A Study to Evaluate the Safety and Tolerability of EXN407

Study Overview
=================
Brief Summary
-----------------
This first in human (FIH), Phase Ib/II study of EXN407 is a randomised, double-masked, vehicle-controlled, multiple dose, dose-escalating study to evaluate the safety and tolerability of EXN407 in subjects with centre involved Diabetic Macular Oedema (DMO), with Centre-subfield macular thickness (CMT) between 280-420 µm and Best corrected visual acuity (BCVA) better than or equal to 69 ETDRS score (approximate Snellen equivalent 20/40 (6/12 letters) in the study eye, which is considered secondary to diabetes mellitus. This study will provide a basis for further clinical development of EXN407 ophthalmic solution.

Official Title
-----------------
A Randomised, Double-Masked Vehicle-Controlled, Multiple Dose, Dose Escalation Study To Evaluate The Safety and Tolerability of EXN407 in Subjects With Centre Involved Diabetic Macular Oedema Secondary to Diabetes Mellitus

Conditions
-----------------
Diabetic Macular Edema

Intervention / Treatment
-----------------
* Drug: EXN407


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is at least 18 years of age inclusive, at the time of signing the informed consent. BCVA better than or equal to 69 ETDRS score (approximate Snellen equivalent 20/40 or 6/12) in the study eye using the ETDRS visual acuity scale at Screening or BCVA less than 69 ETDRS score (approximate Snellen equivalent 20/50 or 6/15) but who, in the Investigator's opinion, is unsuitable for treatment with anti-VEGF by intravitreal injection or refuses it. Subjects should have no more than a 7-letter difference in BCVA at Screening and baseline visit. Ocular media is consistent with SD-OCT imaging and cataracts are not expected in the subject for the duration of the study. The subject has no other retinal disease. Subject or the subject's partner successfully demonstrates their ability to self-administer/administer eye drops at Screening, with multiple attempts allowed at the discretion of the Investigator. Exclusion Criteria: Any other retinal disease in the study eye, other than centre involved DMO or diabetic retinopathy. Poor vision (VA 6/60 or worse) in the contralateral eye. Intraocular inflammation (including trace or greater) in the study eye. History of idiopathic or autoimmune uveitis in either eye. Use of intravitreal anti-VEGF drugs including ranibizumab, bevacizumab, aflibercept in the study eye within 6 months of the Screening Visit, or in the fellow (non study) eye within 3 months of the Screening Visit. Use of topical corticosteroids or topical non-steroidal anti-inflammatory agents in the study eye within 28 days of the Screening Visit. Use of intravitreal corticosteroids in either eye or systemic steroids within 12 months of the Screening Visit. Prior use of Iluvien (without time limitation). Within 180 days prior to the Screening visit, use of medications known to be toxic to the retina, lens or optic nerve (e.g. desferoximine, chloroquine/hydrochloroquine, chlorpromazine, phenothiazines, tamoxifen, and ethambutol). History of (within 90 days of Screening date) cerebral vascular accident (stroke) or MI. Significant renal impairment including subjects on chronic renal dialysis and subjects with a history of nephrectomy or kidney transplant (regardless of renal function). History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions, or severe allergic responses. Positive pregnancy test (all female subjects of childbearing potential must have a urine β-human chorionic gonadotropin [hCG] pregnancy test performed at Screening and within 7 days prior to randomisation) or is known to be pregnant or lactating. Known to have, or history of a positive test result for, hepatitis B or C, HIV, syphilis, tuberculosis, or COVID-19.

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

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort 1<br>Each subject will receive a low-dose 0.5 mg/mL (0.05%) of EXN407 or placebo twice a day in 14 doses over a 7 day period. | Drug: EXN407<br>* EXN407 or placebo will be administered as a single 30 microliters drop twice a day, by unilateral eye drop administration to the study eye only.<br>|
| Experimental: Dose Escalation Cohort 2<br>Each subject will receive a mid-dose 1 mg/mL (0.1%) of EXN407 or placebo twice a day in 14 doses over a 7 day period. | Drug: EXN407<br>* EXN407 or placebo will be administered as a single 30 microliters drop twice a day, by unilateral eye drop administration to the study eye only.<br>|
| Experimental: Dose Escalation Cohort 3<br>Each subject will receive a high-dose 1.5 mg/mL (0.15%) of EXN407 or placebo twice a day in 14 doses over a 7 day period. | Drug: EXN407<br>* EXN407 or placebo will be administered as a single 30 microliters drop twice a day, by unilateral eye drop administration to the study eye only.<br>|
| Experimental: Dose Expansion Cohort<br>The highest well-tolerated dose of EXN407 will be evaluated where subjects will receive EXN407 at the selected dose or placebo twice a day for up to 84 days resulting in a total of 168 doses | Drug: EXN407<br>* EXN407 or placebo will be administered as a single 30 microliters drop twice a day, by unilateral eye drop administration to the study eye only.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective of the study is to evaluate the ocular safety and tolerability (by incidence of ocular adverse events) of EXN407 ophthalmic solution in Dose Escalation phase. | Measured by frequency and severity of ocular AEs in the study and contralateral eyes. | Assessed starting from Day 1 of treatment to Day 36 in Dose Escalation. | 
| The primary objective of the study is to evaluate the ocular safety and tolerability (by incidence of ocular adverse events) of EXN407 ophthalmic solution in Dose Expansion phase. | Measured by frequency and severity of ocular AEs in the study and contralateral eyes. | Assessed starting from Day 1 of treatment to Day 113 in Dose Expansion phase. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the systemic pharmacokinetics of EXN407 ophthalmic solution in subjects with DMO secondary to diabetes mellitus by Tmax. | Measured by characterizing the PK profile by estimating the time of the maximum plasma drug concentration (Tmax) of EXN407 in plasma. | Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose. | 
| To evaluate the systemic pharmacokinetics of EXN407 ophthalmic solution in subjects with DMO secondary to diabetes mellitus by Cmax | Measured by characterizing the PK profile by estimating the maximum observed drug plasma concentration (Cmax) of EXN407 in plasma. | Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose. | 
| To evaluate the systemic pharmacokinetics of EXN407 ophthalmic solution in subjects with DMO secondary to diabetes mellitus by AUC. | Measured by characterizing the PK profile by estimating the area under the curve (AUC) of EXN407 in plasma. | Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose. | 
| To evaluate the systemic pharmacokinetics of EXN407 ophthalmic solution in subjects with DMO secondary to diabetes mellitus by t½. | Measured by characterizing the PK profile by estimating the apparent elimination half-life (t½) of EXN407 in plasma. | Blood draws for PK will be collected only on Day 3(Dose Escalation) and Day 8(Dose Expansion) at the following timepoints: pre-dose and 15 mins, 30 mins, 1, 2, 3,and 4 hours post-dose. | 
| To evaluate the percentage (%) of changes in ocular functional measures as assessed using ophthalmoscopy. | Measured by the changes from baseline in ophthalmic examination finding through ophthalmoscopy. | From Day 1 of Treatment to End of Treatment i.e. assessed upto 36 Days in Dose Escalation and upto 4 months(113 days) in Dose Expansion. | 
| To evaluate the percentage (%) of changes in ocular structural measures as assessed using ophthalmoscopy. | Measured by the changes from baseline in ophthalmic examination finding through ophthalmoscopy. | From Day 1 of Treatment to End of Treatment i.e. assessed upto 36 Days in Dose Escalation and upto 4 months(113 days) in Dose Expansion. |