Study to Assess Safety & Efficacy of GKT137831 in Patients With Primary Biliary Cholangitis Receiving Ursodiol.

Primary biliary cholangitis (PBC) is a disease of the liver. It is caused a sustained attack by the body's immune system on the bile ducts (canals) inside the liver. This continuous assault leads to their gradual destruction and eventual disappearance. This results in obstruction to the flow of bile which gets worse with disease progression. Once the bile duct injury has been established, the disease progresses due to ongoing obstruction of bile flow, inflammation and scarring of the liver tissue(fibrosis). The liver eventually fails.

This research is looking into whether the study drug is better than a dummy drug when given to patients with PBC. This trial will monitor the patients taking part with regular blood tests and ultrasound liver scans before, during, and at the end of the trial. These measures will allow for the ongoing assessment of liver function, and liver stiffness. It is hoped that in patients in whom the study drug is beneficial, the liver function or stiffness may progress at a slower pace, or may even improve during or at the end of the trial. Liver injury, inflammation and fibrosis Participants will be randomly assigned to 1 of 3 treatment groups (active drug once daily, active drug twice daily or placebo). This is a double blinded study so neither the participants nor the staff responsible for their care will know which group they have been assigned to. During the treatment period, participants will take 4 capsules orally at home in the morning and 4 capsules in the evening for 24 weeks.

Participants will be in the trial for 32 weeks in total (about 8 months) and will attend approximately 8 clinic visits.

• GKT137831 (Drug), also known as setanaxib: GKT137831 100mg capsules. To be taken as part of two dose arms which are 400mg twice daily or 400mg once daily.
• Placebo oral capsule (Drug), also known as Placebo: Matching capsules.

Primary outcomes

• The Percent Change in Serum GGT. [Baseline to week 24 (visit 7)]: Percent change in serum GGT from baseline to Week 24 (serum GGT was measured in U/L)

Secondary outcomes

• Absolute Change in Serum GGT [From baseline to Weeks 2, 6, 12, 18 and 24]: Absolute change in serum GGT from baseline to each assessment.
• Percent Change in Serum GGT [From baseline to Weeks 2, 6, 12, 18 and 24]: Percent change in serum GGT from baseline to each assessment (serum GGT was measured in U/L)
• Percent Change in Serum ALP [From baseline to Weeks 2, 6, 12, 18 and 24]: Percent change in serum ALP from baseline to each assessment (serum ALP was measured in U/L).
• Absolute Change in Serum ALP [From baseline to Weeks 2, 6, 12, 18 and 24]: Absolute change in serum ALP from baseline to each assessment.
• Absolute Change in Serum Conjugated Bilirubin. [From baseline to Weeks 2, 6, 12, 18 and 24]: Absolute change in serum conjugated bilirubin from baseline to each assessment.
• Percent Change in Serum Conjugated Bilirubin. [From baseline to Weeks 2, 6, 12, 18 and 24]: Percent change in serum Conjugated bilirubin, from baseline to each assessment (serum conjugated bilirubin is measured in μmol/L).
• Absolute Change in Serum Total Bilirubin. [from baseline to Weeks 2, 6, 12, 18 and 24]: Absolute change in serum total bilirubin, from baseline to each assessment.
• Percent Change in Serum Total Bilirubin. [from baseline to Weeks 2, 6, 12, 18 and 24]: Percent change in Serum Total Bilirubin from baseline to each assessment (serum total bilirubin is measured in μmol/L).
• Absolute Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology). [From baseline to Week 24, in patients with values at baseline and Week 24.]: Absolute change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24.
• Percent Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology). [From baseline to Week 24, in patients with values at baseline and Week 24.]: Percent change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24 (liver stiffness is measured in kPa).
• Percent Change in Serum Levels of Collagen Fragments Indicative of Collagen Formation and Degradation. [From baseline to Weeks 12 and 24.]: Percent change in serum levels of collagen fragments indicative of collagen formation and degradation, from baseline to Weeks 12 and 24 (serum levels of collagen fragments are measured in ng/mL).
• Absolute Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology). [From baseline to Week 24, in patients with values at baseline and Week 24.]: Absolute change in liver stiffness by subgroup (>=9.6 kPa) as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24.
• Percent Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology). [From baseline to Week 24, in patients with values at baseline and Week 24.]: Percent change in liver stiffness by subgroup (>=9.6 kPa) as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24 (liver stiffness is measured in kPa).
• Absolute Change in Pruritis Visual Analogue Scale (VAS) Scores [From baseline to Weeks 12 and 24]: Absolute Change in Pruritis Visual Analogue Scale (VAS) scores from baseline to weeks 12 and 24- Score from 0 to 10, 0= no itch and 10= severe itch, continuous, day and night intolerable itch.
• Percent Change in Pruritis Visual Analogue Scale (VAS) Scores [From baseline to Weeks 12 and 24]: Percent Change in Pruritis Visual Analogue Scale (VAS) scores from baseline to weeks 12 and 24- Score from 0 to 10, 0= no itch and 10= severe itch, continuous, day and night intolerable itch.
• Absolute Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores [From baseline to Weeks 12 and 24]: Absolute Change in PBC-40 Domain scores from baseline to weeks 12 and 24 Symptoms domain: items 1 to 7 of the PBC-40 questionnaire (score from 6 to 35). Itch domain: items 8 to 10 of the PBC-40 questionnaire (score from 0 to 15). Fatigue domain: items 11 to 21 of the PBC-40 questionnaire (score from 11 to 55). Cognitive domain: items 22 to 27 of the PBC-40 questionnaire (score from 6 to 30). Emotional domain: items 28, 30 and 33 of the PBC-40 questionnaire (score from 3 to 15). Social domain: items 29, 31, 32, 34 to 40 of the PBC-40 questionnaire (score from 8 to 50). Higher scores mean worse outcome.
• Percent Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores [From baseline to Weeks 12 and 24]: Percent Change in PBC-40 Domain scores from baseline to weeks 12 and 24 Symptoms domain: items 1 to 7 of the PBC-40 questionnaire (score from 6 to 35). Itch domain: items 8 to 10 of the PBC-40 questionnaire (score from 0 to 15). Fatigue domain: items 11 to 21 of the PBC-40 questionnaire (score from 11 to 55). Cognitive domain: items 22 to 27 of the PBC-40 questionnaire (score from 6 to 30). Emotional domain: items 28, 30 and 33 of the PBC-40 questionnaire (score from 3 to 15). Social domain: items 29, 31, 32, 34 to 40 of the PBC-40 questionnaire (score from 8 to 50). Higher scores mean worse outcome.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

1. Male or female aged 18 to 80 years, inclusive.
2. Willing and able to give written informed consent and to comply with the requirements of the study.
3. PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:

   * History of elevated ALP levels (> ULN) for at least 6 months
   * Positive anti-mitochondrial antibody (AMA) titer or if AMA negative or in low titer (< 1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components \[PDC-E2, 2-oxo-glutaric acid dehydrogenase complex\])
   * Liver biopsy consistent with PBC (based on historic liver biopsy), including non-suppurative, destructive cholangitis affecting mainly the interlobular and septal bile ducts.
4. Serum ALP ≥ 1.5 x ULN.
5. Serum GGT ≥ 1.5 x ULN.
6. UDCA treatment for at least 6 months and stable dose for at least 3 months prior to Visit 1.
7. Subjects being treated for pruritus with colestyramine must be on a stable dose of colestyramine for at least 8 weeks prior to baseline/Day 1 (Visit 2). Subjects must be willing and able to take colestyramine at least 2 hours before or after study medication.
8. Female subjects of childbearing potential must use a highly effective method of contraception to prevent pregnancy for 4 weeks before randomization and must agree to continue strict contraception for 90 days after last administration of investigational medicinal product (IMP). Male participants with female partners of childbearing potential must be willing to use a condom and require their partner to use an additional form of adequate contraception as approved by the Investigator. This requirement begins at the time of informed consent and ends 90 days after the last administration of IMP. Male study participants must also not donate sperm from baseline until 90 days after the last administration of IMP.

Exclusion Criteria:

1. A positive pregnancy test or breast-feeding for female subjects.
2. Any hepatic decompensation, defined as a past or current history of hepatic encephalopathy, gastrointestinal tract bleeding due to esophageal varices, or ascites.
3. International normalized ratio (INR) > 1.2 unless subject is on anticoagulant therapy.
4. ALT > 3 x ULN.
5. Total bilirubin > 1 x ULN.
6. Planned or current plasmapheresis or other extra-corporeal treatments (e.g., molecular adsorbent recirculation system (MARS)) for treatment-refractory pruritus.
7. History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15.
8. Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma.
9. Hepatorenal syndrome (type I or II) or Screening serum creatinine > ULN.
10. Competing etiology for liver disease (e.g., hepatitis C, active hepatitis B, non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), autoimmune hepatitis, primary sclerosing cholangitis, Gilbert's Syndrome).
11. Subjects receiving prohibited medications within 3 months of Screening (Visit 1) according to the list (a, b and c) provided in Section 6.6.2.
12. Treatment with any investigational agent within 4 weeks of Visit 1 or 5 half-lives of the investigational medicinal product (whichever is longer).
13. A history of long QT syndrome.
14. Evidence of any of the following cardiac conduction abnormalities during the screening period:

    * A QTc Fredericia interval >450 milliseconds for males and >470 milliseconds for females.
    * A second or third degree atrioventricular block not successfully treated with a pacemaker.
15. History of cancer in the preceding 5 years, except adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, in situ prostate cancer, in situ breast ductal carcinoma, or superficial bladder cancer stage 0).
16. The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior the Screening Visit (Visit 1), or human immunodeficiency virus (HIV) infection.
17. A history of bone marrow disorder including aplastic anemia, or marked anemia defined as hemoglobin < 10.0 g/dL (or 6.2 mmol/L).
18. Any condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the subject in the study, or which could interfere with the study objectives, conduct, or evaluation.

Participant flow

Outcome results

• The Percent Change in Serum GGT. (Primary), Mean, percent change: GKT137831 400mg Once Daily -4.9 +/- 59.58; GKT137831 400mg Twice Daily -19 +/- 28.89; Placebo Arm -8.4 +/- 21.45
• Absolute Change in Serum GGT (Secondary), Mean, U/L: GKT137831 400mg Once Daily -14.3 +/- 112.66; GKT137831 400mg Twice Daily -48.5 +/- 61.83; Placebo Arm -11.2 +/- 45.96
• Percent Change in Serum GGT (Secondary), Mean, percent change: GKT137831 400mg Once Daily -7 +/- 25.08; GKT137831 400mg Twice Daily -17 +/- 17.25; Placebo Arm -6.2 +/- 13.04
• Percent Change in Serum ALP (Secondary), Mean, percent change: GKT137831 400mg Once Daily -5.5 +/- 10.95; GKT137831 400mg Twice Daily -13.0 +/- 12.71; Placebo Arm -3.6 +/- 11.51
• Absolute Change in Serum ALP (Secondary), Mean, U/L: GKT137831 400mg Once Daily -19.8 +/- 35.95; GKT137831 400mg Twice Daily -45.9 +/- 75.75; Placebo Arm -17 +/- 44.4
• Absolute Change in Serum Conjugated Bilirubin. (Secondary), Mean, μmol/L: GKT137831 400mg Once Daily 0 +/- 1.32; GKT137831 400mg Twice Daily 0.3 +/- 1.61; Placebo Arm -0.1 +/- 1.4
• Percent Change in Serum Conjugated Bilirubin. (Secondary), Mean, percent change: GKT137831 400mg Once Daily 0.9 +/- 16.81; GKT137831 400mg Twice Daily 5.2 +/- 22.79; Placebo Arm 1.3 +/- 28.11
• Absolute Change in Serum Total Bilirubin. (Secondary), Mean, μmol/L: GKT137831 400mg Once Daily -0.2 +/- 2.51; GKT137831 400mg Twice Daily 0.1 +/- 2.76; Placebo Arm -0.4 +/- 3.75
• Percent Change in Serum Total Bilirubin. (Secondary), Mean, percent change: GKT137831 400mg Once Daily -0.6 +/- 23.62; GKT137831 400mg Twice Daily 5.3 +/- 32.42; Placebo Arm 3.3 +/- 39.98
• Absolute Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology). (Secondary), Mean, kPa: GKT137831 400mg Once Daily -0.5 +/- 5.24; GKT137831 400mg Twice Daily -0.3 +/- 7.9; Placebo Arm 0.7 +/- 3.63
• Percent Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology). (Secondary), Mean, percent change: GKT137831 400mg Once Daily 3.3 +/- 34.95; GKT137831 400mg Twice Daily 7.9 +/- 43.68; Placebo Arm 10.1 +/- 33.11
• Percent Change in Serum Levels of Collagen Fragments Indicative of Collagen Formation and Degradation. (Secondary), Mean, percent change: GKT137831 400mg Once Daily -2.58 +/- 21.09; GKT137831 400mg Twice Daily -1.31 +/- 18.23; Placebo Arm 3.64 +/- 27.86
• Absolute Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology). (Secondary), Mean, kPa: GKT137831 400mg Once Daily -1.9 +/- 7.49; GKT137831 400mg Twice Daily -2.1 +/- 2.43; Placebo Arm 0.4 +/- 4.65
• Percent Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology). (Secondary), Mean, percent change: GKT137831 400mg Once Daily -5.3 +/- 35.10; GKT137831 400mg Twice Daily -16.1 +/- 20.71; Placebo Arm 4.2 +/- 30.09
• Absolute Change in Pruritis Visual Analogue Scale (VAS) Scores (Secondary), Mean, score on a scale: GKT137831 400mg Once Daily -0.1 +/- 3.1; GKT137831 400mg Twice Daily 0.3 +/- 2.33; Placebo Arm 0.5 +/- 1.79
• Percent Change in Pruritis Visual Analogue Scale (VAS) Scores (Secondary), Mean, percent change: GKT137831 400mg Once Daily -35.1 +/- 46.13; GKT137831 400mg Twice Daily -11.7 +/- 73.87; Placebo Arm -8.3 +/- 70.68
• Absolute Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores (Secondary), Mean, score on a scale: GKT137831 400mg Once Daily -0.4 +/- 3.34; GKT137831 400mg Twice Daily -0.9 +/- 3.19; Placebo Arm -0.2 +/- 3.52
• Percent Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores (Secondary), Mean, percent change: GKT137831 400mg Once Daily -2.8 +/- 24.68; GKT137831 400mg Twice Daily -2.7 +/- 24.48; Placebo Arm 3.1 +/- 37.21

Adverse events

Time frame: .Approximately 6-7 months

Serious adverse events by term

Other adverse events by term

• Results publication: Invernizzi P, Carbone M, Jones D, Levy C, Little N, Wiesel P, Nevens F; study investigators. Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial. Liver Int. 2023 Jul;43(7):1507-1522. doi: 10.1111/liv.15596. Epub 2023 May 15. PMID 37183520
• Results publication: Jones D, Carbone M, Invernizzi P, Little N, Nevens F, Swain MG, Wiesel P, Levy C. Impact of setanaxib on quality of life outcomes in primary biliary cholangitis in a phase 2 randomized controlled trial. Hepatol Commun. 2023 Feb 20;7(3):e0057. doi: 10.1097/HC9.0000000000000057. eCollection 2023 Mar 1. PMID 36809195

• Study Protocol (PDF, 2018-07-24)
• Statistical Analysis Plan (PDF, 2019-03-15)

• Philippe Wiesel, MD, Study director, Calliditas Therapeutics AB

NIH grants: 2016