Efficacy and Safety Evaluation of Namodenoson in Patients with Non-Alcoholic Steatohepatitis (NASH) with F1-3 Fibrosis: A Phase 2B Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-510548-19-00
Protocol: CF102-212LD
Sponsor: Can-Fite Biopharma Ltd.

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Diseases & Conditions

Metabolic dysfunction-associated steatohepatitis Non-alcoholic steatohepatitis

Objectives

The primary objective of this Phase 2B randomized, double-blind, placebo-controlled study is to **evaluate the efficacy** of namodenoson compared to placebo in subjects with Non-Alcoholic Steatohepatitis (NASH) with F1-3 fibrosis. This is determined by the proportion of subjects achieving a ≥2-point improvement in the non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH CRN). Additionally, the study aims to characterize the **safety profile** of namodenoson in this patient population. The clinical relevance of these objectives lies in the potential of namodenoson to provide a therapeutic option for NASH, a condition with limited treatment options, by improving liver histology and ensuring patient safety.

Secondary objectives include: - Evaluating the efficacy of orally administered namodenoson in subjects with NASH, as determined by the mean Percent Change From Baseline (PCFB) in serum **alanine aminotransferase (ALT)** levels at Week 36. - Assessing the **pharmacokinetics (PK)** of namodenoson in this population. These secondary objectives are crucial for understanding the broader impact of namodenoson on liver function and its pharmacological behavior in the body, which can inform dosing and therapeutic strategies.

Participants

The clinical trial involves a total of **59 participants** diagnosed with **Non-Alcoholic Steatohepatitis (NASH)** with F1-3 fibrosis. The study population includes both male and female subjects, aged 18 years and older, who are in general good health with acceptable hepatic metabolic and synthetic function. Participants were selected based on their willingness to undergo liver biopsies and comply with study procedures. Key lifestyle considerations include the presence of at least two criteria for metabolic syndrome, such as obesity, hypertriglyceridemia, reduced HDL cholesterol, controlled hypertension, or elevated fasting glucose. The trial does not involve a vulnerable population, and participants must have stable regimens of any herbal supplements or alternative treatments for at least three months prior to randomization. The selection criteria ensure a representative sample of individuals with NASH, allowing for the evaluation of the efficacy and safety of the investigational treatment.

Plans and Procedures

The clinical trial is a **Phase 2B randomized, double-blind, placebo-controlled study** designed to evaluate the efficacy and safety of **Namodenoson** in the treatment of **Non-Alcoholic Steatohepatitis (NASH)** with F1-3 fibrosis. The trial aims to assess the proportion of subjects achieving a ≥2-point improvement in the non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and to characterize the safety profile of Namodenoson. The study is expected to last until December 16, 2025, with recruitment having commenced on January 9, 2023.

Participants will be randomly assigned to receive either Namodenoson or a matching placebo, administered orally in capsule form. The maximum daily dose of Namodenoson is 50 mg, with a total maximum dose of 12,600 mg over the treatment period. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The primary endpoint is the proportion of subjects achieving a ≥2-point improvement in NAS at Week 36 relative to baseline, while secondary endpoints include the mean percent change from baseline in serum ALT levels at the same time point.

Participants are expected to be involved in the study for a maximum of 36 weeks. Inclusion criteria require participants to be at least 18 years old, willing to undergo two liver biopsies, and able to comply with all study procedures. Key laboratory values must be within specified ranges, and participants must have a diagnosis of NASH with a NAS of ≥4. Conditions that may lead to early termination from the study include non-compliance with study procedures or the emergence of safety concerns. The trial is not classified as low intervention and is conducted under the sponsorship of CAN-FITE BIOPHARMA LTD.

Treatment

The clinical trial involves the administration of **Namodenoson**, a synthetic ribose-based purine nucleoside with selectivity for the adenosine A3 receptor (A3AR). Namodenoson is provided in a **capsule** form and is intended for **oral use**. The maximum daily dose is 50 mg, with a total maximum dose of 12,600 mg over a treatment period of up to 36 weeks. The active substance, namodenoson, is of chemical origin and is manufactured by CAN-FITE BIOPHARMA LTD. The trial aims to evaluate the efficacy and safety of Namodenoson in subjects with Non-Alcoholic Steatohepatitis (NASH).

A **matching placebo** for Namodenoson is also utilized in this study to maintain the double-blind design. The placebo is designed to mimic the appearance and administration route of the Namodenoson capsules, ensuring that neither the participants nor the investigators can distinguish between the active treatment and the placebo. The placebo is administered orally, following the same dosing schedule as the active treatment, to ensure consistency in the trial protocol.

Efficacy

The efficacy of Namodenoson in the treatment of **Non-Alcoholic Steatohepatitis (NASH)** will be assessed through a Phase 2B randomized, double-blind, placebo-controlled study. The primary endpoint for evaluating efficacy is the proportion of subjects who achieve a ≥2-point improvement in the non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH CRN) at Week 36, relative to Baseline. This endpoint is designed to measure the improvement in liver histology, which is a critical factor in assessing the progression of NASH.

Secondary efficacy assessments will include the mean percent change from baseline (PCFB) in serum alanine aminotransferase (ALT) levels at Week 36. These parameters will be collected and analyzed at specified timepoints to determine the therapeutic impact of Namodenoson compared to placebo. The study will utilize validated scales and laboratory tests to ensure the accuracy and reliability of the efficacy data collected. The trial is structured to provide a comprehensive evaluation of Namodenoson's potential benefits in improving liver function and histological outcomes in patients with NASH.

Inclusion and Exclusion Criteria

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Inclusion Criteria

At least 18 years of age
AST at Screening of ≥20 IU/L
Diagnosis of NASH by biopsy at Screening showing NAS ≥4 by central read, with a score of at least 1 point in each of the 3 histologic categories of steatosis, inflammation, and hepatocellular ballooning (Kleiner 2005). If the subject has had a qualifying liver biopsy within 6 months prior to Baseline, this biopsy can be waived as long as the slides are available for the central read prior to randomization (Section 12.4.9)
Concomitant biopsy-proven Stage 1-3 hepatic fibrosis by NASH CRN criteria by central read (Kleiner 2005)
At least 2 of the following criteria for the metabolic syndrome (Grundy 2005): • Obesity, defined as waist circumference >88 cm for women or >102 cm for men • Hypertriglyceridemia, defined as triglycerides >150 mg/dL (>1.7 mmol/L) or on drug treatment for hypertriglyceridemia • Reduced high-density lipoprotein (HDL) cholesterol, defined as HDL cholesterol <40 mg/dL (<1.03 mmol/L) in men or <50 mg/dL (<1.3 mmol/L) in women • History of hypertension, currently controlled in the judgment of the Investigator • Elevated fasting glucose, defined as ≥100 mg/dL (≥5.6 mmol/L)
Acceptable hepatic metabolic and synthetic function, as indicated at Screening by: • Serum albumin ≥3.5 gm/dL • International normalized ratio (INR) ≤1.3 • Serum total bilirubin ≤2.0 mg/dL (unless subject has known Gilbert’s Syndrome)
The following laboratory values must be documented at Screening: • Absolute neutrophil count ≥1.0 x 109/L • Platelet count ≥150 x 109/L • Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2
Patients taking herbal supplements, homeopathic medications, or other alternative treatments must be on a stable regimen for at least 3 months prior to randomization
Understand and provide written informed consent to participate
Willing to undergo 2 liver biopsies
Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other study-related procedures

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Exclusion Criteria

Presence of ascites, hepatic encephalopathy, or other clinical evidence of cirrhosis
Other active acute or chronic liver disease, such as autoimmune hepatitis, hepatitis B, hepatitis C, alcoholic liver disease, or hepatocellular carcinoma
Seropositivity for markers of viral hepatitis or human immunodeficiency virus (HIV) at Screening. (Notes: If anti-hepatitis C virus (HCV) antibody is positive, a negative HCV ribonucleic acid (RNA) test is required for entry. Any prior treatment for HCV must have been completed at least 2 years prior to the qualifying liver biopsy.)
Weight loss of >5% within 3 months prior to Baseline
History of bariatric surgery within 5 years of Screening
Diabetes mellitus other than Type II
Hemoglobin A1c >9.0% (subjects with diabetes)
Any contraindication to percutaneous liver biopsy
Daily alcohol intake >20 g (2 units=2 standard drinks)/day for women and 30 g (3 units=3 standard drinks)/day for men (on average), as per Alcohol Use Disorders Identification Test (AUDIT) questionnaire at Screening or Baseline
Treatment with therapeutic doses of Vitamin E (≥800-1000 IU daily), or any of the following anti-diabetic medications: GLP-1 receptor agonists (such as Januvia [sitagliptin], Byetta [incretin], etc.), pioglitazone, or SGLT2 inhibitors (“gliflozin” drugs); unless the dose and regimen has been stable for at least 3 months prior to Screening
Active rheumatoid arthritis treated with small-molecule (including methotrexate) or biologic disease-modifying anti-rheumatic agent concurrently or within 1 year prior to Screening
Use of any immunosuppressive medication, anti-inflammatory monoclonal antibody treatment, or chronic systemic corticosteroids >10 mg prednisone-equivalent concurrently or within 1 year prior to Screening.
More than 7 days of treatment with valproic acid, tamoxifen, amiodarone, or anti-cholinergic agents within 3 months prior to Screening
Use of any investigational agent within 4 weeks prior to the Baseline Visit
Concomitant use of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitors and/or substrates with a narrow therapeutic index unless the medication can be taken at least 3 hours before or after taking the investigational product (see Section 12.2)
Uncontrolled or clinically unstable thyroid disease, in the judgment of the Principal Investigator
Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy
Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4), or other heart disease which is, in the Investigator’s judgment, clinically unstable
Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of study drug
QTcF interval on Screening Visit ECG (average of triplicate) or an average of triplicate Baseline Visit ECGs > 450 milliseconds (msec) for males or > 470 msec for females (except when QT prolongation is associated with right or left bundle branch block, in which case enrollment is allowed)
Pregnant or lactating female
Women of childbearing potential (WOCBP), unless they agree to use dual contraceptive methods which, in the opinion of the Investigator, are effective and adequate for the patient’s circumstances while on study drug
Men who partner with a woman of childbearing potential, unless they agree to use effective, dual contraceptive methods (i.e., a condom, with female partner using oral, injectable, or barrier method) while on study drug and for 3 months afterward
A condition which increases proarrhythmic risk, including hypokalemia, hypomagnesemia, or congenital Long QT Syndrome
Ongoing or planned use of a concomitant medication that is on the CredibleMedsTM list of drugs known to cause Torsades des Pointes (Appendix 1)
Active gastrointestinal disease which could interfere with the absorption of oral medication
Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator’s opinion, would make the patient inappropriate for entry into this study