A Study to Evaluate How Ontamalimab Works and Assess Its Safety and Tolerability in People With Nonalcoholic Steatohepatitis With Fibrosis Stages 1 to 4

Takeda

Status and phase: Terminated; Phase 1

Conditions: Steatohepatitis

Treatments: Drug: Ontamalimab

Study type: Interventional

Funder types: Industry

Identifiers

NCT07052682

TAK-647-1001

Details and patient eligibility

About

The main aim of this study is to evaluate the safety and tolerability of ontamalimab in participants with a liver disease called nonalcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH) with scarring in the liver (fibrosis stage 1 to 4). The study will also check if there are any important changes in the body's health markers (biomarkers) from the beginning of the study to see if ontamalimab stops liver scarring and reduces inflammation of the liver.

Participants will be in the study for approximately up to 46 weeks.

Enrollment: 11 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. The participant is willing and able to understand and fully comply with study procedures and requirements, in the opinion of the investigator.
2. The participant and/or the participant's legally acceptable representative has provided informed consent (that is, in writing, documented via a signed and dated informed consent form [ICF] or electronic consent [eConsent] if applicable) and any required privacy authorization prior to the initiation of any study procedures.
3. The participant is aged 18 to 70 years, inclusive, at the time of signing the ICF.
4. The participant has signs of fibrogenic activity (Pro-C3 greater than or equal to [>=] 12.6 nanograms per milliliter [ng/mL], ELF score >=7.7) at the Week -8 (screening visit 1 [SV1]) (applies to all participants regardless of whether historical biopsy results are available at screening).
5. The participant has indication of NASH via biopsy (Nonalcoholic fatty liver disease activity score [NAS] >=3 with at least 1 point in lobular inflammation) and liver fibrosis stage 1 (F1) through fibrosis stage 4 compensated cirrhotic (F4cc) according to NASH Clinical Research Network (CRN).
6. The participant is a male participant or a nonpregnant, nonlactating female participant who, if sexually active, agrees to comply with the contraceptive requirements of the protocol, or a female participant of nonchildbearing potential. Participants of reproductive potential who are sexually active must agree to use appropriate contraception (that is, highly effective methods for female participants and medically appropriate methods for male participants) for the duration of the study and for at least 12 weeks after the last dose of study drug.
7. The participant, if capable of breastfeeding, agrees to forego breastfeeding for the period from informed consent until 12 weeks after the last dose of study drug.

Exclusion criteria

1. The following laboratory findings are exclusionary for all participants if found during screening visits (Week -8 [SV1], Week -6 [SV2] or at Day -4 visit [Visit 4a2]):

   1. Aspartate aminotransferase (AST) levels greater than (>) 5*the upper limit of normal (ULN).
   2. Alanine aminotransferase (ALT) levels >5*ULN.

2. The following laboratory findings are exclusionary for all participants if found during either screening visit (SV1 or SV2):

   1. Alkaline phosphatase (ALP) >=2*ULN.
   2. Serum creatinine >=1.5*ULN or has an estimated glomerular filtration rate (eGFR) less than (<) 45 milliliters per minute per 1.73 square meters (mL/min/1.73 m^2).
   3. International normalized ratio (INR) >=1.3 (except for participants who are receiving anticoagulant treatment).
   4. Total bilirubin level (TBL) >=ULN (except for participants with a documented history of Gilbert's syndrome if direct bilirubin is within normal reference range).
   5. Direct bilirubin >=3*ULN.
   6. Platelet count <60*10^9 per liter (/L).

3. The participant has been diagnosed with decompensated liver disease, or has new signs of decompensation and/or clinically meaningful change in disease status based on the judgment of the investigator (including but not limited to clinically significant changes in TBL, albumin, INR, creatinine, and/or AST and ALT levels) are observed during the screening period, or has any of the following during screening period:

   1. Presence or history of ascites, hepatic encephalopathy, or variceal bleeding.
   2. Presence or history of Child-Pugh >6 (Class B or C), unless due to therapeutic anticoagulation.
   3. Presence or history of model for end-stage liver disease (MELD) score >12. Note: It is the investigator's decision, in consultation with the sponsor, to allow participants to enter the study who have clinically meaningful rising tendencies in liver chemistries or significantly elevated liver chemistries that do not yet satisfy Exclusion Criterion #1 but could be interpreted as clinically concerning (that is, AST or ALT >4*ULN) at any visit during the screening period.

4. The participant has other diagnosed causes of liver disease based on medical history and/or baseline evaluation of laboratory and/or histology results, including, but not limited to viral (example, chronic hepatitis B, hepatitis B virus surface antigen [HBsAg] positive, or hepatitis B core antibody [HBcAB] positive; or chronic hepatitis C or hepatitis C virus antibody [HCVAb] positive and hepatitis C [HCV] ribonucleic acid [RNA] positive; or human immunodeficiency virus [HIV]-antibody positive), alcoholic (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 ounces [oz]/355 milliliters [mL] beer (approximately 5 percentage [%] 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)]), or autoimmune conditions (example, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune hepatitis, drug-induced hepatotoxicity), and other rare liver disease (example, alpha-1-antitrypsin deficiency, Wilson disease, hemochromatosis). Note: If a participant tests negative for HBsAg but positive for HBcAb, the participant would be considered eligible if no presence of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is confirmed by HBV DNA polymerase chain reaction (PCR) reflex testing performed by the central laboratory. 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]).

5. The participant has a history of impaired hemostasis that, in the investigator's judgement, would increase the risk to the participant if he or she participates in the study.

6. The participant has a significant concurrent medical condition at the time of screening or baseline, including, but not limited to, the following:

   1. Any major illness/condition or evidence of an unstable clinical condition (example, hepatic, renal, hematologic, gastrointestinal, endocrine [example, uncontrolled diabetes or type 1 diabetes mellitus, or thyroid disease], neurological [pre-existing demyelinating disorder such as multiple sclerosis or new onset seizures, unexplained sensory motor, or cognitive behavioral, neurological deficits, or significant abnormalities noted during screening], cardiovascular, pulmonary, immunologic [example, Felty's syndrome], or local active infection/infectious illness [any bacterial, fungal, or viral, example, clinically active cytomegalovirus, Epstein-Barr virus, herpes simplex virus]) that, in the investigator's judgment will substantially increase the risk to the participant if he or she participates in the study.

      Note: Participants with hemoglobin A1c (HbA1c) of >=6.5% at screening (SV1; Week -8) without a previous diagnosis of type 2 diabetes mellitus (T2DM) should be excluded from the study. Participants with a previous diagnosis for T2DM are permitted to enter the study if on a stable regimen of antidiabetic therapy for at least 90 days before screening. Participants who are on a stable regimen of antidiabetic therapy for at least 90 days before screening (SV1; Week -8) and have HbA1c of >=9% at Week -8 (SV1) should be excluded.

   2. Presence of acute coronary syndrome (example, acute myocardial infarction, unstable angina pectoris) within 24 weeks before screening.

   3. History of significant cerebrovascular disease within 24 weeks before screening.

   4. Cancer or history of cancer, including hepatocellular carcinoma or cholangiocarcinoma, or lymphoproliferative disease within the previous 5 years (other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix that has been treated with no evidence of recurrence).

   5. Any other severe acute or chronic medical or psychiatric condition or laboratory or ECG abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.

   6. Transplanted organ or history of liver transplantation.

   7. Significant trauma or major surgery within 4 weeks before the first screening visit, or with any major elective surgery planned to occur during the study.

7. The participant has severe active inflammatory bowel disease (IBD). Participants with inactive IBD or active of mild to moderate severity that was documented either by prior endoscopy or in previous medical records for >6 months are permitted to enter if they do not require biological treatment or Janus kinase (JAK) inhibitors. Treatment with leukocyte apheresis or selective lymphocyte, monocyte, or granulocyte apheresis or plasma exchange 30 days before baseline (Day 1).

8. The participant has a severe immune-mediated inflammatory disease (IMID) (example, rheumatoid arthritis, spondylarthritis disease spectrum, connective tissue disorders, cutaneous inflammatory conditions such as psoriasis, atopic dermatitis, hidradenitis suppurativa, asthma, multiple sclerosis). Participants with inactive IMID or active IMID of mild to moderate severity are permitted to enter the study.

9. The participant has a change in body weight >=5% three months before start of the screening or after qualifying liver biopsy. If the participant had a liver biopsy within 24 weeks of screening but experienced a weight change of >=5% since the date of liver biopsy, the liver biopsy must be repeated at screening.

10. The participant has any laboratory abnormality or condition that, in the investigator's opinion, could adversely affect the safety of the participant or impair the assessment of study results.

11. The participant has known hypersensitivity to ontamalimab or formulation excipient.

12. The participant has active or latent infection with mycobacterium tuberculosis (TB) who have not completed a generally accepted full course of treatment before screening.

13. The participant has clinically significant abnormal chest X-ray findings at SV1 (or up to 12 weeks before the first screening visit if available), such as presence of active TB, general infections, heart failure, or malignancy.

14. The participant has a positive interferon-gamma release assay (IGRA) at screening or within 12 weeks before screening even in the absence of previously diagnosed active or latent TB. IGRA screening may be repeated during the screening period if the initial result is indeterminate. The participant may be enrolled if confirmatory IGRA results from the central laboratory are negative. If the confirmatory IGRA results from the central laboratory are positive, the participant should be screen-failed. If both initial and confirmatory IGRA results are indeterminate, the participant may be enrolled after a Mantoux tuberculin skin test is negative and after consultation with the sponsor and a pulmonary or infectious disease specialist who determines low risk of infection (example, the participant would be acceptable for immunosuppressant [example, anti-tumor necrosis factor (TNF) treatment] without additional action). If the time for consultation exceeds the visit window, the participant should be screen-failed and can be rescreened after the consultation establishes eligibility for study participation. This consultation must be included in the participant's medical history.

15. The participant has any unexplained symptoms suggestive of progressive multifocal leukoencephalopathy (PML) based on the targeted neurological assessment during the screening period.

16. The participant has HIV.

17. The participant has a medical condition (example, morbid obesity, claustrophobia) that prevent execution of protocol procedures including percutaneous liver biopsy, liver stiffness measurement (LSM) by FibroScan, and magnetic resonance imaging (MRI).

18. The participant is receiving treatment with vitamin E, thiazolidinediones, or glucagon-like peptide-1 receptor agonists (GLP-1 RA) unless on a stable dose for 3 months before qualifying liver biopsy and not initiated after qualifying liver biopsy and is anticipated to maintain the same dosing regimen throughout study participation.

19. The participant is using drugs, herbs, or supplements historically associated with causing or worsening nonalcoholic fatty liver disease (NAFLD)/NASH within 24 weeks before qualifying liver biopsy or any time after qualifying liver biopsy is performed, including the use of total parenteral nutrition.

20. The participant has a positive urine screen for amphetamines, cocaine, or opioids related to the use of these drugs at screening.

21. The participant is receiving methadone or buprenorphine unless on stable maintenance treatment for at least 6 months before screening. Participants with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator.

22. The participant is using any prohibited concomitant medications as described in the protocol.

23. The participant has received a live (attenuated) vaccine within 4 weeks before baseline or is anticipated to receive a live vaccine during the study.

24. The participant has participated in another investigational study of a drug or device within 30 days before or within 5 half-lives of the prior investigational agent (whichever is longer) before baseline (Day 1).

25. The participant has participated in another investigational study targeting NASH, type 2 diabetes mellitus, or obesity within 6 months before baseline (Day 1).

26. The participant is concurrently participating in another therapeutic clinical study.

27. The participant has previously received ontamalimab.

28. The participant has had previous exposure to anti-integrin or anti-adhesion molecule treatment example, natalizumab, efalizumab, etrolizumab, vedolizumab, or any other investigational anti-integrin/adhesion molecule within 90 days before baseline (Day 1).

29. The participant has had previous exposure to any other biologic drugs with immunomodulatory properties such as anti-TNF, including biosimilars or anti-interleukin (IL)-12/23, or any nonbiologic treatment with immunomodulatory properties such as JAK inhibitors within 90 days or 5 half-lives (whichever is longer) before baseline (Day 1).

30. The participant is unavailable for follow-up assessment or investigator concern for participant's compliance with the protocol procedures.

31. The participant is a study site employee, an immediate family member (example, spouse, parent, child, sibling), or is in a dependent relationship with a study site employee who is involved in conduct of this study or may consent under duress.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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11 participants in 1 patient group

Ontamalimab

Experimental group

Description:

Participants receive ontamalimab 75 milligrams (mg) subcutaneous (SC) injection using a prefilled syringe once every 4 weeks (Q4W) on Day 1 and the last dose is administered at Week 20 with a total treatment period of 24 weeks.

Treatment:

Drug: Ontamalimab