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Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.
Ophthalmology benefiting from active programs for innovative product development in 2018 and onward
The 12 months between Oct. 1, 2017 and Sept. 30, 2018 was a banner period for new entries into the ophthalmology therapeutic armamentarium with the FDA approving nine original New Drug Applications/Biologic License Applications and a first gene therapy. In addition, seven devices for use in ophthalmology received Premarket Approval Application approvals during the same time interval.
The 12 months between Oct. 1, 2017 and Sept. 30, 2018 was a banner period for new entries into the ophthalmic therapeutic armamentarium with the FDA approving nine original New Drug Applications/Biologic License Applications (NDA/BLA) and a first gene therapy. In addition, seven devices for use in ophthalmology received Premarket Approval Application (PMA) approvals during the same time interval. This article recaps the new product entries and takes a look at some emerging therapies that are advancing in clinical development.
Three new medications for IOP reduction were among the NDA approvals. LATANOPROSTENE BUNOD 0.024% (Vyzulta, Bausch + Lomb) is indicated for the reduction of IOP in patients with open-angle glaucoma or ocular hypertension. It is a prostaglandin analog administered once daily, and the first prostaglandin analog that has nitric oxide as a metabolite. Nitric oxide increases outflow through the trabecular meshwork and Schlemm’s canal.
The phase III study compared latanoprostene bunod with timolol. In the phase II VOYAGER study, latanoprostene bunod 0.024% was associated with significantly greater IOP reduction than latanoprost 0.005% (Xalatan, Pfizer).
NETARSUDIL 0.02% (Rhopressa, Aerie Pharmaceuticals) is a rho kinase inhibitor indicated for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension. The first approved rho kinase inhibitor, netarsudil is administered once daily and believed to reduce IOP by increasing aqueous outflow through the trabecular meshwork.
Aerie Pharmaceuticals has also filed an NDA for a fixed-dose combination of NETARSUDIL/LATANOPROST OPHTHALMIC SOLUTION 0.02%/0.005% (Roclatan). At month 12 in the MERCURY 1 clinical trial, IOP was ≤18 mm Hg in 82% of patients treated with netarsudil/latanoprost versus 66% of patients treated with latanoprost and 57% of those receiving netarsudil alone.
A new LATANOPROST OPHTHALMIC EMULSION, 0.005% (Xelpros, Sun Pharma) product is the first and only benzalkonium chloridefree formulation of latanoprost. It is indicated for reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.
LOTEPREDNOL etabonate ophthalmic suspension 1% (Inveltys, Kala Pharmaceuticals) is a corticosteroid indicated for the treatment of postoperative inflammation and pain following ocular surgery. The product is based on proprietary mucus penetrating particle (MPP) technology (AMPPLIFY) that enhances drug delivery through the mucus barrier, enabling twice-daily dosing. In the pivotal trial, the novel loteprednol product demonstrated statistical superiority to placebo in analyses of proportions of patients with complete resolution of ocular inflammation at day 8 and day 15 and pain at days 4, 8, and 15.
DEXAMETHASONE INTRAOCULAR SUSPENSION 9% (Dexycu, Eyepoint Pharmaceuticals) is a corticosteroid indicated for the treatment of postoperative inflammation. It uses a proprietary bioerodible sustained-delivery system (Verisome) and administered as a single 5 Î¼L dose behind the iris at the end of the surgical procedure. In the pivotal trial, anterior chamber cell clearing was achieved by 60% of patients receiving the intraocular dexamethasone injection compared with 20% of placebo-treated controls.
EyePoint Pharmaceuticals gained a second FDA approval in October 2018 for its FLUOCINOLONE ACETONIDE INTRAVITREAL IMPLANT 0.18 mg (Yutiq) with an indication for the treatment of chronic non-infectious uveitis affecting the posterior segment. It uses a nonbioerodible intravitreal micro-insert that is designed for consistent release of fluocinolone over a period of 36 months and can be given as an in-office injection using a single-dose preloaded applicator.
• Topical injection, and more
CYCLOSPORINE OPHTHALMIC SOLUTION 0.09% (Cequa, Sun Pharma) was approved to increase tear production in patients with keratoconjunctivitis sicca. This topical product incorporates nanomicellar technology to improve cyclosporine solubility and bioavailability.
CENEGERMIN-BKBJ OPHTHALMIC SOLUTION 0.002% (Oxervate, DompÃ© farmaceutici) is a recombinant form of human nerve growth factor indicated for the treatment of neutrotrophic keratitis. Results from two randomized, masked controlled clinical trials showed that cenegermin-bkbj was safe, well-tolerated, and significantly more effective than vehicle for restoring corneal epithelial integrity in eyes with stage 2 (moderate, persistent epithelial defect) or stage 3 (severe, corneal ulcer) neurotrophic keratitis.
VORETIGENE NEPARVOVEC-RZYL INTRAOCULAR SUSPENSION for subretinal injection (Luxturna, Spark Therapeutics) is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy who have viable retinal cells as determined by the treating physician(s). It is the first gene therapy approved to treat an inherited disease and the first gene therapy in ophthalmology. Clinical trial results showed that voretigene neparvovec-rzyl had an acceptable safety profile and resulted in rapid improvements in functional vision and visual function that were sustained with follow-up to 2 years.
BRIMONIDINE TARTRATE 0.025% (Lumify, Bausch + Lomb) was approved as an overthe-counter product to relieve redness of the eye due to minor eye irritations.
BENOXINATE HCL AND FLUORESCEIN SODIUM, 0.25%/0.4% (Altafluor Benox, Altaire Pharmaceuticals) offers a fixed combination of the disclosing agent and local ester anesthetic and is indicated for use in procedures requiring both agents.
• Device approvals
The device approvals included a variety of products lens products.
Seven devices for use in ophthalmology received PMA approvals in the year. STAAR Surgical received FDA approval to market the toric version of its phakic IOL (VISIAN TORIC ICL), opening opportunity to treat myopic patients with astigmatism.
In the pseudophakic IOL space, approval of the ENVISTA TORIC IOL (Model MX60T) gave manufacturer Bausch + Lomb its first hydrophobic acrylic IOL for astigmatism correction. The IOL has an aberration-free aspheric optic with fenestrated, step-vaulted, modified C-loop haptics.
The LIGHT ADJUSTABLE LENS AND LIGHT DELIVERY DEVICE (RxSight) also received FDA approval. It is the first medical device system that can make small adjustments to the pseudophakic lens power after cataract surgery.
A new disposable, extended-wear contact lens that can be worn continuously for up to six nights and seven days (SAMFILCON A; Ultra, Bausch + Lomb) was also approved.
After granting Breakthrough Device Designation, the FDA approved the CUSTOMFLEX ARTIFICIAL IRIS (HumanOptics/Clinical Research Consultants) for the treatment of full or partial aniridia resulting from congenital aniridia, acquired defects, or other conditions associated with full or partial aniridia. patients with a missing or damaged iris. The prosthetic device is made of medical-grade silicone. It is thin, foldable, individually customized for size and iris color, and can be used in children and adults. In premarketing evaluation, the artificial iris was associated with high patient satisfaction and demonstrated benefit for reducing light sensitivity.
Two micro-invasive glaucoma surgery (MIGS) devices intended to be implanted during cataract surgery to reduce IOP in patients with primary open-angle glaucoma were approved. The ISTENT INJECT TRABECULAR MICROBYPASS SYSTEM (Glaukos) introduces two stents using a dedicated injector. The Hydrus Microstent (Ivantis) also creates a bypass through the trabecular meshwork.
There were two de novo approvals. The TRUETEAR INTRANASAL TEAR NEUROSTIMULATOR (Allergan) provides a temporary increase in tear production to improve dry eye symptoms in adults with severe dry eye symptoms.
Approval of the IDX-DR (IDx) represents the first FDA-approved autonomous artificial intelligence-based diagnostic device. It is indicated for use by health care providers to automatically detect more than mild diabetic retinopathy in adults with diabetes who have not been previously diagnosed with diabetic retinopathy. It is indicated for use with the TRC-NW400 robotic fundus camera (Topcon Medical).
• Dry eye
More than 30 companies are developing treatments for dry eye disease (DED). In this space is KP-121 from Kala Pharmaceuticals, which is a lower-concentration version (0.025%) of its approved loteprednol etabonate ophthalmic suspension with MPP technology. Two phase III trials have been completed and a third is ongoing.
TopiVert is developing TOP1630, a non-systemic multikinase inhibitor that targets several kinases that are upregulated in DED. In a placebo-controlled phase I/IIa study, TOP1630 improved signs and symptoms by day 15.
Aldeyra Therapeutics reported data from a phase IIb study of REPROXALAP, a smallmolecule reactive aldehyde species scavenger, showing statistically significant superiority to placebo for improving ocular dryness and ocular staining.
OysterPoint Pharma is developing a novel NICOTINE ACETYLCHOLINE RECEPTOR AGONIST that is delivered as an intranasal spray and acts to stimulate natural tear production by depolarizing intranasal trigeminal nerves. Phase III studies are being planned based on encouraging phase IIb data.
MC2 Therapeutics is developing TOPICAL CYCLOSPORINE using its proprietary delivery system (PAD Technology). Positive data were achieved in a phase II vehicle-controlled study.
SHP640, an ophthalmic suspension containing povidone-iodine 0.6% and dexamethasone 0.1%, is being developed by Shire as a treatment for adenoviral conjunctivitis. Phase III studies are ongoing.
Several pharmacotherapies for presbyopia are being investigated in clinical trials. These treatments include EV06 (Novartis) that aims to restore crystalline lens flexibility. Compared with placebo, EV06 demonstrated benefit in a phase I/II study in an analysis of the proportion of participants who achieved 20/40 or better near UCVA at day 90. Novartis is undertaking a reformulation before moving ahead in clinical studies.
Allergan released phase IIa data from a study comparing OXYMETAZOLINE (AGN-199201), low-dose PILOCARPINE (AGN-190584), and both agents together. Data from additional phase II studies are expected.
Orasis Pharmaceuticals is developing CSF1, a proprietary combination product designed to increase depth of focus and improve near vision via a pinhole effect. It showed promise in a small phase IIa placebo-controlled study, and a comprehensive phase IIb study is expected to begin soon.
Presbyopia Therapies is developing a TOPICAL TREATMENT FOR PRESBYOPIA that formulates miotic agents in a proprietary vehicle.
Viewpoint Therapeutics has conducted preclinical studies of VP1-001, a first-in-class compound that disaggregates crystallin. In a canine cataract model, VP1-001 reversed lens opacity. By softening the lens, it might also have benefit as a treatment for presbyopia.
Studies showing the safety and efficacy of low-dose atropine for slowing myopia progression have motivated three companies to undertake development of products for commercialization. NVK-002 from Nevakar is being investigated in a two-stage, three-arm, randomized, multicenter, double-masked, placebo-controlled crossover study.
Sydnexis has a patent-protected, LOW-DOSE ATROPINE FORMULATION and plans to initiate a phase III trial in 2019. Eyenovia is developing a low-dose atropine that is sprayed onto the ocular surface using a proprietary, piezo-print microdose technology. It is also expected to begin a phase III study in 2019.
RANIBIZUMAB delivered via the Port Delivery System (Genentech) is now being evaluated in a phase III study for the treatment of neovascular age-related macular degeneration. In the phase II LADDER study, 80% of patients who received the highest dose went 6 months or longer without needing an implant refill.
BROLUCIZUMAB (Novartis) is a single-chain variable fragment anti-VEGFA agent that demonstrated robust visual gains in patients with neovascular (nAMD). In the phase III study, 50% of patients were treated every 12 weeks and brolucizumab was non-inferior to aflibercept.
GB-102 (Graybug Vision) is a depot formulation of sunitinib malate, a tyrosine kinase inhibitor that is a pan-VEGF receptor antagonist. A phase Ib/IIa switching study is ongoing enrolling treatment-responsive patients with nAMD.
RGX-314 (Regenxbio) is a gene therapy approach to anti-VEGF therapy for nAMD. It is hoped to offer a one-time subretinal treatment and showed promise in an early study.
FARICIMAB (Roche/Genentech) is a unique bi-specific drug that simultaneously inhibits VEGFA and Ang-2. It is being evaluated in phase III studies as a treatment for diabetic macular edema (DME) and nAMD.
OPT-302 (Ophthea) is a soluble form of human VEGF receptor-3 that blocks VEGF-C and VEGF-D. It is being evaluated for use in combination with an anti-VEGF-A agent.
PAN-90806 (PanOptica) is being developed as a topical treatment for neovascular diseases, including nAMD and proliferative diabetic retinopathy plus diabetic macular edema (DME). PAN-90806 blocks activation of the VEGF receptor 2 by inhibiting the receptor’s tyrosine kinase activity. Phase I/II studies for both indications were completed in 2016. Results from a study enrolling patients with treatment-naÃ¯ve nAMD are expected in 2019.
RISUTEGANIB (formerly known as Luminate, Allegro Ophthalmics) is a first-in-class anti-integrin that is being developed as a treatment for DME and nonexudative AMD. In phase II research, risuteganib demonstrated particular benefit for improving vision and anatomic outcomes in patients with DME who were suboptimal responders to previous anti-VEGF therapy.
AKB-9778 (Aerpio Therapeutics) is a small-molecule tie-2 activator administered by subcutaneous injection. Data from a study investigating AKB-9778 for treatment of patients with moderate/severe non-proliferative diabetic retinopathy is expected in 2019.
Editor’s Note: This article is based on a presentation by Emmett Cunningham, MD, at the 2018 OIS@AAO meeting. It provides an overview, but not an all-inclusive list, of ophthalmic approvals and emerging therapies and devices