Aerie in Europe
Addressing unmet needs in glaucoma is just the beginning for ophthalmic pharma innovator.
Aerie’s recently completed state-of-the-art sterile fill facility in Athlone, Ireland
With US Food and Drug Administration approval of its first product in December 2017, newcomer Aerie Pharmaceuticals made history. The company’s proprietary Rho kinase (ROCK) inhibitor eye drop, Rhopressa (netarsudil ophthalmic solution) 0.02%, represented the first new drug class approved in the US for reducing intraocular pressure (IOP) in open-angle glaucoma and ocular hypertension since the prostaglandin class was introduced with latanoprost in 1996. This milestone also meant the company had achieved the objective it was founded to pursue – discovering a drug that targeted the underlying pathological process in glaucoma.
After clearance and successful introduction in the USA, Aerie’s ROCK inhibitor is now under review by the European Medicines Agency. Aerie Chairman and CEO Vicente Anido, Jr, PhD, anticipates a decision by the end of this year. The company is currently planning for potential product introductions, a process spearheaded by Aerie’s new chief commercial officer for Europe. Aerie’s lead molecule is also being studied in Japan, where enrolment in a phase II study was recently completed months ahead of schedule.
Next up for regulatory submission in the EU, once the original molecule is approved, will be the investigational fixed dose combination of the ROCK inhibitor and latanoprost. This once-a-day eye drop treatment was approved by the FDA this year and launched in the US in May as Rocklatan (netarsudil and latanaprost ophthalmic solution) 0.02%/0.005%. In two completed pivotal phase III studies in the USA, the fixed-dose combination proved statistically significantly more effective in reducing IOP than both of its components alone, at all measured time points. In Europe, it is being compared to a leading fixed-dose combination drop in a phase III clinical trial under way in 11 countries.
Both of these drugs were developed to overcome some of the trade-offs associated with conventional glaucoma therapeutics, Dr Anido notes.
“The impact of factors including dosing complexity and tolerability on adherence to medical therapy and clinical outcomes is well established. In designing our glaucoma products to improve conventional outflow facility, we also knew they had to provide once-daily dosing, minimal systemic adverse events and manageable topical adverse events.”
With a growing pipeline and active drug discovery effort, Aerie plans to be a major player in ophthalmic pharma. The firm’s initial focus on glaucoma was driven by the research and vision of its founder, the late David Epstein MD, chairman of ophthalmology at Duke University, into the underlying pathology of open-angle glaucoma, which is the stiffening of the trabecular meshwork. His insight that cytoskeletal changes in conventional outflow pathways could be chemically altered to reduce outflow resistance ultimately led to the company’s search for molecules that block Rho kinase, which was known to regulate stress fiber formation and tissue contraction.
Since these initial discoveries, refinement of small-molecule kinase inhibitors by Aerie scientists has produced a growing library that now encompasses more than 4,000 proprietary molecules, including the firm’s first product candidates. Recognising that many applications of these small molecules in the eye would require sustained delivery, the Aerie team acquired access to a bio-erodible polymer from Netherlands-based DSM for developing implants that steadily release drug for up to six months. It also obtained ophthalmic rights to a scalable platform for producing these sustained-release implants from Envisia in the USA. Aerie is using these enabling technologies to develop treatments for a broad range of ophthalmic conditions, says Chief Scientific Officer Casey C Kopczynski PhD.
Furthest along is an investigational steroid intravitreal implant for treating macular oedema due to retinal vein occlusion, now in a phase II clinical trial. Since small molecules penetrate the retina and are cleared much more quickly than large proteins used in anti-VEGF therapy, sustained release is thought to be critical to reduce injection frequency and avoid dosage spikes that might be toxic, particularly with steroids, Dr Kopczynski says. “With a controlled release, we have the opportunity to enhance both efficacy and safety. Our clinical studies have just started and we are hopeful we can demonstrate efficacy and a favorable adverse event profile over the six-month treatment duration.”
An intravitreal implant that releases an active metabolite of Aerie’s first molecule, inhibiting both Rho kinase and protein kinase C (a promoter of smooth muscle contraction and vasoconstriction), is also entering the clinic as an investigational treatment for neovascular age-related macular degeneration (AMD) and diabetic macular oedema (DME). New therapies are needed in these significant indications because about 40% of DME patients do not respond to anti-VEGF, and many AMD patients become resistant to treatment over time.
“No two patients respond the same way. Glaucoma physicians have multiple drug classes they can use, alone or in combination, to find the best treatment regimen for each patient. We want to give retinal physicians a similar range of treatment choice to better individualise therapy,” Dr Kopczynski says.
Rho kinase inhibitors are good candidates to investigate for retinal diseases because they have anti-inflammatory, anti-neovascular and anti-fibrotic properties. Along with other selective kinase inhibitors they may be useful for treating other ocular conditions involving long-term inflammation, possibly including geographic atrophy and dry eye. A long-acting IOP-lowering implant placed in the anterior chamber and delivering Rho kinase inhibitors for months is also in pre-clinical development. Rho kinase inhibitors may also have neuroprotective properties that are being explored.
DIRECT TO OPHTHALMOLOGISTS
As Aerie enters major segments of the ophthalmic market, beginning with glaucoma, the company is determined to control its own destiny, says Dr Anido. He previously served as Allergan’s president for the Americas and led another public ophthalmic pharmaceutical firm before joining Aerie in 2013. This independent strategy gives Aerie the ability to be more agile in addressing physician and patient need, he believes.
For example, rather than find a distribution partner, Aerie built its own sales organisation in the USA and will do the same in Europe. “We realised that we can serve the majority of glaucoma prescribers in the US with about 100 sales representatives. The retina community is even more compact. If our own people identify, develop, and commercialise our products, Aerie retains global rights to its discoveries while the entire organisation is 100% focused on delivering these innovations to clinicians and patients. There is no dilution of effort or limitation on activity as there might be if we licensed these assets,” Dr Anido says.
GO IT ALONE APPROACH
While waiting for its first EU approval, Aerie is assessing markets for launch and making the rounds of clinical meetings to develop relationships with the treatment community and better understand how to support clinicians’ efforts to improve patient quality of life, Dr Anido says. Consistent with its “go it alone” approach, the firm has completed its own state-of-the-art sterile fill production facility in Athlone, Ireland, to support global product supply. The plant will come on line in early 2020 and already boasts the company’s largest concentration of employees in the EU to date. The Athlone facility complements an implant production lab in the USA.
“We are committed to bringing new drugs with new mechanisms of action to the market for different eye diseases, and therefore are continuing to invest in and expand our development pipeline. We very much value our relationships with physicians and our increasing engagement with the European eye care community will help guide our innovations and shape our offerings for the future,” he concludes.