Evaluation of Lufepirsen Ophthalmic Gel for Safety and Efficacy in Persistent Corneal Epithelial Defects: A Randomized, Double-Masked, Vehicle-Controlled Phase 2 Study

The primary objective of this study is to evaluate the **safety** and **efficacy** of NEXAGON (lufepirsen ophthalmic gel) compared to its vehicle in achieving corneal re-epithelialization that is maintained for a minimum of 28 days in subjects with **Persistent Corneal Epithelial Defects** (PCED). This is assessed by a central reading center through the standardized evaluation of digital images of fluorescein staining of the cornea. The clinical relevance of this objective lies in addressing the unmet need for effective treatments in patients with PCED, which can lead to significant ocular morbidity if not properly managed.

Secondary objectives include:

• **Safety**: Monitoring treatment-emergent adverse events (TEAEs), vital signs (blood pressure, pulse), clinical laboratory tests (hematology, serum chemistry, urinalysis, and hemoglobin A1c for diabetic status), patient-reported outcomes on ocular pain, visual acuity, slit lamp biomicroscopy, NEI grading scale for corneal fluorescein staining, and dilated fundus ophthalmoscopy.
• **Efficacy**: Assessing corneal re-epithelialization maintained for at least 28 days, comparing the number of dose administrations required, time to achieve re-epithelialization, occurrence and severity of ocular pain, change in best-corrected distance visual acuity (BCDVA) using the ETDRS, and determining the optimal effective dose concentration of NEXAGON.
• **Exploratory**: Evaluating changes in corneal sensitivity and levels of aqueous matrix metalloproteinase 9 (MMP-9) in corneal tear fluid.

The clinical trial involves a total of **60 participants** diagnosed with **Persistent Corneal Epithelial Defects**. The study population includes both male and female subjects, with an age range starting from 2 years in the United States and 18 years in other countries. Participants were selected based on the presence of a corneal epithelial defect persisting for at least two weeks and refractory to conventional non-surgical standard of care treatments. The trial does not include a vulnerable population. Participants are required to have no clinical improvement in their condition within two weeks prior to randomization, and the defect must measure at least 1 mm along the largest diameter at the start of the treatment period. Female participants of childbearing potential must adhere to specific contraceptive measures throughout the study. The trial population was chosen to ensure the ability and willingness to comply with all study procedures, and informed consent was obtained from all participants or their legally authorized representatives.

The clinical trial is designed as a **randomized**, **double-masked**, vehicle-controlled Phase 2 study to evaluate the safety and efficacy of NEXAGON (lufepirsen ophthalmic gel) in subjects with **Persistent Corneal Epithelial Defects**. The trial aims to assess the corneal re-epithelialization maintained for a minimum of 28 days, as evaluated by a central reading center through standardized digital imaging of corneal fluorescein staining. The study will involve multiple visits, including an initial screening visit, regular follow-up visits, and an end-of-study visit. The trial is expected to commence recruitment on March 31, 2025, and conclude by March 31, 2026.

Participants will be involved in the study for a maximum treatment period of 114 days, depending on the treatment group allocation. The inclusion visit will determine eligibility based on criteria such as age, the presence of a corneal epithelial defect of at least two weeks' duration, and refractoriness to conventional non-surgical treatments. Follow-up visits will monitor safety and efficacy endpoints, including adverse events, vital signs, ocular pain, visual acuity, and corneal staining assessments. The end-of-study visit will evaluate the primary endpoint of sustained corneal re-epithelialization and secondary endpoints related to safety and efficacy.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will utilize a topical route of administration for the ophthalmic gel, with a maximum daily dose of 0.18 mg and a total dose not exceeding 3.24 mg. The study will ensure that all procedures adhere to ethical standards, with informed consent obtained from all participants or their legally authorized representatives prior to any study-related activities.

The clinical trial involves the evaluation of **NEXAGON**, an **ophthalmic gel** containing the active substance **lufepirsen**. Lufepirsen is a nucleic acid-based compound, also known by the synonym CODA001. The gel is manufactured by Amber Ophthalmics Inc. and is administered topically. The dosage regimen for one formulation involves a maximum daily dose of 0.02 mg/kg, with a total maximum dose of 0.16 mg/kg over a treatment period of 57 days. Another formulation allows for a maximum daily dose of 0.18 mg, with a total maximum dose of 3.24 mg over 114 days. The administration of the gel is intended for subjects with persistent corneal epithelial defects, aiming to promote corneal re-epithelialization.

The study also includes a comparator treatment, referred to as the **NEXAGON vehicle**. This vehicle is a sterile, thermoreversible gel that does not contain the active pharmaceutical ingredient (API), lufepirsen. It is composed of poloxamer 407, sodium phosphate dibasic heptahydrate, potassium dihydrogen phosphate, and sterile water for injection. The vehicle serves as a control to evaluate the efficacy and safety of the active treatment by providing a baseline for comparison. The vehicle is also administered topically, following the same application schedule as the active treatment.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial's primary objective is to assess the safety and efficacy of NEXAGON in achieving sustained corneal re-epithelialization for a minimum of 28 days, as evaluated by a central reading center through standardized digital imaging techniques.

The efficacy of NEXAGON (lufepirsen ophthalmic gel) in the treatment of persistent corneal epithelial defects will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the proportion of subjects achieving corneal re-epithelialization that is maintained for a minimum of 28 days. This will be evaluated based on the assessment of corneal fluorescein staining images of the persistent corneal epithelial defect (PCED) by a central reading center (CRC) at the end of the study (EOS).

Secondary efficacy endpoints include the proportion of subjects achieving corneal re-epithelialization, as assessed by both the CRC and the Investigator, at the end of treatment (EOT). Additionally, the number of dose administrations required to achieve corneal re-epithelialization maintained for a minimum of 28 days post-treatment will be recorded. The time to corneal re-epithelialization, defined as the duration from randomization to the achievement of re-epithelialization, will be measured at all visits. Other secondary measures include the mean change from baseline in ocular pain, based on the Ocular Pain Assessment Scale (OPAS), and the mean change in best-corrected distance visual acuity (BCDVA) using the ETDRS scale at EOS.

Exploratory endpoints will evaluate the mean percentage change from baseline in corneal neuronal sensitivity and the change in MMP-9 levels in subjects' tear fluid at EOS. The assessments will be conducted using standardized digital imaging techniques and validated scales to ensure accuracy and reliability of the data collected throughout the trial.