Ocuphire Meets Endpoints in Phase 3 MIRA-3 Trial Evaluating Nyxol for Reversal of Mydriasis

Ocuphire Pharma announced positive topline results in the MIRA-3 trial, the company’s second phase 3 registration trial investigating its product candidate Nyxol for the reversal of pharmacologically-induced mydriasis (dilation of pupil). Ocuphire announced positive results from its first phase 3 trial, MIRA-2, in March 2021.

Nyxol is a proprietary, preservative-free, stable, investigational eye drop formulation of phentolamine mesylate designed to reduce pupil size by inhibiting contraction of the iris dilator muscle. MIRA-3 was designed as a multicenter, randomized, parallel arm, double-masked, placebo-controlled phase 3 trial evaluating the safety and efficacy of Nyxol in subjects with pharmacologically-induced mydriasis. MIRA-3 enrolled 368 subjects from November 2021 to February 2022 at 16 sites in the U.S.

These topline results demonstrated that the MIRA-3 trial met its primary endpoint with 58% of subjects (study eye) treated with Nyxol returning to ≤ 0.2 mm of their baseline pupil diameter (PD) at 90 minutes compared to only 6% of subjects (study eye) treated with placebo (P<0.0001). The effect was also significant at 60 minutes (Nyxol 42% vs. placebo 2%, P<0.0001). In comparison, only 36% of placebo treated subjects returned back to baseline PD at 6 hours. These results showed clinically meaningful differences between Nyxol and placebo for accelerating reversal of pharmacologically-induced mydriasis.

“The successful completion of the MIRA-3 phase 3 trial is a major milestone in our development program for Nyxol in RM,” said Mina Sooch, MBA, President and CEO of Ocuphire Pharma. “We are delighted with the positive efficacy and safety outcomes which confirm the results from our prior MIRA-2 phase 3 trial. We now have over 900 subjects studied across 10 clinical trials of which over 550 have been exposed to Nyxol. Importantly, today’s announcement means that that we have two FDA registration trials to support potential approval for the RM indication. We intend to file an NDA with the U.S. FDA in late 2022, which, if approved, would position Ocuphire for commercial launch of Nyxol in RM in the second half of 2023. We want to thank the study participants, physicians, study site personnel, and everyone who was involved in the MIRA-2 and MIRA-3 trials for their contribution in advancing this program and bringing us closer to potentially delivering an FDA-approved treatment for RM.”

Nyxol Development Plan and Next Steps in RM

Ocuphire recently completed enrollment of 23 pediatric subjects in the MIRA-4 trial evaluating the safety and efficacy of Nyxol eye drops to reverse pharmacologically-induced mydriasis. Topline results are expected in the second quarter of 2022. If MIRA-4 meets its endpoints, the results would potentially support a broader label for Nyxol in RM to include children as young as age 3. Ocuphire is also on track to complete the Chemistry, Manufacturing and Controls (CMC) section of the NDA as three registration batches of Nyxol have been completed and on stability. The company plans to file an NDA that includes the results of MIRA-1, MIRA-2, MIRA-3, and MIRA-4 with the FDA in late 2022.

Highlights of MIRA-3 Efficacy and Safety Results

MIRA-3 (NCT05134974) is a phase 3 registration trial evaluating the product candidate Nyxol to expedite the reversal of pharmacologically induced mydriasis. In the trial, 368 study participants (336 adults and 32 adolescents at or over age 12) were randomized 2:1 to receive Nyxol (0.75% phentolamine ophthalmic solution) or vehicle control (placebo) 1 hour after receiving one of 3 mydriatic agents. The three mydriatic agents used in this trial were phenylephrine 2.5% (alpha 1 agonist targeting the iris dilator muscle), tropicamide 1% (cholinergic blocker targeting the iris sphincter muscle), and Paremyd (a combination of hydroxyamphetamine hydrobromide 1% and tropicamide 0.25%), which are all commonly used in optometry and ophthalmology offices to dilate patients’ pupils for annual or special exams as well as surgical procedures. The study population was comprised of subjects in the modified Intent to Treat population (mITT).

Summary of MIRA-3 Topline Data

• The primary endpoint was met with 58% of subjects (study eye) treated with Nyxol returning to ≤ 0.2 mm of their baseline pupil diameter at 90 minutes compared to only 6% of placebo treated subjects (P<0.0001) across the three mydriatic agents.
• Key secondary efficacy endpoints also met statistical significance: 
  • Early onset of action with 42% of subjects at baseline PD by 60 minutes post-dose (vs. 2% placebo, P<0.001)
  • Significantly more Nyxol-treated subjects returned to normal PD or smaller than placebo-treated subjects at all time points from 1 hour to 24 hours
  • Similar efficacy was seen with one or two drops of Nyxol (as the study eye was treated with 2 drops and the fellow eye with one)
  • Nyxol was effective regardless of iris color or mydriatic agent used
  • Approximately 4 hours were gained in time to return to normal pupil diameter overall and across mydriatic agents and iris colors
  • Nyxol restored normal distance corrected near vision significantly faster than placebo
• Nyxol demonstrated a favorable safety and tolerability profile. 
  • Nyxol was well tolerated with no serious adverse events or withdrawals due to adverse events
  • The only AE occurring in greater than 5% subjects was mild, transient conjunctival hyperemia (11%)

“Nyxol's unique MOA makes it an ideal agent for reversal of mydriasis, as it does not have the potential safety risks of retinal tears, accommodative spasm and angle closure associated with cholinergic agents like pilocarpine," Jay S. Pepose, MD, PhD, Director of the Pepose Vision Institute, Professor of Clinical Ophthalmology at Washington University School of Medicine, and Ocuphire Medical Advisory Board member and Board member, said in a company news release. "The MIRA-3 and MIRA-2 trials confirm the favorable safety profile and efficacy, showing rapid reversal of mydriasis following dilation with all mydriatic agents tested and in both light and dark iris colors. In addition, the pupil reduction of 1 to 1.5 mm from baseline through 24 hours is a potential read through for our other clinical indications for Nyxol including presbyopia and night vision disturbances.”

Edward Holland, MD, Director of Cornea Services at Cincinnati Eye Institute and Ocuphire Medical Advisory Board member commented, “Pupil dilation is a necessary tool for ophthalmologists and optometrists to screen for and monitor diseases of the eye. However, patients often find dilation problematic, citing unwanted symptoms including inability to read, photophobia, loss of accommodation, and inability to work effectively. Many patients complain about or refuse dilation for these reasons. There are no approved treatments currently available for reversal of mydriasis, and with the announcement today of positive results from MIRA-3, I am very pleased to see the continued progress in advancing Nyxol toward potential FDA approval. If approved, I believe that Nyxol would be widely used in clinical practice, which could increase the overall number of dilated exams as well as improve patient experience, and lead to better eye health for our patients.”

For more information about the MIRA-3 phase 3 trial design, visit www.clinicaltrials.gov(NCT05134974). Ocuphire collaborated closely with Oculos Development Services, a Rush, NY based clinical research organization and subsidiary of Iuvo BioScience, on the execution of the MIRA-3 trial.

Reversal of Mydriasis Market Opportunity

Every year in the U.S., an estimated 100 million eyes dilations are conducted to examine the back of the eye, either for routine check-ups, disease monitoring or surgical procedures, across all eye care practice groups. Depending on the individual and the color of their eyes, the pharmacologically-induced dilation can last anywhere from 6 to 24 hours. Dilated eyes have heightened sensitivity to light and a decreased ability to focus on near objects, causing difficulty reading, working, and driving. Currently, there are no approved or available options to safely reverse mydriasis. Nyxol has the potential to be the first and only FDA-approved agent for RM.

Market research conducted by GlobalData surveyed several hundred patients and eye care providers (optometrists and ophthalmologists) about Reversal of Mydriasis. Over 65% of surveyed patients reported moderate to severe negative impact of a dilated pupil. These data underscore the potential value of the role of the investigational product candidate Nyxol in improving comfort and daily function after pupil dilation. Furthermore, approximately 80% of patients responded that they would be likely to request a dilation reversal drop, and more than 70% of eye care providers would be likely to use a reversal drop. The market research confirmed patients’ willingness to pay out-of-pocket to reverse their dilations, supporting a market size estimate of over $500M. Ocuphire is currently evaluating partnering options for an effective and cost-efficient commercial launch of Nyxol targeted for the second half of 2023.