First in Human Study of a Monoclonal Antibody (SOL-116) Targeting BSSL (Bile Salt-Stimulated Lipase), Single and Multiple Dose Parts

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, first-in-human phase I study. It consists of a single ascending dose part in healthy subjects (Part 1) and in patients with rheumatoid arthritis (Part 2) as well as a multiple dose part in healthy subjects (Part 3). The study will collect information on pharmacokinetics, safety and tolerability.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase I Study Evaluating Safety, Tolerability and Pharmacokinetics of Single Ascending Doses of SOL-116 in Healthy Subjects and Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: SOL-116
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the study and is willing and able to abide by the study restrictions. Males and females aged between 18 and 65 years (inclusive) at Screening. For patients in the RA cohort, an age interval between 18 and 70 years (inclusive). Normal clinically physical findings, apart from RA specific findings (including deviating laboratory values e.g., mild anaemia or swollen joints) for RA patients, including pulse rate, blood pressure, electrocardiogram (ECG), physical examination, and laboratory values (haematological/clinical chemistry) as judged by the Investigator. Healthy subjects must be negative for anti-CCP and have Rheumatoid Factor <1.5 ULN at Screening. For Parts 1 and 3, body mass index (BMI) between 19.0 and 30.0 kg/m2 and body weight between 50 to 100 kg (inclusive) at Screening. For Part 2, body weight between 50 to 120 kg (inclusive) at Screening. Sexually active male patients participating in the study must use a barrier method of contraception (condom) and refrain from sperm donation during the study and for at least 150 days after last dosing if their female sexual partner is of childbearing potential. Acceptable methods of birth control for female partners of male subjects are: hormonal contraceptives (oral contraceptives, implant or injection), intrauterine device (placed at least 1 month before the start of the study). Surgical sterilization of male patients can be accepted as a form of birth control if the sterilization procedure took place at least 6 months prior to the start of the study. Females of childbearing potential must during the study and for at least 230 days after last dosing utilise a method of contraception that can achieve a failure rate of less than 1% per year when used consistently and correctly (defined in study protocol). Females of non-childbearing potential must fulfil one of the following: Irreversibly surgically sterile i.e., hysterectomy, bilateral salpingectomy, the fallopian tubes have been blocked or sealed (sterilization), and bilateral oophorectomy. Spontaneous amenorrhoea during the last 12 months prior to enrolment, and having follicle stimulating hormone (FSH) levels in the postmenopausal range (i.e. ≥ 30 mIU/mL) at Screening. The following inclusion criterion is only applicable for RA patients: Fulfilling the 2010 American College of Rheumatology (ACR)/European Union League Against Rheumatism (EULAR) classification criteria for RA [8]. Treatment with a stable dose of MTX for at least 12 weeks prior to treatment start and planned to continue with MTX during the study. Patients naïve to biological disease modifying anti-rheumatic drug (bDMARD) or who are washed out (at least 5 half-lives) from such therapy before study drug dosing. Patients naïve to conventional/targeted synthetic disease modifying anti-rheumatic drug (csDMARD/tsDMARD), except for MTX, or who are washed out since at least 12 weeks from such therapy before study drug dosing. Use of oral glucocorticosteroids is allowed if equivalent to ≤5 mg/day of prednisolone on a stable dose for a least 4 weeks prior to dosing (Day 1) and expected to remain on that dose level for at least 4 weeks after dosing (Day 1). Exclusion Criteria: History of any clinically significant acute inflammatory joint disease (for the RA cohort; other than RA). Any chronic or long-lasting disease which may interfere with the study objectives or jeopardise the safety of the subjects/patients as judged by the Investigator or responsible physician (for the RA cohort; other than RA). Ongoing infection on Day-1. Serious infection treated with antibiotics and evaluated by physician in the past 14 days prior to Day -1. Current treatment with heparin products. Use of any prescription or non-prescription drugs (excluding paracetamol, hormonal contraceptives), antacids, herbal, and dietary supplements (including St John's Wort) within 14 days (or 28 days if the drug is a potential hepatic enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study drug for healthy subjects and within 4 weeks prior to the first dose of study drug for RA patients, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject/patient safety. In RA patients, MTX and folic acid use are exempted. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.0 times upper limit of normal (ULN); alkaline phosphatase and bilirubin ≥ 1.5 times the ULN at Screening or on Day -1. At screening, these assessments may be repeated once, at the discretion of the Investigator. Serum creatinine > 1.5 times the ULN or eGFR <60 at Screening or on Day -1 (for Part 1 and Part 3). Estimated glomerular filtration rat (eGFR) <60 at Screening or on Day -1 (for Part 2). At Screening, these assessments may be repeated once, at the discretion of the Investigator. Subjects/patients who have experienced surgery within 6 months of the screening visit that could negatively impact on the subject's/patient's participation in the opinion of a Principal Investigator or responsible physician. High blood pressure at Screening or on Day -1, judged as clinically relevant by a Principal Investigator or responsible physician. A repeat test may be performed. Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV) at Screening. Having evidence of active TB or latent TB at Screening as assessed by chest X-ray (RA patients only) and/or by QuantiFERON®-test. Subjects/patients who are currently enrolled in or have recently participated in another interventional clinical study defined as having received the last intervention within 90 days or 5 half-lives of the study drug (whichever is longer) prior to dosing (Parts 1 and 2) vs. prior to first dosing (Part 3) of the study drug. History or known hypersensitivity or allergy, or any form of allergic reactions to any excipients in the study drug or to humanized or murine monoclonal antibodies (or immunoglobulins). Receipt of a vaccine within 4 weeks (COVID-19 vaccine within 6 weeks) prior to dosing and/or the intention to receive a vaccine during the study. Deviation from this should be judged by the Investigator and in dialogue with the Sponsor. Recent confirmed COVID-19 infection, with less than 6 weeks between recovery and dosing of study drug. Blood or plasma donation within 3 months of enrolment. Positive urine drug screen or alcohol test at Screening or on Day -1. History of drug or alcohol abuse, at the discretion of the Investigator, within past 12 months prior to Screening. The subject currently smokes or uses nicotine-containing products. Former smokers will be eligible, provided they have not smoked for at least 1 month prior to Screening. Positive cotinine test results at Screening or on Day -1 are reason for exclusion. Such positive test results can be repeated once to exclude environmental influence on the subject. A positive pregnancy test or lactation at Screening or on Day -1. The following exclusion criteria are only applicable for RA patients: Intra-articular or systemic corticosteroid injection within 4 weeks prior to dosing. Current or expected need of other immunosuppressant medication except MTX and/or intra-articular corticosteroid injections. Known Gilbert's syndrome or Screening laboratory values indicating Gilbert's syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Interventional Model Description: Part 1 single dose: Dose escalation in healthy subjects (up to 6 cohorts). Within each cohort, subjects will be randomized in a 3:1 ratio to receive either SOL-116 (n=6) or matching placebo (n=2) in a double-blind manner. Part 2 single dose in patients with rheumatoid arthritis (1 cohort). The patients will be randomized in a 3:1 ratio to receive either SOL-116 (n=6) or matching placebo (n=2) in a double-blind manner. Part 3 multiple dose in healthy subjects (1 or 2 cohorts). The subjects will be randomized in a 3:1 ratio to receive either SOL-116 (n=6) or matching placebo (n=2) in a double-blind manner.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOL-116 single dose (Parts 1 and 2); multiple dose (Part 3) (SC administration)<br> | Biological: SOL-116<br>* Participants will receive SC injection in a double-blind manner<br>|
| Placebo Comparator: Placebo single dose (Parts 1 and 2); multiple dose (Part 3) (SC administration)<br> | Biological: Placebo<br>* Participants will receive SC injection in a double-blind manner<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability parameters: Adverse events | Number of adverse events (AEs) | From screening through study completion, day 90 | 
| Safety and tolerability parameters: Clinical laboratory evaluations | Number of clinically significant laboratory abnormalities | From screening through study completion, day 90 | 
| Safety and tolerability parameters: Immune reactions | Incidence of immune reactions (hypersensitivity, cytokine release syndrome, immunogenicity) | From screening through study completion, day 90 | 
| Safety and tolerability parameters: Vital signs - Blood pressure value | Blood pressure (mm Hg) | From screening through study completion, day 90 | 
| Safety and tolerability parameters: Vital signs - Pulse value | Pulse value | From screening through study completion, day 90 | 
| Safety and tolerability parameters: Vital signs - Temporal body temperature | Temporal body temperature | From screening through study completion, day 90 | 
| Safety and tolerability parameters: Electrocardiogram (ECG) | Number of clinically significant abnormal findings recorded by investigator based on HR, PR, QRS and QT values of ECG | From screening through study completion, day 90 | 
| Safety and tolerability parameters: Injection site reactions | Incidence of injection site reactions (dryness, redness, swelling, pain/tenderness and itching) | From screening through study completion, day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters for SOL-116: AUC0-inf | Area under the concentration-time curve up to infinite time | From dosing day through study completion, day 90 | 
| PK parameters for SOL-116: AUC0-t | Area under the concentration-time curve up to the last measurable concentration | From dosing day through study completion, day 90 | 
| PK parameters for SOL-116: Cmax | Maximal observed concentration (Cmax) | From dosing day through study completion, day 90 | 
| PK parameters for SOL-116: Tmax | Time to Cmax | From dosing day through study completion, day 90 | 
| PK parameters for SOL-116: T1/2 | Terminal elimination half-life | From dosing day through study completion, day 90 | 
| PK parameters for SOL-116: Vz/F | Apparent volume of distribution following extravascular administration | From dosing day through study completion, day 90 | 
| PK parameters for SOL-116: CL/F | Apparent total body clearance following extravascular administration | From dosing day through study completion, day 90 | 
| PK parameters for SOL-116: Dose proportionality | Dose proportionality after single dose (based on AUC and Cmax) | From dosing day through study completion, day 90 | 
| Immunogenicity parameters: ADA | Concentration of anti-drug antibodies (ADA) | From dosing day through study completion, day 90 |