Discussion
hyperemia, glaucoma, OAG, conjunctival hyperemia, TEAE, TM dysfunction
CORNEA VERTICILLATA, DISEASE PROGRESSION, HYPEREMIA, PGA, GLAUCOMA, EVENTS
This 6-month prospective, double–masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study compared, for the first time, the efficacy and safety of NET/LAT and BIM/TIM in patients with OAG and OHT. For the primary efficacy analysis, NET/LAT FDC demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) from Week 2 through Month 3, the primary efficacy endpoint of the study.The percentages of participants achieving a pre-specified mean, mean change, and percent mean change in diurnal IOP levels were similar in the two treatment groups throughout the study period. There were only two time points at which a statistically significant difference in mean IOP was observed: 08:00 at Week 6 and Month 3 in favour of BIM/TIM. A similar trend with regard to differences at specific time points has been observed in a previous work comparing once-daily netarsudil with twice-daily timolol [In clinical practice, the differences of < 1.0 mmHg (0.9 mmHg and 0.7 mmHg observed at 08:00 at Week 6 and Month 3) are unlikely to be clinically meaningful.Treatment groups were broadly similar in baseline characteristics, although a between-group disparity was observed in prior use of PGA therapy. Despite more participants recording prior PGA use in the NET/LAT arm, and despite high intra-cohort variability in length of this PGA use, prior PGA exposure was not associated with meaningful differences in efficacy or treatment discontinuation.Overall, no serious treatment-related AEs were observed, and AEs were mostly mild or moderate in severity in both treatment groups. The safety profile was consistent with previous MERCURY analyses [Although incidences of conjunctival hyperemia were significantly higher in the NET/LAT arm, the mean conjunctival hyperemia severity score was below 1 (mild) at all time points in both treatment arms and the majority of patients experiencing conjunctival hyperemia continued the study medication. Conjunctival hyperemia events reported in the NET/LAT arm (33.0%) were considerably lower than those reported in the earlier MERCURY-1 (53.4%) and MERCURY-2 (54.5%) studies conducted in the USA [Conjunctival hyperemia in NET/LAT users can be explained by the vasodilatory effects of both components of the FDC, the ROCK inhibitor and the PGA. Latanoprost has previously been associated with an increased incidence of conjunctival hyperemia compared with timolol [Real-world experience with NET/LAT can provide context to the conjunctival hyperemia observations in the MERCURY trials. A recent study found that incidence of conjunctival hyperemia in routine practice was lower (32.9%) than in the randomized controlled clinical trials (53.4% to 63.0%) [Cornea verticillata was only reported in the NET/LAT arm. This TEAE has been reported in the previous MERCURY Phase 3 studies where incidences were asymptomatic and had no impact on patient visual acuity [The observation of a reduced central corneal thickness in the NET/LAT arm was consistent with previous findings that suggest an additive effect of netarsudil and latanoprost, with the change (mean –6.4 µm in the MERCURY-2 Despite the prospective, randomized, multicenter design of this study, it has limitations. The strict inclusion and exclusion criteria may have resulted in a study population that is not fully representative of real-world patients. As ever, controlled trial data should be complemented by clinic-based observational research. Stringent trial processes were challenging to follow for some investigators, resulting in a relatively high proportion of patients affected by protocol deviations. To account for the possibility that these deviations may have impacted on findings, a PP population was analyzed, and the findings were consistent with those of the ITT population; however, the PP group was not statistically powered to determine significance and so conclusions reached using this population must remain speculative. Because disease progression is common in treated patients, a longer-term study that could provide insight into the effects of NET/LAT on progression of glaucoma would be valuable and welcome.In conclusion, the MERCURY studies show, overall, that NET/LAT offers a compelling, alternative FDC treatment option for OAG and OHT. The current MERCURY-3 study presents the first European NET/LAT study clinical data, derived from a large-scale, head-to-head comparison with BIM/TIM. By combining the ROCK inhibitor netarsudil (which increases conventional outflow by targeting TM dysfunction) with latanoprost (which increases unconventional outflow), this study demonstrates that NET/LAT FDC effectively lowers IOP to a similar degree to that of BIM/TIM.