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SUBSPECIALTY NEWS

Coming Soon: Next-Generation Retinal Prostheses

Second Sight and Pixium plan human trials.

■ Two pioneering companies — Second Sight Medical and Pixium Vision — whose goal is to bring a level of functional of vision to the blind or nearly blind, say they are close to the start of human clinical trials for their second-generation devices. The trials could start later this year.

Second Sight Medical (Sylmar, CA), is best-known for the Argus II retinal prosthesis, which was approved by the FDA for late-stage retinitis pigmentosa in 2013. The Argus II has now been implanted in several hundred people worldwide (most recently in South Korea and Taiwan) and has been proven to be safe and effective in discerning shapes and providing a level of mobility, even 5 years after implantation. The Argus II procedure is now covered by Medicare in 28 states and the District of Columbia following the announcement in July of Medicare coverage in 11 more states and the District of Columbia.

Second Sight is now readying the Orion I Visual Cortical Prosthesis, which attaches directly to the visual cortex of the brain (the Argus II attaches to the optic nerve). The company says that the connection to the brain will allow the Orion to be used in treating blindness that is a result of virtually any injury or condition, a major improvement over the limited utility of the Argus II.

A blind patient who was implanted with the basic Orion technology in 2016 (but without a camera) was able to see light spots, which the company viewed as an encouraging sign.

“This first human test confirms that we are on the right track with our Orion I program to treat blind patients who cannot benefit from the Argus II Retinal Prosthesis,” said Second Sight Chairman Robert Greenberg, MD, PhD. “This initial success in a patient is an exciting and important milestone even though it does not yet include a camera. By bypassing the optic nerve and directly stimulating the visual cortex, the Orion I has the potential to restore useful vision to patients completely blinded due to virtually any reason, including glaucoma, cancer, diabetic retinopathy, or trauma.”

In the case of Pixium (Paris, France), the PRIMA is seen as the successor to the IRIS, an epi-retinal implant with 150 electrodes that has already earned the CE mark.

The PRIMA has a number of new features that differentiate it from the IRIS. It receives physiological signals from the sub-retinal level, with the potential capacity for literally thousands of electrodes. In addition, the surgical procedure for the PRIMA has been shortened and the miniaturization of components has led to a more compact device.

Pixium has a number of key research partners, including the Hansen Experimental Physics Laboratory at Stanford University, which is designing advanced microelectronics and photovoltaic arrays that preserve many of the features of natural vision in the PRIMA device.

“PRIMA promises to provide visual acuity exceeding the threshold of legal blindness in human patients,” said Daniel Palanker, PhD, of Stanford, at a neural engineering conference in Montpelier, France. “We continue to work on implants with even smaller pixels to further improve visual acuity.”

The company says the initial goal of the PRIMA is to deliver visual perception at the level of facial recognition.

Argus II Results and Second Sight’s Goals

■ Researchers at the Barraquer Ophthalmological Center in Zaragoza, Spain, reported on the progress of the 3 patients whom they thus far have implanted with the Argus II retinal prosthesis system. One of the patients, a 51-year-old man, is the only patient in the world with Usher Syndrome who has received the Argus II.

The researchers report that in the first 2 months, the 2 women with advanced RP showed much faster progression in rehabilitative therapy and achievements than the man. However, in the third month and continuing for the first year, the man made what the researchers called “extraordinary improvement” in general life tasks and soon became much more independent in daily life compared to the two RP patients. The researchers concluded that the Argus II may be suitable for patients with Usher Syndrome.

In a recent conference call, Second Sight Medical set out its near-term goals, including expanding the market for its Argus II retinal prosthesis to better-sighted individuals (those with hand motion visual function) and implanting the first Orion device, which connects directly to the brain and is designed to be used by patients with all types of blindness.

Ophthotech Outlines Future Research Goals

Focus will be on orphan eye diseases.

■ After the failure of Fovista as a combination treatment for wet AMD, Ophthotech Corporation continues to refocus its research efforts in new directions. The company said it should have between $145 million and $160 million to fund new and ongoing initiatives.

Ophthotech now plans to leverage its clinical experience and retina expertise to identify and develop therapies to treat multiple orphan ophthalmic diseases for which there are limited or no treatment options available. In parallel, the company continues its ongoing age-related retinal programs and its business development efforts to obtain rights to additional products, product candidates, and technologies to treat ophthalmic diseases, particularly those of the back of the eye.

The company’s ophthalmic disease strategy will be led by a randomized, controlled clinical trial assessing the efficacy and safety of Zimura (avacincaptad pegol), its C5 complement inhibitor, for Stargardt disease. Ophthotech is also continuing its programs in age-related eye diseases, including the planned initiation of a phase 2a clinical trial of Zimura in combination with anti-VEGF therapy for wet AMD and a phase 2a clinical trial of Zimura in combination with anti-VEGF therapy for idiopathic polypoidal choroidal vasculopathy. Both of these trials are scheduled to start by the end of this year.

In addition, the company’s phase 2/3 clinical trial of Zimura as a monotherapy for the treatment of geographic atrophy is ongoing. Ophthotech is also now planning initiatives in intermediate/posterior non-infectious uveitis, retinoblastoma, and the retinal manifestations of Von Hippel-Lindau Syndrome.

“We are excited to move the company forward with a goal of becoming a leader in the development and commercialization of ophthalmic therapeutics for orphan diseases and for larger indications in the back of the eye, such as age-related retinal diseases,” stated Glenn P. Sblendorio, CEO and president of Ophthotech. “We believe that we will be well positioned as a company with multiple shots on goal to bring ophthalmic therapeutics to market. We are also continuing our business development efforts with the goal of broadening and advancing our pipeline.”

Loss of Follow-up After Anti-VEGF Injections

Many dropouts had only 1 to 3 injections.

■ Researchers at Wills Eye Hospital conducted a retrospective review to determine if they could find any patterns in patients who received anti-VEGF injections for DME and were subsequently lost to follow-up. The review covered the period from April 2012 to December 2016.

Dropouts were defined as having no visits in the 12 months prior to 12/1/16. Age, gender, and race/ethnicity were all reviewed to determine if demographics were a factor. The number of cumulative injections prior to the loss of follow-up was categorized into three groups (1-3, 4-10, and >10 injections). The association between loss of follow-up and these features were evaluated using the chi-square test. Logistic regression was used to identify independent predictors for loss of follow-up.

A total of 2,537 unique DME patients were in this study, with overall loss of follow-up found in 330 patients (13.0%). The loss of follow-up group was older on average (71 years vs. 65 years). No significant difference was found based on race/ethnicity or gender. In the 1-3 injection group, 196 of 894 patients (21.9%) were lost to follow-up; in the 4-10 injection group, 108 of 892 patients (12.1%) dropped out; and in the >10 injection group, only 26 of 751 patients (3.5%) were lost. The difference in proportion lost to follow-up when comparing each group was statistically significant (P<.001). Age and number of injections were independent predictors of loss of follow-up.

The researchers, who presented their findings at ARVO 2017, concluded that a relatively large proportion of patients who received only 1-3 injections for DME prior to 12/1/15 had no additional visits between 12/1/15 and 12/1/16. Further analysis looking at larger numbers of DME patients along with intervals between injections and return visits will be necessary.

Aerpio Begins Phase 2b Trial in DR

AKB-9778 is being self-administered.

■ Aerpio Pharmaceuticals, a biopharmaceutical company focused on advancing first-in-class treatments for ocular diseases, has begun patient dosing in the company’s TIME-2b study, a phase 2b clinical trial designed to assess the efficacy and safety of Aerpio’s lead candidate AKB-9778 for patients with moderate to severe nonproliferative DR.

AKB-9778 is a small-molecule, Tie2-activating agent that effectively blocks vascular leak and pathologic angiogenesis in multiple disease conditions, initially being studied for diabetic eye diseases. It has proved promising in the earlier phase 2a TIME-2 study as a treatment for both DME and underlying DR. An arm of that study showed self-administered subcutaneous AKB-9778 to be effective in treating DME in combination with ranibizumab 0.3 mg (Lucentis; Genentech).

Because the study patients are all diabetics, most have experience doing their own subcutaneous insulin injections and were able to self-administer after brief training.

The TIME-2b study is a double-masked, placebo-controlled, multicenter trial that will enroll 150 patients randomized 1:1:1 to receive either AKB-9778 15 mg subcutaneously once daily, AKB-9778 15 mg twice daily, or placebo for 12 months. The primary endpoint of the TIME-2b study is the percentage of patients who improve by at least 2 steps in diabetic retinopathy Severity Score (DRSS) in the study eye.

Victor H. Gonzalez, MD, of Valley Retina Institute in McAllen, TX, who enrolled the first patient in TIME-2b, stated, “An early treatment option that potentially improves DR in both eyes without the need for intraocular injections could completely change our approach to diabetic eye disease.”

“The start of our TIME-2b study builds upon our clinical proof of concept data, for which we reported that AKB-9778 monotherapy was able to improve underlying diabetic retinopathy by 2 or more steps in DRSS in both eyes,” said Joseph Gardner, president and CEO of Aerpio. “Our goal with AKB-9778 is to treat early diabetic eye disease before the onset of vision-threatening conditions.”

In another study, Peter Campiocharo, MD, of the Wilmer Eye Institute, completed a 16-patient, 84-day, phase 2a clinical trial using twice-daily, self-administered 15 mg AKB-9778 for macular edema associated with RVO.

Allegro’s Luminate Effective in DEL MAR Trial

Therapy shows durability in combating DME.

■ Allegro Ophthalmics said the DEL MAR phase 2b stage 2 clinical trial met its primary endpoint when used as a sequential therapy in patients with DME. The study evaluated the integrin peptide inhibitor Luminate as a sequential therapy or in combination therapy with anti-VEGF in 80 patients with DME. The 1.0 mg dose of Luminate in sequential therapy demonstrated VA gains equivalent at all time points to bevacizumab (Avastin; Genentech) monotherapy and again showed 12-week durability after the completion of 3 loading doses. Luminate also met its primary and secondary endpoints as a monotherapy treatment for DME in the DEL MAR stage 1 trial.

The primary endpoint of the DEL MAR phase 2 stage 2 study was noninferiority to bevacizumab in mean change in BCVA at 20 weeks when Luminate was used with a single bevacizumab pretreatment (sequential therapy) or in combination with bevacizumab. The Luminate results were achieved after 1 treatment of 1.25 mg bevacizumab followed by 3 1.0-mg Luminate injections (weeks 1, 4, and 8) and 12 weeks off treatment, compared to 5 injections given every 4 weeks with bevacizumab. Mean gain in BCVA was 7.1 letters for patients in the Luminate with bevacizumab pretreatment group compared to 6.7 letters for patients in the bevacizumab control group.

“These study results are very promising,” said David S. Boyer, MD, of Retina Vitreous Associates in Los Angeles. “Not only could Luminate be used as an effective monotherapy with fewer injections, but the latest data suggest that this drug, when used as a sequential therapy with an anti-VEGF agent, may provide physicians and DME patients with a new treatment paradigm for DME. Used this way, Luminate with an anti-VEGF pre-treatment could be used to clear VEGF, decrease VEGF production, and cut inflammation at the same time.”

Researchers Use Gene Editing to Target Angiogenesis in the Retina

Schepens researchers make major preclinical advance.

■ A team of researchers from the Schepens Eye Research Institute of Massachusetts Eye and Ear in Boston has prevented mice from developing angiogenesis of the retina by using CRISPR-Cas9 gene-editing techniques. The research, supported by NIH and NEI grants, was reported in an online article in the journal Nature Communications, and study authors say it could open the door to new methods of treating the most prevalent retinal diseases. CRISPR technology has already been widely studied as a potential approach to treating inherited retinal diseases.

“We know that vascular endothelial growth factor receptor 2 (VEGFR2) plays an essential role in angiogenesis,” said corresponding author Hetian Lei, PhD, assistant scientist at Massachusetts Eye and Ear and assistant professor of ophthalmology at Harvard Medical School. “The CRISPR-Cas9 system can be utilized to edit the VEGFR2 gene, preventing intraocular pathological angiogenesis.

“As this genomic editing gains traction in virtually all medical fields, we are cautiously optimistic that this powerful tool may present a novel therapy to prevent vision loss in eye disease marked by intraocular pathological angiogenesis,” said Dr. Lei. “While further study is needed to determine safety and efficacy of this approach, our work shows that the CRISPR-Cas9 system is a precise and efficient tool with the potential to treat angiogenesis-associated diseases.”

“Hetian’s study has identified an attractive target for genome editing for AMD,” said Luk Vandenberghe, PhD, a coauthor and member of the research team at Massachusetts Eye and Ear. “Clinical translation of these and other approaches that are efficacious and safe however will hinge on further extensive development of technologies specific to editing and a deeper understanding of the genome editing biology and its limitations.”

The researchers employed an adeno-associated virus (AAV) as a delivery vehicle to genomically edit VEGFR2 in mouse pups. A single injection of this therapy was able to prevent retinal angiogenesis in preclinical models. The effect of the therapy favorably compared to a control group of mouse pups that had been induced with angiogenesis but did not receive the gene-editing treatment.

“CRISPR-Cas9 gene editing holds great promise for treating an array of retinal diseases, particularly inherited retinal diseases,” said Joan W. Miller, MD, chief and chair of ophthalmology, Massachusetts Eye and Ear and Massachusetts General Hospital, Harvard Medical School. “Gene-based therapies have potential for angiogenic eye diseases like AMD and diabetic retinopathy, but these diseases are currently well controlled with anti-VEGF agents and long-term delivery strategies of these agents are on the horizon. Genome editing approaches would need to target sufficient neovascular endothelium without affecting normal retinal and choroidal vessels, and this may be a difficult hurdle. Genome editing in inherited retinal diseases may offer greater opportunity.”

Regarding research using gene editing in inherited retinal diseases, Allergan has an agreement with the gene-editing company Editas that initially targets the gene mutation that causes Leber’s congenital amaurosis, and researchers at the University of California San Diego and also at Columbia University (in collaboration with the University of Iowa) are studying the potential of using gene editing as a therapy for inherited retinal diseases.

IN BRIEF

Allegro obtains financing for drug trials

■ Allegro Ophthalmics, a biotechnology company focused on developing novel therapies to treat retinal diseases, has announced the completion of a private round of equity financing for $10.7 million. With this infusion of capital, the company says it is strongly positioned to reach future corporate milestones.

The company’s lead drug candidate, the integrin peptide therapy Luminate, targets integrin receptors that are involved in creating new and aberrant blood vessels. It has met the endpoints for two phase 2 monotherapy studies for the treatment of DME and vitreomacular traction.  In addition, topline results of its phase 2, stage 2 DME clinical trial in which Luminate is being evaluated in combination and as an adjunctive therapy with anti-VEGF, will be announced this year.

pSivida uveitis implant effective in phase 3

■ pSivida Corporation, a leader in the development of sustained-release drug products and technologies, said the company’s second phase 3 trial of Durasert 3-year treatment for posterior segment uveitis achieved the trial’s primary endpoint.

The study involved 153 patients and the primary endpoint was prevention of recurrence of posterior uveitis at 6 months with patients continuing to be followed for 36 months. The Durasert 3-year insert demonstrated a significant reduction in the recurrence of posterior segment uveitis through 6 months; 21.8% of Durasert-treated patients had a recurrence compared to 53.8% of patients in the sham group.

pSivida has applied to the European Medicines Agency for marketing authorization approval of the Durasert implant.

Besse Medical acquires PODIS

■ Besse Medical, a leading pharmaceutical supplier and solutions partner and part of AmerisourceBergen, has added to its portfolio of inventory management solutions by acquiring Physician Office Drug Inventory System (PODIS), a cloud-based inventory and billing reconciliation system.

The PODIS system uses barcode labels to track every dose of medication used in practice offices and interfaces with the practice management system to ensure proper billing and complete payment. Automating the drug ordering and tracking process creates an integrated order-to-reimbursement solution. Practices can seamlessly order medications, track shipments and invoices, and have insight into billing accuracy vs drug utilization.

Beaver-Visitec acquires Vitreq

■ Beaver-Visitec International, a maker of specialized ophthalmic surgical devices, has acquired Netherlands-based Vitreq, which manufactures a range of minimally invasive ophthalmic instruments, primarily for vitreoretinal surgery. Vitreq says its in-house team of R&D, engineering, and manufacturing professionals collaborates with noted surgeons to produce a portfolio of high-quality instruments.

FDA to review Spark approval request

■ Spark Therapeutics, a pioneering gene therapy company, said the FDA has accepted for filing the Biologics License Application (BLA) and granted priority review for voretigene neparvovec, an investigational, potential one-time gene therapy candidate for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD). The investigational gene therapy, which has the proposed trade name LUXTURNA, has the potential to be both the first pharmacologic treatment for IRD and the first gene therapy for a genetic disease in the United States.

B+L launches Stellaris Elite retina surgery system

■ Bausch + Lomb has introduced the Stellaris Elite vision enhancement system for retina surgery in the US market. This system, which received FDA clearance in April, features numerous advancements, as well as the capability to easily integrate future technologies, such as the Vitesse hypersonic vitrectomy system, which has been designed for compatibility with the Stellaris Elite system.

“Specifically designed for retina surgery, this Stellaris Elite model represents a new level of surgical control and efficiency,” said Chuck Hess, vice president and general manager, U.S. Surgical, Bausch + Lomb. “The system offers leading-edge technologies and a broad range of options and accessories.”

Quantel laser gets FDA approval

■ Quantel Medical has received FDA approval for the Easyret fully integrated 577nm yellow photocoagulator, used to treat certain forms of macular edema and peripheral retinal pathologies. The company says the Easyret has a range of settings to treat ocular pathologies, including DR, macular edema, and central serous chorioretinopathy. Surgeons can use either SingleSpot treatment mode, MultiSpot for a pattern of simultaneous targets, or the SubLiminal mode, which enables them to customize short pulses to accurately manage the thermal effect on targeted tissues.

Topcon launches research support effort

■ Topcon Medical Systems has established the Topcon Research Foundation to support studies sponsored by independent investigators and institutions using Topcon products to advance ophthalmology. Researchers and institutions may apply for a grant by submitting their request and study details to www.topconresearchfoundation.com .