Omlonti (Omidenepag Isopropyl) for the Reduction of Elevated Intraocular Pressure
Disease burden and clinical landscape
Glaucoma is an increasing and prominent cause of irreversible blindness. It is estimated to affect 64.3 million patients globally in 2013 and the affected population is predicted to increase beyond 110 million by 2040. The disease pathophysiology is multifactorial, but intraocular pressure (IOP) remains the singular modifiable risk factor across all clinical phenotypes. IOP control continues to be the mainstay of glaucoma treatment, involving either topically instilled IOP-lowering agents or surgery.
A plethora of pharmacological options are available for reducing IOP which vary in cost, dosing schedule, IOP-lowering potential and adverse event (AE) profile. The American Academy of Ophthalmology (AAO) and European Glaucoma Society (EGS), recommend an initial monotherapy approach, with a preference for prostaglandins, followed by non-selective beta-blockers, alpha-adrenergic agonists, selective beta-blockers and topical carbonic anhydrase inhibitors. Despite the variety of options, novel agents are still required as adequate IOP reduction cannot be achieved with monotherapy in all patients. Approximately 40% of patients will require adjunctive treatment to adequately maintain IOP control within 2 years of initiating prostaglandin monotherapy.
On 22 Sep 2022, the US FDA approved Omlonti® (Omidenepag isopropyl ophthalmic solution) 0.002% eye drops for the reduction of elevated Intraocular Pressure (IOP) in patients with primary Open-Angle Glaucoma (OAG) or Ocular Hypertension (OHT). Before this, Omlonti was launched in Japan in November 2018 (as Eybelis ophthalmic solution), with successful regulatory approvals in over 5 countries and regions since.
Its active metabolite, Omidenepag, is a selective non-prostaglandin prostanoid EP2 receptor agonist. Omlonti has been shown to reduce IOP by a novel mechanism; it binds to the EP2 receptor, which increases aqueous humor outflow via both the conventional and uveoscleral pathways. The recommended dosage is one drop in the affected eye once daily in the evening. Unopened bottles must be stored in the refrigerator and can be kept at room temperature for up to 31 days once opened for use.
Efficacy and safety
Omlonti’s regulatory approval was based on results from 3 pivotal Phase III Randomized Controlled Trials (RCT) in subjects with OAG or OHT with an average baseline IOP of 24-26mmHg. The first US-based Phase III study confirmed Omlonti’s non-inferiority to timolol. Two further Phase III trials conducted in Japan and Asia demonstrated Omlonti’s non-inferiority to latanoprost. Further details of the Japanese AYAME Phase III trial are described in Table 1. Across all 3 studies, IOP reduction in the Omlonti arms ranged from 5-7mmHg. Corresponding IOP reductions in comparator arms ranged from 5-7mmHg and 6-8mmgHg for timolol and latanoprost, respectively.
The safety of Omlonti has been evaluated in 12 clinical studies, 10 of which investigated its safety at a once-daily dose. Omlonti appears to be safe and well tolerated by adult subjects (N=1,111) with OAG/OHT and by pediatric subjects (N=6) with juvenile OAG. The most common adverse reactions with an incidence ≥ 1% include conjunctival hyperaemia (9%), photophobia (5%), vision blurred (4%), dry eye (3%), instillation site pain (3%), eye pain (2%), ocular hyperaemia (2%), punctate keratitis (2%), headache (2%), eye irritation (1%), and visual impairment (1%).
Table 1 AYAME Phase III Study
Study Design/ Population
Conducted across 39 centres in Japan over 3 months
At baseline, patients who received Omlonti or latanoprost had a mean ± SD diurnal IOP of 23.78 ± 1.73 mm Hg and 23.40 ± 1.51 mm Hg, respectively
|Randomized 1:1 to Omlonti 0.002% of latanoprost 0.005% once daily for 4 weeks||The primary endpoint (change from baseline in mean diurnal IOP at week 4): At week 4, least-squares mean ± SE reduction in IOP from baseline with Omlonti (−5.93 ± 0.23 mm Hg) was non-inferior to that of latanoprost (−6.56 ± 0.22 mm Hg; 95% CI between groups: 0.01-1.26)||
The current body of evidence has veritably established the utility and safety of Omlonti in OAG and OHT, expanding upon the evolving landscape of IOP reduction therapies. Notwithstanding, there remains uncertainty surrounding its cost-efficacy and place-in-therapy due to the lack of robust information regarding its relational and combination treatment effects. We await the results of further trials and real-world evidence to shed light on its efficacy against other comparators, and over a longer period of time to assess its tolerability and sustained efficacy.
- Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis – PubMed. Accessed September 30, 2022. https://pubmed.ncbi.nlm.nih.gov/24974815/
- Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268-1279. doi:10.1001/archopht.120.10.1268
- Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-713; discussion 829-830. doi:10.1001/archopht.120.6.701
- Guidelines. Accessed September 30, 2022. https://www.eugs.org/eng/guidelines.asp
- Primary Open-Angle Glaucoma PPP 2020 – American Academy of Ophthalmology. Accessed September 30, 2022. https://www.aao.org/preferred-practice-pattern/primary-open-angle-glaucoma-ppp
- Schmier JK, Lau EC, Covert DW. Two-year treatment patterns and costs in glaucoma patients initiating treatment with prostaglandin analogs. Clin Ophthalmol. 2010;4:1137-1143. doi:10.2147/OPTH.S13884
- 215092s000lbl.pdf. Accessed September 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215092s000lbl.pdf
8. Aihara M, Lu F, Kawata H, Iwata A, Odani-Kawabata N, Shams NK. Omidenepag Isopropyl Versus Latanoprost in Primary Open-Angle Glaucoma and Ocular Hypertension: The Phase 3 AYAME Study. American Journal of Ophthalmology. 2020;220:53-63. doi:10.1016/j.ajo.2020.06.003