New data published in Ophthalmology covers the full phase 3 clinical trial results from two pivotal studies evaluating the safety and efficacy of Ocuphire Pharma Inc.’s RYZUMVI (phentolamine ophthalmic solution [POS] 0.75%) for the treatment of pharmacologically-induced mydriasis.
Let’s start with this solution.
As a preservative-free formulation, RYZUMVI features the active ingredient phentolamine.
- About phentolamine: This is a non-selective alpha-1 and alpha-2 adrenergic antagonist known to enhance the antimicrobial properties of macrolide antibiotics against Gram-negative bacteria.
And how does this solution work?
POS reversibly binds the alpha-1 adrenergic receptors located on the iris dilator muscle, resulting in a potential reduction in pupil diameter without impacting the ciliary muscle.
- The pupil connection: The radial iris dilator muscles around the pupil—largely responsible for pupil dilation—are activated by the alpha-1 adrenergic receptors.
In relation to this indication: The drop “directly antagonizes the mydriatic effect of an α-1 adrenergic agonist,” thus causing an indirect reversal of mydriasis (RM).
RYZUMVI is FDA approved, right?
Yes it is! The FDA approved the solution for RM in September 2023.
The recommended dosage, per its prescribing information (PI):
- Adult and pediatric patients (age 12+)
- One to two drops instilled in each dilated eye following the completion of an ophthalmic exam or procedure.
- Pediatric patients (ages 3 to 11)
- One drop instilled in each dilated eye following completion of an ophthalmic exam or procedure.
Now talk about these phase 3 trials.
First thing to know: The phase 3 trials were part of the MIRA clinical trial program, which consisted of four studies and 600+ participants:
- MIRA-1 (NCT04024891)
- MIRA-2 (NCT04620213)
- MIRA-3 (NCT05134974)
- MIRA-4 (NCT05223478)
- Pediatric safety trial
To note: Ocuphire previously reported that RYZUMVI demonstrated a favorable safety and tolerability profile for RM across all studies.
And which two trials were included in this new research?
MIRA-2 and MIRA-3, both of which were randomized, parallel arm, double-masked, placebo-controlled studies, were conducted at 28 clinical sites between November 2020 and March 2022.
Here’s some cumulative trial info :
- Participant info: 553 patients (ages 12-80)
- The setup: Patients randomized 1:1 (MIRA-2) and 2:1 (MIRA-3) to receive either:
- RYZUMVI in both eyes (OU)
- Placebo (OU)
- For both RYZUMVI and placebo groups: Drops were administered 1 hour after mydriasis, induced by instillation of either:
- 2.5% phenylephrine
- 1% tropicamide
- Paremyd (1% hydroxyamphetamine / 0.25% tropicamide)
- For both RYZUMVI and placebo groups: Drops were administered 1 hour after mydriasis, induced by instillation of either:
And the outcome measures?
For both trials, the primary outcome was the percentage of patients’ study eyes that returned to ≤ 0.2 mm from baseline pupil diameter (measured at 90 minutes after administration)
To note: Safety measures were treatment-emergent adverse events (TEAEs) and tolerability measures (such as conjunctival hyperemia).
Now the clinical data.
In regards to the primary endpoint in each study …
The study authors reported that a statistically significant greater percentage of participants who were treated with RYZUMVI had “study eyes that showed (RM) at 90 minutes (post-administration) compared with the placebo treatment.”
- The numbers:
- MIRA-2: 48.9% vs 6.6%; p<0.0001
- MIRA-3: 58% vs 6%; p<0.0001
And at 60 minutes?
Similarly, a statistically significant greater percentage of patients treated with RYZUMVI sv placebo also showed RM:
- MIRA-2: 24.5% vs 5.5%; p<0.0001
- MIRA-3: 42% vs 2%; p<0.0001
What about at 24 hours?
At 24 hours post-pharmacological dilation, “between 28 to 34% of placebo-treated subjects had not returned to baseline (pupil dilation),” investigators reported.
This compared to 8 to 11% of participants treated with RYZUMVI (p<0.0001).
Based on this data, what were the conclusions?
The study authors noted that RYZUMVI’s “rapid onset” reduced pupil dilation with 60 to 90 minutes, and had a “statistically significant time savings of 3 to 4 hours to return to baseline (pupil dilation) compared to placebo.”
Important to note: This rapid reversal in all participants was done with one or two drops—“regardless of mydriatic agent or iris color.”
And participants’ feedback?
The authors stated that more patients who received RYZUMVI reported noticing a “perceived benefit in the resolution of visual symptoms caused by pharmacologically induced mydriasis compared to placebo, with statistically significant differences noted as early as 1 hour.”
Lastly: How did RYZUMVI’s safety profile fare?
As with its previous phase 3 trials: favorably.
As for TEAEs: These were “predominantly mild” in the RYZUMVI group for both trials and included:
- Conjunctival hyperemia (12.8% in MIRA-2 and 11% in MIRA-3)
- Mild instillation site discomfort (38.3% in MIRA-2 and 27% in MIRA-3)
Cumulatively, the most common adverse effects were:
- Mild transient conjunctival hyperemia (11.2%)
- Instillation site discomfort (10.9%)
- Dysgeusia (3.6%)
Sounds promising! And lastly: What other indications is RYZUMVI being evaluated for?
Two others:
- Presbyopia
- Latest clinical update: Ongoing phase 3 LYNX-2 trial initiated In April 2024, with topline data expected by Q1 2025.
- Night vision disturbances (NVD)
- Specifically: Decreased visual activity [VA] under low [mesopic] light conditions post-keratorefractive surgery
Latest clinical update: First patient dosed in phase 3 VEGA-2 pivotal trial in September 2023