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 disease (DED) 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.
DRY EYE DISEASE
To date, ReGenTree has sponsored a Phase 2/3 clinical trial (“ARISE-1”) and two Phase 3 clinical trials in patients with DED (“ARISE-2” and “ARISE-3”). All Phase 3 trials were conducted in the U.S. In May 2016, we reported the results of the 317-patient ARISE-1 trial and in October 2017, we reported the results of the ARISE-2 trial. The ARISE-2 study, which was sponsored by ReGenTree, demonstrated a number of statistically significant improvements in both signs and symptoms of DED with 0.1% RGN-259 versus placebo, albeit not in the designated co-primary endpoints, 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.
Topline results from ARISE-3 were reported on March 18, 2021. Further statistical analysis was performed as part of the process to fully understand patient data and the effects of RGN-259 compared to placebo by evaluating various subgroups of patients within ARISE-3 with pooled data from all three ARISE clinical trials. The conclusions from these expanded analyses were that the use of RGN-259 has demonstrated statistically significant and clinically relevant improvements in both signs and symptoms of dry eye syndrome after one and two weeks of treatment when measured across all three phase 3 clinical trials in over 1,600 patients, while confirming its excellent safety profile.
ReGenTree has been working with outside FDA regulatory consulting firms to define its regulatory strategy, which will include seeking a Special Protocol Assessment (SPA) in October 2022 for an additional dry eye trial (ARISE-4) in 2023. The SPA program allows FDA specialists to provide input and collaborate with a sponsor (ReGenTree) in setting up clinical protocols and statistical analysis plans, which is binding. By participating together at this stage of the protocol development, the sponsor and FDA have a clear understanding of the requisite trial protocol.
RGN-259 has also been used to treat neurotrophic keratitis (NK) patients with non-healing ulcers, initially under a “Compassionate Use” IND. Four patients were treated 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 subsequently conducted a Phase 3 clinical trial in patients with chronic NK through its ReGenTree, llc joint venture.
The Phase 3 NK trial (SEER-1), a small study in an orphan population, enrolled a total of 18 patients. On May 14, 2020, the Company reported that the trial was closed and reported the results of SEER-1. Six out of 10 patients in the RGN-259 treated group and 1 out of 8 patients in the placebo treated group achieved complete corneal healing in four weeks. In terms of the primary endpoint, “ratio of corneal wound healed patients after four weeks’ administration”, the statistical difference was slightly over 0.05 (p = 0.0656, Fisher’s exact test), due to the limited number of patients in each group. When another statistical analysis method was used to analyze the same primary endpoint (Chi square test), there was statistical significance, p = 0.0400. In addition, in a pre-specified secondary endpoint evaluating corneal epithelial healing at day 43 (two weeks post-treatment) and the durability of RGN-259 treatment, we also confirmed a clear statistical difference using the Fisher’s exact test, p = 0.0359. Several other efficacy parameters were either highly significant or strongly trending toward statistical significance in the RGN-259 group indicating the depth of patient response to RGN-259.
Recently, ReGenTree annoucnced that it has signed a Letter of Intent with a global ophthalmology contract research organization (CRO) to start the two simultaneous phase 3 clinical trials for NK in October 2022 in the U.S. and Europe. The FDA requires two successful phase 3 trials in most circumstances prior to submitting a new drug or biologics application (NDA or BLA) and simultaneously conducting these trials should reduce the time required to complete phase 3. ReGenTree will seek to confirm the efficacy observed in SEER-1.