENHANCE Phase 3 Study (Original Design)
Seladelpar 5 mgSeladelpar 10 mg
Seladelpar 5 mg
Seladelpar 10 mg
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ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; ELISA, enzyme-linked immunosorbent assay; ULN, upper limit of normal.Seladelpar was administered orally once daily. Seladelpar or placebo was administered as an add-on to UDCA therapy for patients who tolerated UDCA; for patients with UDCA intolerance, the study drug was administered as a monotherapy.The study was discontinued because of unexpected histological findings that were later determined to be pre-existing in the nonalcoholic steatohepatitis seladelpar program.
• 18 to 75 years old, male or female with a diagnosis of PBC based on any 2 of the following criteria:• History of ALP above 1.0x ULN for at least 6 months• Positive AMA titer (>1:40 on immunofluorescence or M2 positive by ELISA) or positive PBC-specific ANA• Documented liver biopsy results consistent with PBC
• UDCA for the past 12 months (stable dose) OR intolerant to UDCA• ALP ≥1.67x ULN; ALT/AST ≤3x ULN; total bilirubin ≤2x ULN
Key Inclusion Criteria
Week 26
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• Intolerance or inadequate response to UDCA• ALP ≥1.67x ULN, bilirubin ≤ 2x ULN• Includes patients with severe pruritus
• Seladelpar 10 mg and 5/10 mg titration vs placebo (1:1:1 randomization)• Stratified by ALP value (<350 U/L vs ≥350 U/L) and pruritus Numerical Rating Scale (NRS) (<4 vs ≥4)
End Points
Design
Enrolled Patients
Placebo Seladelpar 5 mg Seladelpar 10 mgSafety/mITT Population 87 89 89
Month 3 56 56 55
Month 6 23 26 20
Study Population
Primary Endpoint:• Composite responder
rate at Month 3
Secondary Endpoints: • Proportion of patients with ALP ≤ 1.0 x ULN at 6 and 12 months• Change from baseline in pruritus NRS using e-diary at 6 months
Original placebo-controlled, double-blind 52-week study designPrimary Endpoint:• Composite responder
rate at Month 3*
Key Secondary Endpoints: • ALP normalization at Month 3• Change from baseline in pruritus NRS at Month 3
(patients with baseline NRS ≥4)
Other Secondary Endpoints:• Previous 3 endpoints at Month 6Endpoints
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Blinded analysis after early termination. The safety analysis set included any patient who received at least 1 dose of study drug. The mITT analysis set included any patient randomized and dosed.
ENHANCE Design and Analysis Plan
*Composite responder: ALP <1.67x ULN, ≥15% decrease in ALP, total bilirubin ≤ULN.
Amended Endpoints (No dose titration prior to Month 6)
mITT, modified intention-to-treat.
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Female, n (%) 85 (98%) 82 (92%) 83 (93%)Age, years 56 (8) 55 (10) 56 (9)Caucasian, n (%) 80 (92%) 83 (93%) 77 (87%)Duration of PBC, years 8 (6) 8 (6) 8 (6)History of Pruritus, n (%) 57 (66%) 66 (74%) 65 (73%)Pruritus NRS ≥4 27 (31%) 27 (30%) 27 (30%)UDCA Dose, mg/kg/day 15 (3) 16 (4) 15 (4)UDCA Intolerant, n (%) 2 (2%) 6 (7%) 8 (9%)ALP ULN: 116 U/L 293 (106) 290 (104) 291 (109)ALT ULN: 41 U/L 44 (21) 48 (21) 47 (21)AST ULN: 34 U/L 37 (17) 40 (14) 40 (15)GGT ULN: 38 U/L 229 (193) 231 (212) 243 (228)Total bilirubin ULN: 1.1 mg/dL 0.71 (0.32) 0.76 (0.35) 0.72 (0.32)Immunoglobulin M ULN: 230 mg/dL 358 (264) 332 (202) 316 (181)
Seladelpar 10 mg (n=89)
Seladelpar 5 mg (n=89)
Demographic and Baseline CharacteristicsmITT population
Placebo (n=87)
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GGT, gamma-glutamyl transferase.Mean (SD) unless otherwise specified.
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10.3
47.5
64.6
0
20
40
60
80
100
Month 1
Prop
ortio
n of
Pat
ient
s (%
)
P<0.0001
P<0.0001
P<0.05
(n=78) (n=80) (n=79)
5 mgPlacebo 10 mg
12.5
57.1
78.2
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P<0.0001
P<0.0001
P<0.05
Month 3
(n=56) (n=55)(n=56)
Month 6
21.7
61.570.0
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0006
P=0.002
ns
(n=26) (n=20)(n=23)
78% of patients on seladelpar 10 mg achieved the primary composite endpoint with high statistical significance at 3 months
ALP <1.67x ULN, ≥15% decrease in ALP, total bilirubin ≤ULNPrimary Composite Endpoint Achieved at 3 months
ns, not significant.P values by Cochran-Mantel-Haenszel (CMH) test.CymaBay, Data on File 2020.
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ALP ≤1x ULNKey Secondary Endpoint Achieved: ALP Normalization Rate
05.0
12.7
0
10
20
30
40
50
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0441
P=0.0013
ns
Month 1
(n=78) (n=80) (n=79)
0
11.5
30.0
0
10
20
30
40
50
Prop
ortio
n of
Pat
ient
s (%
)
ns
P=0.0023
ns
Month 6
(n=26) (n=20)(n=23)
27% of patients on seladelpar 10 mgnormalized ALP by 3 monthsP values by CMH test.
CymaBay, Data on File 2020.12
5 mgPlacebo 10 mg
Month 3
Prop
ortio
n of
Pat
ient
s (%
)
ns
P<0.0001
P<0.01
05.4
27.3
0
10
20
30
40
50
(n=56) (n=55)(n=56)
P<0.01
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ALP Relative and Absolute Change at Month 3
LS Mean and P values by analysis of covariance (ANCOVA).CymaBay, Data on File 2020.
-3.7
-35.7
-44.2-50
-40
-30
-20
-10
0
LS M
ean
Cha
nge
in A
LP (%
)
P<0.0001
P<0.0001
P=0.0013
(n=56) (n=54) (n=53)
ALP Absolute ChangeALP Relative Change
-2.3
-101
-122-140
-120
-100
-80
-60
-40
-20
0
LS M
ean
Cha
nge
in A
LP (U
/L)
P<0.0001
P<0.0001
P=0.0286
(n=56) (n=54) (n=53)
5 mgPlacebo 10 mg
Significantdose-dependent relative and absolute reductions
in ALP were observedat 3 months
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Patients with baseline ALT >ULNALT Normalization at Month 3
P values by CMH test.CymaBay, Data on File 2020.
17.9
51.7 50.0
0
20
40
60
80
100Pr
opor
tion
of P
atie
nts
(%)
P=0.0102
P=0.0201
ns
Month 3
(n=29) (n=28)(n=28)
5 mgPlacebo 10 mg
In patients with elevated baseline ALTon seladelpar 10 mg
50% normalized ALT by 3 months
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mITT populationMonth 1(n=78)
Month 3(n=56)
Month 6(n=23)
Month 1(n=78)
Month 3(n=54)
Month 6(n=24)
Month 1(n=78)
Month 3(n=53)
Month 6(n=18)
ALT % Change -2.0% -4.0% 2.4% -14% -23% -23% -6% -17% -35%
GGT % Change -6.7% -6.5% 0.1% -28% -30% -24% -34% -36% -37%
AST % Change 1.3% -0.2% 1.4% -6.6% -8.5% -15% 3.8% -4.8% -17%
Total bilirubin % Change -1.3% 0.9% 1.7% -2.8% -6.1% -3.1% -9.9% -4.0% -15%
IgM % Change -2.6% -5.7% -3.4% -5.7% -10% -8.7% -7.3% -12% -12%
Seladelpar 10 mgSeladelpar 5 mgPlacebo
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Month 1, 3, and 6 treatment effects in mITT populationImprovement in Other Serum Liver Tests
Seladelpar demonstrated broad anti-cholestaticand anti-inflammatory effects
IgM, immunoglobulin M.
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Patients with baseline NRS ≥4Key Secondary Endpoint Achieved: Treatment Improvement in Pruritus
LS Mean and P values by ANCOVA.CymaBay, Data on File 2020.
-1.14 -1.22
-2.38
-5
-4
-3
-2
-1
0
LS M
ean
Cha
nge
in N
RS
P=0.0111
ns
P=0.0170
(n=26) (n=26) (n=27)
Month 1
-2.47 -2.46
-4.24-5
-4
-3
-2
-1
0
LS M
ean
Cha
nge
in N
RS
ns
ns
ns
Month 6(n=6) (n=9) (n=7)
In patients with moderate and severe pruritus (baseline NRS of 6.2), significant improvements in pruritus were seen with seladelpar 10 mg at 3 months
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-1.55-2.01
-3.14
-5
-4
-3
-2
-1
0
P=0.0164
ns
ns
Month 3(n=18) (n=17) (n=18)
LS M
ean
Cha
nge
in N
RS
5 mgPlacebo 10 mg
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16.7
38.9 42.1
0
20
40
60
80
100
≥4-point Reduction
5.6
22.2
36.8
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
P=0.0183
≥2-point Reduction
33.3
50.0
68.4
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
) P=0.0361
≥3-point Reduction
Dose-Ordered Reductions in Pruritus NRS Observed at Month 3
Prop
ortio
n of
Pat
ient
s (%
)
P values by CMH test. Non-significant P values not shown.CymaBay, Data on File 2020.
Dose-ordered reductions in NRS were seen at 3 monthsin patients with moderate and severe pruritus
(n=18) (n=18) (n=19) (n=18) (n=19)(n=18) (n=18) (n=19)(n=18)
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5 mgPlacebo 10 mg
Patients with baseline NRS ≥4
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Safety Population, n (%)
Patients with at least 1 AE 64 (73.6) 56 (62.9) 58 (65.2)
Any treatment-related AE 16 (18.4) 25 (28.1) 15 (16.9)
Any treatment-related AE ≥ Grade 3 (CTCAE)* 0 0 0
Any AE with outcome of death 0 0 0
Any SAE 3 (3.4) 3 (3.4) 1 (1.1)
Any treatment-related SAE 0 0 0
Any AE leading to study drug discontinuation 2 (2.3) 2 (2.2) 2 (2.2)
Safety Overview
Placebo (n=87)
Seladelpar 5 mg (n=89)
Seladelpar 10 mg (n=89)
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Summary of treatment-emergent adverse events
*No Grade 3 ALT/AST elevations.
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; SAE, serious adverse event.
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Safety Population, n (%)
Abdominal pain upper 3 (3.4) 8 (9.0) 6 (6.7) 14 (7.9)Pruritus 11 (12.6) 3 (3.4) 10 (11.2) 13 (7.3)Nausea 4 (4.6) 5 (5.6) 7 (7.9) 12 (6.7)Headache 1 (1.1) 5 (5.6) 7 (7.9) 12 (6.7)Upper respiratory tract infection 2 (2.3) 6 (6.7) 4 (4.5) 10 (5.6)
Arthralgia 5 (5.7) 5 (5.6) 4 (4.5) 9 (5.1)Constipation 2 (2.3) 5 (5.6) 3 (3.4) 8 (4.5)Urinary tract infection 0 2 (2.2) 5 (5.6) 7 (3.9)Fatigue 8 (9.2) 2 (2.2) 4 (4.5) 6 (3.4)Dry mouth 0 5 (5.6) 1 (1.1) 6 (3.4)Sinusitis 5 (5.7) 2 (2.2) 1 (1.1) 3 (1.7)
Treatment-Emergent Adverse EventsOccurring in ≥5% of patients in any randomized treatment
Placebo (n=87)
Seladelpar 5 mg (n=89)
Seladelpar 10 mg (n=89)
Seladelpar Total (n=178)
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Treatment-Emergent Serious Adverse Events
Safety Population, n (%)Patients with at least one serious TEAE 3 (3.4) 3 (3.4) 1 (1.1) 4 (2.2)
Any treatment-related SAE 0 0 0 0List of SAEs by preferred term
Cellulitis 0 0 1 (1.1) 1 (0.6)Pyelonephritis acute 1 (1.1) 0 0 0Cognitive disorder 0 1 (1.1) 0 1 (0.6)Partial seizures 1 (1.1) 0 0 0Leukocytosis 0 1 (1.1) 0 1 (0.6)Adenoid cystic carcinoma 0 1 (1.1) 0 1 (0.6)Rectal polyp 1 (1.1) 0 0 0
Placebo (n=87)
Seladelpar 5 mg (n=89)
Seladelpar 10 mg (n=89)
Seladelpar Total (n=178)
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A 52-week Phase 3 global registration study(RESPONSE) to begin enrolling patients in Q1 2021
Safety and Efficacy of Seladelpar in Patients With PBC
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• 78% of patients achieved primary endpoint with 10 mg dose• Seladelpar 10 mg had a statistically significant effect on ALP normalization• Seladelpar 10 mg had a statistically significant reduction in pruritus• 10 mg dose is optimal with consistently greater effects on all endpoints• Overall, seladelpar was generally safe and well tolerated
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Argentina Australia AustriaBelgiumCanadaChileFranceGermanyGreeceHungaryIsrael
We gratefully acknowledge the study patients, investigators, site staff, and the ENHANCE team!Acknowledgements
ItalyKoreaMexico Netherlands New Zealand Poland Romania Russia Spain UKUSA
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Thank You
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