New drugs target multiple mechanisms in glaucoma

Ophthalmologists can expect more choices in drug therapies for glaucoma. That is good news for Barbara Wirostko, MD, clinical adjunct associate professor at the University of Utah Moran Eye Center, Salt Lake City, UT, who co-moderated a session on new outflow drugs.

“My years in industry taught me that our models do not always translate well to real-life patients and safety is always a consideration,” Dr. Wirostko said. “But I would welcome new mechanisms of action for my patients.”

Dr. Wirostko may get her wish (See “Challenges for outflow drugs in glaucoma” on Page 00). A half-dozen companies reviewed current research efforts. And while none have started pivotal phase III trials, all are working with new mechanisms of action. Some companies are developing outflow drugs and some are working on neuroprotective agents. Half are focused on outflow drugs.

“Outflow is where the pathology is,” said co-moderator Gary Novack, PhD, president, Pharmalogic Development, San Rafael, CA. “We don’t have a new outflow drug from this century or even from the last.”

There is no guarantee of success, but these six have a better chance than most, said Stuart Abelson, MD, MBA, president and CEO of Ora Inc. and co-moderator of the drug session.

“These are the rare few who have demonstrated compelling data and have been able to attract capital in an extremely challenging funding environment for early stage life science companies,” Dr. Abelson said.

Acorn Biomedical

Lack of adherence is a recognized problem for all glaucoma eye drops. Acorn is developing a once-daily, oral adenosine A3 receptor agonist to reduce compliance problems as well as low ocular bioavailability of topical agents.

“Decreased adenosine increases the trabecular meshwork outflow and decreases aqueous humor production, thereby decreasing IOP,” said Alan Jacobs, MD, PhD, president and CEO. “We have seen very durable activity and an additive effect with prostaglandin. And A3 receptor agonists in other clinical trials have shown a lowering of IOP. We have good clinical validation of the IOP target.”

Acorn’s lead compound, ACN-1052, also has anti-inflammatory properties.

Aerie Pharmaceuticals

“There is tremendous need for new treatment options in glaucoma, new mechanisms of action and once-a-day dosing,” said Thomas van Haarlem, MD, president and CEO. “We have three new agents in our pipeline, all of them first in class.”

One agent, 13324, has dual targets and is expected to compete directly with prostaglandins as first-line therapy, he said. A selective rho kinase inhibitor, 12286, is being tested alone and as a fixed-dose combination with travoprost for second-line therapy.

All three agents are moving on a similar timeline, and are expected to reach the market at about the same time.

Amakem

Many promising rho-associated protein kinase inhibitors, or ROCK inhibitors, have failed ophthalmic trials over adverse event concerns, particularly hyperemia. Amakem is turning the problem into a solution. Its ROCK inhibitor, AMA0076, is designed to degrade into an inactive form soon after application.

“As a topical drop, 76 migrates to the trabecular meshwork, where it relaxes smooth muscle to open the outflow,” said CEO Jack Elands, PhD. “Drug that remains on the surface is inactivated to avoid hyperemia. We hope to dose high enough to reduce IOP and avoid hyperemia.”

Phase 2 ascending dose trial results will be available later this year, he said.

Inotel Pharmaceuticals

Trabodenoson is a highly selective, adenosine mimetic that increases outflow via the trabecular meshwork. The mechanism of action complements existing agents, including timolol, dorzolomide, and latanoprost, and dramatically improves IOP reduction.

“IOP reduction is already better than all of the marketed second-line agents,” said Paul Howes, president and CEO. “Our safety and bioavailability profile is better than all marketed agents. Clinical efficacy in IOP reduction is evident 24 hours after dosing, which strongly supports once-a-day dosing.”

The drug remodels the trabecular meshwork toward normal IOP, he continued. There are no changes in hyperemia from placebo run-in, no systemic effects, and no dropouts for drug-related adverse events in phase I or phase II trials to date.

ONO Pharma USA

There is also room for improvement in current prostaglandin therapy. Ono is developing an EP3 agonist, ONO-9054, to be used in combination with prostaglandin. EP3 receptor agents have more modest IOP-lowering effects than EP2 or EP4 agents, but EP3 agents produce less ocular irritation, said Douglas Ross, PhD, senior director for preclinical development. And when combined with latanoprost, ONO-9054 showed greater IOP lowering than latanoprost plus timolol.

Phase I trials of ONO-9054 are complete, he said, and phase II is underway. ONO’s typical strategy is to develop a compound through phase II, then partner with a larger pharma for commercialization.

Quark Pharmaceuticals

Interfering with RNA has been an attractive target since RNA interference was discovered in 1998. Quark is developing a short synthetic interfering RNA (siRNA) to target glaucoma, QPI-1007, by targeting the pro-apoptotic gene caspase 2.

“We can introduce an anti-apoptotic effect in retinal ganglial cells, thereby preserving their vitality,” said Shai Erlich, PhD, chief medical officer.

The company is also working on a second siRNA against an unnamed gene. Both compounds show strong neuroprotective effects but act through different mechanism. Combination treatment may provide some degree of vision restoration in glaucoma.

Callout

‘Outflow is where the pathology is. We don’t have a new outflow drug from this century or even from the last.’

Gary Novack, PhD

Pharmalogic Development