Clinical Evaluation of Safety and Tolerability of KDR2-2 Eye Drops in Healthy Volunteers With Pharmacokinetic Assessment

A Phase 1 Randomized, Double Blinded, Placebo-Controlled Single Dose and Repeat Dose Escalation Study to Evaluate Safety and Tolerability and Pharmacokinetic Characteristics of KDR2-2 in Adult Healthy Male and Female Volunteers

A Phase 1 randomized, double blinded, placebo-controlled, single dose escalation (SDE) and repeat dose escalation (RDE) study to evaluate safety and tolerability, and PK of KDR2-2 in healthy volunteers. The planned single dose levels are 0.03, 0.06, 0.12, and 0.24 mg/eye, and repeat dose levels are 0.06, 0.12, and 0.24 mg/eye, QID, × 6 days (one dose in the morning on Day 7). Subjects are randomized to KDR2-2 or placebo dosing (6:2 for SDE, or 8:2 for RDE) in each cohorts of relative dosing levels.

This is a Phase 1 randomized, double blinded, placebo-controlled, single dose and repeat dose escalation study to evaluate safety and tolerability, and PK of KDR2-2 in healthy volunteers.

The trial will include a screening period, a treatment period, and a follow-up period of 7 days for single dose escalation (SDE) or repeat dose escalation (RDE) after last administration. The screening period will be up to 28 days prior to investigational product administration. The screening process will initiate upon completion of the informed consent process. Once consent is provided by each participant, a thorough screening process will take place, including detailed medical history, physical examination and ophthalmology examination, vital signs, concomitant medications, safety labs, 12 lead electrocardiogram, serum pregnancy test, urinalysis, serology panel, assessment of inclusion and exclusion criteria. Upon completion of the screening, qualified subjects will be randomized to KDR2-2 or placebo (6:2 for SDE, or 8:2 for RDE). Each enrolled subject will receive one single or repeat assigned dose of KDR2-2 or placebo. The investigator and subjects will be blinded to treatment assignment. During the study, subjects will be evaluated for safety and tolerability, and PK of KDR2-2. In each cohort, a sentinel group of two subjects will be dosed first: one sentinel with KDR2-2, and the other with the placebo. The remaining subjects of the same cohort will be dosed at least 24 hours after sentinel dosing with approval from the principal investigator upon assessing the sentinel group.

KDR2-2 or placebo will be topically administered in the right eye as a single or repeat instillation on Day 1. Subjects will have end-of-study (EOS) follow-up visits on Day 8 (±1) for SDE or Day 15 (±1) for RDE.

The planned single dose levels are 0.03, 0.06, 0.12, and 0.24 mg/eye, and repeat dose levels are 0.06, 0.12, and 0.24 mg/eye, QID, × 6 days (one dose in the morning on Day 7). The Starting dose of KDR2-2 in repeat dose escalation stage will be at least 2 dose levels below the highest single dose level shown to be safe, for example, if 0.24 mg is proven to be safe during SDE, the starting dose during RDE will be 0.06 mg. Other higher dose level(s) might be optional based on emerging data from this study.

Inclusion Criteria:

Subjects must meet all the following criteria to be enrolled in the trial:

1. Able to understand and willing to sign the ICF

2. Healthy male and female subjects, non-smokers, 18-55 years of age

3. With no significant medical history, and in good health as determined by detailed medical history (neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease), full physical examination, vital signs, 12-lead electrocardiogram (ECG), urinalysis and laboratory tests at screening. For eligibility purposes, abnormal laboratory or vital signs results may be repeated once if abnormal result is observed at the initial reading. Moreover, abnormalities found in the ECG may need to be confirmed by repeated measurements.

4. Subjects must have adequate organ function according to the following laboratory values at Screening and on Day-1. Repeat testing is allowed for verification, at the discretion of the Investigator:

   • Bone marrow function (absolute neutrophil count ≥ 1500/mm3 and platelet count ≥ 100,000/mm3)
   • Adequate liver function [alanine aminotransferase (ALT) ≤ 1.5 × upper limit normal (ULN) and alkaline phosphatase ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL]
   • Adequate renal function creatinine clearance 60 mL/min based on Cockcroft - Gault equation, or serum creatinine level ≤ 1.5 times the ULN.

5. Be a female of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal and have an FSH > 40 mIU/mL, or surgically sterile [defined as having a bilateral oophorectomy, hysterectomy or tubal ligation]) or agree to one of the following to prevent pregnancy and, if a woman of childbearing potential, have a negative serum pregnancy test at screening:

   • If a sexually active woman of childbearing potential (sexually active with a non-sterile male partner) agrees to prevent pregnancy by using double methods of contraception as follow until at least 30 days after the administration of the investigational product:

     1. simultaneous use of intra-uterine contraceptive device, placed at least 4 weeks prior to study drug administration, and condom for the male partner;
     2. simultaneous use of hormonal contraceptives, starting at least 4 weeks prior to study drug administration and must agree to use the same hormonal contraceptive throughout the study, and condom for the male partner;
     3. simultaneous use of diaphragm with intravaginally applied spermicide and male condom for the male partner, starting at least 7 days prior to study drug administration.

   • Male subjects who are not vasectomized for at least 6 months and who are sexually active with a non-sterile female partner must agree to use double methods of contraception below from the first dose of randomized study drug until 7 days after their dose and must not donate sperm during their study participation period:

     1. simultaneous use of a male condom and, for the female partner, hormonal contraceptives (used since at least 4 weeks) or intra-uterine contraceptive device (placed since at least 4 weeks);
     2. simultaneous use of a male condom and, for the female partner, a diaphragm with intravaginally applied spermicide.

6. Body mass index (BMI) 19.0-32.0 kg/m2 and body weight ≥ 50.0 kg for males and ≥ 45.0 kg for females.

7. Blood pressure ≤ 139/89 mm Hg at screening and on Day -1. If abnormal findings deemed by the Investigator as not clinically significant, it may be repeated.

8. Subjects are able to follow the study protocol and complete the trial.

Exclusion Criteria:

Subjects who meet any of the following criteria cannot be enrolled:

1. History of severe infection within 4 weeks prior to administration; signs and symptoms of any active infection regardless of severity within 2 weeks prior to administration.
2. History of eye infection, or trauma or surgeries including LASIK.
3. Subjects with a single eye.
4. History of hypersensitivity to similar drugs to KDR2-2 or their excipients.
5. Clinically significant abnormalities on ocular examination, including slit lamp, that would hinder the assessment of the eye or data collection at the discretion of the Investigator and/or ophthalmologist.
6. Any corrected visual acuity < 20/20, or intraocular pressure ≥ 20 mmHg.
7. Subjects who wear contact lenses within 1 month prior to administration, or will wear contact lenses during the trial.
8. Use of any prescription drugs excluding hormonal contraception, herbal supplements, or nonprescription drugs, including oral anti-histamines (for seasonal allergies) or ophthalmology drugs, within 1 month (30 days) or 5 half-lives (whichever is longer) prior to study drug administration, or dietary supplements within 1 week prior to study drug administration, unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with the study. Over-the-counter multivitamins will be permitted. If needed, paracetamol/acetaminophen may be used, but must be documented in the concomitant medications/significant non-drug therapies page of the source data. Exclusion applies to the use of Tropicamide 1% for the dilated retinal examination during baseline and final visit. Any questions of concomitant medications should be directed to the Sponsor.
9. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the first dosing, administration of a biological product in the context of a clinical research study within 90 days prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration.
10. Donation of blood 12 week prior to dosing.
11. Pregnant, or nursing females.
12. A history of psychiatric and psychological condition that, in the judgment of the investigator, may interfere with the planned treatment and follow-up, affect subject compliance or place the subject at high risk from treatment-related complications
13. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTcF interval > 450 milliseconds [ms], Bazett Formula: QTc = QT/RR0.5）at Screening and on Day -1.
14. Active hepatitis B or C. HBV carriers without active disease (HBV DNA titer < 1000 cps/mL or 200 IU/mL), or cured Hepatitis C (negative HCV RNA test) may be enrolled, in the judgement of the investigator.
15. Human immunodeficiency virus (HIV) positive.
16. Immunization with a live or attenuated vaccine is prohibited within 4 weeks prior to study drug administration. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed)
17. History of significant alcohol abuse within one year prior to screening or regular use of alcohol within six months prior to the screening visit (more than fourteen units of alcohol per week [1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]) or positive alcohol breath test at screening
18. History of significant drug abuse within one year prior to screening or use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, phencyclidine [PCP], opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening
19. Positive urine drug screen, cotinine test, or alcohol breath test at screening
20. Any reason which, in the opinion of the Investigator and Monitor, would prevent the subject from participating in the study.