Glaucoma is a prominent cause of irreversible blindness, with a global prevalence of 3.45% among individuals between 40-80 years of age. 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 and 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 mono-therapy approach, with a preference for prostaglandins (e.g. latanoprost), followed by non-selective beta-blockers (e.g. timolol), alpha-adrenergic agonists (e.g. brimonidine), selective beta-blockers (e.g. betaxolol) and topical carbonic anhydrase inhibitors (e.g. brinzolamide).
In June 2021, the Health Sciences Authority (HSA) Singapore approved the use of latanoprostene bunod ophthalmic solution (Vyzulta, 0.024%) for reducing IOP in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). In a pharmacological landscape fraught with a drought of innovative drug therapies since the 2000s, Vyzulta’s entry seeks to exploit new treatment paradigms with its novel dual mechanism of action.
Dual Mechanism of Action
The once-daily eye drop by Bausch & Lomb is a prostaglandin analog (PGA) that is hydrolysed into prostanoid FP receptor agonist latanoprost acid (active metabolite) and butanediol mononitrate. The latter is further metabolised to 1,4-butanediol and nitric oxide (NO; active metabolite).
It regulates IOP by increasing aqueous humour outflow through the uveoscleral pathway (mediated by latanoprost acid) and through the trabecular meshwork pathway (mediated by NO).
Clinical Efficacy
The safety and efficacy of Vyzulta were evaluated in two multinational Phase III randomised controlled trials (RCTs), APOLLO and LUNAR. The RCTs (n=831) compared Vyzulta with timolol maleate ophthalmic solution 0.5% in patients with OAG or OHT and consisted of a 3-month, active-controlled period followed by a 3-month (LUNAR) or 9-month (APOLLO) open-label safety extension period.
The primary endpoint was to assess non-inferiority of Vyzulta vs timolol 0.5% in terms of IOP reduction at three time points (8AM, 12PM and 4PM) at weeks 2,6 and 12. Non-inferiority was determined if the upper limit of the 95% CI for treatment difference did not exceed 1.5mmHg at all time points. If non-inferiority was established, superiority at each time point was demonstrated if the upper limit of the 95% CI did not exceed 0mmHg.
- In APOLLO, the treatment difference between Vyzulta and timolol 0.5% ranged from -1.03mmHg to -1.37mmHg in favour of Vyzulta. In LUNAR, the treatment difference between arms ranged from -0.44mmHg to -1.34mmHg, similarly in favour of Vyzulta.
- Both RCTs and a subsequent pooled analysis demonstrated the non-inferiority of Vyzulta to timolol 0.5% in terms of IOP lowering efficacy at all 9 time points i.e. over 3 months.
- Vyzulta’s superiority over timolol 0.5% was subsequently demonstrated in APOLLO and the pooled analysis of both studies, at all time points.
- In LUNAR, superiority criteria were met for all time points except the 8AM time point at Week 2.
The positive findings were further confirmed in JUPITER (n=130), a 52-week single-arm, safety study evaluating Vyzulta in Japanese patients with OAG or OHT. Treatment with Vyzulta resulted in a sustained 22% mean reduction in IOP at Week 4 through to Week 52. The mean IOP was 14.4mmHg at Week 52, representing a 26% reduction from baseline in the study eye.
VOYAGER, a Phase II dose-ranging study (n=413) compared Vyzulta to latanoprost (Xalatan) and found that Vyzulta was associated on average with an additional 1.2mmHg of IOP lowering compared to latanoprost.
Safety and Tolerability
Study data demonstrates that Vyzulta remains well tolerated for over 12-months in adults with OAG or OHT. The most common adverse events (AE) reported in APOLLO and LUNAR were conjunctival hyperaemia (6%), eye irritation (4%) and eye pain (3%). A similar AE profile was observed in the JUPITER study. A pooled analysis of APOLLO and LUNAR further characterised that the overall incidence of ocular AEs with Vyzulta was comparable with those of other PGAs.
Of note, Vyzulta contains the preservative benzalkonium chloride (0.2mg/mL) and clinicians should consider issues relating to preservative intolerance and contact lens compatibility when initiating treatment. Vyzulta should also be avoided in patients below the age of 16 (due to safety concerns relating to increased pigmentation with long-term use) or in patients with active intraocular inflammation (due to a risk of exacerbation).
Cost-Efficacy Outcomes
Optimising patient outcomes and obtaining payer support for costly new health technologies are often a dichotomous balance. In the absence of local cost-efficacy information, a pharmacoeconomic review by the Canadian Agency for Drugs and Technologies in Health (CADTH) published in August 2019 provides insight from the perspective of the Canadian public healthcare payer. Based on manufacturer-submitted price proposals accurate as of February 2019, the CADTH found that Vyzulta was associated with an additional benefit of 0.015 quality adjusted life years (QALYs) at an additional cost of CA$2,160 when compared to generic latanoprost, resulting in an incremental cost-utility ratio (ICUR) of CA$142,801 per QALY gained. Generic latanoprost remains the dominant option in consideration of Canada’s published willingness-to-pay (WTP) threshold of approximately CA$50,000/QALY.
Vyzulta in Practice
The current body of evidence has veritably established the utility and safety of Vyzulta 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 treatment effects.
Further studies are needed to assess Vyzulta in clinical settings such as normotensive (NTG) and closed angle glaucoma (CAG). Examining if Vyzulta confers similar benefits in CAG may be of particular interest given the trabecular meshwork occlusion inherent to the disease pathology. Robust RCTs are also needed to compare its efficacy against other PGAs, and over a longer period of time to assess its tolerability and sustained efficacy.
