MEDICAL SERVICES

THERAPEUTIC UPDATE

HERE’S WHAT’S NEW AND WHAT’S COMING IN GLAUCOMA, DRY EYE DISEASE AND THE RETINA

Key Opinion Leaders

TO PROVIDE the highest levels of care, clinicians must gain an understanding of the most up-to-date research into therapeutics for the eye. In this article, key opinion leaders provide information regarding the latest treatments, those from the last 18 months, in glaucoma, dry eye disease and retinal disease. The KOLs also provide a summary of those treatments in — or beyond — Phase II trials.

These sections were written by Drs. Christopher Quinn and Elana Rosenberg (glaucoma); Dr. William Townsend (dry eye disease) and Dr. Kaitlyn A. Sapoznik (retinal disease).

GLAUCOMA

IOP remains the only factor of glaucomatous vision loss that clinicians can control. Therefore, it makes perfect sense that the latest glaucoma procedures and treatments in the pipeline are geared toward lowering IOP.

Here’s a look:

• Medications. Several new eye drops and drug-delivery systems appear poised for submission for FDA approval. With regard to drops, Rhopressa (Aerie Pharmaceuticals), Roclatan (Aerie Pharmaceuticals) and Trabodenoson (Inotek Pharmaceuticals) are the ones to watch.

Rhopressa is a Rho kinase (ROCK) inhibitor that lowers IOP by increasing fluid outflow through the trabecular meshwork via the inhibition of the actin cytoskeleton contractile tone of smooth muscle and by decreasing episcleral venous pressure. Phase III trials are ongoing, according to the manufacturer.

Roclatan combines Rhopressa and latanoprost (Xalatan, Pfizer), to bring together the IOP-lowering mechanisms of both into one drug. A Phase III trial is ongoing, according to the manufacturer.

Finally, Trabodenoson is a highly selective adenosine mimetic. Stimulation of A1 adenosine receptors in the trabecular meshwork cause upregulation of proteases that digest and remove accumulated trabecular meshwork proteins, which have been implicated in reduced aqueous outflow and increased IOP.

With regard to drug-delivery systems, sustained release travoprost (OTX-TP, Ocular Therapeutics Inc.), Bimatoprost SR (Allergan) and an as-yet-to-be-named punctal plug from Mati Therapeutics are on their way.

OTX-TP is an intracanalicular polyethylene glycol hydrogel. The drug, travoprost, is contained within microparticles. Once inserted into the lacrimal canaliculus, the hydrogel expands to conform to the canaliculus. The result: sustained drug release onto the ocular surface for up to three months.

Bimatoprost SR is an intraocular implant via intracameral injection that delivers a sustained release of bimatoprost for up to six months and longer in some patients. The implant, once inserted into the anterior chamber, biodegrades.

Finally, Mati Therapeutics is working on a punctal plug delivery system with latanoprost as the active agent.

• Minimally Invasive Glaucoma Surgery (MIGS). The FDA-approved procedures are endoscopic cyclophotocoagulation (ECP) (ENDO Optiks/Beaver Visitec), the iStent (Glaukos) and Trabectome (NeoMedix).

ECP decreases aqueous humor production, as it ablates the ciliary body epithelium. It may be performed transclerally or endoscopically at the time of cataract extraction.

iStent and Trabectome improve aqueous outflow, enabling IOP reduction. Specifically, the iStent, at 1mm long and 0.33mm high, is inserted into Schlemm’s canal under gonioscopic visualization at the time of cataract surgery. Randomized clinical trials reveal that combined phacoemulsification and stent placement moderately lower IOP compared with cataract surgery alone, according to an article by Fea A.M., in the March 2010 “Journal of Cataract & Refractive Surgery.”

The Trabectome is an electrocautery probe inserted through a clear corneal incision, typically at the time of cataract extraction, to ablate the visualized trabecular meshwork and, thus, appears to lower IOP and decrease medication dependence, according to an article by Minckler D.S., Baerveldt D., and Alfaro M.R., et al. in the June 2005 “Ophthalmology.”

The Hydrus MicroStent (Ivantis), CyPass Micro-stent (Transcend Medical), iStent Supra (Glaukos) and XEN gel stent (AqueSys) are undergoing U.S. clinical trials.

The Hydrus MicroStent is a 7mm stent inserted into Schlemm’s canal to increase outflow by dilating and stabilizing the canal structure. A study on Hydrus, comprised of 100 eyes of patients with OAG and cataract, who either received cataract surgery or cataract surgery plus MicroStent placement, revealed 80% of the treatment group achieved a 20% or greater drop in IOP compared with 46% of the control group at two years, following medication removal, according to a July 2015 article by Pfeiffer N., Garcia-Feijoo J., and Martinez-de-la-Casa J.M., et al. in “Ophthalmology.”

The CyPass Micro-stent passes through an abinterno incision and is lodged in the suprachoroidal space. The COMPASS study for the stent had 505 patients enrolled at 27 U.S. clinical sites for two years of follow-up, according to the manufacturer’s website, with promising results. (Further information was not available.)

The iStent Supra is a 4mm tube made of polyethersulfone and titanium that is inserted through an abinterno incision into the suprachoroidal space. Phase III and IV trials are ongoing.

Finally, the XEN gel stent (AqueSys, recently acquired by Allergan), is a 6mm stent made of a gelatin that hydrates when injected into the subconjunctival space, creating a low-lying posterior bleb, which is beneficial for preventing leakage and preserving corneal tear film. The company has an ongoing Phase III study looking at the device in refractory glaucoma and a Phase IV study evaluating the XEN implant in moderate glaucoma.

	CHRISTOPHER QUINN, O.D., F.A.A.O., is owner and president of Omni Eye Services, which has multiple locations in New York and New Jersey. He is vice president of the AOA, a past president of the New Jersey Society of Optometric Physicians and a member of American Public Health Association – Vision Care Section. He is also an AAO fellow.
	ELANA ROSENBERG, M.D., practices at Omni Eye Services. She is a member of the American Academy of Ophthalmology and American Glaucoma Society.

DRY EYE DISEASE

It has been 13 years since cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) received FDA approval, and it remains the only FDA-approved prescription drug for dry eye disease (DED). The pipeline, however, is still flowing with novel DED treatments. Here, I discuss a few:

• Thymosin beta-4 (Tβ4). Tβ4 is a naturally occurring peptide commonly found in platelets and serum; it promotes collagen deposition, regeneration and remodeling of injured or damaged tissues. Michigan Cornea Consultants conducted a Phase II study of Tβ4 eye drops in patients suffering from severe DED. Subjects were randomly assigned to instill drops six times per day, according to a May 2015 article by Sosne G., Dunn S.P., and Kim C., in “Cornea” and in ClinicalTrials.gov (NCT01393132). The study group instilled Tβ4 (0.1%) in a preservative-free base, while the control group used drops identical to the study preparation but without Tβ4. Subjects in the treatment group had a 35.1% reduction of ocular discomfort compared with the vehicle control group. Also, the treatment group showed a 59.1% reduction of total corneal fluorescein staining compared with the vehicle control group. The study demonstrated that Tβ4 is safe, well tolerated and promotes healing of the corneal surface. Tβ4 is part of an ongoing Phase III study, by RenGen Tree LLC.

• Lifitegrast. lifitegrast (Shire) is an integrin antagonist that decreases the T-cell mediated inflammation associated with DED. Integrins are receptor cell adhesion molecules — proteins that cells use to both bind to and interact with the extracellular matrix, according to an article by Tauber J., Karpecki P., and Latkany R., et al. in the December 2015 “Ophthalmology.” Lifitegrast is designed to block the interaction between the cell membrane and T-lymphocytes and also inhibits T-lymphocyte activation, adhesion and migration. Shire recently resubmitted its New Drug Application, adding data from OPUS-3, a phase III efficacy and safety trial, to address an FDA request for more information.

• Lumenis M22 Intense Pulsed Light (IPL) system. A device that has been introduced to the care of DED is the Lumenis M22 Intense Pulsed Light (IPL) system. IPL delivers intense pulsations of non-coherent light to alter or heal damaged tissue, especially skin. This technology uses a broad range of wavelengths (515nm to 1200nm) for specific applications.

The results of a feasibility study to evaluate the effect of IPL applied to the eyelids of individuals with meibomian gland dysfunction were reported in an article by Craig J.P., Chen Y.H. and Turnbull P.R., in the February 2015 “Investigative Ophthalmology & Vision Science.” One eye was treated; the fellow eye acted as a control. The treatments were applied three times over a 45-day period. The authors reported improvement in lipid layer grade, noninvasive TBUT, visual acuity and a reduction in symptoms. No difference was noted in tear evaporation rate or tear meniscus height. Another FDA trial is in the recruitment phase.

WILLIAM TOWNSEND, O.D., practices in Canyon, Texas as part of a multi-location optometric group. He is an adjunct professor at the University of Houston College of Optometry and is treasurer of the Ocular Surface Society of Optometry. Email him at drbilltownsend@gmail.com.

RETINA

In the last decade, anti-VEGF injections have become the main therapeutic intervention for several retinal diseases, including wet AMD. That said, some patients do not respond, and some can lose responsiveness to treatment. In addition, other etiologies, such as geographic atrophy (GA) secondary to AMD lack effective therapy. Here’s a look at what’s on the horizon to solve these problems.

• E10030. This drug (Fostiva, Ophthotech) acts synergistically with current anti-VEGF therapy. Specifically, it targets a platelet-derived growth factor; two Phase III trials are ongoing to determine its benefit when used as an adjunct to ranibizumab (Lucentis, Genentech/Roche), aflibercept (Eylea, Regeneron) or bevacizumab (Avastin, Genentech), compared with monotherapy for wet AMD, according to ClinicalTrials.gov (NCT01940900 and NCT01940887).

E10030 causes alterations of the neovascular tissue by means of pericyte loss, which may increase the efficacy of anti-VEGF therapy, according to an article by Jaffe G.J., Elliot D., and Wells J.A., et al. on the drug’s Phase I study in the January 2016 “Ophthalmology.”

• Ranibizumab. Proliferative diabetic retinopathy (PDR) has historically been treated with pan-retinal photocoagulation (PRP). However, it has recently been shown that PDR treated with ranibizumab is comparable to traditional PRP treatment within a two-year time period, according to an article by the Writing Committee for the Diabetic Retinopathy Clinical Research, et al. in the November 2015 “JAMA.” Treatment with ranibizumab is advantageous in that the retinal tissue is not destroyed, and visual field is better preserved.

• Squalamine eye drops. Data from the Phase II IMPACT study on the use of anti-angiogenic squalamine eye drops (OHR Pharmaceutical Inc.) in conjunction with ranibizumab for wet AMD demonstrate an increase in VA when ranibizumab is combined with these drops compared with ranibizumab alone, according to a news release from OHR Pharmaceuticals. In addition to VEGF, the squalamine molecule also inhibits platelet-derived growth factor and basic fibroblast growth factor, which are also involved in the pathways of angiogenesis. Phase III trials are expected.

• Lampalizumab. The CHROMA (NCT02247479) and SPECTRI Phase III (NCT02247531) trials are ongoing and will continue to build upon results from the MAHALO study to determine the efficacy of intravitreal lampalizumab (Roche) injections in GA progression. According to an investor update from Roche, released at the initiation of these trials, lampalizumab, which targets complement factor D, showed a 20% reduction in GA lesion progression and may have increased benefits to those with a particular genetic biomarker (complement factor I), according to data from the MAHALO study.

• Doxycycline. The phase II/III TOGA study is ongoing to investigate the potential therapeutic benefit of oral doxycycline (Oracea, Galderma Laboratories Inc.) in GA. Doxycycline is well known for its anti-inflammatory properties and, according to ClinicalTrials.gov (NCT01782989), subjects enrolled in the TOGA study will be randomized to Oracea (40 mg doxycycline) or a placebo capsule daily for a 24-month treatment period and the rate of GA enlargement and change in BCVA will be evaluated.

• MC-1101. MC-1101 (MacuCLEAR Inc.) is a 1% topical ophthalmic solution in Phase II/III clinical trials for early to intermediate dry AMD. According to ClinicalTrials.gov (NCT02127463), the solution is intended to increase choroidal blood flow. Thus, it may provide benefits in subjects with dry AMD.

• Gene therapy. While Leber’s congenital amaurosis is rare, a Phase III clinical trial (Spark Therapeutics) for gene therapy manipulation of the RPE65 gene is ongoing for this disorder, according to a September 2015 article by Schimmer J. and Breazzano S., in “Human Gene Therapy Clinical Development.” Hopefully, this clinical trial can also provide strategies to further the potential application of retinal gene therapy to commonly encountered retinal diseases, such as AMD. OM

KAITLYN A. SAPOZNIK, O.D., is an adjunct clinical lecturer at Indiana University School of Optometry (IUSO) in Bloomington, IN. In addition, she is working toward her Ph.D. in Vision Science at IUSO. Visit tinyurl.com/OMComment to comment on this article.