Innovation and delivery are the keys to untapped ophthalmology space

NEW YORK – Despite the appeal of shorter development timelines – and the potential of a multibillion-dollar market – ophthalmology drug development has lagged behind work in other disease areas in terms of new targets, biomarker development and even the number of players operating in the space.

"There's still an enormous amount of unmet need," said Nouhad Husseini, vice president of business development at Regeneron Pharmaceuticals Inc. Compared to what's happening in cancer, for instance, "it's night and day. There are very few companies working in ophthalmology."

Even Regeneron came to the space "almost by accident," Husseini added. The Tarrytown, N.Y.-based firm ended up developing bestselling wet age-related macular degeneration (AMD) drug Eylea (aflibercept) from its platform technology – another version of the VEGF inhibitor is approved for cancer.

While Eylea and other VEFG inhibitors Lucentis (ranibizumab, Roche) and Avastin (bevacizumab, Roche AG) have marked a huge change in the wet AMD space, other areas of ophthalmology such as uveitis and dry AMD offer no treatment options. And even dry eye disease has limited therapies available. Eleven Biotherapeutics Inc. reported failure last year with EBI-005 in a phase III dry eye trial. Meanwhile, Shire plc, has had better luck, disclosing positive phase III data late last year, which it included in its new drug application resubmission to the FDA for lifitegrast, which previously received a complete response letter. (See BioWorld Today, May 19, 2015, and Oct. 20, 2015.)

One impediment to ophthalmology development is simply a lack of adequate tools, an irony noted by Husseini. "One thing about the eye is you can visualize the eye; there aren't any other organs where you can take a device and see what your drug is doing to it. But we're at very crude techniques."

That makes it especially difficult to measure success in trials for diseases such as glaucoma. "You're not regrowing cells; you're just trying to get them to lose vision a little bit slower," Husseini said, adding that the space needs a "breakthrough" in imaging techniques that can be readily linked to regulatory requirements.

The space also needs to find ways to fully tap into the science. There are 220 unique genetic markers for eye diseases, said Tony Gibney, managing director of Leerink Partners, who moderated the panel on ophthalmology at the BIO CEO & Investor Conference last week. "We're really just scratching the surface of what we have."

NEW TARGETS NEEDED

In glaucoma, particularly, there have been few advances in terms of mechanisms of action. As more than one panelist noted, the glaucoma space hasn't seen a new mechanism of action since the 1990s. It affects roughly 4 million patients in the U.S. – "multiply that by about 10 for [worldwide] numbers," said Guy Eakins, vice president of scientific affairs at Brightfocus Foundation. And about 5 percent to 10 percent of patients receiving treatment are refractory. Surgical treatments for glaucoma, he added, have a failure rate "somewhere in the 30 to 40 percent" rate.

Glaucoma patients typically start treatment with a prostaglandin analogue such as latanoprost. For those that require a second-line therapy – about 50 percent of patients – timolol, a beta-blocker, is often added. With prostaglandin, the primary side effect is hyperemia, or red eyes. Beta-blockers, however, can carry risks of bronchospasm or cardiovascular effects.

There are fixed-dose combinations, including Santen Pharmaceutical Co. Ltd.'s Taptiqom (tafluprost/timolol maleate), which has gained approval in Europe. The FDA, however, has "taken a different approach," ruling that the risk-benefit risk of the combo therapy is unacceptable, said David Southwell, president and CEO of Inotek Pharmaceuticals Corp.

Inotek, of Lexington, Mass., is working on trabodenoson, an adenosine mimetic designed to work by boosting the natural function of the trabecular meshwork, the main passageway for transporting aqueous humor out of the eye.

"Glaucoma is always viewed as a front of the eye [disease], but it's actually back of the eye," he explained. The back of the eye gets degraded due to pressure from the vitreous in the front of the eye. "So, ultimately, we need a product that gets to the back of the eye and treats the receptor."

Trabodenoson, delivered as an eye drop, is in phase III development, where it is going up against placebo, rather than the usual noninferiority-styled study against a timolol control arm. (See BioWorld Today, July 24, 2015.)

Also advancing is Aerie Pharmaceuticals Inc.'s Rho kinase and norepinephrine transporter inhibitor Rhopressa (AR-13324), a triple-action eye drop designed to reduce aqueous production, increase trabecular outflow and decrease episcleral venous pressure. The drug missed its endpoint in a noninferiority trial against timolol in April, but hit its intraocular pressure (IOP)-lowering objectives in a second study. Aerie has said it anticipates filing for approval this year. (See BioWorld Today, April 27, 2015, and Sept. 18, 2015.)

Other firms are working on bolstered versions of prostaglandins. Valeant Pharmaceuticals International Inc.'s Bausch & Lomb subsidiary, along with partner French biotech Nicox SA, submitted a new drug application seeking FDA approval of Vesneo (latanoprostene bunod ophthalmic solution 0.024 percent). Described as a nitric oxide-donating prostaglandin receptor agonist, Vesneo is designed to be metabolized into two actives upon instillation into the eye: the prostaglandin, which acts on the uveoscleral pathway, and nitric oxide, which acts on the trabecular meshwork and Schlemm's canal.

All of those products target IOP. But "neuroprotection is very important down the line," said Brightfocus' Eakins, whose organization has supported a small trial testing the use of ciliary neurotrophic factor (CNTF) in patients with glaucoma. Encapsulated CNTF was administered to 11 patients and data demonstrated increases in visual acuity, he said.

Eakins didn't identify the program, but Neurotech Pharmaceuticals, of Cumberland, R.I., is developing an intraocular device using its Encapsulated Cell Therapy technology to release neurotrophic factor CNTF and conducted a phase I study involving 11 patients whose disease progressed despite maximally tolerated IOP reduction or whose visual field defect was affecting fixation. Preliminary data were presented last year at the American Glaucoma Society meeting.

One interesting observation from the CNTF study, Eakins noted, was the thickening of the retinal fiber layer. "It's the first time we've seen it. Is it a biomarker?" he asked. "Can we tie it back to treatment?" Identifying those biomarkers will be critical for a neuroprotective approach.

Regenerating the retinal ganglion cells that comprise the optic nerve could also be done via stem cell therapy. At least that is what Ocata Therapeutics Inc. (acquired by Astellas Pharma Inc.) hopes to do. The company is in preclinical development with its human ganglion progenitor cells, which so far in animal models, appears to protect against damage while forming new ganglion nerve cells.

IMPROVING COMPLIANCE

Companies in the ophthalmology space also have to put in serious thought about administration, since compliance is one of the biggest barriers to current treatment. That was an issue Jeffrey L. Cleland thought about when he worked previously at Roche AG unit Genentech Inc. on wet AMD drug Lucentis, a drug that requires monthly injections straight into the eye.

"The key challenge is, do you really want to take 10 to 15 injections a year?" he asked. Patients often find it difficult to continue treatment after that first year. On top of that, injections can cause scarring. "You can't reverse the scarring over time, so you really need a delivery platform that gets that burden down to a couple of times per year."

Cleland is interim CEO of Graybug Inc., a spinout of Johns Hopkins University's Wilmer Eye Institute that is working on a microparticle-based drug for wet AMD. The goal is to reduce the treatment burden by using polylactic-co-glycolic acid, cutting the frequency of intravitreal injections down to between every three months to five months, or potentially longer. (See BioWorld Today, March 11, 2015.)

Regeneron's Husseini conceded the need for less frequent dosing, "especially as we move into treating younger patients" who are not thrilled about the prospect of regular injections into their eyes for the remainder of their lives.

He also suggested that adding or replacing VEGF therapy might result in less frequent treatment. While "VEGF is very good," it isn't a cure, Husseini said, adding that a small number of patients don't respond. Regeneron, which bolstered its ophthalmology offerings in 2013, gaining rights from Sanofi SA to antibodies targeting platelet-derived growth factor (PDGF) and angiopoietin2, is working on combining those with VEGF.

New York-based Ophthotech Corp. already is testing a PDGF/VEGF combination. In October, the firm completed enrollment in its second phase III trial testing its Fovista (pegpleranib) plus Genentech's Lucentis. Initial top-line data are expected in the fourth quarter of this year.

Whether that combination can improve on VEGF alone remains to be seen, and Husseini remains cautious. "My own bias on that is that it's a very high bar.

"But there are a lot of shots on goal and we're very much of the view [that] we're willing to wait for robust clinical data and make an assessment [whether] this is really an advance over standard of care," he added.

Also in the pipeline, though earlier-stage, are topical, or eye drop, versions of VEGF drugs. One firm, Panoptica Inc., reported promising early signals of anti-VEGF activity from a phase I/II study testing PAN-90806 at the Ophthalmology Innovation Summit meeting in Las Vegas last year.

But topical eye drops face challenges, too. The main issue with eye drops also is compliance, Inotek's Southwell noted. Glaucoma patients often don't administer eye drops as directed because of the hyperemia side effect.

"So there are two ways to resolve this," Southwell said. The first involves developing a drug without the side effects, "which is what our approach has been. We hope that we'll be the first, or one of the first, to add IOP lowering of prostaglandin without increasing eye redness associated with it."

The second approach is to develop new delivery mechanisms, such as the punctal plugs in development by firms such as Ocular Therapeutix Inc. and Mati Therapeutics Inc. Designed to be inserted non-invasively through the puntum, or tear duct, punctal plugs deliver a steady rate of drug, usually over a period of months.

Ocular reported positive phase IIb data last year from its OTX-TP (travoprost) candidate, a sustained-release prostaglandin. Mati, which picked up its punctal plug system from QLT Inc., is advancing latanoprost-containing PPDS as its lead program.

Working on an ocular insert, Forsight Vision5 Inc. has launched a phase II study in glaucoma. The candidate, the Bimatoprost Ring, is designed to rest under the eyelids and release drug into the eye over a period of months.

There's also Envisa Therapeutics Inc., which is developing ENV515, a biodegradable form of travoprost designed to work for more than six months after a single dose. Based on the firm's Particle Replication In Non-Wetting Templates, or PRINT, technology, ENV515 has demonstrated promising efficacy so far, hitting its endpoint of IOP lowering in a phase IIa trial last year. (See BioWorld Today, Nov. 25, 2015.)

For the burgeoning field of gene therapy, ophthalmology also has proved the most promising and druggable space. One the reasons, said Regeneron's Husseini, is that "it's really about the delivery," and the fact that it allows for local delivery into the eye.

Spark Therapeutics Inc. has won over investors so far with its gene therapy SPK-RPE65, which could become the first gene therapy cleared in the U.S. Spark reported positive phase III data last year a rare ophthalmology indication, RPE65-mediated, inherited retinal dystrophies. Another company at work is Avalanche Biotechnologies Inc., which has AVA-101, an adeno-associated virus serotype 2 product targeting wet AMD. It's designed to transduce retinal pigment epithelium, or RPE, cells. (See BioWorld Today, Oct. 6, 2015.)

One of the biggest challenges with gene therapy, however, has been consistency in getting sufficient virus vector to the disease site.

"There are still certainly many hurdles to making gene therapy widely successful in the eye," Husseini said. "So we view [this] as early days, but very promising technology."

Graybug's Cleland was a more skeptical. "I've followed [gene therapy] for 20 years, and I don't think it's advanced," he said.

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