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Challenges for outflow drugs in glaucoma


Editor’s Note:During the New Horizons Forum, Barbara Wirostko, MD, co-moderated the session entitled, “New Horizons in Glaucoma Pharmaceuticals – Outflow Drugs.” Before the companies delivered their presentations about their developments, Dr. Wirostko provided an overview of this pharmaceutical segment. This article is a summary of her presentation.

We, as ophthalmologists, would welcome a new IOP-lowering agent, especially if it worked through a novel mechanism on the trabecular meshwork and was additive to the current hypotensive agents.

Unfortunately, having some good efficacy such that it can lower IOP equal to or “non-inferiorly” to the standard of care is not good enough to get these drugs on the market and to the patient. The reality is that the cost comparison and the ability to get these drugs reimbursed is a key driver for new and novel outflow agents being developed.

These new compounds must compete with the once-a-day, highly efficacious, well-tolerated prostaglandins (PGAs) that are now off and/or coming off patent.

In order to get reimbursed at an attractive price point, compared to a generic PGA, a new IOP-lowering agent must beat these PGAs on some front. They must offer an advantage above and beyond the PGAs in order to be reimbursed above the generic PGA price.

Challenge with hurdles

So can these IOP-lowering agents currently in development accomplish this? It is a challenge with several hurdles.

Although a trabecular meshwork (TM) outflow agent, preferably a vasodilating agent, or extracellular matrix (ECM) modulating agent, would be highly attractive, one hurdle is we don’t have good preclinical models to simulate the TM disease state. Normotensive animals are great models for safety and translate well for efficacy to humans for aqueous suppressants and even PGAs, but we are challenged to feel comfort in predicting efficacy off of these models for TM modulators.

Even hypertensive models developed through such therapies as TM laser, episcleral sclerosis, and TM occlusion with microbeads don’t correctly and effectively mimic the underlying pathophysiology inherent in the glaucoma disease. Demographics, race, environmental factors, aging, and stiffening within the outflow system all appear to play a role in primary open-angle glaucoma. Our models don’t reproduce the multifactorial and multifaceted process that underlies elevated IOP associated in our glaucoma populations.

The compounds in recent development for IOP-lowering through TM modulation and in particular vasodilation and ECM remodeling have made it into phase II, but have yet to process to phase III at least in the United States.

As a class, the Rho kinase inhibitors (ROCK i), a TM-outflow modulator, have had the largest number of shots on goal with Aerie currently in the lead in development. Aerie finished several phase II studies with AR-12286, the ROCK i, and AR-13324, the combined ROCK i and norepinephrine transport inhibitor.

Amaken is also developing a topical selective ROCK i (AMA0076), which is currently in the clinic in their first in-human study. Altheos ATS907 entered the clinic as a topical drop in 2012 for their first in-human study.

Kowa is developing their topical ROCK i (K-115) as a twice-a-day drug in Japan and has moved into a Japan centric phase III study. Inspire/Merck (INS115644 and INS117548), Santen (DE-104), and Senju/ Novartis (SNJ-1656) have all discontinued their ROCK i programs. The various reasons again have not been formally disclosed, but one can speculate it is either safety, most likely the local hyperemia and/or limited efficacy and frequent dosing.

Other modulators

Other novel outflow modulators include Inotek’s INO-8875, a highly selective Adenosine-1 receptor agonist, which also is being evaluated for the treatment of elevated IOP associated with open-angle glaucoma and ocular hypertension. Inotek’s lead candidate, Trabodenoson, recently completed a multiple-dose phase II trial in late 2012.

Perhaps, it is the fact that the efficacy seen in animal models hasn’t translated 100% to humans. Perhaps, it is the commercial and market drivers that have proven to be too high a hurdle, demanding a once-a-day drug with near 30% IOP-lowering capability and minimal side effects. Perhaps, it is the challenge of reducing the conjunctival hyperemia, a physiologic side effect that occurs with the vasodilating agents.

In particular with ROCK i’s, this is their inherent mechanism of action; smooth muscle relaxation and vasodilation. Thus, it is hard to separate the efficacy and safety, thus creating a very limited therapeutic index. With these challenges, it will be interesting to see what compounds working on the TM to lower IOP progress into phase III and into the market.

Author Info:

Barbara Wirostko, MD, is clinical adjunct associate professor at the University of Utah and Moran Eye Center, Salt Lake City, UT. Dr. Wirostko served as the chief medical officer for Altheos from 2010 to 2012.

e. barbara.wirostko@gmail.com>


‘These new compounds must compete with the once-a-day, highly efficacious, well-tolerated prostaglandins (PGAs) that are now off and/or coming off patent.’

Barbara Wirostko, MD


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