A First-in-human Study of the Safety, Tolerability, and PK of XFB-19 in Healthy Adult Volunteers

Study Overview
=================
Brief Summary
-----------------
Xfibra, Inc. is conducting a phase 1, randomised, double-blind, placebo-controlled, first-in-human study of the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of XFB-19 in healthy adult volunteers in lung fibrosis.

Detailed Description
-----------------
Xfibra, Inc. is conducting this clinical research study to test a potential new drug called XFB 19 that is being developed for idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (IPF) is a serious lung disease. When you breathe in (inhale), oxygen moves through tiny air sacs in your lungs and into your bloodstream. From there, it travels to your organs. IPF causes scar tissue to grow inside your lungs and makes it hard to breathe. It gets worse over time. IPF scar tissue is thick, like the scars you get on your skin after a cut. It slows oxygen flow from your lungs to your blood, which can keep your body from working as it should. Idiopathic means the cause is unknown. IPF usually affects people who are around 70 to 75 years old and is rare in people under 50. IPF has been linked to exposure to certain types of dust, such as metal or wood dust, viral infections, a family history of IPF (around 1 in 20 people with IPF has another family member with the condition), acid reflux disease, and smoking. It is not known whether some of these factors directly cause IPF. The progressive lung injury, inflammation, and lung scarring lead to dyspnea (shortness of breath), limited physical activity, malaise, and muscle wasting with most deaths in patients with IPF resulting from progression of scar tissue in the lungs. Although current medications are available to improve health and survival in patients with IPF, the medications are not curative, and are associated with adverse effects in a significant percentage of IPF patients. The advantages of XFB-19 over currently available therapies are its specificity, in that it only affects a carefully selected target which may allow recovery from IPF and lung injury, and potentially reverse lung fibrosis. Although many laboratory and animal studies have been completed, this is the first time XFB-19 is being tested in humans. Therefore, side effects in humans are unknown. This study will be conducted in two parts - Part A (single dose) and Part B (multiple dosing). The purpose and main goals of this study are: To determine whether XFB-19 is safe and well tolerated in humans To determine a safe dose of XFB-19 to be used in future studies To test how much XFB-19 gets into the blood and how long it takes to be cleared from the body To determine the effect of XFB-19 on the body by performing blood tests XFB-19 is considered experimental because it has not yet been approved by the TGA (Therapeutic Goods Administration) in Australia, or any other regulatory agency responsible for approving medicines. There may be risks in taking this experimental drug that are unknown.

Official Title
-----------------
A Phase 1, Randomised, Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of XFB-19 in Healthy Adult Volunteers

Conditions
-----------------
Idiopathic Pulmonary Fibrosis (IPF)

Intervention / Treatment
-----------------
* Drug: XFB-19
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the study, including possible risks and adverse effects. Adult males and females, 18 to 55 years of age (inclusive) at screening. Body mass index ≥ 18.0 and ≤ 30.0 kg/m2 with a body weight ≥ 45 kg at screening. Be non-smokers (including tobacco, e-cigarettes, and marijuana) for at least 3 months prior to first study drug administration and have a negative breath test for cotinine at the Screening Visit and at check-in on Day -1. Medically healthy without clinically significant abnormalities (in the opinion of the Investigator) at the Screening Visit and prior to dosing including: Physical examination without any clinically significant findings Systolic blood pressure in the range of 90 to 160 mmHg (inclusive) and diastolic blood pressure in the range of 50 to 95 mmHg (inclusive) after 5 minutes rest in supine position Heart rate (HR) in the range of 40 to 100 bpm (inclusive) after 5 minutes rest in supine position Body temperature (tympanic or oral) in the range of 35.5°C to 37.7°C (inclusive) No clinically significant findings in serum chemistry, haematology, coagulation, and urinalysis tests Triplicate 12-lead ECGs (taken after the volunteer has been supine for at least 5 minutes) with QT intervals corrected using Fridericia's method (QTcF) ≤ 450 msec for males and ≤ 470 msec for females and no clinically significant abnormalities Female volunteers must: Be of nonchildbearing potential, i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or postmenopausal (defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone [FSH] level > 40 IU/L at the Screening Visit) OR If of childbearing potential, must agree not to donate ova, not to attempt to become pregnant, and, if engaging in sexual intercourse with a male partner, must agree to use an acceptable method of contraception (Section 8.3.2) from the time of signing the participant informed consent form (PICF) until at least 30 days after the last dose of the study drug Male volunteers must agree not to donate sperm, and, if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception (Section 8.3.2) from the time of signing the consent form until at least 65 days after the last dose of study drug. Have suitable venous access for blood sampling. Be willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions. Exclusion Criteria: History or presence of any clinically significant (as determined by the PI) cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, or neurological disease, including any acute illness or major surgery, within the past 3 months. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic, or antiviral medications. Any history of malignant disease in the last 5 years (excluding surgically resected skin squamous cell or basal cell carcinoma). Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia. Use of or plans to use systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 3 months prior to the first study drug administration. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia. Liver function test (LFT) results > 1.5 times the upper limit of normal (ULN) for gamma glutamyl transferase (GGT), bilirubin (total, conjugated, and unconjugated), alkaline phosphatase (ALP), aspartate aminotransferase (AST), or alanine aminotransferase (ALT). Volunteers with bilirubin, ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs. Positive test results for human immunodeficiency virus (HIV-1 or HIV-2) antibodies, hepatitis C virus (HCV) antibodies, or hepatitis B surface antigen (HBsAg) at the Screening Visit. Positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via polymerase chain reaction or commercially validated antigen test (taken if clinically indicated on Day -2). Presence of sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs. Estimated creatinine clearance (CrCl) < 60 mL/min using the Cockcroft-Gault formula or serum creatinine more than 1.5 x ULN. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or regularly consuming more than 4 standard drinks per day where 1 standard drink is 10 g of pure alcohol and equivalent to 285 mL beer [4.9% Alc./Vol], 100 mL wine [12% Alc./Vol], or 30 mL spirit [40% Alc./Vol]) within 12 months prior to the Screening Visit. Positive drugs of abuse or alcohol breath test results at the Screening Visit or at CRU check in (Day -1). Use of any prescription or over-the-counter (OTC) medication (including herbal products, diet aids, and hormone supplements) within 10 days or 5 half-lives of the medication (whichever is longer) prior to the first study drug administration, excepting use of contraceptives and occasional use of paracetamol (up to 1 g every 8 hours or 3 g per day maximum for no more than 3 consecutive days). Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the Investigator, would interfere with the volunteer's ability to participate in the study. Known hypersensitivity to any of the study drug ingredients. Use of any vaccinations within 10 days prior to first study drug administration. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit or a positive urine pregnancy test (with confirmatory positive serum pregnancy test) at CRU check-in (Day -1). Breastfeeding. Donation of blood or plasma or loss of whole blood of more than 500 mL within 30 days prior to first study drug administration or receipt of a blood transfusion within 2 months prior to first study drug administration. Participation in another clinical study of an investigational drug within 30 days or 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration. Any other condition or prior therapy that in the opinion of the Investigator would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: In Part A, 24 healthy volunteers will be enrolled in a total of 3 cohorts (Cohorts 1 to 3) with ascending doses of XFB-19: 5mg (Cohort 1), 10mg (Cohort 2), and 20mg (Cohort 3). Each cohort will enroll 8 participants with 6 participants randomised to receive XFB-19 and 2 participants randomised to receive placebo. In Part B, 16 healthy volunteers will be enrolled in a total of 2 cohorts (Cohorts 4 and 5). Each cohort will enroll 8 participants with 6 participants randomised to receive XFB-19 and 2 participants randomised to receive placebo. Cohorts 4 and 5 will accept the second highest and highest XFB-19 doses for evaluation from Part A.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: XFB-19<br>Part A: XFB-19 SC injection at the following dose levels: Cohort 1: 5 mg Cohort 2: 10 mg Cohort 3: 20 mg Part B: XFB-19 SC injection at the 2 highest acceptable dose levels from Part A: Cohort 4: second highest acceptable dose level from Part A Cohort 5: highest acceptable dose level from Part A | Drug: XFB-19<br>* XFB-19 is a first-in-class synthetic tetra-peptide (Acetyl-Lys-D-Ala-D-Val-Asp-NH2) that inhibits the activation of the human CCAAT-enhancer binding protein beta (C/EBPβ) thus mediating the activation of lung myofibroblasts. Activation of myofibroblasts is responsible for the development of lung fibrosis in idiopathic pulmonary fibrosis (IPF).<br>|
| Placebo Comparator: Placebo<br>10 healthy volunteers will be randomized and assigned to the Placebo arm in Part A (Cohorts 1, 2 and 3) and Part B (Cohorts 4 and 5). | Drug: Placebo<br>* No active ingredient drug use to blind participants and investigators<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of XFB-19 | Assessment of adverse events (AEs) for 40 healthy volunteers using the CTCAE v5.0 grading scale | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal clinical laboratory test (hemoglobin) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal clinical laboratory test (hematocrit) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal clinical laboratory test (creatinine) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal clinical laboratory test (alanine aminotransferase (ALT)) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal clinical laboratory test (aspartate amino transferase (AST)) for 40 healthy volunteers , serum chemistry, coagulation, and urinalysis | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal blood pressure (mmHg) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal pulse rate (beats per minute) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal respiratory rate (breaths per minute) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal body temperature (°C or °F) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of the change in QTc intervals using electrocardiograms (ECGs) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal coagulation test (aPTT (Activated partial thromboplastin time) and INR (International Normalized Ratio)) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal urine sample analysis (including assessment urine pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, nitrite, urobilinogen, and leukocytes) for 40 healthy volunteers | 4 months | 
| Safety and Tolerability of XFB-19 | Assessment of abnormal body mass index calculation (BMI = kg/m2) using a person's weight in kilograms (kg) and height in meters squared (m2) for 40 healthy volunteers | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of XFB-19 - Plasma Cmax | Cmax: Maximum observed concentration of XFB-19 in the blood | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Plasma Tmax | Tmax: Time of maximum observed concentration of XFB-19 in the blood | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Plasma Ctrough | Ctrough: the concentration reached by XFB-19 immediately before the next dose is administered | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Plasma AUC0-tlast | AUC0-tlast: Area under the concentration-time curve from time zero until the last observed concentration | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Plasma AUC0-inf | AUC0-inf: Area under the concentration-time curve from time zero to infinity (extrapolated) | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Apparent terminal elimination half-life (t1/2) | T½ el: Terminal elimination half-life of XFB-19 | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Terminal elimination rate constant (λz) | λz: Terminal elimination rate constant of XFB-19 | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Total apparent body clearance (CL/F) | CL/F: Apparent body clearance, calculated as Dose / AUC0-inf | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Apparent volume of distribution (Vz/F) | Vz/F: Apparent volume of distribution, calculated as Dose / λz * AUC0-inf | 4 months | 
| Pharmacokinetics (PK) of XFB-19 - Apparent steady state volume of distribution (Vss/F) | Vss/F: Apparent volume of distribution at steady-state, calculated as Dose / (λz * AUC0-inf) | 4 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Idiopathic Pulmonary Fibrosis (IPF), Sequential lung epithelial cell injury, Lung fibrosis, human C/EBPβ-Thr266, phosphorylation by p90 ribosomal S6 kinase (p90RSK)