A Study of ALG-000184 Drug to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics After Single and Multiple Doses in Healthy Volunteers and CHB Subjects

Study Overview
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Brief Summary
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A Randomized Study of ALG-000184 Drug to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics After Single and Multiple Doses in Healthy Volunteers and CHB Subjects

Official Title
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A Phase 1, Double-Blind, Randomized, Placebo-Controlled, First-in-Human Study of Orally Administered ALG-000184 to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics After Single-Ascending Doses (Part 1) and Multiple-Ascending Doses in Healthy Volunteers (Part 2), and Multiple Doses in Subjects With Chronic Hepatitis B (Part 3)

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: ALG-000184
* Drug: Placebo
* Drug: Entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for All Subjects: Female subjects must have a negative serum pregnancy test at screening Subjects must have a 12-lead electrocardiogram (ECG) that meets the protocol criteria Inclusion Criteria for Healthy Volunteers: In addition to inclusion criteria 1-2, the following inclusion criteria also apply to HV's (Parts 1 and 2) Male or female between 18 and 55 years of age, extremes included. Subjects must have a body mass index (BMI; weight in kg divided by the square of height in meters) of 18.0 to 32.0 kg/m2, extremes included. CHB Subjects: In addition to inclusion criteria 1-4, the following inclusion criteria also apply to CHB subjects: All of the Following criteria apply to Part 3 at screening: 5 .Subjects must be 18 to 65 years of age, extremes included. 6.CHB subjects must have a BMI of 18.0 to 35.0 kg/m2, extremes included. 7.CHB subjects who at screening, have not received treatment with an approved or investigational medicine, or have never received treatment with HBV antiviral medicines All of the following criteria apply to Part 4 Cohorts A & B, unless otherwise specified, at Screening: 8.Subjects must be 18 to 65 years of age, extremes included. 9.Subjects must have a BMI of 18.0 to 35.0 kg/m2, extremes included 10.Subjects must be HBeAg positive (HBeAg ≥LLOQ and HBeAb negative) 11.Subjects enrolled in Part 4 Cohort A and B must have a history of Chronic Hepatitis B 12. Subjects must have ALT and AST must have ≤1.2×ULN or ≤5×ULN All of the following criteria apply to Part 5 at Screening 13.Subjects must be 18 to 65 years of age, extremes included. 14. Subjects have a BMI of 17.0 to 35.0 kg/m2, extremes included 15.Subjects could belong to any of the following treatment categories: treatment naïve (TN), currently not treated (CNT) , virologically suppressed. Exclusion Criteria Exclusion Criteria for All Subjects: Subjects with any previous or current illness that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject, or pose an additional risk in administering study drug to the subject, or that could prevent, limit, or confound the protocol specified assessments or study results' interpretation Subjects with a past history of cardiac arrhythmias, risk factors for Torsade de Pointes syndrome (e.g., hypokalemia, family history of long QT syndrome, or history of clinical evidence at screening of significant or unstable cardiac disease etc. Subjects with a history of clinically significant drug allergy Subject with a current history of clinically significant (as determined by investigator) skin disease requiring intermittent or chronic treatment Excessive use of alcohol, defined as regular consumption of ≥14 standard drinks/week for women and ≥21 standard drinks/week for men Subjects with Hepatitis A, B, C, D, E or HIV-1/HIV-2 infection or acute infections such as SARS- CoV-2 infection Exclusion Criteria for Healthy Volunteers (Parts 1 and 2): In addition to exclusion criteria 1-6, the following exclusion criteria also apply to HV's (Parts 1 and 2) Unwilling to abstain from alcohol use for 48 hours prior to start of dosing through end of study follow up. Positive alcohol or cotinine test at screening and Day -1. Subjects with renal dysfunction (e.g., estimated creatinine clearance <90 mL/min/1.73 m2at screening, calculated by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula). Exclusion Criteria for CHB Subjects (Parts 3, 4, and 5): All exclusion criteria listed above for healthy volunteers apply also to CHB subjects, except for exclusion Criteria 9 (requirement relative to cotinine).All the following exclusion criteria apply to Parts 3, 4, and 5, unless otherwise specified. Subjects who are positive for anti-HBs antibodies. For HBeAg-positive subjects, they should be negative for anti-HBe antibodies (Parts 4 and 5) Subject with any history or current evidence of hepatic decompensation such as: variceal bleeding, spontaneous bacterial peritonitis, ascites, hepatic encephalopathy, or active jaundice (within the last year). History or current evidence of cirrhosis. Subjects with liver fibrosis that is classified as Metavir Score ≥F3 liver disease Subjects with signs of hepatocellular carcinoma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALG-000184<br>Oral tablet(s) of ALG-000184 in HV or CHB subjects once daily for up to 4 weeks | Drug: ALG-000184<br>* Single or multiple doses of ALG-000184<br>|
| Placebo Comparator: Placebo<br>Oral tablet(s) of placebo in HV or CHB subjects once daily for up to 4 weeks | Drug: Placebo<br>* Single or multiple doses of Placebo<br>|
| Active Comparator: Entecavir in combination with ALG-000184<br> | Drug: ALG-000184<br>* Single or multiple doses of ALG-000184<br>Drug: Entecavir<br>* multiple doses of Entecavir<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | The number and severity of treatment emergent adverse events as assessed by DAIDS v2.1 | up to 8 days for Part 1 | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | The number and severity of treatment emergent adverse events as assessed by DAIDS v2.1 | up to 21 days for Part 2 | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | The number and severity of treatment emergent adverse events as assessed by DAIDS v2.1 | up to 112 days for Part 3 | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | The number and severity of treatment emergent adverse events as assessed by DAIDS v2.1 of ALG-184 in combination with Entecavir (Parts 4 and 5) | Up to 336 days for parts 4 & 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration [Cmax] | Pharmacokinetic parameters of ALG-000184 in plasma | Predose up to 343 Days | 
| Area under the concentration time curve [AUC] | Pharmacokinetic parameters of ALG-000184 in plasma | Predose up to 343 Days | 
| Time to maximum plasma concentration [Tmax] | pharmacokinetic parameters of ALG-000184 in plasma | Predose up to 343 Days | 
| Half-time [t1/2] | Pharmacokinetic parameters of ALG-000184 in plasma | Predose up to 343 Days | 
| Minimum Plasma Concentration [Cmin] | Pharmacokinetic parameters of ALG-000184 in plasma | Predose up to 343 Days | 
| Change in HBV DNA from baseline through Day 392 in Multiple Dose HBV Infected Patients |  | Screening up to Day 392 |