Prostaglandin-associated periorbitopathy syndrome (PAPS): Addressing an unmet clinical need

ABSTRACT

Background: Topical prostaglandin analogs (PGAs) are widely approved and preferred first-line options for glaucoma and elevated intraocular pressure (IOP). However, prostaglandin-associated periorbitopathy syndrome (PAPS) is now a well-recognized clinical and cosmetic concern for patients receiving PGAs, especially during long-term and unilateral therapy. PGA-associated periocular changes occur in a substantial proportion of patients, with older patients (>60 years) at greater risk of clinical presentation. PAPS may hinder long-term management of glaucoma, including treatment adherence, ophthalmic surgery outcomes, and reliable IOP measurements. Recommendation: New therapeutic approaches may address this unmet clinical need. Omidenepag isopropyl (OMDI) is a novel, non-prostaglandin, selective EP₂ receptor agonist in ongoing development, which provides a unique pharmacological mechanism of action. OMDI appears to provide IOP reductions comparable to PGAs, but without PAPS-related undesirable effects. OMDI may offer a suitable long-term option for patients who demonstrate decreased efficacy, or failure, of PGAs, plus patients with significant PAPS, while fulfilling international guidelines.

KEYWORDS:

• PGA
• periorbitopathy
• PAPS
• Omidenepag isopropyl
• glaucoma

INTRODUCTION

Defining Prostaglandin-associated Periorbitopathy Syndrome (PAPS)

The progressive optic neuropathy associated with glaucoma results in loss of visual acuity and constriction of visual fields. Topical prostaglandin analogs (PGAs) are widely approved and preferred as a first-line treatment option for the management of glaucoma and ocular hypertension (OHT). These agents include latanoprost (0.005%), travoprost (0.004%), bimatoprost (0.01% and 0.03%), and tafluprost (0.0015%), and are characterized by a potent intraocular pressure (IOP)-lowering efficacy, few systemic side effects, and good adherence associated with once-daily regimens.^1,2 However, PGAs have been reported to induce periocular changes and development of local periorbitopathic side effects early, in >40% of patients treated for ≥3 months, and increases over time, in >60% of patients after just 6 months of topical treatment.^2,3 In fact, the development of early-onset periorbitopathy has even been identified as early as within a month of PGA initiation.⁴

The term prostaglandin-associated periorbitopathy (PAP) was first coined by Dr Stanley Berke in 2012,⁵ and is now well recognized as comprising a significant constellation of clinical and cosmetic changes in any one of up to ten factors (see Table 1, Figure 1, and 2).^6,7 Notable signs of PAP include flattening of the lower eyelid bags (FLEB), deepening of the upper eyelid sulcus (DUES), upper eyelid ptosis, orbital fat atrophy, and ciliary hypertrichosis.^1,8,9 Upper eyelid retraction or eyelid redness have also been reported as less recognized aspects of the PAP spectrum.¹⁰

Table 1. Clinical and cosmetic signs of prostaglandin-associated periorbitopathy syndrome (PAPS)

1. Deepening of the upper eyelid sulcus (DUES)	6. Inferior scleral show
2. Flattening of the lower eyelid bags (FLEB)	7. Tight orbit
3. Upper eyelid ptosis	8. Ciliary hypertrichosis
4. Orbital fat atrophy	9. Hyperpigmentation of the periorbital skin
5. Mild enophthalmos	10. Involution of dermatochalasis

Figure 1. A case of DUES caused by treatment with benzalkonium chloride (BAK)-preserved tafluprost ophthalmic solution.

The most prominent feature of PAPS is the appearance of, or worsening of, DUES. This case shows a case of DUES caused by treatment with BAK-preserved tafluprost ophthalmic solution. This 59-year-old woman showed DUES OS 2 months after starting tafluprost ophthalmic solution (b; white arrow). (a–d) Time points: 0 months (starting point), 2, 4, and 6 months after starting tafluprost, respectively.Images provided by Sakata R. Figure reproduced with permission from Sakata et al. (Jpn J Ophthalmol. 2014 Mar;58(2):212–7. doi: 10.1007/s10384-013-0299-8.)⁶; copyright 2014 Japanese Ophthalmological Society (within Japanese Journal of Ophthalmology).

Figure 2. Notable signs of PAPS.

Notable clinical and cosmetic signs of PAPS include FLEB, DUES, upper eyelid ptosis, and orbital fat atrophy.(A; left) A 25-year-old female who had used bimatoprost for glaucoma in both eyes for 25 months. Conjunctival injection and signs of PAPS, including DUES, mild inferior scleral show, and mild dermatochalasis, were observed. (B; right) A 68-year-old male who had been using bimatoprost eye drops in both eyes for several years. Both eyes showed marked upper eyelid lipoatrophy (i.e. DUES).Informed consent has been obtained for both patients. Images provided by Chang PY (A; left) and Sakata R (B; right).

In 2015, Sarnoff and Gotkin referred to the constellation of PAP symptoms as prostaglandin-associated periorbitopathy syndrome (PAPS).¹¹ In one study, the prevalence of PAPS (defined as the presence of DUES and at least three additional clinical manifestations) was reported as >40% in patients treated with a PGA for ≥3 months, with older patients (>60 years) demonstrating up to three times the risk of clinical presentation (OR 3.0; 95% CI: 1.2–7.8).³

The most prominent feature of PAPS is the appearance of, or worsening of, DUES,^6,10,12 which is one of the most significant adverse cosmetic outcomes associated typically with application of bimatoprost and travoprost,^1,12 although it has also been observed with induction of topical treatment with latanoprost and tafluprost (see Figure 1).^6,13 Retrospective studies and case series suggest that development of DUES is associated with the use of all available PGAs, with incidence varying depending on the agent.^4,14 In a small series of Japanese patients (n = 25) newly diagnosed with open-angle glaucoma (OAG), 60% were reported to have developed DUES as early as 3 months after switching from latanoprost to bimatoprost. The incidence of DUES was significantly higher in older patients and in non-myopic eyes (p < .01), but not related to sex or IOP reduction. In patients assessed by a clinician as having DUES, over half also self-reported their cosmetic changes at 6 months.^1,12

In addition, the choice of pre-operative PGA and cosmetic changes associated with the presence of DUES can have a significant impact on ophthalmic clinical measures (such as IOP measurement) and surgical outcomes (for example, with trabeculectomy).^15,16 In a small, retrospective study, following trabeculectomy for OAG, patients with PGA-associated DUES before surgery were observed to be at a significantly higher risk of recurrent IOP elevation up to 24 months post-surgery than patients without DUES (p < .0001). Bimatoprost use was found to be the highest risk (and only significant independent factor) for post-trabeculectomy recurrence of IOP elevation.¹⁵

Long-term use of PGAs (with preservatives) may also have some biomechanical and pathological impact on the ocular surface, including changes in corneal hysteresis and corneal resistance factor, decreases in central corneal thickness, delays in corneal wound healing, and occurrences of conjunctival hyperemia and dry eye disease.¹⁷ Clinical data have previously demonstrated numerous intraoperative situations in which eyelid tissues appear abnormal in patients on long-term treatment with a PGA, often adding complexity to ptosis repair surgery.¹⁸

In patients treated with PGA for unilateral glaucoma, PAPS may cause visible facial asymmetry,² potentially reducing adherence to treatment as well as patients’ confidence. In addition, PAPS may also hinder successful and long-term clinical management of glaucoma, including filtration surgery, and even reliable IOP measurements. Thus, PAPS may be of significant clinical concern for patients receiving treatment with PGAs, especially for those receiving long-term treatment and the elderly.

With bilateral PGA treatment, significant reductions in patient interpupillary distance (IPD) may provide an indicator of developing PAP.¹⁹ Following PGA instillation, IPDs have demonstrated significant shortening (–0.80 ± 2.1 mm) compared with control patients (p < .001); change in IPD after bimatoprost instillation (–2.20 ± 0.97 mm) was significantly (p < .001) greater than with other PGAs, including travoprost, latanoprost, and tafluprost (–0.65 ± 2.09 mm). Over 85% of patients receiving bimatoprost demonstrated IPD decreases of ≥2 mm.¹⁹

It is proposed that management of PAPS and associated symptoms can usually be achieved by simple discontinuation of the causative therapy, which often results in partial-to-complete reversal of PAP characteristics (as early as 4–6 weeks).²⁰ Much like the onset of PAPS, observation of PAP reversal is more noticeable in those treated unilaterally, so thorough documentation and measurements can be helpful in assessing the extent of atrophy reversal.

This review aims to highlight an unmet clinical need in patients with PAPS requiring lowering of IOP, and evaluate new clinical solutions – including a novel, non-prostaglandin, selective EP₂ (a prostaglandin E receptor) agonist.

PAPS AND NEW CLINICAL SOLUTIONS

Non-prostaglandin Selective EP2 Agonists

For more than two decades, EP₂ agonists have been the subject of anti-glaucoma research and development, leading to the commercial approval of omidenepag isopropyl (OMDI) in Japan (known as EYBELIS™).²¹

OMDI is a novel, non-PGA derivative currently in Phase III global clinical development for lowering IOP, which has demonstrated improvements in signs and symptoms of PAPS in patients switched from PGA therapy.^7,8,22 OMDI provides an alternative pharmacological mechanism of action to PGAs, lacking measurable binding to the prostaglandin F (FP) receptor, and instead selectively binding to EP₂: a G-protein-coupled receptor expressed widely in ocular tissues, including the trabecular meshwork and ciliary body involved in conventional and uveoscleral outflow.⁷ OMDI demonstrates a similar pharmacokinetic profile across Japanese and Caucasian subjects.²³

PGAs Mechanism of Action

PGAs have high specificity for the FP receptor, which has a crucial role in reducing IOP by both increasing the outflow and decreasing resistance to outflow of aqueous fluid from the eyes.^11,24 Long-term, repeated treatment with prostaglandin F_2α (PGF_2α) in preclinical models provides a long-lasting reduction in IOP, which persists following treatment cessation. This long-term effect is likely due to expansion of the intermuscular spaces in the ciliary body through extracellular matrix remodelling.²⁵

In addition, PGA exposure is hypothesized to influence expression of matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMP) in a tissue-specific manner, with decreased expression of certain MMPs in collagen correlating to increased periorbitopathy.²⁶ PGA-mediated activation of MMP promoters leads to alterations in MMP and TIMP levels, which are responsible for remodeling the extracellular matrix (ECM) by increasing uveoscleral and trabecular outflow, and ultimately resulting in reduction of IOP. However, remodeling of the ECM scaffold has been postulated to play a role in PAPS by increasing fibrous tissue in pterygium epithelial cells, and in conjunctival scarring, indicating a time-dependent effect of PGAs on the tissue ultrastructure that maintains ocular and periorbital physiology. Such dysregulation in the ECM scaffold has a role in eyelid malpositions and may have implications for ptosis and PAP through alterations of MMP/TIMP dynamics.²⁶

In preclinical models, PGAs inhibit adipogenesis through FP receptor stimulation, which may lead directly to reduced orbital fat.²⁷ PGF_2α and PGAs bind to the prostaglandin F_2α receptor (FP_2α) on orbital preadipocytes and activate mitogen-activated protein kinase (MAPK), resulting in phosphorylation and inactivation of peroxisome proliferator activated receptor gamma (PPARγ) – leading to inhibition of adipocyte differentiation, decreased lipoprotein lipase (LPL) levels (a marker for adipocyte differentiation), and decreased fat accumulation within adipocytes (see Figure 3).¹¹

Figure 3. Mechanism of action and impact of PGAs on adipose changes in PAP.

FP_2α: prostaglandin F_2α receptor; LPL: lipoprotein lipase; MAPK: mitogen-activated protein kinase; P: phosphorylation;PGA: prostaglandin analog; PGF_2α: prostaglandin F_2α; PPARγ: peroxisome proliferator activated receptor gamma.Adapted from: Sarnoff et al. (2015).¹¹

PGAs are also associated with eyelash growth and increased pigmentation of the periorbital skin. Exposure promotes cell growth, inducing a growth phase in resting follicles and hypertrophic follicle changes. These changes result in increased length and thickness of lashes, additional lash rows, conversion of vellus to terminal hairs in canthal areas, as well as increased growth and pigmentation of ancillary hairs around the eyelids.²⁸

OMDI Mechanism of Action

Prostaglandin E₂ (PGE₂) is an endogenous lipid with potent IOP-lowering effects; it has four distinct receptors: EP₁, EP₂, EP₃, and EP₄.^21,25 OMDI is an isopropyl ester derivative that hydrolyzes to an active EP₂ agonist metabolite during corneal penetration, which targets the intracellular signaling cascade and elevates cyclic adenosine monophosphate levels (see Figure 4).^29,32,33

Figure 4. Receptor-based mechanism of action.

cAMP: cyclic adenosine monophosphate; DP₁: PGD₂ receptor 1; DP₂: PGD₂ receptor 2; EP: prostaglandin E receptor; FP: prostaglandin F receptor; IOP: intraocular pressure; IP: prostacyclin receptor; OMDI: omidenepag isopropyl; PAP: prostaglandin-associated periorbitopathy; PGD₂: prostaglandin D2: PGE₂: prostaglandin E₂; PGI₂: prostacyclin;PGF_2α: prostaglandin F_2α; TP: thromboxane A₂ receptor; TxA₂: thromboxane A₂.Adapted from: Doucette et al. (2017)²⁵; Taketani et al. (2014)²⁷; Johnstone et al. (2002)²⁸; Mohan et al. (2012)²⁹; Dutkiewicz et al. (2000)³⁰; Fuwa et al. (2018).³¹

Available PGAs for the reduction of IOP have a strong binding affinity for FP, but very weak or no binding affinity to the EP₂ receptor.²² Elevations in Ca²⁺ detected with the PGF_2α pathway following PGA application are associated with elevated tyrosinase activity and associated iris pigmentation³⁰; by comparison, OMDI is not associated with elevated tyrosinase activity, as it has no effect on any other prostaglandin receptors.

The IOP-lowering effect of OMDI is induced by enhancement of both conventional and uveoscleral outflow routes, potentially through relaxation of the ciliary muscle, which constitutes part of the uveoscleral outflow apparatus. Thus, the impact of an EP₂ agonist would include the enhancement of drainage due to an increase in the ciliary intermuscular space via relaxation.²² Notably, EP₂ agonists promote similar effects (to those described earlier with PGF_2α analogs) by upregulating MMPs and remodeling the ECM to produce intermuscular spaces in the ciliary body for aqueous egress.³⁴ In addition to the enhancement of outflow of aqueous humor via uveoscleral outflow,³¹ EP₂ receptor agonists may facilitate conventional trabecular outflow pathways by decreasing the quantity of collagenous materials, resulting in stable IOP reductions.^22,35,36 Preclinical models of OHT demonstrate that OMDI significantly increased the rates of both aqueous facility and uveoscleral outflow by 71% and 176%, compared with vehicle (p < .05 for both).³⁶ In dose-finding studies, OMDI significantly decreased mean diurnal IOP from baseline in patients with primary OAG or OHT in both eyes, resulting in clinically relevant reductions that were superior to placebo and non-inferior to latanoprost (p < .005).³⁷

In contrast to FP agonists, EP₂ agonists do not promote eyelash growth and do not inhibit adipogenesis. OMDI studies report no significant effects on eyelash growth or the eyelash growth cycle over 52 weeks of treatment.^7,38 A key difference is that OMDI affects adipogenesis of 3T3-L1 cells in a different manner to PGAs, suggesting it would not be associated with the characteristic orbital fat atrophy observed in PGA-mediated DUES (as shown in Figure 3).^32,39

Thus, a selective EP₂ agonist has the potential to lower IOP similar to current PGF_2α analogs, but with PAPS being unlikely with the former.³⁴

OMDI PHASE III STUDIES IN LOWERING IOP

Multiple Phase II studies of OMDI have been conducted (in the United States and Japan). These dose-finding studies have demonstrated OMDI to be generally well tolerated with clinically relevant IOP-lowering effects in patients with primary OAG and OHT. In these studies, maximum IOP reductions were achieved within 1 week of treatment initiation, demonstrating an early onset of action that was maintained for up to 3 months.³⁷

OMDI 0.002% has been approved by authorities in Japan (2018) for the treatment of glaucoma and OHT to lower IOP; a global clinical development program is ongoing and includes four Phase III studies. The randomized, investigator-masked, active-controlled, parallel-group AYAME study demonstrated that once-daily OMDI was non-inferior to once-daily latanoprost (0.005%) in reducing IOP in Japanese patients with primary OAG or OHT (n = 190) for up to 4 weeks.⁴⁰ The ongoing, non-inferiority PEONY study is designed to examine mean diurnal IOP reduction at 3 months versus latanoprost (n = 370).⁴¹

Of the two open-label studies, the 52-week, single-arm RENGE study primarily assessed change in mean diurnal IOP in Japanese patients with primary OAG (including normal tension glaucoma and exfoliation glaucoma), or OHT in both eyes; OMDI treatment resulted in sustained IOP reductions over 12 months across patients with either normal (≥16 to <22 mmHg) or hypertensive IOP (≥22 to ≤34 mmHg) at baseline.³⁸ The multicenter FUJI study reported clinically significant reductions in IOP from baseline at Week 4 (−2.99 mmHg, p < .0001) in patients switched to OMDI following low or no response to latanoprost 0.005% during an 8-week run-in period (≤15% IOP reduction over 8 weeks).⁴²

Important Safety Considerations

Phase III clinical studies highlight that OMDI 0.002% is generally well tolerated in the IOP-managed patient population with no serious safety concerns presenting in those that are complete. In the Phase II and III studies, OMDI was associated with conjunctival hyperemia, a common side effect of FP receptor agonists. In the 4-week AYAME study, the incidence of conjunctival hyperemia was 24.5% (compared with 10.4% in the latanoprost group) but was reported as mild, transient, and not associated with treatment discontinuation.⁴⁰ Conjunctival hyperemia is a well-recognized side effect of ocular hypotensive treatment, with varying incidences in FP agonists (between 4% and 50% of patients), as well as being observed in up to 20% of patients receiving brimonidine and up to 53% of patients receiving netarsudil.⁴⁰ The incidence observed in the AYAME study, as well as in both the FUJI and RENGE studies (7.7% and 14.6–18.9%, respectively),^38,42 falls within this typical range.⁴⁰ The exact cause of OMDI-induced hyperemia is currently unknown, yet short-term assessment (up to 6 hours after administration of one drop of OMDI) of conjunctival hyperemia patterns suggests that OMDI predominantly affects small blood vessels only.⁴³ A longer-term study would be required to determine the exact time course of hyperemia during OMDI treatment.⁴⁰

Increased central corneal thickness (CCT) was reported more frequently following OMDI than latanoprost in the AYAME study.⁴⁰ CCT change from baseline ranged from 13.0–18.7 µm (approximately 3%; mean 15 µm) and remained constant throughout the study period. Investigators considered these increases in CCT not to be clinically significant, being within the range of physiological change that occurs after one night of sleep (3–8% overnight corneal swelling). There was no reported corneal edema associated with CCT changes, as evaluated by slit-lamp microscopy, and no impact on visual acuity was observed.⁴⁰

IMPROVEMENTS IN PAPS SIGNS IN PATIENTS SWITCHING FROM PGA THERAPY TO OMDI

Notably, within the clinical trials previously mentioned, none of the eyes treated with OMDI experienced abnormal eyelash growth or PAPS.³⁴ Patients switched from a long-term, conventional PGA to OMDI have reported significant improvements in the signs of PAPS.^7,8 A recent Japanese case series described patients (n = 11 eyes) with PAP that were prospectively switched from conventional PGAs (mean duration of 65 months [range, 24–112 months]) to OMDI and were assessed 3 months and 6 months later. At 6 months, three patients show improvements in DUES, two in FLEB, and two in ciliary hypertrichosis.⁸ Recovery of periorbital skin hyperpigmentation was the most dramatic change reported, with eight patients showing resolution at 6 months. There was no improvement in upper eyelid ptosis in any patient across the 6-month study duration.⁸

In a longer-term follow-up study, lessening of DUES was the most observed improvement following a 12-month switch to OMDI; patients (n = 12) had previously received PGAs for a mean duration of 61 months (range, 24–115 months). Reduction in DUES was observed in ≤50% of patients and was most frequent in prior users of bimatoprost and travoprost, with the majority of responders showing a reduction in DUES by Month 3 of treatment.⁷ However, it is important to consider that the lessening of DUES may be due to cessation of conventional PGAs alone, and not OMDI directly.

Improvements in FLEB and periorbital skin hyperpigmentation were also demonstrated over the 12-month study, whereas recovery of ciliary hypertrichosis was the least observed sign with ≤8% of patients improved by study completion. It was considered that the impact of PGA on the eyelash growth cycle may be long-lasting.⁷ Patients included in the 12-month follow-up study were also monitored for IOP, which was maintained within expected levels. No significant changes in IOP were observed during the follow-up period, with mean IOP measurements of 16.5 ± 1.5 mmHg, 15.4 ± 1.9 mmHg, 15.5 ± 1.7 mmHg, and 15.9 ± 1.8 mmHg at baseline, and 3, 6 and 12 months, respectively (p = .394 by one-way ANOVA).⁷

DISCUSSION

IOP-lowering treatment with PGAs is a standard of care for primary OAG and OHT. Now, after over two decades of first-line use, the consequences of long-term exposure have become more familiar.³⁴ PAPS is an often-overlooked consequence that appears following long-term PGA use, with most side effects being cosmetic in nature – including eyelash growth, periorbital skin pigmentation, DUES, and FLEB. While not typically a reason to avoid or discontinue therapy in many patients, the occurrence of these manifestations can limit the use of PGAs, especially in unilateral therapy and younger patients who are more concerned about cosmetic appearances.³⁴ Within glaucoma, patient-delivered regimens rely heavily on treatment adherence, and therefore the reversal or avoidance of PAPS remains a clinical unmet need.

Alongside the visually disconcerting manifestations of PAPS, which is often more noticeable in unilateral treatment, PAPS may also be asymptomatic and be associated with a variety of functional limitations, pertaining to clinical practice and surgery – such as overestimation of IOP measurement due to tight orbit syndrome. Severe cases of PAPS, although relatively uncommon, have the potential to hinder eyedrop retention and lead to complexity in ophthalmic surgery.³⁴

One option typically considered to manage PAPS is the discontinuation of the causative therapy. However, cessation of treatment is associated with a range of inherent issues, such as increasing IOP and worsening of glaucoma itself, as well as a need to resort to other topical or systemic medications, which may be less efficacious and be associated with other side effects linked to long-term management. In addition, PGA-therapy switching itself is unlikely to be a long-term solution for PAPS. Outcomes from a prospective, open-label study in Japanese patients with primary OAG suggest that switching from bimatoprost to latanoprost offers a potential avenue for reversing DUES, although the study included a limited self-reporting population (n = 13) over a 6-month follow-up, and not all patients experienced improvements.¹²

Following failure or resistance to first-line treatments for IOP reduction, both the European Glaucoma Society and Asia-Pacific Glaucoma Society recommend that patients are switched to an alternative drug class rather than considering same-class combination therapy.^44,45 Clinical studies indicate that OMDI 0.002% may provide an effective solution for switching patients with glaucoma from PGA monotherapy.^40,42 It is suggested that OMDI may not cause PAPS, likely due to its unique mechanism of action, which does not inhibit adipogenesis, and therefore offers benefits to many patients.³⁴ Outcomes from the Phase III AYAME study suggest that OMDI may provide IOP-lowering benefits comparable with those of latanoprost.⁴⁰ However, no data exist directly comparing the IOP-lowering effects of other PGAs and OMDI. Further research may be necessary to characterize the IOP-lowering benefits of OMDI in comparison with other first-line treatments in glaucoma and the long-term efficacy and safety profile of this drug.

In children and young adults with a history of childhood glaucoma, mild-to-moderate changes in the ocular adnexa have been reported following long-term PGA exposure.⁴⁶ Incidence of eyelash trichomegaly and hypertrichosis (76%), high upper eyelid crease (69%), upper eyelid ptosis (52%), and superior sulcus hollowing (52%) were the most frequently observed features of PAPS associated with PGA treatment in this young patient population.⁴⁶ Moreover, both patients and their caregivers are often sensitive to cosmetic orbital changes. The impact of potential future decades of cumulative PGA exposure on both physical appearance and normal development should also be considered, especially when initiating monocular therapy.⁴⁶ Thus, management of unilateral glaucoma may be a key clinical consideration in preventing asymmetrical DUES, with OMDI providing an important treatment option for relatively young patients requiring long-term IOP management.

Initial opportunities for OMDI treatment could include management of OHT, and patients with OAG receiving monotherapy who do not require significant IOP lowering. For example, good candidates, for a different class of eye drops other than PGAs, could include patients who already have deep-set eyes at baseline or those who need only unilateral treatment. In addition, the reductions in uveoscleral flow rate associated with OMDI administration may provide benefits for patients with angle-closure glaucoma; current clinical evaluations have predominantly included patients with primary OAG and OHT. Yet, research has also demonstrated significant IOP-lowering efficacy in treatment-naïve patients with normal tension glaucoma.⁴⁷

Further long-term clinical data are required to fully elucidate the value and position of OMDI in the treatment paradigm of IOP-lowering (including to confirm any clinically meaningful differences to PGAs) and PAPS resolution, as well as to evaluate its additivity to other classes of IOP-lowering therapy.

CONCLUSIONS

The evolution and subsequent impact of PAPS are significant clinical concerns among patients receiving long-term treatment with PGAs, especially those with unilateral therapy. There is an unmet need for medical therapy that is more effective and/or well tolerated, and which could be considered a practical long-term option. OMDI appears to provide IOP reductions comparable with those of PGAs with a markedly different safety profile and to lower IOP in non- or low responders to latanoprost. Although the modest IOP reductions reported in comparative studies may limit the appeal of OMDI for first-line treatment versus PGAs, the avoidance of PAPS and associated long-term cosmetic and clinical consequences should be key clinical factors to consider a switch in glaucoma treatment. The addition of OMDI to the IOP-lowering armamentarium provides an alternative for lessening PAPS typically associated with PGAs while also fulfilling international guideline criteria following PGA recalcitrancy or failure. Further research and large head-to-head comparisons of OMDI are required, with particular emphasis on extended time frames, to identify any significant clinical benefit OMDI may offer over standard-of-care treatments.

LITERATURE SEARCH

Electronic search of the PubMed (MEDLINE) database was performed for the years 2010–2021 with the keywords ‘prostaglandin’, ‘PGA’, ‘periorbitopathy’, ‘PAP’, ‘PAPS’, ‘omidenepag isopropyl’, ‘OMDI’, ‘glaucoma’, ‘intraocular pressure’, and ‘IOP’. Some articles that were not found by the PubMed search were taken from the citations of other articles and books. Case reports were only included if they contributed new information about characteristics, diagnosis or treatment of the disease. We included reports of orbital Only articles with English translation were included.

Acknowledgments

Medical writing support was provided by Synergy Vision.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors of this review article were sponsored by Santen Pharmaceutical Asia Pte. Ltd. alongside the decision to submit the article for publication. The research, preparation and writing of the article were independent of the sponsor.