Improving the Lives of Patients with Liver Diseases
Transcript of Improving the Lives of Patients with Liver Diseases
Effects on Pruritus and Sleep Disturbance in Patients with Primary Biliary Cholangitis (PBC) after 1 Year of Treatment
with Seladelpar, a Peroxisome Proliferator-Activated Receptor Delta Agonist: Results of an Open-label Phase 2 Study
Andreas E. Kremer, Marlyn Mayo, Christopher Bowlus, Guy Neff, Mark Swain, Michael Galambos, Aparna Goel, Palak Trivedi, Gideon Hirschfield, Richard Aspinall, Stuart Gordon, Brian Borg, Stephen A. Harrison, Paul J.
Thuluvath, David Jones, Yvonne Doerffel, Cynthia Levy, Carmen Stanca, David Sheridan, John Vierling, Mitchell Shiffman, Joseph Odin, Bruce Bacon, Tarek Hassanein, Douglas Thorburn, Christoph Berg, David Bernstein,
Aliya Gulamhusein, Charles Landis, Adam Peyton, Lynsey Corless, Peter Buggisch, Marcus-Alexander Woerns, Sandrin Bergheanu, Monika Varga, Yu Li, Ke Yang, Klara Dickinson, Pol Boudes, Charles A. McWherter,
Alexandra Steinberg, Yun-Jung Choi
June | 2020
Digestive Disease Week (DDW) 2020 Virtual Meeting 1
2Digestive Disease Week (DDW) 2020 Virtual Meeting
Disclosures
Consultant / Advisor: Beiersdorf, CymaBay, Elsevier, GSK, Guidepoint, Intercept, Janssen, MSD
Speaker: Abbvie, BMS, CMS, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Janssen, Lilly, MSD, Zambon
3Digestive Disease Week (DDW) 2020 Virtual Meeting
Phase 2 Open Label Study in PBCIncomplete response or intolerance to UDCA*
Seladelpar 5 mg (n = 49)
Seladelpar 10 mg (n = 52)
Seladelpar 5/10 mg
Entry Criteria: ALP ≥ 1.67 x ULN; ALT/AST ≤ 3 x ULN; Total Bilirubin ≤ 2 x ULN
Week 12†
* Seladelpar is an add-on to UDCA for patients with an inadequate response to UDCA in the prior 12 months (mITT population).† At week 12, a dose adjustment in the 5/10 mg group was made based on patient response and tolerability. ǂ Patients with ALP ≤ 1.67 x ULN, ≥ 15% drop in ALP from baseline and normal total bilirubin.
Long Term Extension
Option for Dose Adjustment
Primary Outcome: % Change in ALP from baseline
Secondary Outcomes: Composite responder rateǂ, ALP normalization, changes in liver, metabolic and inflammatory markers
1 Year
4Digestive Disease Week (DDW) 2020 Virtual Meeting
Effect of Seladelpar on Pruritus in Patients with PBC
Pruritus is a common symptom of PBC that diminishes quality of life Phase 2 PBC Study Design
− Patient reported outcomes were collected at clinic visit by recall methods Pruritus and Quality-of-Life Measures
− Visual Analog Scale (VAS)− 5-D Itch− PBC-40
5Digestive Disease Week (DDW) 2020 Virtual Meeting
Demographic and Baseline Characteristics of PBC Patients
mITT Population Seladelpar 5/10 mg
Seladelpar 10 mg
N 49 52Female, n (%) 48 (98%) 48 (92%)Age, years 58 (8) 58 (10)BMI, kg/m2 26 (5) 28 (5)White, n (%) 47 (96%) 47 (90%)Duration of PBC, years 10 (7) 10 (6)History of Pruritus, n (%) 36 (73%) 36 (69%)UDCA Dose, mg/kg/day 15 (3) 15 (4)UDCA intolerant, n (%) 4 (8%) 3 (6%)ALP ULN: 116 U/L 353 (193) 301 (138)ALT ULN: 41 U/L 46 (25) 46 (21)Total bilirubin ULN: 1.1 mg/dL 0.76 (0.36) 0.83 (0.33)GGT ULN: 38 U/L 244 (150) 239 (196)Mean (SD)
6Digestive Disease Week (DDW) 2020 Virtual Meeting
Pruritus VASBaseline vs. 1 Year
0102030405060708090
100
VAS
Seladelpar Seladelpar 5/10 mg 10 mg
Baseline 1 Year Baseline 1 Year
7Digestive Disease Week (DDW) 2020 Virtual Meeting
Effect of Seladelpar Treatment on Pruritus after 1 Year By severity of pruritus at baseline
5/10 mg 10 mg 5/10 mg 10 mg 5/10 mg 10 mg 5/10 mg 10 mgn: 7 11 22 22 9 11 3 4
Baseline VAS: VAS = 0 0 < VAS < 40 40 ≤ VAS < 70 70 ≤ VAS ≤ 100 (mm)
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
ImprovedSameWorsened
VAS Change by 20 mm at 1 YearNo pruritus Mild Moderate Severe/
Very Severe
8Digestive Disease Week (DDW) 2020 Virtual Meeting
Correlations between Changes in Pruritus Measures at 1 YearVAS vs. Total 5-D Itch, PBC-40 Itch or Fatigue
∆ Total 5-D Itch ∆ PBC-40 Itch ∆ PBC-40 Fatigue
∆ VA
S
r = 0.65p < 0.0001
r = 0.61p < 0.0001
r = 0.40p = 0.0001
5/10 mg 10 mg
9Digestive Disease Week (DDW) 2020 Virtual Meeting
5-D Itch: DurationHow many hours a day have you been itching?
5-D Itch: Duration5/10 mg 10 mg
Baseline At 1 Year Baseline At 1 Year
Baseline Total 1 2 3 4 5 Total 1 2 3 4 5
1: Less than 6 hrs/day 30 28 2 0 0 0 38 36 2 0 0 02: 6-12 hrs/day 7 3 3 1 0 0 6 6 0 0 0 03: 12-18 hrs/day 1 1 0 0 0 0 2 1 1 0 0 04: 18-23 hrs/day 0 0 0 0 0 0 0 0 0 0 0 05: All day 2 2 0 0 0 0 1 1 0 0 0 0
Total 40 34 5 1 0 0 47 44 3 0 0 00102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
10Digestive Disease Week (DDW) 2020 Virtual Meeting
5-D Itch: DegreeIntensity of itching
5-D Itch: Degree5/10 mg 10 mg
Baseline At 1 Year Baseline At 1 Year
Baseline Total 1 2 3 4 5 Total 1 2 3 4 5
1: Not present 15 12 3 0 0 0 17 14 2 1 0 0
2: Mild 13 4 7 2 0 0 13 4 9 0 0 0
3: Moderate 10 3 2 5 0 0 12 5 5 2 0 0
4: Severe 3 0 2 1 0 0 5 0 2 2 1 0
5: Unbearable 0 0 0 0 0 0 5 0 0 0 0 0
Total 41 19 14 8 0 0 47 23 18 5 1 00102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
11Digestive Disease Week (DDW) 2020 Virtual Meeting
5-D Itch: DirectionHas itching gotten better or worse?
5-D Itch: Direction5/10 mg 10 mg
Baseline At 1 Year Baseline At 1 Year
Baseline Total 1 2 3 4 5 Total 1 2 3 4 5
1: Completely resolved 8 7 0 0 1 0 9 7 1 0 1 02: Much better, but
still present 9 4 2 0 3 0 4 2 1 1 0 03: Little bit better, but
still present 4 2 1 0 1 0 1 1 0 0 0 0
4: Unchanged 16 2 6 0 6 2 31 7 8 3 13 0
5: Getting worse 2 1 0 0 1 0 2 0 2 0 0 0
Total 39 16 9 0 12 2 47 17 12 4 14 00102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
12Digestive Disease Week (DDW) 2020 Virtual Meeting
5-D Itch: DisabilityImpact of itching on the activities
5-D Itch: Disability with Highest Score
5/10 mg 10 mgBaseline At 1 Year Baseline At 1 Year
Baseline Total 1 2 3 4 5 Total 1 2 3 4 5
0: N/A 1 1 0 0 0 0 0 0 0 0 0 01: Never affects 15 14 1 0 0 0 20 18 1 1 0 02: Rarely affects 8 6 2 0 0 0 6 3 3 0 0 03: Occasionally affects 9 3 4 0 2 0 8 3 3 2 0 04: Frequently affects 3 1 1 0 1 0 9 3 1 3 2 05: Always affects 5 0 3 1 1 0 4 2 0 2 0 0
Total 41 25 11 1 4 0 47 29 8 8 2 0
Activities: Sleep, Leisure/Social, Housework/Errands, Work/School
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
13Digestive Disease Week (DDW) 2020 Virtual Meeting
5-D Itch: Distribution of Itching LocationsPresentation of itching body parts
Number of Itch Locations Per Patient
Median 5/10 mg 10 mg
Baseline 3 5
1 Year 2 1
0 5 10 15 20 25 30
GroinChest
ButtocksFace
Tops of Hands/FingersPoints of Contact w/ Clothing
ThighsSoles
Lower legsPalms
AbdomenTops of Feet/Toes
ForearmsUpper ArmsHead/Scalp
Back
5/10 mg
Number of Patients0 5 10 15 20 25 30
10 mg
Number of Patients
Day 11 Year
Day 11 Year
14Digestive Disease Week (DDW) 2020 Virtual Meeting
5-D Itch: Impact of Itching on Sleep
5-D Itch: Sleep5/10 mg 10 mg
Baseline At 1 Year Baseline At 1 Year
Baseline Total 1 2 3 4 5 Total 1 2 3 4 5
1: Never affects sleep 19 17 2 0 0 0 24 21 3 0 0 02: Occasionally delays falling
asleep 10 7 3 0 0 0 8 5 3 0 0 03: Frequently delays falling
asleep 7 3 3 1 0 0 2 0 2 0 0 04: Delays falling asleep andoccasionally wakes me up at night 2 1 1 0 0 0 9 4 2 1 2 0
5: Delays falling asleep andfrequently wakes me up at night 2 0 1 0 1 0 4 2 0 2 0 0
Total 40 28 10 1 1 0 47 32 10 3 2 00102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
15Digestive Disease Week (DDW) 2020 Virtual Meeting
PBC-40: Itch
Q8. Itch disturbed my sleep Q9. I scratched so much Q10. I felt embarrassed because I made my skin raw of the itching
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
Did not apply/no itchNeverRarelySometimesMost of the timeAlways
16Digestive Disease Week (DDW) 2020 Virtual Meeting
PBC-40: Fatigue
Q13. Fatigue interfered with my daily routine
Q17. Fatigue just suddenly hit me
Q18. PBC drained every ounce of energy out of me
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
0102030405060708090
100
Prop
ortio
n of
Pat
ient
s (%
)
BL 1 Yr BL 1 Yr
5/10 mg 10 mg
NeverRarelySometimesMost of the timeAlways
17Digestive Disease Week (DDW) 2020 Virtual Meeting
Conclusions
Seladelpar treatment for 1-year reduced pruritus burden in PBC− Most patients with baseline VAS ≥ 40 mm improved by ≥ 20 mm− Correlated improvements: VAS, 5D-Itch and PBC-40 Itch− Sleep disturbance reduced by 5D-Itch and PBC-40
ENHANCE Placebo-Controlled Results (Fall 2020)− Placebo, 5 and 10 mg− Numeric Rating Scale (NRS) e-Diary− Quality-of-life (daily activities, fatigue and more)
Seladelpar symptom improvement supports further evaluation in PBC