RGN-259

Among RegeneRx’s highest priorities is development of RGN-259, a Tβ4-based sterile and preservative-free eye drop, as a novel treatment for dry eye and neurotrophic keratitis (NK), a persistent corneal defect caused by diabetes and herpes zoster virus, among other pathologies. NK is an orphan disease as there are fewer than 200,000 cases in the U.S. and in December 2013, we received orphan drug status from the U.S. FDA for RGN-259 for the treatment of NK. Through our U.S. joint venture, we initiated Phase 3 clinical trials in September, 2015 in patients with dry eye syndrome and neurotrophic keratopathy.

RGN-259 represents a new approach to corneal healing, as there is currently no pharmaceutical agent that has shown corneal repair and anti-inflammatory properties. Preclinical studies have shown that Tβ4 promotes cell migration, increases cell-cell and cell-matrix contacts through increase laminin-5 production, and reduces both apoptosis and inflammation in the cornea. 

No Phase 1 ophthalmic trial was required for RGN-259 by the FDA after its assessment of our dermal Phase 1 safety data and relevant preclinical data. 

DRY EYE SYNDROME

Phase 3 (ARISE-3)

In May 2019, RegeneRx, through its U.S. joint venture, ReGenTree, llc, announced ARISE-3, a Phase 3 clinical trial to evaluate RGN-259, a sterile, preservative-free eye drop in 700 patients with dry eye syndrome (DES) at approximately fifteen nationwide clinical sites across the U.S., including hospitals and clinics specializing in ophthalmology, comparing the drug candidate to placebo.  The trial is again being managed by Ora, Inc. and completion is expected during mid-2020.  With ARISE-3, we are focusing more fully on clinical management based on know-how that we have learned from ARISE-1 and ARISE-2 which, we believe, will limit the risk of clinical trial failure. Furthermore, in the FDA approval process for new dry eye products, we believe that all data from previous trials, as well as this ongoing study, will be analyzed and included in the Data Totality concept.

Phase 3 (ARISE-2)

In October 2017, we reported the results of the ARISE-2 trial. The ARISE-2 study, which was sponsored by ReGenTree and managed by Ora, Inc., demonstrated a number of statistically significant improvements in both signs and symptoms of DES with 0.1% RGN-259 versus placebo, while showing excellent safety, comfort, and tolerability profiles. The ocular discomfort symptom showed a statistically significant reduction in the RGN-259-treated group at day 15 as compared to placebo (p=0.0149) in the change from baseline. For sign, RGN-259 also improved the dry eye patient’s ability to withstand an exacerbated condition in a patient subgroup with both compromised corneal fluorescein staining and Schirmer’s test at baseline. In this population, RGN-259 showed superiority over placebo in reducing corneal fluorescein staining in the change from baseline at days 15 and 29 (p=0.0207 and 0.0254, respectively). RGN-259 confirmed its global effects on dry eye syndrome and fast onset in multiple sign and symptom efficacies with no safety issues in the ARISE-1 and ARISE-2 studies as well as in the pooled data, although ARISE-2 was not successful in duplicating the results of ARISE-1 where the study population was limited and less diversified. There were no significant drug-related adverse or serious adverse events and RGN-259 was well-tolerated and comfortable for the patients with no irritation upon instillation.

Phase 2/3 (ARISE-1)

A 317-patient, double-masked, vehicle-controlled Phase 2/3 clinical trial in patients with moderate to severe dry eye was completed in 2016.  Major findings in the trial were as follows:

• RGN-259 demonstrated statistically significant improvements in both signs and symptoms of dry eye with 0.05% and 0.1% RGN-259 compared to placebo in a dose dependent manner during a 28-day dosing period. While the primary outcome measures were not met, several key related pre-specified endpoints and subgroups of patients with more severe dry eye showed statistically significant treatment effects. These results confirm the findings from the previous Phase 2 trial providing clear direction for the clinical regulatory pathway and remaining registration trials for RGN-259.     
• RGN-259 was evaluated using the Controlled Adverse Environment (CAESM) Model developed by Ora, Inc., the product development firm managing the program. The CAESM was utilized to screen and enroll an enriched patient population and measure a patient's ability to withstand an acute adverse environmental challenge of the ocular surface. 
• On the final day of dosing (Day 28), patients receiving 0.1% RGN-259 had a statistically significant reduction in ocular discomfort during CAESM exposure when compared to placebo (Intent-to-Treat Population (ITT), p=0.043). Importantly, this result was also observed in the previous Phase 2 trial in patients treated with 0.1% RGN-259 (ITT, p=0.024), thereby demonstrating a symptom endpoint in two independent trials. A statistically significant ocular discomfort improvement after CAESM exposure on Day 28 was also observed in the 0.05% and 0.1% RGN-259 treatment arms when compared to placebo (ITT, p=0.0366 and p=0.0072, respectively) indicating a dose dependent response. 
•  Efficacy in an environmental setting was also demonstrated in more symptomatic patients at baseline, with statistically significant improvements in ocular discomfort observed at day 28 prior to CAESM in patients receiving 0.05% and 0.1% RGN-259 compared to placebo (p=0.022 and p=0.006, respectively). These data suggest that RGN-259 has a fast-acting treatment effect on a dry eye symptom during exposure to an adverse environment as well as in the natural environment after 28 days of dosing.
• RGN-259 also improved a common objective endpoint – ocular surface staining after 28 days of dosing in patients with compromised tear film break-up time at baseline. In this population, patients receiving 0.1% RGN-259 had a statistically significant reduction in corneal fluorescein staining prior to entering the CAESM on Day 28 when compared to placebo (p=0.034). The same result was observed in the previous Phase 2 trial for patients treated with 0.1% RGN-259, although it was not statistically significant in the smaller sample size of this previous Phase 2 trial. 
• Additionally, a change from baseline analysis (Day 28 minus Day 0) demonstrated a statistically significant improvement in inferior corneal staining for the 0.1% RGN-259 treatment arm when compared to placebo (p=0.003). This finding was also observed at Day 14 compared to placebo (p=0.035). These data suggest that RGN-259 has a fast-acting treatment effect on a dry eye sign after 14 and 28 days of dosing. 
• There were no significant drug-related adverse or serious adverse events and RGN-259 was well-tolerated and comfortable for the patients with no irritation upon instillation.

Phase 2

A 72-patient, double-masked, vehicle-controlled Phase 2 clinical trial in patients with moderate to severe dry eye was completed in 2011. Major findings in the trial were as follows: 

• No drug-related or serious adverse events
• Statistically significant sign and symptom improvements seen in patients receiving RGN-259. The U.S. FDA requires statistically significant improvements in both signs and symptoms of dry eye for marketing approval. 
• Other positive sign and symptom trends were noted in the trial. 
• Conclusion: The positive results of this Phase 2 exploratory trial reflect RGN-259’s reported mechanisms of action and provide us with FDA-approvable endpoints to be targeted in future clinical trials. 

Physician-sponsored Phase 2 clinical trial

In 2012, a double-masked, vehicle-controlled, physician-sponsored Phase 2 clinical trial evaluating RGN-259 for the treatment of severe dry eye was conducted by ophthalmologists at the Kresge Eye Institute, Wayne State University, and Beaumont Hospital, both in Detroit, Michigan. Nine patients with severe dry eye (18 eyes) were treated with RGN-259 or vehicle control six times daily over a period of 28 days. They were evaluated upon entering the study after a two week washout period, at weekly intervals during the treatment phase, at the end of the 28-day treatment period, and at a follow-up visit 28 days after treatment. RGN-259 was found to be safe and well-tolerated and met key efficacy objectives with statistically significant sign and symptom improvements compared to vehicle control, at various time intervals, including 28 days post-treatment. Of particular note were the differences between

RGN-259 and vehicle control 28 days post-treatment, or the follow-up period. The RGN-259-treated group had a 35.1% reduction of ocular discomfort compared to vehicle control (p=0.0141), and a 59.1% reduction of total corneal fluorescein staining compared to vehicle control (p=0.0108). 

Consistent with the reduction of ocular discomfort and fluorescein staining at the 28-day follow-up visit, other improvements seen in the RGN-259-treated patients included tear film breakup time and increased tear volume production. Likewise, these improvements were seen at other time points in the study. 

NEUROTROPHIC KERATOPATHY 

RGN-259 has also been used to treat neurotrophic keratitis (NK) patients with non-healing ulcers under a “Compassionate Use” IND. Dr. Steven Dunn, a corneal specialist, treated 4 patients for 28 days and 2 additional patients for 49 days with RGN-259. The eye ulcers either completely healed or demonstrated significant improvement by the end of treatment or shortly thereafter (See figure below). During the 30-day follow-up period patients remained healed even though the treatment regimen had been completed. 

In 2013, RGN-259 was given orphan status by the U.S. FDA for the treatment of NK. Subsequently, RegeneRx held an end of Phase 2 meeting with the FDA and is currently conducting a Phase 3 clinical trial in patients with chronic NK through its ReGenTree, llc joint venture. 

The Phase 3 clinical NK trial, (SEER-1), is a smaller study in an orphan population and has enrolled 17 patients. To participate in the trial the patients were required to have a persistent epithelial defect (non-healing corneal wound).  In 2018, ReGenTree previously disclosed that 7 of 17 patients enrolled SEER-1 had completely healed. While these preliminary observations are encouraging, it should be noted that the patients and treating physicians remain masked while the trial is on-going, so it is not known whether the healed patients are in the RGN-259 group, placebo group, or distributed among both.  We expect ReGenTree will report top line data in the next few months in 2020.