Evaluating the Safety, Tolerability, and Pharmacokinetics of DF-003 in Healthy Subjects

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate the safety, tolerability, and pharmacokinetics (PK; drug metabolism) of DF-003 after oral administration of single and multiple ascending doses in healthy subjects. The choice of using healthy subjects is standard in establishing the preliminary safety and PK profile of a drug. DF-003 is a potent small molecule inhibitor of alpha-kinase 1 (ALPK1), which plays an important role in immunity and inflammation. DF-003 can inhibit the immune inflammatory response and has been shown to reduce renal fibrosis in preclinical models. Thus, this study aims to determine the role of DF-003 in the treatment of chronic kidney disease. This study will include 2 parts. Part 1 is a single ascending dose (SAD) phase with an optional food effect (FE) assessment, while Part 2 is a multiple ascending dose (MAD) phase. Part 1 - SAD Phase with optional FE assessment will include approximately 64 subjects (up to 8 cohorts of 8 subjects each) and Part 2 - MAD Phase will include approximately 32 subjects (up to 4 cohorts of 8 subjects each). Therefore, up to 96 subjects will be included in the study. Study participants will be screened approximately 42 days within the first scheduled administration of study medication. Screening data will be reviewed to determine subject eligibility. In Part 1, subjects will be randomly assigned to receive a single oral dose of DF-003 (3 x 1 milligram capsules) or matching placebo. The doses to be evaluated in Part 2 will be determined based on review of the available safety and PK data from Part 1. Subjects will be monitored for adverse events (AEs) and data will be collected for physical examination, eye examination, vital signs, 12-lead electrocardiogram (ECG), Holter monitoring, and clinical laboratory findings at various timepoints throughout the study.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled, First-in-Human Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Orally Administered DF-003 Following Single (Part 1) and Multiple (Part 2) Ascending Doses in Healthy Subjects

Conditions
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Healthy, Safety and Tolerability

Intervention / Treatment
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* Drug: DF-003
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form (ICF). Ability to understand and stated willingness to comply with all study procedures and availability for the duration of the study, and likeliness to complete the study as planned, per the Investigator's opinion. Healthy adult male or female. If male, meets one of the following criteria: Is able to procreate and agrees not to donate sperm from the first study drug administration to at least 90 days after the last study drug administration in addition to: Having a female partner who is postmenopausal, surgically sterile, or otherwise incapable of becoming pregnant, OR Having a female partner who is a woman of childbearing potential and agrees to use a highly effective method of contraception from the first study drug administration to at least 90 days after the last study drug administration, OR Is unable to procreate; defined as surgically sterile (ie, has undergone a vasectomy at least 180 days prior to the first study drug administration). If female, meets one of the following criteria: Physiological postmenopausal status, defined as the following: Amenorrhea for at least 12 months prior to the first study drug administration (without an alternative medical condition); AND Follicle stimulating hormone (FSH) levels ≥40 mIU/mL at Screening; In the absence of 12 months of amenorrhea, 2 FSH measurements at least 3 months apart and in the postmenopausal range must be documented. Surgical postmenopausal status, defined as having had a bilateral oophorectomy or bilateral salpingo-oophorectomy with FSH levels ≥ 40 mIU/mL at Screening. Aged at least 18 years but not older than 55 years at the time of Screening. Body mass index (BMI) within 18.0 kg/m^2 to 32.0 kg/m^2, inclusively. Non- or ex-smoker (An ex-smoker is defined as someone who completed stopped using nicotine products for at least 3 months prior to the first study drug administration). Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination, vital signs, eye examination, and/or ECG, as determined by an Investigator. A 12-lead ECG that meets the following criteria (ECG intervals will be based on the mean value of triplicate ECGs [rounded to the nearest whole number] collected at Screening): Heart rate ≥45 to ≤100 beats per minute QT interval corrected for heart rate (QTc) according to Fridericia's formula (QTcF) ≤450 ms (males) or ≤470 ms (females) QRS interval <120 ms PR interval ≤200 ms Exclusion Criteria: Female who is lactating. Female who is pregnant according to the pregnancy test at Screening or prior to the first study drug administration Female using the following systemic contraceptives: oral, patch or vaginal ring, in the 28 days prior to the first study drug administration. Female using hormone replacement therapy in the 28 days prior to the first study drug administration. Female using the following systemic contraceptives: injections or implant, or hormone-releasing intrauterine device in the 13 weeks prior to the first study drug administration. History of significant hypersensitivity to products related to DF-003 (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs. Presence or history of significant gastrointestinal, liver or kidney disease, or surgery (with the exception of cholecystectomy and appendectomy) that may affect drug bioavailability. History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic, rheumatologic, neoplastic, metabolic, or dermatologic disease. Presence of clinically significant ECG abnormalities at the Screening visit, as defined by medical judgment. Use of contact lenses or eyeglasses. Presence of clinically significant visual acuity or slit-lamp biomicroscopy abnormalities at the Screening visit, as defined by medical judgement. History or family history of chronic inflammatory skin disease (eg, psoriasis, atopic dermatitis, drug-related rash, or chronic urticaria), or immune or autoimmune related disorders, diseases, or syndromes. Major surgery (eg, requiring general anesthesia) within 12 weeks before Screening, during the study, or within 12 weeks after the last dose of study drug. NOTE: Subjects with planned surgical procedures to be conducted under local anesthesia may participate. Presence of renal dysfunction at Screening (eg, estimated glomerular filtration rate < 90 mL/min/1.73 m^2 calculated by the Chronic Kidney Disease Epidemiology Collaboration formula). Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic). Any clinically significant illness including current acute or chronic infections in the 28 days prior to the first study drug administration. Use of any prescription drugs in the 28 days prior to the first study drug administration, that in the opinion of an Investigator would put into question the status of the participant as healthy. Use of St. John's wort in the 28 days prior to the first study drug administration. Use of any over-the-counter medications 7 days prior to the first study drug administration. Subjects will be reminded that over-the-counter medications include cold preparations, aspirin, vitamins and natural products used for therapeutic benefits, and antacid preparations. Positive test result for alcohol and/or drugs of abuse at Screening or prior to the first drug administration. Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen, or hepatitis C virus tests. Any other clinically significant abnormalities in laboratory test results at Screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data. Intake of an IP in the 4 weeks (or 5 half-lives, whichever is longer) prior to the first study drug administration. Intake of any biological products in the 12 months prior to the first study drug administration. Current participation in another clinical or medical interventional research study. Employee of the Sponsor, Investigator or study site with direct involvement in the proposed study or other studies under the direction of that Investigator or study site, as well as family members of the employees or Investigator. Donation of plasma in the 7 days prior to the first study drug administration. Donation of 1 unit of blood to American Red Cross or equivalent organization or donation of over 500 mL of blood in the 56 days prior to the first study drug administration. Presence or history of eye lens opacification (cataracts) and eye lens degeneration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Sequential Assignment
Interventional Model Description: The study will include 2 parts: 1) Single ascending dose phase with optional food effect (FE) assessment, and 2) multiple ascending dose phase.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DF-003 (Single Ascending Dose, Part 1)<br>Participants will receive a single oral dose of 3 mg DF-003 (1 mg x 3). | Drug: DF-003<br>* Oral administration by capsules (1 mg, 5 mg, or 25 mg).<br>|
| Placebo Comparator: Placebo (Single Ascending Dose, Part 1)<br>Visually matching 0 mg DF-003 capsules. | Drug: Placebo<br>* Visually matching 0 mg DF-003 capsules.<br>|
| Experimental: DF-003 (Multiple Ascending Doses, Part 2)<br>Participants will receive DF-003 once daily by oral administration for 14 days. The specific doses given will be based on data collected in Part 1 of the study. This part of the study may include 1 mg, 5 mg, or 25 mg capsules. | Drug: DF-003<br>* Oral administration by capsules (1 mg, 5 mg, or 25 mg).<br>|
| Placebo Comparator: Placebo (Multiple Ascending Doses, Part 2)<br>Visually matching 0 mg DF-003 capsules. | Drug: Placebo<br>* Visually matching 0 mg DF-003 capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) | Safety and Tolerability | Up to 83 days | 
| Incidence of Serious Adverse Events (SAEs) | Safety and Tolerability | Up to 83 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Time to maximum plasma concentration (tmax) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC(0-t)) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Area under the plasma concentration-time curve from zero to infinity ((AUC(0-∞)) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Terminal half-life (t½) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Apparent plasma clearance of drug after extravascular administration (CL/F) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Apparent volume of distribution after extravascular administration (Vz/F) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Maximum plasma concentration at steady state (Cmax,ss) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Time to steady state Cmax (Tss,max) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Concentration at time t (Ct) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Concentration immediately before next dose (Ctrough) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Apparent plasma clearance of drug after extravascular administration at steady state (CLss/F) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Apparent volume of distribution at steady state after extravascular administration (Vz,ss/F) for DF-003 | Pharmacokinetics | Up to 83 days | 
| Accumulation ratio (Rac) at Cmax for DF-003 | Pharmacokinetics | Up to 83 days | 
| Accumulation ratio area under the concentration-time curve for DF-003 | Pharmacokinetics | Up to 83 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DF-003