Evaluation of Cenegermin Eye Drop Solution at Two Concentrations for Safety and Efficacy in Patients with Dry Eye Disease: A Randomized, Vehicle-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of two concentrations (5 mcg/mL and 10 mcg/mL) of a new formulation of recombinant human nerve growth factor (rhNGF) ophthalmic solution compared to a vehicle. The aim is to demonstrate the superiority of at least one concentration in improving ocular symptoms in patients with **dry eye disease**. This is clinically relevant as it addresses the need for effective treatments in managing the symptoms of dry eye, a condition that can significantly impact quality of life.

Secondary objectives include evaluating the efficacy of the rhNGF ophthalmic solution in: - Improving reflex tear production - Enhancing tear film stability - Maintaining ocular surface integrity, specifically corneal and conjunctival epitheliopathy - Improving best corrected distance visual acuity (BCDVA) - Alleviating associated symptoms of dry eye - Enhancing quality of life Additionally, the study aims to assess the safety and tolerability of the new formulation. These objectives are crucial for a comprehensive understanding of the therapeutic potential and safety profile of the rhNGF solution in treating dry eye disease.

The clinical trial investigating the efficacy of a new formulation of rhNGF ophthalmic solution for **dry eye disease** (DED) includes a total of 191 participants. The study population comprises both male and female subjects aged 18 years and older, representing various races, ethnicities, and eye colors. Participants were selected based on a confirmed diagnosis of dry eye disease for at least six months prior to enrollment, with specific clinical features such as a SANDE questionnaire Global Score of 50 or higher, Schirmer-I test results between 2 mm and 10 mm/5 minutes, and a fluorescein tear film break-up time of less than 10 seconds. The trial includes individuals with a best corrected distance visual acuity score of at least 0.1 decimal units in each eye. Females of childbearing potential were required to have a negative pregnancy test. The study population is characterized by their ability and willingness to comply with study procedures, and all participants provided informed consent approved by the Institutional Review Board (IRB). The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, double-masked, vehicle-controlled, parallel group study to evaluate the safety and efficacy of a new formulation of recombinant human nerve growth factor (rhNGF) eye drop solution at two different concentrations in patients with **dry eye disease**. The trial will span a total duration of 8 weeks, including a 4-week treatment period followed by a 4-week follow-up. Participants will be randomly assigned to receive either the rhNGF eye drop solution at concentrations of 5 mcg/mL or 10 mcg/mL, or a vehicle control. The primary objective is to demonstrate the superiority of at least one concentration of rhNGF over the vehicle in improving ocular symptoms of dry eye.

The study will involve several visits, starting with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as a diagnosis of dry eye disease for at least 6 months and a SANDE questionnaire Global Score of 50 or higher. Following the screening, participants will attend a baseline visit where initial assessments will be conducted. Subsequent visits will occur at weeks 4 and 8, during which primary and secondary endpoints will be evaluated. The primary endpoint is the mean change from baseline to week 8 in symptoms of dry eye assessed by the SANDE Global Score. Secondary endpoints include changes in Schirmer-I test results, corneal fluorescein staining, and other ocular assessments.

Participant involvement is expected to last for the entire 8-week duration of the trial. However, conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of adverse events that necessitate discontinuation. Safety will be monitored throughout the study, with particular attention to treatment-emergent adverse events. The trial is set to commence recruitment on April 15, 2024, with an estimated end date of March 31, 2025.

The clinical trial involves the administration of **rhNGF New Lyo Formulation**, an experimental medication formulated as **eye drops, solution**. The active substance in this formulation is **cenegermin**, a protein-based compound. The medication is available in two concentrations: 5 mcg/mL and 10 mcg/mL. The maximum daily dose for the 5 mcg/mL concentration is 0.6 µg, with a total maximum dose of 16.8 µg over a 28-day treatment period. For the 10 mcg/mL concentration, the maximum daily dose is 1.2 µg, with a total maximum dose of 33.6 µg over the same period. The route of administration is ophthalmic, and the medication is delivered using a combination of devices, including a Luer lock syringe, pipette, and vial adapter, all of which have CE marks.

In addition to the experimental treatment, the study utilizes a **placebo**. The placebo is a lyophilized product packaged in 2R siliconized glass class I vials, reconstituted with either 1 mL or 2 mL of diluent. The diluent comprises DMSO, Sesame Extract 98%, Kollifor HS 0.15%, Sodium Chloride, and Water for Injection. The reconstitution and administration of the placebo are performed using an adapter and a syringe, followed by administration with a pipette.

Auxiliary treatments in the study include **fluorescein sodium**, **tropicamide**, and a combination of **calcium chloride, potassium chloride, and sodium chloride**. Fluorescein sodium is administered as eye drops with a maximum daily dose of 1 drop and a total maximum dose of 10 drops over a 2-day period. Tropicamide is also administered as eye drops, with a maximum daily dose of 2 drops and a total maximum dose of 4 drops over 2 days. The combination of calcium chloride, potassium chloride, and sodium chloride is not specified for ophthalmic use, and its administration details are not applicable in this context.

The efficacy of the new formulation of Recombinant Human Nerve Growth Factor (rhNGF) eye drop solution will be assessed in a Phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel group study. The primary efficacy endpoint is the mean change from baseline to Week 8 in symptoms of dry eye, as assessed by the Symptoms Assessment in Dry Eye (SANDE) Global Score. Secondary efficacy endpoints include the proportion of patients improving to Schirmer-I test without anesthesia ≥10mm/5min in the study eye, mean change from baseline in Schirmer-I score without anesthesia, total corneal fluorescein staining, fluorescein tear break-up time (fTBUT), and symptoms questionnaire (SANDE) scores for severity and frequency. These assessments will be conducted at specified time points, including weeks 4 and 8.

Additional secondary endpoints involve the mean change from baseline in total conjunctival lissamine green staining, ocular pain assessed by the OPAS questionnaire’s pain scale, best corrected distance visual acuity (BCDVA), and quality of life (QoL) as assessed by the OPAS questionnaire’s QoL score. Safety will be monitored by the incidence and frequency of Treatment-Emergent Adverse Events (TEAEs) throughout the study, including the run-in period. The study will also evaluate changes in corneal endothelial cell density, the proportion of patients with specific ocular conditions on dilated fundus exam, and bulbar conjunctival redness. The treatment discontinuation rate due to tolerability issues will also be recorded. These efficacy parameters will be measured using validated scales and laboratory tests at designated time points, ensuring a comprehensive evaluation of the treatment's impact on dry eye disease.