Omidenepag isopropyl noninferior to latanoprost for ocular hypertension, glaucoma

The ocular hypotensive agent omidenepag isopropyl (OMDI) was noninferior to the current standard of care, latanoprost, in reducing intraocular pressure (IOP) in individuals with ocular hypertension (OHT) or primary open-angle glaucoma, results of the phase III AYAME study have shown.

Latanoprost is the first FP agonist approved, and has been used globally as first-line treatment, for these ocular disorders. [Clin Ophthalmol 2014;8:1967-1985] “[However,] adequate IOP reduction cannot be achieved with FP agonists in all patients, necessitating adjunctive therapy or switching to an alternative agent,” said the researchers.

“In addition, ~40 percent of patients will require adjunctive treatment to adequately maintain IOP control within 2 years of initiating FP agonist monotherapy,” they continued. FP agonists are also linked to prostaglandin-associated peri-orbitopathy, including orbital fat loss, upper eyelid sulcus deepening, abnormal eyelash growth, and periocular skin and iris pigmentation. [JAMA 2014;311:1901-1911; Lancet 2017;390:2183-2193; Eye Lond 2012;26:1465-1472]

“[Although] the clinical and psychological burden of these appearance-altering adverse events (AEs) is currently unknown, [the] deepening of the upper eyelid sulcus related to FP agonists may have an impact on -lowering outcomes of trabeculectomy,” they explained. “[T]here may be a need for a topical IOP-lowering medication that has noninferior efficacy to latanoprost and does not contribute to these AEs.”

OMDI has gained approval for OHT and glaucoma treatment in Japan in 2018. [www.ube-ind.co.jp/ube/en/news/2018/20180921_01.html, accessed January 26, 2021] “[Our findings suggest that] OMDI could be considered a candidate for first-line treatment of glaucoma and OHT,” said the researchers.

After the washout period, 190 individuals (mean age 63.6 years, 54 percent female, 58 percent with a primary diagnosis of OHT) were randomized 1:1 to receive OMDI 0.002% or latanoprost 0.005%, one drop in each eye nightly for 4 weeks. [Am J Ophthalmol 2020;220:53-63]

Week 4 saw similar diurnal IOP reductions between OMDI and latanoprost (least-squares mean [LSM] change, –5.93 vs –6.56 mm Hg; p=0.048), suggesting the noninferiority of the former to the latter. However, despite the statistically significant difference, the researchers noted that this was not clinically significant, as it was below the noninferiority margin, was smaller than the observed reduction with placebo, and was within the measurement limit threshold.

Treatment-related ocular AEs were more frequent with OMDI vs latanoprost, the most common being conjunctival hyperaemia (24 percent vs 10 percent). Nonetheless, this is a known side effect of ocular hypotensive treatment. [Surv Ophthalmol 2008;53:S93-S105]

The differences in AE incidences may be due to the different mechanisms of action of the active compounds, as some elements of ophthalmic solutions may trigger AEs, noted the researchers. Moreover, AEs either improved or resolved during treatment or following discontinuation, and no serious AEs were reported in either arm. Four patients discontinued due to AEs, but none were caused by the study drug.

In patients with early glaucoma, a 20-percent IOP reduction (or a target of <21 mm Hg) is recommended. In the current study, 77 percent of OMDI recipients had a mean diurnal IOP reduction of at least 20 percent by week 4. “[These] suggest that treatment with OMDI may be useful in this patient population,” they said.

In late-stage glaucoma however, the recommended IOP reduction is 30 percent (or a target of <18 mm Hg). In AYAME, despite the mean diurnal IOP value of <18 mm Hg at week 4, 73 percent of OMDI recipients did not achieve a 30-percent IOP reduction. “These findings continue to confirm the need of new ocular hypotensive agents with different mechanisms of action, particularly in patients with advanced glaucoma who require a lower target IOP level,” they said.

The IOP-lowering effect of OMDI also appears more pronounced in US vs Japanese cohorts. “This might [have been due to] the lower IOP values typically observed in Japanese vs white populations at study entry,” the researchers noted.

Larger, longer randomized trials are thus warranted to ascertain the clinical efficacy and safety of OMDI in this setting. Phase III trials in Asia (outside Japan) and the US are also underway to evaluate treatment responses in different patient populations.