A Study of TAK-781 in Healthy Volunteers and in Participants With Non-Cirrhotic Primary Sclerosing Cholangitis (PSC)

Inclusion Criteria

• •1. The participant is willing and able to fully comply with all trial procedures and requirements, in the investigator's opinion.
• •2. The participant has provided informed consent (that is, in writing, documented via a signed and dated informed consent form (ICF) or electronic consent \[e-consent\] if applicable) and any required privacy authorization prior to the initiation of any trial procedures.
• •3. Male at birth and female at birth participants aged 18 to 68 years, inclusive, at the time of consent.
• •4. The participant is judged to be in good health (for example, no evidence of cardiovascular, liver, metabolic, gastroenterological, or kidney disease) by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, ECG, and vital sign measurements performed at the first screening visit.
• •5. The participant must have a body mass index (BMI) of less than 30.0 kilograms per square meter (kg/m\^2) at the time of screening.
• •6. Has not had frequent or heavy use (that is, near-daily) of medical or recreational cannabis for at least 3 months before screening.
• •7. The participant must not be a person of childbearing potential (POCBP) defined by at least 1 of the following criteria:
• •* Surgically sterile for at least 6 weeks at screening (defined as having undergone one of the following procedures: hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).
• •* Postmenopausal at screening (defined as no menses for 12 months without an alternative medical cause). A high follicle-stimulating hormone (FSH) level (greater than or equal to \[\>=\]40 international units/liter \[IU/L\] in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
• •* Has no uterus as a result of congenital condition. The participant must not donate ova for at least 6 months after the last dose of trial intervention.
• •8. Male participants (based on sex at birth) must use highly effective contraception, from the date of signing the ICF, throughout the duration of the trial, and for 6 months after the last dose of trial intervention. The participant must not donate sperm for at least 6 months after the last dose of trial intervention.
• •1. The participant is willing and able to fully comply with all trial procedures and requirements, in the investigator's opinion.
• •2. The participant has provided informed consent (that is, in writing, documented via a signed and dated ICF or e-consent if applicable) and any required privacy authorization prior to the initiation of any trial procedures.
• •3. Male at birth and female at birth participants aged 18 to 68 years, inclusive, at the time of consent.
• •4. Confirmed diagnosis of large-duct PSC based on any 2 of the following 3 criteria:
• •* Historical evidence of an elevated alkaline phosphatase (ALP) greater than \[\>\] upper limit of normal (ULN) from any laboratory.
• •* Historical liver biopsy with histologic features consistent with large-duct PSC, in the appropriate clinical context (such as cholestatic liver enzyme profile, inflammatory bowel disease \[IBD\] history).
• •* Historical abnormal cholangiography consistent with PSC as measured by magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography, or percutaneous transhepatic cholangiography.
• •5. The participants must have a fibrogenesis biomarker over pre-defined level.
• •6. The participants must have evidence for moderate/advanced fibrosis but not cirrhosis as defined by enhanced liver fibrosis (ELF) \>=7.7 but less than or equal to(\<=)11.3 at Visit 1.
• •7. No evidence of cholangiocarcinoma or any other malignancy on magnetic resonance imaging (MRI) at screening.
• •8. Participants with a certain concomitant disease are allowed to enroll if pre-defined criteria are met.
• •9. Participants must have certain additional laboratory parameters in specified ranges at screening.
• •10. Has not had frequent or heavy use (that is, near-daily) of medical or recreational cannabis for at least 3 months before screening.
• •11. A female and male participant (based on sex at birth) must use highly effective contraception, from the date of signing the ICF, throughout the duration of the trial, and for 6 months after the last dose of trial intervention. The participant must not donate ova or sperm for at least 6 months after the last dose of trial intervention.
• •12. A POCBP must have a negative serum pregnancy test at first screening visit and urine pregnancy test on second screening visit and Day 1 before dosing.
• •13. Participants must be able to be educated regarding the correct process/procedure, verbally state understanding and comply with the correct process/procedure of the administration SC IP for the duration of the trial.
• •19. Participants who test positive for hepatitis C virus (HCV) ribonucleic acid (RNA) at screening. Participants who are hepatitis C antibody (HCVAb) positive without evidence of HCV RNA may be considered eligible (spontaneous viral clearance or previously treated and cured \[defined as no evidence of HCV RNA at least 12 weeks before screening Visit1\]).
• •20. The participant tests positive for human immunodeficiency virus (HIV) at screening or currently receiving antiretroviral therapy.
• •21. Has undergone major surgery or donated or lost 1 unit of blood (approximately 500 milliliters \[mL\]) within 4 weeks before the screening visit.
• •22. Currently has or previously had a significant illness, as judged by the investigator, within 2 weeks of the first dose of trial intervention.
• •23. The participant is unable to refrain from or anticipates using prohibited or excluded medications, herbal preparations, grapefruit juice, and other restricted substances or the required washout period prior to administration of the first dose of trial intervention throughout the trial and until the follow-up visit.
• •24. The participant is unable to refrain from or anticipate using smoking, vaping or nicotine-containing products 2 weeks before screening until the last follow-up visit.
• •25. Clinically relevant drug or alcohol abuse within 12 months of screening.
• •* A positive drug screen is exclusive unless it can be explained by a prescribed medication.
• •* Participant with alcohol consumption greater than 4 units on any day or 14 units per week for male participants, or greater than 3 units on any day or 7 units per week for female participants \[1 unit of alcohol is present in one 12 ounce (oz)/355 mL beer (approximately 5 percent (%) alcohol), one 5 oz/148 mL glass of wine (approximately 12% alcohol), and one 1.5 oz/44 mL measure of 80-proof liquor (approximately 40% alcohol)\].
• •17. Participants who test positive for HCV RNA at screening. Participants who are HCVAb positive without evidence of HCV RNA may be considered eligible (spontaneous viral clearance or previously treated and cured \[defined as no evidence of HCV RNA at least 12 weeks before baseline\]).
• •18. The participant tests positive for HIV at screening or currently receiving antiretroviral therapy.
• •19. History of malignancy diagnosed or treated within 5 years prior to screening.
• •20. The participant is unable to refrain from or anticipates using prohibited or excluded medications, herbal preparations, grapefruit juice, and other restricted substances or the required washout period prior to administration of the first dose of trial intervention throughout the trial and until the follow-up visit.
• •21. The participant has not had frequent or heavy use (\>=20 cigarettes per day) of smoking, vaping or nicotine-containing products or has not smoking-related complications.
• •22. Clinically relevant drug or alcohol abuse within 12 months of screening.
• •* A positive drug screen is exclusive unless it can be explained by a prescribed medication.
• •* Participant with alcohol consumption greater than 4 units on any day or 14 units per week for male participants, or greater than 3 units on any day or 7 units per week for female participants \[1 unit of alcohol is present in one 12 oz/355 mL beer (approximately 5% alcohol), one 5 oz/148 mL glass of wine (approximately 12% alcohol), and one 1.5 oz/44 mL measure of 80-proof liquor (approximately 40% alcohol)\].
• •23. Use of any prohibited concomitant medication is not allowed unless the participant has completed the washout period prior to Day 1.
• •24. Participants should not be currently taking ursodeoxycholic acid, unless they have completed the washout period prior to Day 1.
• •25. Severe allergic or anaphylactic reactions to any components of N-acetylgalactosamine small-interfering RNA therapeutics.
• •26. Use of any investigational drug, biologic, or medical device, or participation in an interventional clinical trial, is prohibited within 4 weeks prior to screening or within 5 elimination half-lives for investigational drugs or biologics with a known half-life (whichever is longer). This restriction includes any pharmacologic, endoscopic, or other interventional procedures intended to modify or alter the course of PSC or its underlying disease processes.
• •27. History of clinically significant unstable or untreated illness or any other major medical disorder that may have interfered with participant treatment, assessment, or compliance with the protocol.
• •28. Any acute or chronic condition or other disease that, in the opinion of the investigator, would limit the ability of the participant to complete and/or participate in the clinical trial.
• •29. Presence of any other conditions (for example, geographic or social), actual or projected, that the investigator determines would restrict or limit the participation of the participant for the duration of the trial.
• •30. Individuals who are employed by the sponsor, a participating contract research organization (CRO), or the trial site - including permanent staff, temporary or contract workers, or designees directly involved in the conduct of the trial are excluded from participation. This exclusion also applies to immediate family members of employees of the sponsor, CRO, or trial site.