Single Ascending Dose Study to Evaluate Safety Tolerability, Pharmacokinetics, and Pharmacodynamics of PVT201 in Healthy Subjects and Patients (PBC/PSC)

Prior treatment

• Use of any prescription medication within 14 days prior to the dose of study drug and/or over-the-counter medication/vitamins/supplements/herbal/plant-derived medications within 7 days prior to the dose of study drug.
• Concurrent enrollment in another clinical study, or participation in another clinical study within 30 days prior to Screening.
• Positive urine drugs of abuse test at Screening, upon admission to the clinic on Day -1.
• Subjects who have previously undergone liver transplantation.
• Positive urine drugs of abuse test at Screening, upon admission to the clinic on Day -1.
• Immunosuppressant therapies including methotrexate, azathioprine, or long-tern systemic corticosteroids within 2 months prior to Day 1.
• Treatment with any other investigational therapy or device within 6 weeks or within 5 half-lives, whichever is longer, prior to Day 1.
• Known substance abuse or medical, psychological, or social conditions other than PBC or PSC, or prior therapy that in the opinion of the PI would make the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

Other illness

• Any active infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications.
• History of hypersensitivity reaction, anaphylaxis or other CS reactions or known allergy to the study drug or its ingredients including but not limited to dextran.
• History of any clinically significant disorder which, in the opinion of the Investigator would make implementation of the protocol or interpretation of study results difficult, or that would put the participant at risk by participating in the study.
• Positive Hepatitis B surface antigen (HBsAg), Hepatitis C (HepC) virus antibody, or human immunodeficiency (HIV) antibody tests.
• Known substance abuse or medical, psychological, or social conditions that in the opinion of the study doctor would make the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.
  • PBC/PSC PATIENT ELIGIBILITY CRITERIA
• Current or a history of hepatic decompensation events.
• Subject is diagnosed with Gilbert's Syndrome.
• History of ileectomy, colostomy, colectomy, splenectomy, or thymectomy.
• Any active infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications.
• Co-existing liver or biliary diseases, such as choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, acute infection of bile duct system or gall bladder, history of gastrointestinal bleeding (secondary to portal hypertension), hepatorenal syndrome, cholangiocarcinoma diagnosed or suspected liver cancers.
• Presence of conditions that may cause non-hepatogenic ALP elevations (eg, Paget's disease) or conditions that may lead to a life expectancy of less than 2 years.
• History of active malignancy within the past year except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
• Positive Hepatitis B surface antigen (HBsAg), Hepatitis C (HepC) virus antibody, or human immunodeficiency (HIV) antibody tests.
• History of hypersensitivity reaction, anaphylaxis or other CS reactions or known allergy to the study drug or its ingredients including but not limited to dextran.

Lab values

• Laboratory results at Screening that indicate inadequate renal function, with estimated creatinine clearance of \< 60 mL/min/1.73m2.
• Liver function test results elevated more than 1.5-fold above the upper limit of normal for GGT, ALP, AST or ALT.
• Total bilirubin \> 1.5-fold above the upper limit of normal.
• Laboratory Screening Results:
  • AST \>5 x ULN,
  • ALT \>5 x ULN,
  • ALP \> 10 x ULN,
  • Total bilirubin \> 1.5 x ULN,
  • Albumin \< 35 g/L,
  • Total white blood cells (WBC) \<3000 cells/mm3,
  • Absolute neutrophil count (ANC) \<1500 cells/mm3,
  • Platelet count \<130,000/mm3, unless on stable anticoagulants at the discretion of the investigator,
  • Prothrombin time (international normalized ratio, INR) \>1.3,
  • Serum creatinine \>175 µmol/L or creatinine clearance \<50 mL/min.

Other

• Participant has undergone splenectomy or thymectomy.
• Positive alcohol breath test at Screening, upon admission to the clinic on Day -1.
• Participant has a positive cotinine test upon admission to the clinic on Day -1.
• Participant is breastfeeding/lactating or pregnant, or planning to breastfeed or become pregnant during the study.
• Positive alcohol breath test at Screening, upon admission to the clinic on Day -1.
• Participant has a positive cotinine test at Screening, upon admission to the clinic on Day -1.
• Participant is breastfeeding/lactating or pregnant, or planning to breastfeed or become pregnant during the study.

• Healthy male or female, aged between 18 and 65 years, inclusive at Screening.
• Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, with body weight ≥ 50.0 kg and \< 120.0 kg.
• Carry the HLA DRB4\*0101 or DRB4\*0103 allele.
• Participant is medically healthy (in the opinion of the Investigator), as determined by pre-study medical history and without CS abnormalities.
• Female participants must be of non-child-bearing potential, or, if of child-bearing potential:
  • Must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test on Day -1.
  • Must agree not to donate ova or attempt to become pregnant from the time of signing consent until at least 30 days after the dose of study drug.
  • If not exclusively in a same-sex relationship or abstinent as a committed lifestyle, must agree to use adequate contraception established at Screening until at least 30 days after the dose of study drug.
• Male participants must:
  • Agree not to donate sperm from the time of signing consent until at least 90 days after the dose of study drug.
  • If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception from the time of signing consent until at least 90 days after the dose of study drug.
• Male or female, aged between 18 and 75 years, inclusive at Screening.
• Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive, with body weight ≥ 50.0 kg and \< 120.0 kg.
• Carry the HLA DRB4\*0101 or DRB4\*0103 allele.
• Participant is medically healthy (in the opinion of the Investigator), as determined by pre-study medical history and without CS abnormalities.
• Male or female with a diagnosis of primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC).
• For subjects on any medication used to treat the symptoms of PBC or PSC (examples: UDCA, OCA, seladelpar), subjects must be on a stable dose for a minimum of 2 months prior to Day 1 and expected to stay on treatment for duration of study participation OR must have been off treatment for at least 2 months prior to Day 1.
• Subjects with inflammatory bowel disease (IBD) must have been on stable therapy \> 2 months prior to Day 1.
• Female participants must be of non-child-bearing potential, or, if of child-bearing potential:
  • Must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test on Day -1,
  • Must agree not to donate ova or attempt to become pregnant from the time of signing consent until at least 30 days after the dose of study drug,
  • If not exclusively in a same-sex relationship or abstinent as a committed lifestyle, must agree to use adequate contraception established at Screening until at least 30 days after the dose of study drug.
• Male participants must:
  • Agree not to donate sperm from the time of signing consent until at least 90 days after the dose of study drug,
  • If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception from the time of signing consent until at least 90 days after the dose of study drug.

Criteria the registry did not label

• HEALTHY VOLUNTEER ELIGIBILITY CRITERIA