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Jay S Pepose,1,2 Paul J Hartman,3 Harvey B DuBiner,4 Marc A Abrams,5 Robert J Smyth-Medina,6 Sayoko E Moroi,7 Alan R Meyer,8 Mina P Sooch,8 Reda M Jaber,8 Konstantinos Charizanis,8 Seth A Klapman,8 Arin T Amin,8 Jonah E Yousif,8 Eliot S Lazar,9 Paul M Karpecki,10 Charles B Slonim,11 Marguerite B McDonald12 1Pepose Vision Institute, St. Louis, MO, USA; 2Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; 3Department of Ophthalmology, University of Rochester, Rochester, NY, USA; 4Clayton Eye Center, Morrow, GA, USA; 5Case Western Reserve University, Cleveland, OH, USA; 6North Valley Eye Medical Group, Mission Hills, CA, USA; 7The Ohio State University Wexner Medical Center, Columbus, OH, USA; 8Ocuphire Pharma Inc, Farmington Hills, MI, USA; 9elCON Medical, Buffalo, NY, USA; 10Kentucky College of Optometry, University of Pikeville, Pikeville, KY, USA; 11Oculos Development Services, LLC, Tampa, FL, USA; 12Department of Ophthalmology, New York University Langone Medical Center, New York, NY, USACorrespondence: Konstantinos CharizanisOcuphire Pharma, Inc., 37000 Grand River Ave, Farmington, MI 48335, USATel +1 (352) 328 9117Email kcharizanis@ocuphire.comPurpose: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population.Patients and Methods: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia.Results: Use of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo (P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥ 1 line of improvement in photopic DCNVA at day 8 (P = 0.0018), day 15 (P = 0.0072), and day 16 (P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo.Conclusion: Although mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies.Keywords: IOP, presbyopia, night vision disturbances, dim light vision disturbances, pupil diameter, ORION-1

Purpose: To evaluate the safety and efficacy of 0.75% phentolamine ophthalmic solution (POS), an α-adrenergic antagonist, in reversal of pharmacologically induced mydriasis., Design: Two phase 3, multicenter, placebo-controlled, randomized, double-masked clinical trials in healthy participants., Participants: Five hundred fifty-three healthy 12- to 80-year-old participants were randomized 1:1 (MIRA 2) and 2:1 (MIRA 3) to receive either POS or placebo eye drops in both eyes., Methods: Participants received POS or placebo administered 1 hour after mydriasis, induced by instillation of either 2.5% phenylephrine, 1% tropicamide, or 1% hydroxyamphetamine / 0.25% tropicamide., Main Outcome Measures: Percent of participants returning to within 0.2 mm of baseline pupil diameter in study eye 90 minutes after POS administration. Safety measures included treatment-emergent adverse events and tolerability measures, including conjunctival hyperemia., Results: A total of 553 participants were randomized to treatment with placebo (n = 215) or POS (n = 338). A statistically significant greater percentage of participants treated with POS showed reversal of mydriasis at 90 minutes compared to placebo (MIRA 2: 48.9% vs. 6.6% [P < 0.0001]; MIRA 3: 58% vs. 6% [P < 0.0001]) and as early as 60 minutes (MIRA 2: 27.7% vs. 2.2% [P < 0.0001]; MIRA 3: 42% vs. 2% [P < 0.0001]). Between 28% and 34% of participants receiving placebo did not returned to baseline PD at 24 hours after pharmacologic dilation compared with 8% to 11% of patients treated with POS (P < 0.0001)., Conclusions: Treatment with POS reduced PD within 60 to 90 minutes, with a statistically significant time savings of 5 to 6 hours to return to baseline PD compared with placebo. One or 2 drops of POS rapidly reversed mydriasis in all participants regardless of mydriatic agent or iris color. More participants receiving POS reported a benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared with placebo, with statistically significant differences noted as early as 1 hour. The safety profile was favorable, with the most common adverse effects being mild transient conjunctival hyperemia (11.2%), instillation site discomfort (10.9%), and dysgeusia (3.6%)., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD., Methods: In this placebo-controlled, randomized, double-masked clinical trial, 24 adult patients with severe DLD were randomized in a 2:1 ratio to receive either one dose of PMOS or placebo. Subjects were eligible if they reported experiencing severe night vision difficulty that was not eliminated by distance spectacle correction and scored ≥0.3 log units below the normal range of contrast sensitivity assessed under mesopic conditions with glare at ≥2 spatial frequencies. Key efficacy outcomes were change from baseline in pupil diameter, contrast sensitivity, and visual acuity. Safety measures including intraocular pressure, conjunctival hyperemia, and systemic effects were also assessed., Results: Eight subjects were randomized to placebo (63% female; mean age 47 years) and 16 were randomized to PMOS (75% female; mean age 42 years). Mean (SD) pupil diameter of PMOS-treated subjects decreased significantly - 1.3 mm (0 to - 2.8 mm) with p < 0.0001. Mean contrast sensitivity with glare in PMOS-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (p ≤ 0.03). PMOS also demonstrated improvements in the numbers of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of PMOS-treated eyes registered mesopic LCVA 5 letter (69% vs. 31%, p = 0.029) and 10 letter (34% vs. 6%, p = 0.04) improvement, with a trend at 15 letters (19% vs. 0%, p = 0.16). PMOS was well tolerated with the only reported side effect being a mild increase in conjunctival hyperemia., Conclusion: PMOS was well tolerated and effectively reduced pupil size with improvements in contrast sensitivity and visual acuity in adults with severe DLD. Future Phase 3 studies should be conducted to further evaluate its potential to treat DLD., Trial Registration: The trial registration number is NCT04004507 (02/07/2019). Retrospectively registered., (© 2022. The Author(s).)

Significance: After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations., Purpose: The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication., Methods: In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points., Results: Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours., Conclusions: Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile., Competing Interests: Conflict of Interest Disclosure: The publication of this article was sponsored by Ocuphire Pharma, Inc. ARM, MPS, RMJ, KC, JEY, SAK, and ATA are or were employees, directors/officers, or paid consultants for Ocuphire Pharma. PMK, MBM, ESL, JSP, and GDH are on the medical advisory board for Ocuphire Pharma. PMK, SAF, SMM, and SRK were principal investigators for this clinical trial funded by Ocuphire Pharma. CBS serves as Chief Medical Officer of Oculos Development Services, LLC, which was the contract research organization for this clinical trial. The authors indicated that they have no other conflicts of interest with regard to the content of this article. The authors listed report a financial conflict of interest (PMK, SAF, SMM, SRK, CBS, ARM, MPS, RMJ, KC, JEY, SAK, ATA, MBM, GDH, ESL, and JSP). The sponsor (Ocuphire) provided financial and material support and participated in study design, analysis, and interpretation. The authors were responsible for the preparation of this article and the decision to submit this article for publication. Each of the authors had (full/limited) access to the study data and takes full responsibility for their presentation in this article., (Copyright © 2021 American Academy of Optometry.)

APE1/Ref-1 (also called Ref-1) has been extensively studied for its role in DNA repair and reduction-oxidation (redox) signaling. The review titled: " The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease" by Caston et. al. summarizes the molecular functions of Ref-1 and the role it plays in a number of diseases, with a specific focus on various types of cancer [1]. Previous studies have demonstrated that Ref-1 plays a critical role in regulating specific transcription factors (TFs) involved in a number of pathways, not only in cancer, but other disease indications as well. Disease indications of particular therapeutic interest include retinal vascular diseases such as diabetic retinopathy (DR), diabetic macular edema (DME), and neovascular age-related macular degeneration (nvAMD). While Ref-1 controls a number of TFs that are under redox regulation, three have been found to directly link cancer studies to retinal diseases; HIF-1α, NF-κB and STAT3. HIF-1α controls the expression of VEGF for angiogenesis while NF-κB and STAT3 regulate a number of known cytokines and factors involved in inflammation. These pathways are highly implicated and validated as major players in DR, DME and AMD. Therefore, findings in cancer studies for Ref-1 and its inhibition may be translated to these ocular diseases. This report discusses the path from cancer to the potential treatment of retinal disease, the Ref-1 redox signaling function as a possible target, and the current small molecules which have been identified to block this activity. One molecule, APX3330, is in clinical trials, while the others are in preclinical development. Inhibition of Ref-1 and its effects on inflammation and angiogenesis makes it a potential new therapeutic target for the treatment of retinal vascular diseases. This commentary summarizes the retinal-relevant research that built on the results summarized in the review by Caston et. al. [1]., Competing Interests: Conflict of Interest CH and JY conducted internships at Ocuphire Pharma, KC is an independent consultant, MB is head of clinical development and strategy at Ocuphire Pharma and MRK is a member of the Ocuphire medical advisory board and CSO and co-founder of Apexian Pharmaceuticals which developed APX3330 for oncology. TWC and MRK are inventors on patent applications licensed to Ocuphire. MM has no conflicts.

For some neurological disorders, disease is primarily RNA mediated due to expression of non-coding microsatellite expansion RNAs (RNA(exp)). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain, resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound-knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNA(exp) in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)