Glaucoma, dry eye drugs center of pharmaceutical opportunities

The pharma drought is coming to a close. After decades of same-old medications for glaucoma and ocular surface disease, a series of new agents with new mechanisms of action (MOA) are moving toward marketing approval.

“The population is aging and the prevalence of glaucoma in America alone will probably more than double over the next 30 years,” said David A. Hollander, MD, MBA, chief medical officer, Ora, an ophthalmic contract research organization in Hanover, MA. “We still have essentially the same five classes of ophthalmic intraocular pressure (IOP)-lowering medications we have had for decades. It is time for some additions to the armamentarium for treating out patients.”

Hollander moderated an overview of “New Horizons in Pharmaceuticals” as part of the New Horizons Forum at the 2017 Glaucoma 360 meeting. The session highlighted four companies with strong drug candidates for glaucoma and ocular surface disease.

Aerie Pharmaceuticals

Aerie has two new glaucoma products with multiple new MOA in phase III trials. If approved, they will be the first new MOA in the glaucoma market for more than 20 years.

“Rhopressa (netarsudil) is a single agent that lowers IOP through three different mechanisms,” said Tom Mitro, president and COO. “Rhopressa is a Rho kinase inhibitor, so it restores outflow through the trabecular meshwork (TM). Secondly, it is a norepinephrine transport inhibitor, so it reduces aqueous production. Finally, it lowers episcleral venous pressure. We expect to have Rhopressa approved and on the market about a year from now.”

The drug also offers two efficacy advantages over current IOP-lowering agents, Mitro pointed out. It is dosed once daily versus twice daily and lowers IOP as effectively at night as it does during the daytime. The drug showed no drug-related adverse events during clinical trials and no serious systemic adverse events.

Roclatan is a once-daily, fixed-dose combination of netarsudil and latanoprost. The combination is more effective at lowering IOP than either of its components, Mitro said. More than 40% of patients achieved an IOP of 15 mm Hg or less and nearly 33% of patients dropped to 14 mm Hg or less with no significant adverse events.

“We were delighted with how well Roclatan performed, but not surprised,” Mitro said. “We will unveil a second phase III trial around midyear and initiate phase III trials in Europe and hope to file an (FDA) NDA in late 2017 or early 2018.”

Bausch + Lomb

Bausch + Lomb

Bausch and Lomb (B + L) is taking a different route to a dual-MOA product. Latanoprostene bunod (Vyzulta) breaks down into latanoprost acid, the active ingredient in latanoprost, and butanediol mononitrate, which releases nitric oxide.

“Latanoprostene bunod (LBN) is the first nitric-oxide donating prostaglandin F2α analogue for ophthalmic use,” said Jason L. Vittitow, PhD, senior director for clinical affairs. “We have latanoprost acid, which targets to uveoscleral outflow, and nitric oxide, which increases outflow through the TM.”

Nitric oxide is an endogenous signaling molecule which regulates cellular relaxation and contractility. In glaucoma, the TM is contracted, which impedes aqueous outflow. Nitric oxide acts to relax and expand the TM, enhancing outflow, Vittitow added.

In phase III studies with patients who had a baseline IOP of about 26 mm Hg, once-daily LBN outperformed twice-daily timolol. IOP lowering was maintained over the course of the 12-month trial. About 90% of patients in the LBN arm had 25% or greater lowering of IOP and about 60% had 35% or greater IOP lowering.

That compares to 44% in the timolol arm, a differential of about 60% in favor of LBN, Vittitow said.

“There were no drug-related adverse events (AE) and the most common, non-ocular AE was headache,” Vittitow reported. “About 45% of patients on LBN had hyperemia that was noted at the slit lamp, compared to a baseline of 32%, and 80% were characterized as mild.”

Inotek Pharmaceuticals

Inotek Pharmaceuticals

Inotek Pharmaceuticals is targeting the TM by mimicking the adenosine-mediated control of IOP seen in the healthy eye. Trabodenoson is a selective adenosine A₁ receptor agonist that increases the expression, secretion, and activation of several matrix metalloproteinases (MMPs). These MMPs remodel the extracellular matrix of the TM and restore its mechanosensitivity to increase aqueous outflow and lower IOP.

The is active, said Cadmus C. Rich, MD, MBA, vice president of medical affairs and clinical development. But trabodenoson failed the primary endpoint the first phase III trial in ocular hypertension and primary open-angle glaucoma, MATrX-1.

“There were several secondary endpoints that were met,” Rich said. “The higher 6% dose in the trial had a statistically significant difference from placebo if you look across the average of all time points.”

Phase III results for trabodenoson were nearly identical with phase II results, he said, but the phase III trial showed significant clinical activity in the placebo group that was not seen in phase II. Early analysis suggest that the placebo group had a number of outliers and was not appropriately matched to the active group.

“Trabodenoson is clearly active and extremely well tolerated,” Rich said. “The data support once-daily dosing and we will be meeting with the FDA to discuss a path forward.”

A combination trial with latanoprost is expected to report topline results in mid-2017.  Earlier data show strong IOP lowering for the combination and trabodenoson has a strong history in reperfusion injury, stroke, and myocardial infarction with a solid history of cytoprotection. Combination products account for about 75% of the glaucoma market, which makes trabodenoson/latanoprost a potentially rewarding combination.

Allergan

Allergan

Ocular surface disorders affect up to 75% of glaucoma patients. More than half of adults in the United States complain of dry eye symptoms and a quarter are getting anything more potent than artificial tears.

“Neurostimulation may be an option for dry eye,” said Aziz Mottiwala, vice president of marketing, U.S. Eye Care. “Neurostimulation is one of the fastest growing segment of healthcare as it addresses adherence and other challenges of traditional treatment and taps into a natural response.”

Allergan is introducing an intranasal tear stimulator, which temporarily increases tear production through neurostimulation. (FDA approved the device in April 2017 since Glaucoma 360).

Dry eye begins with the lacrimal functional unit (LFU). All elements of tear production in the LFU, lacrimal gland, goblet cells, and meibomian gland are linked to the central nervous system by the trigeminal nerve. A large portion of tear production is intended to facilitate the passage of air through the nasal mucosa, which puts the trigeminal nerve within easy reach through the nasal cavity.

Stimulating the trigeminal nerve can trigger production of complete and natural tears, including the lipid layer, aqueous layer, and mucin layer.

“The ability to tap into the natural response and create a natural tear on demand can be a compelling option for patients with dry eye, particularly those with a high burden of topical medications,” Mottiwala said. “Neural stimulation is an approach that comes at 90º degrees from the usual approach, a unique an innovative way of treating a problem that so many clinicians see is so many of their patients.”

Shire

Shire

Dry eye got a new treatment class with the approval of lifitegrast (Xiidra) in 2016, lymphocyte function-associated antigen-1, of LFA1 antagonists. Lifitegrast is still the first and only member of the class.

“There is significant unmet needs in dry eye, glaucoma, age-related macular degeneration, and other ocular diseases associated with aging,” said Robert J. Dempsey, MBA, vice president and U.S. franchise head, ophthalmics. “There are only a small number of companies in this space and none of them bring Shire’s commitment to finding solutions in rare diseases and specialty areas.”

Like any drug, lifitegrast has side effects. The most common adverse events are dysguesia, slight burning or stinging upon installation or blurred vision. Early and clear communication with patients is the key to managing side effects.

“When physicians have these discussions with patients upfront, these significant adverse events seem to be well-tolerated by patients,” Dempsey said. “To set patients up for success, we highly recommend having the discussions in advance and avoiding surprises.”

Look for additional new products in near areas of the eye. Shire, which built its experience in biotech agents, is taking a biotech approach to meeting unmet needs in both the anterior and poster segments.

“We have a high level of commitment from our CEO and board of directors to become a major player in the ophthalmic space,” Dempsey said. “Our core focus is the new chemical entities that will address those unmet needs.”