Reviewing what is in the anterior segment topical ophthalmic pipeline

Recent ophthalmic therapeutic developments making headlines in the treatment of posterior segment ocular conditions have overshadowed the many therapeutic developments utilizing topically administered ophthalmic agents in the treatment of anterior segment conditions. Topically administered ophthalmic agents in late-stage development, and those under regulatory evaluation, are truly innovative with a focus on first-in-class indications and advancements in drug delivery.

Here is a rundown on the clinically relevant data that, pending regulatory evaluation and marketing approval, will inform our real-world utilization of highly anticipated therapeutic agents under development for treating anterior segment conditions.

Inflammation and dry eye disease

Upregulation of inflammation at the level of the ocular surface, a central driver of dry eye disease, may be addressed through the long-term use of topical ophthalmic immunomodulatory agents with anti-inflammatory properties.¹ The identification of new treatment targets that play a significant role in the inflammatory cascade have led to a growing group of late-stage investigative therapies for treating dry eye disease as well as allergic conjunctivitis and acute anterior uveitis.

Reproxalap (Aldeyra Therapeutics) is a reactive aldehyde species (RASP) modulator being evaluated in the treatment of dry eye disease and allergic conjunctivitis, as well as for systemic anti-inflammatory applications.² RASP modulation reduces inflammation through reduction of cytokine release and inflammasome activity.^3,4

A new drug application (NDA) is being evaluated by the FDA for reproxalap for the treatment of signs and symptoms of dry eye disease.² The submission is supported by data from 5 clinical trials, which includes evaluation of approximately 2000 patients.^2,5 A variety of subjective and objective clinical trial primary and secondary end points were utilized throughout the phase 2 and 3 trials, which included reduction of RASP levels present in the tears, Schirmer score measures, conjunctival redness, symptoms of dry eye disease, and fluorescein staining.^2,5-8

Although the phase 2/3 TRANQUILITY trial (NCT04674358) did not meet the prespecified primary end point related to conjunctival redness, it did meet an objective end point related to Schirmer testing, which informed the phase 3 TRANQUILITY 2 trial (NCT05062330).6 TRANQUILITY 2 included 361 participants in whom reproxalap ophthalmic solution (0.25%) was administered 7 times over 2 consecutive days prior to exposure to a low-humidity dry eye chamber for 90 minutes. The primary outcome measures assessed and met were Schirmer test mean change from baseline and Schirmer test greater than or equal to 10-mm change from baseline with a secondary outcome measure of conjunctival redness.^5,7

Although working through the efficacy data related to varying end points across numerous trials can be onerous, the study design of TRANQUILITY and TRANQUILITY 2 is of potential clinical relevance. The frequent (7 times/d) dosing of reproxalap with end points assessed on day 2 allows for insight into the agent’s rapid onset demonstrated through rapid objective improvement.^4,5

Adverse effects (AEs) were common in the phase 2b trial (NCT03404115) but mild overall.8 In total, 93% of 100 patients treated with reproxalap 0.25% reported discomfort upon instillation, and 92.4% of all cases had ocular AEs reported as mild.8 Based on the described ocular AEs, if reproxalap 0.25% is to be approved and made commercially available, careful attention to patient selection as well as thorough counseling, including a clear understanding of patient expectations, will be central to adherence.

When evaluating efficacy and tolerability data, the impact of the inactive ingredients of a therapeutic are often underappreciated. Although cyclosporine-based ophthalmic products are well established in terms of efficacy in reducing inflammation associated with dry eye disease, an investigational cyclosporine therapeutic utilizes an alternative vehicle that may impact its efficacy and tolerability.

Currently under evaluation by the FDA with a Prescription Drug User Fee Act (PDUFA) target action date of June 8, 2023, is CyclASol (Novaliq) 0.1% cyclosporine A in EyeSol.⁹ EyeSol is a water-free technology that increases ocular surface contact time to increase bioavailability and, due to low surface tension, allows for a smaller drop size in comparison with water-based products.¹⁰

In the phase 2b/3 ESSENCE-1 study (NCT03292809), patients with predominantly aqueous deficient dry eye disease not responding to artificial tears received CyclaSol 0.1% twice daily with the primary efficacy end points of corneal fluorescein staining and symptomatic improvement utilizing the Ocular Surface Disease Index (OSDI) questionnaire evaluated at week 4.¹¹

Although the objective primary end point of improvement in baseline area in mean total corneal fluorescein staining was met in comparison to the vehicle group, both groups showed statistically significant improvement in OSDI score without statistically significant difference between the vehicle and treatment groups (P = .2634).¹¹

Although no serious treatment-related AEs were identified, 7 individuals in the treatment group discontinued the trial and the 3 individuals in the vehicle group discontinued the trial.¹¹ The specified reasons for discontinuation in the treatment group were determined to be “patient choice” in 3 cases, adverse events (foreign body sensation and eyelid edema) in 2 cases, and administrative reasons in 2 cases.¹¹ The most common ocular AEs encountered were visual acuity reduced (3.1% treatment group vs 1.8% vehicle group), instillation site pain (2.5% vs 1.2%, respectively) and vision blurred (1.2% vs 2.4%, respectively).¹¹

ESSENCE-2 top-line results were consistent with the results of ESSENCE-1 with objective improvement vs placebo in corneal fluorescein staining and improvement in symptoms compared with baseline and comparable to improvement observed in the vehicle group.¹²

Steroid-sparing anti-inflammatory agents including biologic agents are a mainstay of current systemic immunomodulation. Due to their molecular complexity and high molecular weight, whole monoclonal antibodies, including commercially available TNF-α inhibitors, although efficacious when administered intravenously or subcutaneously, would not be expected to penetrate the cornea to reach therapeutic levels if able to be compounded into an ophthalmic preparation.

Recently, licaminlimab (Oculis), a single chain antibody fragment, has been developed that in a phase 2 pilot study (NCT02482129) showed response (defined as a 2-step reduction from baseline anterior chamber inflammation) in 56% of individuals with acute anterior uveitis.¹³ All ocular AEs in the treatment group were determined to most likely be related to the underlying disease rather than treatment.¹³ Positive early results support further investigation of a steroid-sparing topical ophthalmic biologic agent.¹³

Meibomian gland dysfunction

Lid hygiene, dietary supplementation, and procedure-based treatments have formed the basis for successful treatment of meibomian gland dysfunction, with real-world challenges associated with adherence and access to therapies.

The first potential pharmaceutical treatment for the signs and symptoms of dry eye disease associated with meibomian gland dysfunction, NOV03 (100% perfluorohexyloctane [F6H8]; Bausch + Lomb, Novaliq) is a water-free, preservative-free compound under review by the FDA with a PDUFA target date of June 28, 2023.¹⁴

NOV03 prevents aqueous evaporation and stabilizes the tear film due to its interaction with the natural lipid layer of the tear film.¹⁵ NOV03 has been evaluated in the phase 2 SEECASE trial (NCT03333057) and phase 3 GOBI (NCT04139798) and MOJAVE (NCT04567329) trials.^14-17

Primary end points of total corneal fluorescein staining and subjective visual analogue scale eye dryness end points at day 57 were met in MOJAVE with 4 times daily dosing.¹⁵ Ocular AEs were similar in the treatment and control groups (9.6% vs 9.7%, respectively), with blepharitis as the most frequently reported ocular AE in 1.6% of study patients vs 0.3% of patients in the control group.¹⁵

Also under investigation for the treatment of meibomian gland dysfunction is AZR-MD-001 0.5% (Azura Ophthalmics); positive results from a phase 2b trial (NCT03652051) were recently announced, as were plans to proceed with a pivotal phase 3 trial in 2023.¹⁸ AZR-MD-001 is a selenium sulfide–based ophthalmic ointment that disrupts the hyperkeratinization that occurs in meibomian gland dysfunction by reducing disulfide bonds.¹⁸

In the phase 2b trial, AZR-MD-001 0.5% was applied to the lower eyelid at bedtime with coprimary end points of significant improvement in the number of glands secreting meibum and significant improvements in OSDI score from baseline.¹⁸

Demodex blepharitis

Repurposed from the veterinary space, the development of the antiparasitic agent formulated as a topical ophthalmic agent, TP-03 (lotilaner ophthalmic solution 0.25%; Tarsus Pharmaceuticals), has shown positive results in its pivotal phase 2b/3 clinical trial SATURN-1 (NCT04475432) and phase 3 trial SATURN-2 (NCT04784091) forming the basis of the NDA accepted November 2022 with a PDUFA action date of August 25, 2023.¹⁹

In SATURN-1, twice-daily dosing of lotilaner ophthalmic solution 0.25% for 43 days showed statistically significant difference in the proportion of patients with no more than 2 collarettes on the upper lid versus the vehicle alone (81.3% vs 23.0%), proportion of patients whose Demodex mites were eradicated (44.0% vs 7.4%) and proportion of subjects who had no more than 2 collarettes and the absence of erythema of the upper lid (13.9% vs 1.0%).²⁰ 91.9% of patients receiving TP-03 reported the drop to be “neutral to very comfortable” at study conclusion without reaching statistically significant difference from the vehicle group.²⁰ Instillation site pain was the most frequently countered ocular AE experienced in 11.8% of the study group and 7.7% in the control group.²⁰ Overall ocular AEs were mild and experienced in 19.8% of the study group and 21.5% of the control group.²⁰

Reversal of mydriasis

The development of Nyxol (preservative-free phentolamine ophthalmic solution 0.75%; Ocuphire Pharma) highlights and offers a potential solution related to the symptomatic visual challenges patients experience following pharmacologic pupillary dilation regardless of diagnostic agent utilized of iris pigmentation.²¹ Phentolamine is a nonselective α1 and α2 blocker that acts to relax the iris dilator muscle when applied topically.²¹ Phentolamine is FDA approved and utilized for systemic administration in the treatment of pheochromocytoma and for reversal of oral anesthesia.

Submission of the NDA for 0.75% phentolamine ophthalmic solution was announced on December 6, 2022. The submission was supported by data from the MIRA-1 phase 2b trial (NCT04024891), MIRA-2 (NCT04620213) and MIRA-3 (NCT05134974) phase 3 trials, and MIRA-4 (NCT05223478) phase 3 trial in pediatric patients 3 years and older.^21-23

In MIRA-2 and MIRA-3, eyes were dilated with either 2.5% phenylephrine, 1% tropicamide, or hydroxyamphetamine 1% and tropicamide 0.25% (Paremyd; Akorn) where after 1 hour, 2 drops of phentolamine 0.75% or placebo were instilled in the study eye and 1 drop was instilled in the fellow eye.²⁴ The primary end point measure was the percentage of study eyes with pupil diameter returning to baseline at 90 minutes. Primary end points were met in MIRA-2 and MIRA-3.

In MIRA-3, 58% of subjects returned to baseline (within 0.2 mm) pupil diameter at 90 minutes vs 6% of subjects in the placebo group.²² At 60 minutes, 42% of study eyes returned to baseline (within 0.2 mm) pupil diameter vs 2% in the placebo group.²² No serious AEs were reported. Mild, transient conjunctival hyperemia was observed in 11% of patients, with no other AE occurring in more than 5% of study patients.²² Importantly from the perspective of potential clinical relevance, the tolerability of phentolamine 0.25% appears to be well supported by data from MIRA-3, where no patients withdrew from the trial due to AEs.²²

Bottom line

Topical ophthalmic agents under investigation for the treatment of anterior segment conditions may not always make headlines in the same way as those for treating or delaying progression of vision-threatening posterior segment disease. But years of development, application of technology and resources, and the continued drive for improved patient outcomes and quality of life have set the stage for what may be a remarkable year for therapeutic innovations in managing anterior segment conditions.

References

1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15(3):276-283. doi:10.1016/j.jtos.2017.05.008

2. Aldeyra Therapeutics submits new drug application to the U.S. Food and Drug Administration for reproxalap for the treatment of signs and symptoms of dry eye disease. News release. Aldeyra Therapeutics. November 29, 2022. Accessed December 6, 2022. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-submits-new-drug-application-us-food-and

3. Higdon A, Diers AR, Oh JY, Landar A, Darley-Usmar VM. Cell signalling by reactive lipid-species: new concepts and molecular mechanisms. Biochem J. 2012;442(3):453-464. doi:10.1042/BJ20111752

4. Kauppinen A, Niskanen H, Suuronen T, Kinnunen K, Salminen A, Kaarniranta K. Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells—implications for age-related macular degeneration (AMD). Immunol Lett. 2012;147(1-2):29-33. doi:10.1016/j.imlet.2012.05.005

5. Aldeyra Therapeutics achieves primary endpoint in phase 3 TRANQUILITY2 trial in dry eye disease and intends to submit new drug application for symptoms and three sign endpoints of dry eye disease. News release. Aldeyra Therapeutics. June 8, 2022. Accessed December 6, 2022. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-achieves-primary-end point-phase-3

6. Aldeyra Therapeutics announces top-line results from the phase 3 TRANQUILITY trial in dry eye disease. News release. Aldeyra Therapeutics. December 20, 2021. Accessed December 6, 2022. https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-announces-top-line-results-phase-3

7. The TRANQUILITY 2 trial: a phase 3 clinical trial to assess the efficacy and safety in subjects with dry eye disease. ClinicalTrials.gov. Updated August 3, 2022. Accessed December 4, 2022. https://clinicaltrials.gov/ct2/show/NCT05062330?term=Reproxalap+Ophthalmic+Solution&draw=2&rank=7

8. Clark D, Tauber J, Sheppard J, Brady TC. Early onset and broad activity of reproxalap in a randomized, double-masked, vehicle-controlled phase 2b trial in dry eye disease. Am J Ophthalmol. 2021;226:22-31. doi:10.1016/j.ajo.2021.01.011

9. Novaliq announces FDA acceptance of the new drug application for CyclaSol for the treatment of dry eye disease. News release. Novaliq. October 24, 2022. Accessed December 6, 2022. https://www.novaliq.com/press-releases/2022/10/24/novaliq-announces-fda-acceptance-of-the-new-drug-application-for-cyclasol-for-the-treatment-of-dry-eye-disease/

10. Agarwal P, Scherer D, Günther B, Rupenthal ID. Semifluorinated alkane based systems for enhanced corneal penetration of poorly soluble drugs. Int J Pharm. 2018;538(1-2):119-129. doi:10.1016/j.ijpharm.2018.01.019

11. Sheppard JD, Wirta DL, McLaurin E, et al. A water-free 0.1% cyclosporine A solution for treatment of dry eye disease: results of the randomized phase 2B/3 ESSENCE study. Cornea. 2021;40(10):1290-1297. doi:10.1097/ICO.0000000000002633

12. Novaliq announces positive topline results for second phase 3 trial (Essence-2) of CyclASol in dry eye disease. News release. Novaliq. December 21, 2021. Accessed December 6, 2022. https://www.novaliq.com/press-releases/2021/12/21/novaliq-announces-positive-topline-results-for-second-phase-3-trial-essence-2-of-cyclasol-in-dry-eye-disease/

13. Pasquali TA, Toyos MM, Abrams DB, Scales DK, Seaman JW 3rd, Weissgerber G. Topical ocular anti-TNFα agent licaminlimab in the treatment of acute anterior uveitis: a randomized phase II pilot study. Transl Vis Sci Technol. 2022;11(6):14. doi:10.1167/tvst.11.6.14

14. Bausch + Lomb and Novaliq announce U.S. FDA filing acceptance for investigational treatment NOV03 (perfluorohexyloctane). News release. Bausch + Lomb. September 6, 2022. Accessed December 6, 2022. https://www.prnewswire.com/news-releases/bausch--lomb-and-novaliq-announce-us-fda-filing-acceptance-for-investigational-treatment-nov03-perfluorohexyloctane-301617943.html

15. Tauber J, Wirta DL, Sall K, Majmudar PJ, Willene D, Krӧsser S; SEECASE study group. A randomized clinical study (SEECASE) to assess efficacy, safety, and tolerability of NOV03 for treatment of dry eye disease. Cornea. 2021;40(9):1132-1140. doi:10.1097/ICO.0000000000002622

16 Sheppard JD, Kurata FK, Epitropoulos A, Krӧsser S, Vittitow J. Efficacy of NOV03 (perfluorohexyloctane) on signs and symptoms of dry eye disease associated with meibomian gland dysfunction: the Mojave study. Invest Ophthalmol Vis Sci. 2022;63(7):1531-A0256.

17. Bausch + Lomb presents data from second pivotal phase 3 trial of investigational treatment NOV03 (perfluorohexyloctane) at the Association for Research in Vision and Ophthalmology Annual Meeting. News release. Bausch + Lomb. May 3, 2022. Accessed December 6, 2022. https://ir.bauschhealth.com/news-releases/2022/05-03-2022-115916452

18. Azura Ophthalmics presents positive results from phase 2b clinical trial of AZR-MD-001 in meibomian gland dysfunction at Ophthalmology Innovation Summit XII. News release. Azura Ophthalmics. December 9, 2022. Accessed December 9, 2022. https://azuraophthalmics.com/press-releases/azura-ophthalmics-presents-positive-results-from-phase-2b-clinical-trial-of-azr-md-001-in-meibomian-gland-dysfunction-at-ophthalmology-innovation-summit-xii/

19. Tarsus Pharmaceuticals. Tarsus Corporate Presentation. December 2022. Accessed December 9, 2022. https://ir.tarsusrx.com/static-files/a4f36edb-9d92-46a2-a8c4-49a3efd6ea94

20. Yeu E, Wirta DL, Karpecki P, Baba SN, Holdbrook M; Saturn I Study Group. Lotilaner ophthalmic solution, 0.25%, for the treatment of Demodex blepharitis: results of a prospective, randomized, vehicle-controlled, double-masked, pivotal trial (Saturn-1). Cornea. Published online August 11, 2022. doi:10.1097/ICO.0000000000003097

21. Ocuphire Pharma announces submission of new drug application to FDA for Nyxol eye drops for reversal of mydriasis. News release. Ocuphire Pharma. December 6, 2022. Accessed December 9, 2022. https://www.ocuphire.com/news-media/press-releases/detail/393/ocuphire-pharma-announces-submission-of-new-drug

22. Ocuphire announces positive topline results from MIRA-3 phase 3 FDA registration trial for Nyxol in the reversal of mydriasis. News release. Ocuphire Pharma. March 29, 2022. Accessed December 9, 2022. https://www.ocuphire.com/news-media/press-releases/detail/367/ocuphire-announces-positive-topline-results-from-mira-3

23. Karpecki PM, Foster SA, Montaquila SM, et al. Phentolamine eye drops reverse pharmacologically induced mydriasis in a randomized phase 2b trial. Optom Vis Sci. 2021;98(3):234-242. doi:10.1097/OPX.0000000000001656

24. Safety and efficacy of Nyxol (0.75% phentolamine ophthalmic solution) to reverse pharmacologically-induced mydriasis. ClinicalTrials.gov. Updated March 18, 2021. Accessed December 9, 2022. https://clinicaltrials.gov/ct2/show/NCT04620213