Upcoming catalyst for Aerie Pharmaceuticals (odds: 70%)

Aerie Pharmaceuticals (NASDAQ: AERI) is developing a new class of once-daily eye drop for the treatment of glaucoma. Results of two Phase III trials, known as Rocket 1 and Rocket 2, are expected in 2015Q2 and mid-2015. If approved, the drug will represent the first new mechanisms of action for lowering intraocular pressure (IOP) in over 20 years.

Glaucoma is one of the largest segments in the global ophthalmic market. According to IMS, glaucoma market exceeded $4.5 billion in the U.S., Europe and Japan in aggregate. Xalatan (latanoprost), the best-selling glaucoma drug, together with Xalacom (latanoprost/timolol), generated peak annual sales of $1.75 billion in 2010.

There are four classes of glaucoma drugs:

Classes Drugs Market share
prostaglandin analogues latanoprost, travoprost, bimatoprost 51%
beta blockers timolol, carteolol, levobunolol, betaxolol 15%
alpha agonists brimonidine, apraclonidine, epinephrine 10%
carbonic anhydrase inhibitors acetazolamide, dorzolamide, brinzolamide 8%

Aerie’s Rhopressa (AR-13324) inhibits Rho Kinase (ROCK) and norepinephrine transporter (NET), which are both novel targets for glaucoma.

In 1997, scientists at Yoshitomi Pharmaceutical found a ROCK inhibitor called Y-27632 inhibits smooth-muscle contraction[1]. Thus, ROCK inhibitors can lower IOP by blocking trabecular meshwork cell contraction.

NET is responsible for the reuptake of extracellular norepinephrine, a neurotransmitter released by neurons. Inhibiting NET prolongs the activation of target cells, which reduces the production of eye fluid.

In the Phase IIb trial, Rhopressa 0.01%, Rhopressa 0.02%, and latanoprost demonstrated mean IOP reductions of 5.5, 5.7, and 6.8 mmHg[2]. The IOP-lowering effect of Rhopressa was 1.1-1.3 mmHg less than that of latanoprost and did not show non-inferiority.

In the Phase III trials, Aerie took timolol instead of latanoprost as the active comparator. According to historical data[3], the IOP-lowering effect of timolol was similarly 1.2 mmHg less than that of latanoprost. I believe Rhopressa has a great chance to show non-inferiority to timolol.

The main adverse event was transient hyperemia, or eye redness, which was observed in 18%, 24% and 11% of patients in Rhopressa 0.01%, Rhopressa 0.02%, and latanoprost, respectively. It is no doubt a spot for Rhopressa, but we needn’t worry too much. Both bimatoprost and travoprost reported high rate of eye redness.

In 2014, Japan approved Kowa’s twice-daily ROCK inhibitor, Glanatec (ripasudil 0.4 %), for the treatment of glaucoma when other drugs are not effective or cannot be administered. The drug seems not better than Rhopressa because eye redness was observed in 96% of patients.

Although Rhopressa appears a little inferior to latanoprost, the drug offers a new once-daily option with novel mechanism of action. Moreover, Rhopressa plus latanoprost has shown to be superior to latanoprost in a Phase IIb trial.

[1] Nature. 1997, 389(6654), 990-994.
[2] Ophthalmology. 2015, 122(2), 302-307.
[3] Eur J Ophthalmol. 2000, 10(2), 95-104.

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