Efficacy
The two individual trials, APOLLO and LUNAR, were very similar in terms of study design and study populations as per the baseline characteristics. Given these similarities, the reason for the differences in the key primary and one of the key secondary outcomes between the trials is unclear.
IOP was assessed extensively in both trials (e.g., mean IOP at each time point, patients with IOP less than or equal to 18 mm Hg, patients with IOP reduction greater than or equal to 25%) and was determined to be an appropriate surrogate outcome, since visual field loss and vision loss would take several years to manifest, according to the clinical expert consulted for this review.11
While the focus on IOP reduction seen in these trials was relevant and consistent with the literature, several other outcomes identified by patients were not assessed as efficacy outcomes. Visual acuity and appearance of the optic nerve were considered as safety outcomes in the trials and were not assessed statistically. APOLLO and LUNAR were limited with respect to the assessment of patient-reported outcomes. Outcomes related to HRQoL and VRQoL were identified as important to patients, but were not assessed in either of the trials. There is insufficient evidence to support a correlation between glaucoma treatment and patient-reported outcomes.11 The absence of patient-reported outcomes introduces uncertainty with respect to the clinical relevance of the results. Outcomes related to visual field loss and glaucoma symptoms were not assessed in either of the trials.
The 1.5 mm Hg noninferiority margin was selected based on discussion with the FDA on historical glaucoma noninferiority studies as well as on historical data from landmark glaucoma trials. However, no minimal clinically important differences (MCIDs) for IOP were identified in the published literature. The use of 1.5 mm Hg as the noninferiority margin may not have been clinically meaningful given that IOP levels typically fluctuate between 2 mm Hg and 5 mm Hg.2 The proportion of patients who reached the normal range (defined as less than 18 mm Hg in IOP after 3 months) was higher for the LBN 0.024% ophthalmic solution arms than the timolol maleate 0.5% arms, with treatment differences of 11.6% (APOLLO) and 6.6% (LUNAR). The difference in the proportion of patients with IOP reduction greater than or equal to 25% at all nine time points was greater in the LBN 0.024% ophthalmic solution arms than in the timolol maleate 0.5% arms (15.3% in APOLLO, 12.5% in LUNAR). The improvements related to treatment with LBN 0.024% ophthalmic solution indicate modest clinical relevance, according to the clinical expert consulted for this review.
Visual acuity (assessed through BCVA) and the appearance of the optic nerve remained similar between arms at both baseline and month 3 in both trials.
Overall, LBN 0.024% ophthalmic solution appeared to be better than timolol maleate 0.5%, with unknown or perhaps only modest clinical implications.
Open-label safety extension trials of nine months’ and three months’ duration for APOLLO and LUNAR, respectively, assessed patients who either continued on or switched to treatment with LBN 0.024% ophthalmic solution (Appendix 6). The results of these safety extensions indicate no notable differences in mean IOP at different time points, nor in mean diurnal IOP between treatment groups. Additionally, results pertaining to visual acuity and the appearance of the optic nerve were similar to the results observed in the efficacy phase at month 3 (Appendix 6). These open-label safety extensions were limited by the uncontrolled and unblinded nature of the safety phases. While the durations of the safety extensions were likely sufficient to observe harms associated with LBN 0.024% ophthalmic solution, the durations of the efficacy phases of the trials were too short to observe the long-term effects of LBN 0.024% ophthalmic solution on IOP and visual acuity compared with relevant comparators.
An open-label, uncontrolled, single-arm, Japanese study (JUPITER) was designed to assess the long-term safety and efficacy of LBN 0.024% ophthalmic solution once daily in one or both eyes of patients with OAG or OHT (Appendix 6). The results of this trial revealed a mean IOP in week 52 (n = 121) of 14.42 mm Hg, with a statistically significant reduction of IOP from baseline of 5.25 mm Hg. While these findings showed favourable results for the use of LBN 0.024% ophthalmic solution, the study remains descriptive in nature due to the lack of a comparator arm and its uncontrolled, open-label nature. In addition, the results from this study cannot necessarily be generalized to patients of other races due to anatomical differences in the eyelids of Japanese patients, who often have increased IOP measurements during the manual manipulation needed to perform GAT.
The choice for using timolol maleate 0.5% as the active comparator presents a major limitation to the study design as it is based on information inconsistent with current guidance from multiple agencies, including the Canadian Ophthalmological Society, the American Academy of Ophthalmology, and NICE. These agencies acknowledge that in the past, beta-blockers were considered first-line therapy; however, they state that currently, PGAs are the most common first-line therapy due to favourable effectiveness, once-daily administration, and tolerability compared with other drugs, including beta-blockers.2,17,18 Based on this evidence, timolol maleate 0.5% was not the most relevant comparator with respect to applicability to the Canadian population. Using a beta-blocker that is not a currently accepted first-line therapy increases the likelihood of noninferiority and superiority for LBN 0.024% ophthalmic solution. It can be argued that a PGA would have been a more relevant comparator, given the information provided by the agencies. Direct evidence from a 29-day dose-finding phase II trial (VOYAGER) compared various concentrations of LBN ophthalmologic solutions with the PGA latanoprost 0.005% ophthalmic solution and found statistically significantly lower mean study-eye diurnal IOPs for LBN ophthalmologic solution 0.024%.32 VOYAGER’s conclusion was not supported by the results of the manufacturer-provided ITC of phase III trials.
The results of the ITC indicate that treatment with LBN 0.024% ophthalmic solution is likely favourable over placebo; however, little can be elucidated about its efficacy compared with other products. Overall, the results of this analysis must be interpreted with caution because their utility and robustness are limited by issues with transparency in the systematic review methods and analysis as well as by the absence of control for heterogeneity.
Harms
In APOLLO and LUNAR, the most common ocular AEs (in the study eye) were related to conjunctival hyperemia and eye irritation. In APOLLO, serious adverse events (SAEs) occurred in 1.1% and 1.5% of patients in the LBN 0.024% ophthalmic solution arm and timolol maleate 0.5% arm, respectively. In LUNAR, SAEs occurred in 2.2% and 0% of patients in the LBN 0.024% ophthalmic solution arm and timolol maleate 0.5% arm, respectively. Withdrawals due to adverse events (WDAEs) similarly occurred across treatment arms in both trials, with the most common WDAEs related to eye disorders.
The product monograph notes the potential for ophthalmologic harms related to bacterial keratitis, eyelash changes, intraocular inflammation, macular edema, and pigmentation. The occurrence of these AEs was not of note in APOLLO and LUNAR.
Across trials, ocular AEs (in the study eye) occurred more frequently in the LBN 0.024% ophthalmic solution arm compared with the timolol maleate 0.5% arm. In LUNAR, differences in ocular AEs specifically relating to conjunctival hyperemia and eye irritation show a marked increase for patients treated with LBN 0.024% ophthalmic solution compared with timolol maleate 0.5%. While there is also an increase seen in APOLLO, it is numerically much smaller than that observed in LUNAR. Given the similar design of the efficacy phases and the similarity in baseline characteristics between the two trials, it is unclear why this substantial difference in ocular AEs exists for LUNAR but not for APOLLO. In comparison with the efficacy phases of APOLLO and LUNAR, no new or cumulative safety concerns emerged from the open-label extension studies. In these safety extensions, the most common ocular treatment-emergent adverse events reported were eye irritation, eye pain, and conjunctival hyperemia. During the LUNAR study, in both the efficacy and safety phases, the percentage of patients reporting conjunctival hyperemia (in the study eye and in the treated fellow eye) was higher in the LBN 0.024% arm than in the timolol maleate 0.5% crossover to LBN 0.024% arm. A similar difference was not apparent in the APOLLO trial. In both phases of the LUNAR trial, patients in the LBN 0.024% treatment arm experienced a higher incidence of ocular disorders. During the LUNAR safety phase, the number of new patients with ocular AEs in the timolol maleate 0.5% crossover to LBN 0.024% arm appeared to offset the difference observed between the two treatment arms in the efficacy phase. This pattern was not observed in APOLLO. No notable pattern of SAEs was observed in the APOLLO and LUNAR extension studies.
Overall, the safety profiles in terms of eye-related complications favoured timolol maleate 0.5% versus LBN 0.024% ophthalmic solution. The manufacturer-supplied ITC did not perform analysis on harms-related outcomes.
Potential Place in Therapy2
Glaucoma is the leading cause of irreversible blindness globally12–14 and is estimated to affect 2.7% of Canadians aged 40 years and older.5 The term glaucoma includes a group of diseases that are broadly classified as open- or closed-angle. Currently, the only proven treatment for all types of glaucoma is lowering IOP,11 which can be done with medication, laser, or surgery.15 The initial management of glaucoma is usually medical, with eye drops. There are currently five classes of medications to manage glaucoma: prostaglandin analogues, beta-blockers, carbonic anhydrase inhibitors, alpha2 adrenergic agonists, and miotics. Some patients are not able to achieve sufficient IOP lowering (often termed target pressure) with the current available medication (due either to lack of efficacy or tolerance) and progress to interventions such as laser or surgery.16
Latanoprostene bunod 0.024% (Vyzulta) represents a new class of IOP-lowering medication. In addition to acting as a prostaglandin analogue, LBN is expected to release nitric oxide, which in turn is expected to reduce IOP by relaxing the trabecular meshwork and Schlemm’s canal to improve outflow. This represents a new mechanism of action that may facilitate IOP lowering in patients who are unable to achieve their target pressure with currently available glaucoma hypotensive medications.
Since all glaucomas are treated by lowering IOP, Vyzulta could potentially be of benefit for both open- and closed-angle glaucomas. The first-line medical therapies for glaucoma, barring any contraindications, are the prostaglandin analogues. This medication class is very effective in lowering eye pressure. The medications are easy to use (given that they are used only once a day) and well tolerated. The Ontario Drug Benefit program requires a limited-use form for many glaucoma medications, including the prostaglandin analogues. The limited-use code is to confirm that either the patient was unsuccessful with a beta-blocker or that a beta-blocker is contraindicated.
Despite this requirement, prostaglandin analogues are usually initiated before a beta-blocker due to the reasons cited previously. However, many patients cannot be controlled with one class of medication; for these patients, adjunctive hypotensive drops are prescribed. The second hypotensive drop is usually a beta-blocker. Additional hypotensive drops are added if a target pressure is not achieved, whether due to lack of response, insufficient eye pressure reduction, or intolerance. Maximal medical therapy is usually three or four classes of medication. If a patient has not reached their target pressure but is not on three or four classes of medication, either due to intolerance or nonresponse, then Vyzulta should be considered, as it is a new class of hypotensive drop. Vyzulta would be considered a single drug with two mechanisms of action and would replace a prostaglandin. Some ophthalmologists may also consider using Vyzulta as a first-line therapy; however, the high rate of hyperemia may limit its widespread us as a first-line drug.
