Will drugs in trials actually deliver?

Dry eye, glaucoma, AMD specialists could receive new weapons.

By Karen Blum, contributing editor

After a serious lull in novel eye pharmaceutical development, ophthalmologists are hopeful about encouraging clinical trial results and possible drug approvals for dry eye, glaucoma, uveitis and other ophthalmic conditions.

Many “companies are investing in a lot of R&D to come up with exciting new products that will allow us different avenues for treatment,” says V. Nicholas Batra, MD, chief surgeon and medical director of Batra Vision Medical Group in San Leandro, Calif.

This year alone, we’ve seen the following FDA approvals:

• Avedro’s Photrexa Viscous (riboflavin ophthalmic solution with 20% dextran), Photrexa (riboflavin ophthalmic solution with 0% dextran), and its KXL System (UVA light) for corneal collagen cross-linking for the treatment of progressive keratoconus

• AbbVie’s Humira (adalimumab) for the treatment of noninfectious intermediate, posterior and panuveitis

• Shire’s Xiidra (lifitegrast ophthalmic solution) for the treatment of dry eye disease

• Sun Pharma and InSite Vision's BromSite, a topical anti-inflammatory indicated for the treatment of postoperative inflammation and prevention of ocular pain in patients undergoing cataract surgery.

Here are some pending agents your colleagues are tracking.

Dry eye disease

Dry eye is coming in to its own, says John Sheppard, MD, MMSc, president of Virginia Eye Consultants in Norfolk, Va. “Twenty years ago all we did was randomly pick from one, two or three tears,” because there was nothing else. Cornea specialists had already figured out that steroids helped dry eye, but the available steroids were significantly risk-laden for prolonged therapy.

Lifitegrast is the first drug approved to treat dry eye since 2003. It is comprised of a synthetic material that blocks the binding of intracellular adhesion molecule-1 (ICAM-1) with lymphocyte function-associated antigen-1 (LFA-1) on T-cell surfaces, inhibiting T-cell activation, proliferation and cytokine release in the eye, which regulates inflammation.

Dr. Sheppard and Parag A. Majmudar, MD participated in many of the compound’s clinical trials.^1-3

“It’s going to be a huge lift for dry eye patients,” says Dr. Majmudar. Restasis (cyclosporine ophthalmic emulsion, Allergan), works in a good percentage of patients, he notes, and lifitegrast may be an additive to cyclosporine or perhaps even show a faster onset of action: “Not only does [Xiidra] prevent the activation of newly expressed T-lymphocytes, but it may actually be able to switch off the ones that are already circulating.”

Allergan is working on a multidose, preservative-free version of cyclosporine with a proprietary cap, says Dr. Sheppard. Preservative can be put into the bottle but when the drop goes through the cap, it deactivates the preservative, thereby becoming less toxic to the eye, he says. This technology is a true win for patients, he notes — the multidose vial, convenience, hopefully a lower cost, but also a preservative-free medication.

Allergan also has completed phase 3 clinical trials of its Oculeve Intranasal Tear Stimulator, a handheld device inserted into the nose, designed to activate efferent nerves that stimulate the lacrimal gland.⁴ “The phase 3 clinical trials [showed] the degree to which they create tear secretion and reduce surface ocular irritation and staining of the cornea,” Dr. Sheppard says. The device “offers us potential synergy with the traditional dry eye prescription drugs that inhibit inflammation.” The company aims to submit a premarket submission to the FDA in the second half of 2016.

After promising phase 2 results, Kala Pharmaceuticals has started two, phase 3 trials of its mucus-penetrating particle (MPP) loteprednol etabonate⁵ two-week induction therapy that treats redness in dry eye disease. The company’s MPP platform allows therapeutic agents to pass through the mucus layer of the ocular surface tear film, facilitating penetration into the targeted epithelial tissues.

“We’ve always used steroids off-label for dry eye,” Dr. Sheppard says. “This pair of phase 3 trials will very likely conclusively show us the safety and efficacy of pulse induction therapy using steroids.”

Glaucoma

In the glaucoma space, ophthalmologists say they’re eagerly awaiting the approval of Rho-kinase (ROCK) inhibitors, novel medications that work through the trabecular meshwork to lower IOP and increase outflow from the eye. “We’ll have the first new mechanism of action for glaucoma in two decades,” Dr. Sheppard says.

It may have better efficacy than current drops, and that’s “because it works by a different mechanism of action to increase outflow and also reduces the production of aqueous,” Dr. Majmudar says. “It may be additive or synergistic with some of the other medications, specifically the prostaglandin analogues used in a high percentage of patients, so we may be able to see a big impact in lowering IOP.”

Rhopressa is a once-daily eyedrop that inhibits Rho-kinase and the norepinephrine transporter, both novel biochemical targets for lowering IOP. This occurs via three mechanisms of action: through ROCK inhibition, it increases fluid outflow through the trabecular meshwork; it reduces episcleral venous pressure; and through NET inhibition, it reduces the production of aqueous.¹² Phase 3 trials began in July 2014, and its manufacturer, Aerie, expects to file an NDA in the third quarter of this year.

Roclatan, a single-drop fixed-dose combination of Rhopressa and latanoprost, aims to lower IOP through the same three methods as Rhopressa, along with the prostaglandin increasing fluid outflow through the uveoscleral pathway. Phase 3 trials began last September; the company expects to file an NDA for this product in the second half of 2017.

Other agents ^7-11 are also in development, but the closest to the finish line are Aerie’s Rhopressa and Roclatan.

“There’s a lot of promise with these inhibitors, many of which are available internationally,” Dr. Batra says. “The question is what are the long-term side effects and how long will they last. Those are the things that are still under development.”

Other products in progress use different mechanisms to treat glaucoma. Bausch+Lomb and Nicox S.A.’s Vesneo^13,14 (latanoprostene bunod) is a single-agent drop designed to lower IOP in patients with open-angle glaucoma or ocular hypertension. The FDA, in its recent review, while not mentioning problems with the product per se said there were some deficiencies, unspecified, at B+L’s manufacturing facility in Tampa. According to a July Nicox press release, the company intends to meet with agency officials to “address those concerns.”

If approved, the drug would be the first nitric oxide-donating prostaglandin receptor agonist available for this indication. The drug is rapidly metabolized to latanoprost acid and nitric oxide, which plays a key role in IOP regulation in healthy eyes. Latanoprostene bunod is thought to increase aqueous humor outflow by acting on both the uveoscleral pathway via latanoprost acid, and trabecular meshwork and Schlemm’s canal via nitric oxide signaling.¹⁵

Inotek’s Trabodenoson, designed to restore the eye’s natural pressure control ability, is in phase 3 trials. The agent, a first-in-class, highly selective A1 subtype adenosine mimetic for glaucoma and ocular hypertension, binds to epithelial cells in the trabecular meshwork, up-regulating gelatinases that clean out and remodel the meshwork, increasing outflow and restoring a healthier IOP.¹⁶ Another version with latanoprost is in phase 2 trials.

Also, Allergan is testing a sustained release form of bimatoprost, delivered through a biodegradable intracameral implant, that would offer four to six months of antiglaucoma therapy with a single injection. It’s also now in phase 3 trials.

Because the primary problem in treating glaucoma is patient compliance, says Dr. Sheppard, this design would avoid peaks/drops in pressure or missed doses, as well as ocular surface toxicity.

AMD

A few agents in phase 2 or early phase 3 trials look promising for treating geographic atrophy (GA) or dry AMD, Dr. Sheppard says. MacuCLEAR’s MC-1101 is a repurposed compound formerly approved as an antihypertensive drug that, applied as a drop, aims to stop dry AMD from progressing to wet AMD. “That’s the holy grail,” Dr. Sheppard says. Other agents include Novartis’ intravitreal injection LGF3,¹⁶ which targets the immune system’s C5 complement pathway to treat/prevent GA lesions, and Acucela/Otsuka’s oral drug emixustat hydrochloride,^17,18 the first compound in the visual cycle modulator drug class, designed to slow the progression of GA associated with dry AMD.

Uveitis/Inflammation

Mapracorat is an anti-inflammatory medication under development by Bausch+Lomb.¹⁹ It is a novel nonsteroidal selective glucocorticoid receptor agonist related to treating uveitis, Dr. Batra says. Mapracorat, along with Nepafenac and BromSite, are “all pretty interesting because they give us different pathways to attack inflammation and immune mediation.”

Some manufacturers are testing dexamethasone in combination, such as InSite Vision’s AzaSite Plus, a topical azithromycin 1% plus dexamethasone 0.1%, and DexaSite, a low-dose (0.1%) dexamethasone formulated in InSite Vision’s patented DuraSite polymer vehicle.

Now in confirmatory phase 3 trials for noninfectious acute anterior uveitis, EyeGate Pharma’s EyeGate II delivery of dexamethasone phosphate (EGP-437)²⁰ uses iontopheresis, which applies an electric current to the charged ophthalmic active in solution to increase its mobility and tissue penetration, Dr. Sheppard says. Another contender, Aldeyra’s topical aldehyde inhibitor NS2, works by trapping pro-inflammatory aldehydes. Phase 2/3 trials are ongoing for both uveitis and allergy.

For noninfectious posterior segment uveitis, Dr. Sheppard says he anticipates widespread adoption of Santen’s intravitreal injections of the immunosuppressant sirolimus (DE-109),²¹ which the FDA approved after successful phase 3b trials.

Conjunctivitis

Shire’s FST-10022, in phase 2 clinical trials for the treatment of infectious conjunctivitis, are topical ophthalmic drops comprised of 0.6% povidone iodine and 0.1% dexamethasone to kill both bacterial and viral cells causing the infection as well as control inflammation, says Dr. Majmudar.

Primary care physicians and pediatricians might prescribe FST-100 more than ophthalmologists, especially those who concentrate on surgery; they don’t tend to see much viral conjunctivitis, Dr. Majmudar says. “We’ll see what happens in the long term with clinical trials and how it plays out, but it has a very promising future if it can get approved.” OM

Dr. Batra is a consultant for Alcon, Bausch + Lomb and AMO. Dr. Majmudar is a consultant for Shire and has been an investigator in the company’s clinical trials. Dr. Sheppard is a consultant, adviser, speaker and/or investigator for 40+ companies including Alcon, Allergan, Bausch + Lomb, EyeGate, Kala, Shire and Santen.

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