Latanoprost was a game-changing glaucoma therapy and still remains a go-to treatment for many ophthalmologists more than two decades later. PROFESSOR JOHN GRIGG – an investigator on an important clinical trial for the drug in 1996 – traces its history and explains how it fits into the treatment algorithm today.
Glaucoma eye drop therapies have faced many triumphs and setbacks over the decades, but for pharmaceutical companies the quest for a ‘Holy Grail’ treatment has always boiled down to three factors: universal effectiveness, reduced side effects and compliance.
Intraocular pressure (IOP)-lowering medications can be traced back to the 1870s with a cholinergic agonist derived from the West African calabar bean initially used for miosis in iridectomy cases, then later found to lower IOP and address angle-closure attacks. During the course of the 20th century, however, beta blockers, adrenergics, miotics and systemic carbonic anhydrase inhibitors emerged as the four main families of anti- glaucoma drugs.
But as Professor John Grigg – an academic ophthalmologist and specialist within the Sydney Eye Hospital’s glaucoma unit – explains, up until the 1990s ophthalmologists were eager for a breakthrough first line therapy that was as effective as existing products, but required less effort for patients and fewer side effects.
“At that time, timolol was the gold standard and was a twice daily medication, but that was prohibited in people with asthma and respiratory illnesses because it can induce cardiac failure,” Grigg, who is also head of clinical ophthalmology and eye health at the University of Sydney’s Save Sight Institute, explains.
“We also had Betoptic (betaxolol) which is a selective beta-blocker but it wasn’t as effective as timolol. Other than that, there was pilocarpine which needed to be given four times a day, so compliance was difficult, and then there was epinephrine, an adrenalin compound but it caused allergic eye disease – there were a lot of eye drops, but they all had drawbacks.”
That was until a new compound – latanoprost (Xalatan now distributed by Aspen in Australia) – shot to prominence after its performance in clinical trials in the mid-1990s. After two decades of development, the once-a-day eye drop represented a major leap forward in terms of effectiveness, safety and tolerability.
Latanoprost was the first in a new class of prostaglandin analogs. Grigg says it still remains one of the most-prescribed glaucoma drops among Australian ophthalmologists under the brand name Xalatan, despite the availability of several generics. Other well-known therapies to later join this group were Travatan (travoprost) and Lumigan (bimatoprost), which now provide more alternative treatment options for ophthalmologists.
As one of his first jobs as a young academic in 1996, Grigg was an investigator in a Phase 3 trial under prominent Australian ophthalmologist Clinical Professor Ivan Goldberg comparing latanoprost with timolol. They followed approximately 30 patients at the Sydney Eye Hospital for several years, forming part of a global trial that paved the way for regulatory approval in Australia in 1997.
“Suddenly we had a drug that had less side effects and only needed to be used once a day – it was a breath of fresh air. Patients with latanoprost often had a 25% IOP reduction at first and then this would flatten out to be a 20% reduction over two years, whereas timolol would have about a 10% reduction, it was quite a dramatic difference,” he says.
“Latanoprost’s main side effects were it causes your eye lashes to grow longer and darker, and if you have hazel-coloured eyes it can turn them brown because it increases melanin production. You do get some irritation, there can be some red eye, but it still causes the least amount of side effects compared with other drops.” Grigg says a defining feature of latanoprost at the time was its mechanism of action.
“In glaucoma medications you have drops that inhibit inflow and some that increase outflow. Latanoprost works by increasing outflow through the uveoscleral pathway, so it doesn’t go through the trabecular meshwork, it actually increases space in the ciliary body to drain through that into the suprachoroidal space, so it’s exploiting a mechanism that was used to deal with trauma in the eye as we’ve evolved.”
Another interesting finding from the 1996 study was that patients who had been taking other glaucoma therapies had developed resistance (tachyphylaxis), therefore they weren’t getting any therapeutic benefit.
“That taught me that it’s good to stop the drops to see whether the patient has developed tachyphylaxis, and then start to tailor your eye drops to what the patient responds to,” Grigg says.
Sixteen years later in a 2012 update of latanoprost’s use in glaucoma and ocular hypertension in the journal SpringLink, the authors wrote that latanoprost monotherapy reduced IOP levels by 22% to 39% over one to 12 months’ treatment. It was significantly more effective than timolol twice daily in three of four large randomised, double-blind trials. Latanoprost also demonstrated a stable long-term IOP-lowering effect, with no sign of diminishing effect during prolonged treatment.
The treatment landscape
Following the success of the clinical trials, latanoprost was commercialised and first approved in Sweden in 1996 and then in Australia in 1997 by Pharmacia & Upjohn. Following the merger of Pharmacia and Pfizer in 2003, Xalatan was approved in the US that year. The brand name Xalatan continues alongside the well-known latanoprost/timolol combination therapy Xalacom.
Combined, the off-patent Xalatan/Xalacom accounted for US$281 million (AU$363 million) in revenue for Pfizer globally in 2019, however 2020 would be the final calendar year in which the company would hold on to the drugs in Australia.
Last September, it was announced Aspen Pharmacare Australia would acquire the branded glaucoma treatments. It stemmed from a merger between Mylan and Pfizer-owned Upjohn who were only allowed to join forces if they divested Xalatan and Xalacom.
The condition was imposed by the Australian Competition and Consumer Commission (ACCC) which had concerns about how the merger could impact competition and therefore pricing for consumers. For medicines based on latanoprost and latanoprost/timolol, it was particularly concerned that remaining competitors would not be a sufficient constraint on the merged entity.
From a clinical perspective, Grigg says Xalatan remains one of the most widely prescribed by Australian eyecare professionals due to its familiarity, while still presenting one of the lowest side effect profiles.
He says other prostaglandin analog Lumigan – slightly more effective but with more side effects – and Travatan, which has similar effectivity which maybe tolerated by some patients, are also at ophthalmologists’ disposal. And Xalacom – which combines latanoprost/ timolol in a single formulation – is usually used when therapies like Xalatan or Lumigan haven’t reduced IOP enough. With concerns about the impact of topical drugs on the ocular surface, some manufacturers have also diversified to offer preservative-free options.
While glaucoma eye drops have typically been a first line treatment, Grigg says selective laser trabeculoplasty (SLT) – traditionally a second line treatment – has begun to increase into the realm of initial treatment options.
The flashpoint for this was a study out of the Moorfields Eye Hospital in the UK. Published in The Lancet, the researchers found at 36 months, 74% of SLT patients required no drops to maintain their IOP target and were within target IOP at 93% visits compared with 91% in the eye drops group. No glaucoma surgery was required to lower IOP in the SLT group compared to 11 in eye drop group requiring glaucoma surgery in the study timeframe. And from an ophthalmology cost perspective, there was a 97% probability of SLT as first treatment being more cost-effective than eye drops first at a willingness to pay £20,000 (AU$35,700) per quality- adjusted life-year gained.
“There’s been a changing pattern as a result of the Moorfields study where more people are considering SLT as a first line treatment whereas previously it had always been eye drops first then SLT second – and that’s happening in Australia,” Grigg explains.
“Now I think they hold equal place and so that’s where patient factors come into play. People may be hesitant to have surgery in general, and you’re more wary of offering SLT to patients with inflammation. For people with uveitic glaucoma – it’s not an absolute contra-indication – but perhaps SLT’s not the best first line therapy. There’s also angle closure where after laser iridotomy, people still need drops to keep the pressure down; so there are secondary types of glaucoma where SLT isn’t appropriate, and the eye drops still are.”
He continues: “Precision medicine is the key. Until you know that patient you don’t know what their fears or concerns are; whether they’d prefer to put a drop in every night or have laser and not be aware [of their glaucoma]. You can only know as you understand their health needs and issues, and so then you can tailor the treatment to their lifestyle or medical conditions.”
In terms of compliance, Grigg says latanoprost’s once-a-day application overcame major barriers compared with its competitors, and Xalacom’s combined formulation – removing the need for two sets of eye drops – was also a welcome advance.
However, correct drop installation remains as “a never-ending conversation” with many patients who wrongly attempt to blink the drop into their eye or use more than one drop. Dexterity issues for patients with conditions like arthritis also create problems.
Another benefit of the Xalatan/Xalacom therapies, Grigg says, is the Xal-Ease device, which helps patients correctly position the eye drop container over their eye to deliver a single drop of medication.
“It’s a really nice device and you can get it for free from the chemist. It’s made for the Xalatan and Xalacom bottles and really helps with compliance,” he says.