Reviewed by Neeru Gupta, MD, PhD, MBA, and Kuldev Singh, MD, MPH
While no new drug shook up the world of glaucoma in 2015, a variety of promising agents made incremental advances toward the market with their true potential as yet unproven. Manufacturers have continued to refine approaches to existing drugs.
“We have limited drug choices and frequent side effects,” said Neeru Gupta, MD, PhD, MBA, professor and chief of Glaucoma, University of Toronto, with the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto. “Our surgical interventions are not without potentially serious complications. We’re looking for new drugs with a new target and minimal side effects.”
Existing drugs can successfully lower IOP, but often cause irritating side effects. The inconvenience of applying multiple drops per day also makes adherence a challenge for many patients.
While a new non-prostaglandin drug is unlikely to replace prostaglandin analogues as the preferred first-line agent of choice in the near future, several drugs have the potential to be useful adjuncts to such therapy, according to Kuldev Singh, MD, MPH, professor of ophthalmology and director, Glaucoma Service, Stanford University School of Medicine, Stanford, CA.
One drug, however, is fairly far along in the process for regulatory approval (Rhopressa, Aerie Pharmaceuticals). According to the manufacturer, the drug inhibits both Rho-kinase (ROCK) and noreprinephrine transporters.
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Rho-kinase plays a role in the transport of fluid out of the eye through the trabecular meshwork. Inhibiting this enzyme relaxes the trabecular meshwork in cells allowing fluid to exit. Noreprinephrine transporters are involved in producing aqueous fluid. The combination should result in less liquid production and a quicker exit for what is produced.
Preclinical results have demonstrated that Rhopressa also lowers episcleral venous pressure, which contributes approximately half of IOP in healthy subjects, and may have an anti-fibrotic effect on the trabecular meshwork and the potential to increase perfusion of the trabecular meshwork, according to the company.
In another potential advantage, the manufacturer noted it will offer the product in once-per-day doses rather than the two or three-per-day drop dosing required for many drugs on the market.
The drug received mixed phase III results in 2015. In the Rocket-1 trial reported in April, the agent could not match the beta-blocker, timolol maleate, in lowering IOP in patients with baseline IOP below 27 mm Hg. In September, the company noted the product proved non-inferiority compared with timolol in Rocket-2, in subjects with baseline IOPs greater than 20 and below 25 mm Hg. The manufacturer said it is planning to file a new drug application (NDA) with the FDA by September 2016.
Next: Another phase III trial
In the meantime, Aerie Pharmaceuticals announced that as of September it has initiated a phase III trial of Roclatan, a combination of Rhopressa with latanoprost.
Rhopressa is not the only Rho-kinase inhibitor in the pipeline. Ripasudi—already approved in Japan—also showed good results versus timolol, according to studies published in April.
Honing in on a different mechanism, Inotek Pharmaceuticals is testing trabodenoson, an adenosine mimetic designed not only to reduce IOP, but also to provide some additional protection for retinal ganglion cells. The company said it was beginning phase III trials in the fourth quarter of 2015.
“The real opportunities with most of the novel non-prostaglandin drugs currently being assessed are with regard to adjunctive therapy, or as first-line agents for those in whom prostaglandin therapy is ineffective or not tolerated,” Dr. Singh said. “We don’t really have an ideal second agent on the market that can add an average of 3 to 4 mm Hg of IOP lowering to a prostaglandin analogue, either as an adjunctive drug, or a combination with a prostaglandin.”
Dr. Singh speculated that no agent in the near future will replace prostaglandins as the ideal first-line agent unless it has prostaglandin in it.
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In an effort to build a better prostaglandin, Bausch + Lomb and Nicox have combined latanoprost acid, a prostaglandin analogue with nitric oxide, to create latanoprostene bunod (Vesneo), a single-agent eye drop dosed once daily. Latanoprost acid acts on the uveoscleral pathway while nitric oxide acts on the trabecular meshwork and Schlemm’s canal—together increasing acqueous humor outflow, the company hypothesizes.
Following successful trials, the company announced in September that the FDA plans to review its NDA under a Prescription Drug User Fee Act deadline of July 21, 2016.
Dr. Gupta and her colleagues are hoping their research into the lymphatic system will provide a useful target for new therapies.
“If you look at many of the textbooks, they say the eye has no lymphatics,” she explained. “What’s exciting is that over the past few years we’ve discovered not only their existence in the ciliary body of the eye, but we have also discovered that they help move fluids out of the eye and they can be medically stimulated.”
Next: 'Old wine in better bottles'
‘Old wine in better bottles’
If they cannot match the efficacy and safety of drugs on the market now, some companies are hoping they make mediations more convenient and improve adherence.
Such is the approach with Alcon’s fixed-combination brinzolamide 1%/brimonidine 0.2% (Simbrinza), approved by FDA in 2013. At the end of 2014, a head-to-head trial showed that taking the two drugs together in one drop created a medication that was just as effective but more convenient than taking the two separately.
Convenience is also the idea motivating Ocular Therapeutix, which is developing OTX-TP, an intracanalicular depot composed of polyethylene glycol hydrogel and travopost. Once inserted into the tear drainage system, the hydrogel expands to conform to the surrounding tissue. Travopost is then released into the tear film in a controlled fashion.
Studies of OTX-TP have shown up to 3 months of statistically significant IOP-lowering efficacy. But in results of a phase II trial released in October, the drug could not match timolol in lowering IOP, so the company is planning modifications before launching its phase III trials.
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Another external drug delivery platform is the Helios implant from ForSight Vision5, which rests on the surface of the eye under the eyelids. Dr. Singh said he is impressed by this approach for drug delivery.
“Given that most patients with glaucoma are asymptomatic which undoubtedly contributes to the problem of noncompliance, I expect drug delivery approaches that do not require penetration of ocular tissues to be more broadly adopted, all other things being equal than those that are more invasive,” he said.
Allergan’s bimatoprost SR intracameral implant works by releasing bimatoprost slowly while the device degrades. In a phase I/II trial released in November, it matched the IOP-lowering effects of bimatoprost applied conventionally over the course of 16 weeks.
Next: Generic drugs stirring controversy
While innovations have grabbed most of the headlines, generic versions of older drugs are also stirring some controversy. Generics theoretically offer large cost savings, but Dr. Singh noted he is sometimes surprised by the high prices of generic prostaglandins and has also noticed there is large variability in the magnitude of savings passed on by pharmacies to patients.
Dr. Singh also pointed out that even if the drug is the same, the bottle design for some of the generics may vary with unpredictable release of medications. “Running out of drugs in less than 30 days due to streaming from poorly designed bottles can meaningfully contribute to noncompliance,” he said.
As new drugs make their way onto the stage, the complexity of prescribing drugs for glaucoma looks likely to expand along with the options.
“While we are hungry for new molecular entities and some advances are clearly coming, novel drug delivery platforms may be at least equally important in terms of advancing glaucoma care,” Dr. Singh said.
Neeru Gupta, MD, PhD, MBA
e: [email protected]
Dr. Gupta disclosed a relationship with Bausch + Lomb.
Kuldev Singh, MD, MPH
e: [email protected]
Dr. Singh disclosed relationships with Aerie, Alcon, Allergan, Santen and ForSight V5.