Innovation in glaucoma thriving

By Fred Gebhart

Big Pharma is on the hunt for new glaucoma drugs. Evidence to date says they are closing on new approvals.

“The pace of therapeutic development is picking up in a big way,” said Stuart Abelson, MBA, president and CEO of Ora, an ophthalmic contract research organization. “Capital is flowing and programs are moving forward in all phases. Ora’s business is growing for a second year in a row at over 100%, adding resources and helping companies move their programs along.”

Abelson co-moderated an overview of “New Horizons in Glaucoma Pharmaceuticals” session with Joel Schuman, MD, FACS, chairman of the Ophthalmology Department, University of Pittsburgh. The session highlighted four companies with strong new drug candidates.

AßSee Pharma

This German company is pursuing what could become the first neuroprotective agent against glaucoma and dry age-related macular degeneration (AMD). The company name, AßSee, is derived from amyloid beta, a peptide thought to play a role in the development of Alzheimer’s disease as well as ocular disease.

An age-related accumulation of Aß in the retinal tissues appears to be linked with glaucoma through toxicity to retinal ganglion cells and with AMD through toxicity to retinal epithelial cells, explained AßSee CEO Alexander Gebauer, MD, PhD. The company’s lead compound, MRZ-99030, impedes formation of these toxic Aß oligomers and promotes the formation of nontoxic forms that are cleared from ocular tissues. The agent is administered as eye drops.

“This is the only topical Aß agent under development,” Dr. Gebauer said. “In a rodent model, we saw the death of retinal ganglion cells almost completely stopped by MRZ-99030 eye drops. We saw a 95% protection effect with no increase in IOP. We have phase I results and chronic toxicology with very promising data and excellent safety.”

The company plans parallel clinical trials for glaucoma and dry AMD, with phase IIb trials scheduled to begin this year.

“We were encouraged from speaking with the FDA about our regulatory strategy and clinical program,” Dr. Gebauer said. “Hopefully, we can bring this compound to market within the next couple of years.”

Aerie Pharmaceuticals

Aerie is pursuing multiple mechanisms of action to tap the $4.5 billion global glaucoma market. The company is moving forward with two compounds, a dual-action Rho kinase (ROCK)  + norepinephrine transport (NET) inhibitor and a triple action ROCK+NET inhibitor + latanoprost.

“These are both once-a-day topical products, which makes them easy for patients to use,” said Thomas Mitro, president and COO. “Both have demonstrated great safety and efficacy in clinicals. Our products can help meet the unmet medical needs in this huge marketplace.”

Lead compound AR-13324 lowers IOP by inhibiting ROCK to enhance outflow through the trabecular meshwork and inhibiting aqueous production by inhibiting NET. Clinical trial data suggest that the compound may also lower episcleral venous pressure to enhance the overall IOP-lowering effect. The agent is effective in lowering IOP regardless of baseline pressure. Phase III trials are set for later this year.

The second agent, P-1G324, is a fixed combination dose of AR-13324 and latanoprost. The combination of ROCK/NET inhibition plus uveoscleral outflow maximizes the potential for IOP lowering, Mitro said. A phase IIb is currently under way and data should be reported later this year.

Amakem Therapeutics

Belgium-based Amakem is working on its own ROCK inhibitor, AMA0076.

“The elephant in the glaucoma room is hyperemia,” said CEO Jack Elands, PhD. “Hyperemia is a significant problem with the prostaglandins and is even worse with most of the ROCK inhibitors. Patients don’t want hyperemia and if you add a ROCK inhibitor to a prostaglandin, you are adding two hyperemic drugs. That is not good.”

Amakem’s solution is a ROCK with localized action. Drug that penetrates the cornea moves quickly to the trabecular meshwork, where it increases outflow and reduces IOP. Drug that remains on the cornea is quickly metabolized and eliminated. The localized action all but eliminates hyperemia in animal models and in clinical trials to date.

“Hyperemia, the lack of hyperemia, is what distinguishes AMA0076 from other ROCK inhibitors,” Dr. Elands said. “In our early clinical trials, you have to look closely to see hyperemia. For people in normal conversation in everyday life, you don’t see hyperemia at all.”

The agent is also effective at lowering IOP. A 28-day trial showed a mean IOP lowering of 20%. IOP measurements taken in the morning showed a clear IOP-lowering effect from eye drops administered the previous evening.

“We have moved from animal models to clinical proof of concept with IOP lowering and no hyperemia,” Dr. Elands said. “We are now in phase II dose finding to optimize our formulation.”

Ono Pharma USA

Ono has a long history of work with prostaglandin ligands, a history that is fueling development of a novel FP/EP-3 dual receptor agonist to treat glaucoma. Data from a 25-day clinical trial in ocular hypertension and open angle glaucoma suggest that the company is on track to produce its first-ever glaucoma drug.

“Our preclinical studies showed significant and profound IOP lowering that was greater than latanoprost alone or in combinations with other agents,” said Andrew Wood, PhD, global clinical director. “The phase I safety and tolerability studies that compared three doses against placebo gave very similar data.”

The trial used three doses, 3, 10, 20, and 30 μg/mL as a single dose followed by 14 days of daily dosing. After 14 days of dosing, the 10 μg/mL and 30 μg/mL doses showed a 35% IOP lowering. Latanoprost, based on historical data, provides a 26.8% to 34.4% reduction in IOP over a similar period. IOP lowering was sustained up to 33 hours after the last dose.

“The duration of IOP lowering strongly suggests that this might be a once-a-day dosing drug,” Dr. Wood said. “These results suggest the need for additional phase II trials to compare safety and efficacy to other IOP lowering agents, particularly the prostaglandins.”