A Safety and Efficacy Study of 2 Dosing Regimens of Recombinant Human Nerve Growth Factor (rhNGF) Eye Drop Solution Compared With Vehicle in Patients With Dry Eye Disease.

A 4-Week, Phase II, Multicenter, Randomized, Double-Masked, Vehicle-Controlled, Parallel Group Study With 4 Weeks of Follow-Up to Evaluate 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

Primary objective

• To evaluate the efficacy of 5 μg/mL and 10 μg/mL concentrations of the new formulation of rhNGF ophthalmic solution versus vehicle, in order to demonstrate superiority of at least 1 of the concentrations over vehicle in the improvement of ocular symptoms of dry eye in participants with dry eye disease (DED)

Key secondary objectives

• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in increasing the number of participants with improved reflex tear production as compared to vehicle at week 4
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving reflex tear production as compared to vehicle at week 4
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving ocular surface integrity (corneal epitheliopathy) as compared to vehicle at week 4

Secondary objectives

• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving reflex tear production as compared to vehicle at week 8
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving tear film stability as compared to vehicle at weeks 4 and 8
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving ocular surface integrity (corneal and conjunctival epitheliopathy) as compared to vehicle at weeks 4 and 8
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving the severity and frequency of dry eye symptoms as compared to vehicle at weeks 4 and 8
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving dry eye symptoms as compared to vehicle at week 4
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving associated symptoms in DED as compared to vehicle at weeks 4 and 8
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving the quality of life in participants with DED as compared to vehicle at weeks 4 and 8
• To evaluate the efficacy of the new formulation of rhNGF ophthalmic solution in improving best corrected visual acuity in DED as compared to vehicle at weeks 4 and 8

Safety objectives

• To evaluate safety/tolerability of the new formulation of rhNGF ophthalmic solution
• To evaluate safety of the new formulation of rhNGF ophthalmic solution
• To evaluate tolerability of the new formulation of rhNGF ophthalmic solution

This was a phase 2, multi-center, randomized, double-masked, parallel-arm, vehicle-controlled, dose-finding, clinical study to evaluate the safety and efficacy of 2 concentrations (5 μg/mL and 10 μg/mL) of a reconstituted lyophilized formulation of rhNGF, administered as 1 drop of an ophthalmic solution 3 times a day (TID) in both eyes for 4 weeks in participants with DED.

Participants were evaluated at the screening visit (day -12 ± 2; visit 1), baseline (day 1; visit 2), week 2 (day 13 ± 1; visit 3), week 4 end of treatment (EOT; day 28 ± 1; visit 4), and week 8 end of follow-up and end of study (EOS; day 56 ± 2; visit 5).

At the screening visit (visit 1), participants who signed informed consent and met all eligibility criteria were enrolled and instructed to discontinue all topical ophthalmic medications; during the run-in period, they were only allowed to use investigational product (vehicle) ophthalmic solution provided by the sponsor. The first eye drop of the vehicle was applied to both eyes of participants at the site by the investigator during visit 1. Participants were instructed on how to prepare the investigational product (vehicle) daily at home and then how to self-administer 1 drop TID in both eyes. A Patient Diary for the run-in phase was supplied to the participant. At the conclusion of the day 1 baseline visit (visit 2), participants still meeting all eligibility criteria were randomly assigned 1:1:1 to a 4-week treatment regimen of investigational product (vehicle, or rhNGF [5 μg/mL or 10 μg/mL]), administered as follows:

• 1 drop of rhNGF ophthalmic solution at 5 μg/mL in each eye TID, at approximately 6-hour intervals, for 4 weeks
• 1 drop of rhNGF ophthalmic solution at 10 μg/mL in each eye TID, at approximately 6-hour intervals, for 4 weeks
• 1 drop of vehicle in each eye, TID, at approximately 6-hour intervals, for 4 weeks.

Eligible participants were also dispensed a 2-week supply of the investigational product (vehicle or rhNGF) to administer at home between visits 2 and 3. They received another 2-week supply during visit 3. A Patient Diary for recording the treatment phase was supplied to the participant.

At visit 2 (baseline visit) a study eye was determined. Namely, the study eye was the worse eye. Assuming that all inclusion/exclusion criteria were met in both eyes, the worse eye (study eye) was determined based on the lower Schirmer-I (without anesthesia) score. If the Schirmer-I score was identical in both eyes, the study eye was determined based on the worse score for corneal and conjunctival NEI staining (total score for corneal staining followed by total score for conjunctival). If the staining score was identical in both eyes, then the right eye was assigned as the study eye.

Participants who prematurely discontinued the treatment (for any reason) were asked to complete the remaining assessments planned by the protocol and received commercially available preservative-free AT, TID, provided by the sponsor. In case of withdrawal from the study, participants were asked to complete the assessment expected for visit 4 as an Early Exit Visit.

Following the completion of the treatment period, participants were followed up for an additional 4 weeks and were evaluated at 8 weeks (visit 5). During the 4-week follow-up period, no treatment was allowed except for commercially available preservative free AT TID provided by the sponsor.

A Patient Diary for the follow-up period was supplied to the patient.

Inclusion Criteria:

• Male or female aged ≥18 years of any race/ethnicity and eye color.

• A diagnosis of dry eye disease at least 6 months before enrollment (current use or recommended use of artificial tears for the treatment of dry eye).

• Moderate-to-severe dry eye characterized by the following clinical features:

  1. Symptoms Assessment in Dry Eye (SANDE) questionnaire global score ≥50, and
  2. Schirmer-I test without anesthesia >2 mm and <10 mm/5 minutes, and
  3. Total corneal fluorescein staining grade ≥3 (NEI scale) and/or total conjunctival lissamine green staining score ≥3 assessed by the NEI grading system, and
  4. Fluorescein tear film break-up time (fTBUT) < 10 seconds The same eye must have fulfilled all the above criteria.

• Best corrected distance visual acuity (BCDVA) score on ETDRS chart of ≥0.1 decimal units (≤1.0 logarithm of the minimum angle of resolution [logMAR]) in each eye at the time of study enrollment

• Negative pregnancy test in females of childbearing potential.

• Only participants who satisfy all informed consent requirements were included in the study; the participant and/or his/her legal representative must have read, signed, and dated the informed consent document before any study-related procedures were performed; the informed consent form signed by participants and/or legal representatives must have been approved by the Institutional Review Board (IRB) for the current study.

• Have the ability and willingness to comply with study procedures.

Exclusion Criteria:

• Inability to speak and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments.

• Evidence of an active ocular infection in either eye.

• Presence of any other ocular disorder or condition requiring topical ocular medication during the entire duration of the study.

• Possibility of the need for ocular surgery at the time of inclusion in the study or anticipated ocular surgery expected during the participation in the study

• History of severe systemic allergy or severe ocular allergy [including seasonal conjunctivitis, AKC (Atopic KeratoConjunctivitis), VKC (Vernal KeratoConjunctivitis)] or chronic conjunctivitis and/or keratitis other than dry eye.

• Ocular scarring due to irradiation, alkali burns, Stevens-Johnson syndrome and ocular cicatricial pemphigoid.

• Destruction of conjunctival goblet cells such as in Vitamin A deficiency.

• Severe blepharitis or obvious inflammation of the lid margin.

• Intraocular inflammation defined as Tyndall score >0.

• Medical history of tumor malignancy in the previous 3 years

• Systemic disease not stabilized within 1 month before the screening visit (e.g., diabetes with glycemia out of range, thyroid malfunction) or judged by the investigator to be incompatible with the study (e.g., current systemic infections) or with a condition incompatible with the frequent assessment required by the study.

• History of a serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or had a clinically significant allergy to drugs, foods, topical anesthetic eye drop or other local anesthetics or other materials, including ocular vital dyes, tropicamide eye drops, commercial artificial tears.

• Known or suspected allergy to sesame and other seeds, tree nuts, and/or peanuts, and/or any other component of the new rhNGF formulation.

• Fertile patients (i.e., not surgically sterilized, or postmenopausal women for at least 1 year) are excluded from participation in the study if they do not practice abstinence from heterosexual intercourse as per usual and customary lifestyle, or are unwilling to use an acceptable form of contraception such as condom with spermicidal cream or jelly for males, or for females if they meet any one of the following conditions:

  1. Currently pregnant (positive urine pregnancy test at screening or baseline visits) or planning to become pregnant during the duration of the treatment phase of the clinical trial.
  2. Participant is breastfeeding.
  3. Unwilling to use birth control measures such as mechanical barrier methods (spermicide in conjunction with a barrier such as a condom or diaphragm or intrauterine device) during the entire course of and 30 days after the study treatment period, or,
  4. Unwilling to continue to use highly effective birth control measures such as hormonal contraceptives (oral, implanted, transdermal, or injected) during the entire course of and 30 days after the study treatment period.

• Any concurrent medical condition that, in the judgment of the principal investigator, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the participant's well-being.

• Contact lenses or punctum plug use in either eye during the washout, treatment, and follow-up phases of the study (previous use is not an exclusion criteria but must be removed and discontinued at the Screening visit).

• Medical history of drug addiction or alcohol abuse (>1 drink /day for women and >2 drinks /day for men following USDA dietary Guidelines 2020-2025).

• Any prior ocular surgery, including but not limited to amniotic membrane transplant, refractive [PTK (Excimer Laser Phototherapeutic Keratectomy) / LASIK (Laser-Assisted In Situ Keratomileusis) / Epi-LASIK (Epithelial Laser In Situ Keratomileusis) / LASEK (Laser-Assisted Subepithelial Keratectomy) / SMILE (Small Incision Lenticule Extraction)], palpebral, cataract surgery, trabeculectomy, vitrectomy and Pan-Retinal Photocoagulation (PRP) within 90 days before the screening visit.

• Participation in a clinical trial with a new active substance, including medical devices, during the previous 60 days.

• Participation in another clinical trial study at the same time as the present study.