Long-Term Efficacy and Safety of Open-Label Seladelpar Treatment in Patients With Primary Biliary Cholangitis (PBC): Interim Results for 2 Years From the ASSURE Study

Palak J. Trivedi1*, Cynthia Levy2, Kris V. Kowdley3, Stuart C. Gordon4, Christopher L. Bowlus5, Maria Carlota Londoño Hurtado6, Gideon M. Hirschfield7, Aliya Gulamhusein8, Eric J. Lawitz,9 Alejandra Villamil10, Alma Ladron de Guevara Cetina11, Marlyn Mayo12, Ziad Younes13, Oren Shibolet14, Kidist Yimam15, Daniel Pratt16, Jeong Heo17, Ulrike Morgera18, Pietro Andreone19, Andreas E. Kremer20, Christophe Corpechot21, Aparna Goel22, Adam Peyton23, Hany Elbeshbeshy24, Carrie Heusner25,

Sarah Proehl25, Shuqiong Zhuo25, Daria B. Crittenden25, and Charles A. McWherter25

  1. NIHR Birmingham BRC, University of Birmingham, Birmingham, UK; 2. University of Miami School of Medicine, Miami, FL; 3. Liver Institute Northwest, Seattle, WA; 4. Henry Ford Health System, Detroit, MI; 5. University of California, Davis, Sacramento, CA; 6. ERN-LIVER, University of Barcelona, Barcelona, Spain; 7. University Health Network, Toronto General Hospital, Toronto, ON, Canada; 8. Toronto General Hospital, Toronto, ON, Canada; 9. Texas Liver Institute, San Antonio, TX; 10. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina;
  1. Centro de Investigación y Gastroenterología, Mexico City, Mexico; 12. University of Texas Southwestern Medical Center, Dallas, TX; 13. Gastro One, Germantown, TN; 14. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 15. California Pacific Medical Center, San Francisco, CA;
  1. Massachusetts General Hospital, Boston, MA; 17. Pusan National University Hospital, Busan, South Korea; 18. Charité, Universitätsmedizin Berlin, Berlin, Germany; 19. University of Modena and Reggio Emilia, Modena, Italy; 20. University Hospital Zürich, Zürich, Switzerland;
  1. Saint-AntoineHospital, Paris, France; 22. Stanford Health Care, Stanford, CA; 23. Eastern Pennsylvania Gastroenterology and Liver Specialists, Allentown, PA; 24. Saint Louis University School of Medicine, St. Louis, MO; 25. CymaBay Therapeutics, Inc., Fremont, CA *Corresponding author: P.J.Trivedi@bham.ac.uk

Poster ST-13

Background

  • Seladelpar is a first-in-class, potent, and selective PPARδ agonist, or delpar, with anti-cholestatic,anti-inflammatory, and anti-pruritic activities
  • In the pivotal placebo-controlled,double-blind, Phase 3 RESPONSE (NCT04620733) study, seladelpar was safe and well tolerated, achieving significantly greater improvements in liver biochemistry parameters and pruritus compared with placebo
  • The ASSURE (NCT03301506) study is a Phase 3 open-label study of the long-term safety and efficacy of seladelpar 10 mg in patients with PBC
  • Patients could enter ASSURE through 2 pathways
    • Direct rollover from the RESPONSE study
    • Participation in a previous seladelpar PBC study ("Legacy studies")
  • Interim 2-year efficacy and safety results through January 31, 2024, are reported for
    337 patients enrolled in the ongoing ASSURE study
    • The Primary Analysis Population is defined as those patients who were administered the 10 mg dose of seladelpar

Study Design

Legacy Studies

Dose Ranging Phase 2

Phase 3 Long-Term Safety Study*

Gap

(NCT02955602)

(NCT03301506)

Open-label, 2, 5, or 10 mg

Open-label, 5 or 10 mg

12 months

21 months

Phase 3 ENHANCE*

Gap

(NCT03602560)

Placebo-controlled, 5 or 10 mg

Phase 3 ASSURE

12 months

Open-label, 10 mg

Phase 1b Hepatic Impairment

Ongoing

(NCT04950764)

Open-label, ≤10 mg

<30 days

Phase 3 RESPONSE

(NCT04620733)

Pivotal placebo-controlled, 10 mg

12 months

RESPONSE ROLLOVER

LEGACY STUDIES

Placebo

Seladelpar 10 mg

Crossover to seladelpar 10 mg

Composite Response

ALP Normalization

RESPONSE ROLLOVER

LEGACY STUDIES

Placebo

Seladelpar 10 mg

Crossover to seladelpar 10 mg

AST Percentage Change From Baseline

GGT Percentage Change From Baseline

Safety Overview

TEAE Category, n (%)

RESPONSE Rollover Patients

Legacy Patients

Crossover Seladelpar

Continuous Seladelpar

(N=179)

(N=54)

(N=104)

Subjects with ≥1 TEAE

42

(77.8)

73

(70.2)

149 (83.2)

Treatment-emergent SAE

7 (13.0)

6

(5.8)

24

(13.4)

Grade ≥3 TEAE

5

(9.3)

9

(8.7)

27

(15.1)

Treatment-related treatment-emergent SAE

0

0

0

TEAE with action taken as permanent

1

(1.9)

2

(1.9)

11 (6.1)

withdrawal of study drug

TEAE leading to study discontinuation

1

(1.9)

1

(1.0)

7

(3.9)

TEAE with fatal outcome

0

0

1

(0.6)

  • 1 fatal outcome was due to autoimmune hemolytic anemia
    • Assessed to be unrelated to seladelpar by both the investigator and the sponsor

Common AEs (≥5% of Overall Patient Population)

TEAEs by Preferred Term, n (%)

RESPONSE Rollover Patients

Legacy Patients

Crossover Seladelpar

Continuous Seladelpar

(N=179)

(N=54)

(N=104)

COVID-19

5 (9.3)

5 (4.8)

38 (21.2)

Pruritus

0

10 (9.6)

24 (13.4)

Urinary tract infection

2 (3.7)

7 (6.7)

17 (9.5)

Nausea

2 (3.7)

5 (4.8)

16 (8.9)

Diarrhea

5 (9.3)

2 (1.9)

15 (8.4)

Fatigue

1 (1.9)

5 (4.8)

14 (7.8)

Nasopharyngitis

0

5 (4.8)

15 (8.4)

Abdominal pain upper

1 (1.9)

5 (4.8)

12 (6.7)

Arthralgia

4 (7.4)

3 (2.9)

11 (6.1)

Liver-Related AEs (Overall, Occurring in >1 Patient)

RESPONSE Rollover Patients

Legacy Patients

TEAEs Overall & by Preferred Term, n (%)

Crossover Seladelpar

Continuous Seladelpar

(N=179)

Patient Disposition

357 Assessed for Eligibility

339 Enrolled

17 Excluded for Not Meeting Inclusion Criteria

Change in Pruritus NRS

(N=54)

(N=104)

n (%)

n (%)

n (%)

Subjects with ≥1 liver-related TEAE

0

7 (6.7)

18

(10.1)

AST increased

0

0

6

(3.4)

ALT increased

0

0

5

(2.8)

Blood bilirubin increased

0

0

4

(2.2)

Crossover Seladelpar

Continuous Seladelpar

Legacy

55 Rolled Over From

104 Rolled Over From

180 From Seladelpar

27 Discontinued Treatment

RESPONSE Placebo

RESPONSE Seladelpar

Legacy Studies

9 Adverse event

1 Discontinued Treatment

7

Sponsor closed site

4

Withdrew consent

1 Discontinued Treatment

1 Adverse event

1

PBC clinical outcome

1 PBC clinical outcome

1 Adverse event

1

Death

1 Required prohibited

1

Noncompliance

concomitant medication

1

Lost to follow-up

54 Primary Analysis

104 Primary Analysis

179 Primary Analysis

1

Pregnancy

2 Other

Population

Population

Population

ONGOING STUDY

Patients as of January 31, 2024

Time Point

≥26 Weeks

≥12 Months

≥18 Months

≥24 Months

Number of

Crossover Seladelpar

52

14

2

0

Patients in

Continuous Seladelpar

123

116

103

28

Each Arm

Legacy

172

165

133

97

Time points for Crossover Seladelpar and Legacy groups indicate time in ASSURE. Time points for Continuous Seladelpar indicate time in both RESPONSE and ASSURE.

Demographics and Characteristics at ASSURE Baseline

Category

RESPONSE Rollover Patients

Legacy Patients

Crossover Seladelpar

Continuous Seladelpar

Seladelpar 10 mg

(N=54)

(N=104)

(N=179)

Age, years, mean (SD)

57.9 (9.3)

58.0 (10.1)

58.8 (9.6)

Female sex, n (%)

50 (92.6)

99 (95.2)

169 (94.4)

Race or ethnicity, n (%)

American Indian or Alaska Native

3

(5.6)

2 (1.9)

6

(3.4)

Asian

4

(7.4)

6 (5.8)

14 (7.8)

Black or African American

2

(3.7)

2 (1.9)

3

(1.7)

White

45 (83.3)

93 (89.4)

153 (85.5)

Hispanic or Latino

23 (42.6)

24 (23.1)

24 (13.4)

BMI, kg/m2, mean (SD)

26.9 (5.1)

27.8 (6.1)

27.4 (6.0)

Patients with cirrhosis at baseline, n (%)

7

(13.0)

16 (15.4)

35 (19.6)

Child-Pugh Class A, n (%)

7

(100)

15 (93.8)

31 (88.6)

Child-Pugh Class B, n (%)

0

1 (6.3)

4

(11.4)

Patients with cirrhosis at baseline and

1

(14.3)

0

8

(22.9)

portal hypertension, n (% of cirrhotics)

MELD score ≥12, n (%)

0

2 (1.9)

1

(0.6)

ALP,§ U/L, mean (SD)

288.7 (125.5)

183.1 (112.1)

274.2 (133.1)

Total bilirubin, mg/dL, mean (SD)

0.7 (0.3)

0.7 (0.5)

0.8 (0.4)

ALP Percentage Change From Baseline

Total Bilirubin Percentage Change From Baseline

ALT Percentage Change From Baseline

In Patients With NRS ≥4 at Baseline

ALT Normalization

In Patients With Elevated ALT at Baseline

Total Bilirubin Normalization

In Patients With Elevated Total Bilirubin at Baseline

Hyperbilirubinemia

0

2 (1.9)

2 (1.1)

Ascites

0

1 (1.0)

2 (1.1)

Hepatic cyst

0

2 (1.9)

1 (0.6)

Portal hypertension

0

2 (1.9)

1 (0.6)

Oesophageal varices

0

1 (1.0)

2 (1.1)

Ocular icterus

0

0

2 (1.1)

  • 7.4% of subjects overall had liver-related AEs by predefined search strategy
    • Most were Grade 1 or 2
    • 5 subjects had events that led to discontinuation (events of blood bilirubin increased, hepatorenal syndrome, hyperbilirubinemia, jaundice, and oesophageal varices haemorrhage)
      • 3 events (2 SAEs) were adjudicated by the CERC as PBC clinical outcomes (variceal bleed in 1 patient [186 days on study], ascites requiring treatment in 2 patients [309 and 473 days on study])
      • 3 subjects were reviewed by the CERC and none were adjudicated as positive for DILI
  • All muscle-related AEs were Grade 1 or 2
    • None led to discontinuation
  • There was 1 proteinuria renal event of Grade 1

CONCLUSIONS

  • 2-yearresults from the ASSURE long-term extension study of seladelpar for the treatment of PBC demonstrated
    • Durable effect on markers of cholestasis and liver injury was maintained for up to 2 years
    • Sustained reduction in pruritus in patients with baseline NRS ≥4 was observed
    • Seladelpar appears safe and well tolerated
    • Results are consistent with the pivotal Phase 3 RESPONSE study

REFERENCE

Hirschfield GM, et al. N Engl J Med. 2024;390(9):783-794.

DISCLOSURES

DBC, CH, SP, SZ, and CAM are employees of CymaBay Therapeutics, Inc.

ACKNOWLEDGEMENTS

We gratefully acknowledge the study patients, investigators, site staff, and the ASSURE team.

This analysis was sponsored by CymaBay Therapeutics, Inc. (Fremont, CA, USA). Medical writing and editorial assistance were provided by John Gatiss, Katherine Murnen, and Howard Wolfson (ClinicalMind, New York, NY, USA) and were funded by CymaBay Therapeutics, Inc.

AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BL, baseline; BMI, body mass index; DILI, drug-induced liver injury; GGT, gamma-glutamyltransferase; M, month; MELD, Model for End-Stage Liver Disease; NRS, numerical rating scale; PPAR, peroxisome proliferator-activated receptor; SAE, serious adverse event; TEAE, treatment-emergent adverse event. *Early terminated. Patients were eligible to enroll in ASSURE after completing the study, but they had to meet screening criteria and had variable time to entry. 1 patient of the total patient population (N=357) was eligible but did not receive seladelpar and thus was not formally enrolled. §Mean ALP values are from ASSURE entry. At RESPONSE entry, the mean ALP (SD) for placebo patients (N=65) was 313.8 (117.7) U/L and for seladelpar patients (N=128) it was 314.6 (123.0) U/L. At RESPONSE entry for patients with NRS ≥4, mean (SD) baseline NRS was 6.1 (1.4) for seladelpar patients and 6.6 (1.4) for placebo patients; mean (SD) baseline NRS in Legacy patients with NRS ≥4 (at ASSURE baseline) was 6.4 (1.7). By predefined MedDRA search strategy.

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CymaBay Therapeutics Inc. published this content on 05 June 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 05 June 2024 06:52:07 UTC.