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SUBSPECIALTY NEWS: Gene-derived anti-VEGF, 16-week dosing on the horizon, and more.

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Data Promising on Gene-Derived Anti-VEGF

The eye becomes a miniature drug factory.

■ Regenxbio, which is conducting an 18-patient, phase 1 clinical trial of its RGX-314 gene-therapy-derived anti-VEGF for wet AMD, reported that its highest-dosed cohort (6 patients) had an encouraging response that included a mean 8-letter gain in BCVA and a mean reduction in central retinal thickness.

Three of the 6 patients in what the company called a “difficult-to-treat” study group, required no anti-VEGF injections at 6 months following a single injection of RGX-314.

The data from the highest-dosed cohort showed great improvement over the two lower-dosed cohorts. The company is now planning to treat a fourth cohort with an even higher dose of RGX-314.

Regenxbio is dosing its patients via subretinal injection, while a competitor, Adverum, which is about to begin its initial clinical trial for gene-derived anti-VEGF in wet AMD, is employing the more commonly used intravitreal administration. Gene-therapy-derived anti-VEGF has been described as implanting a miniature drug factory in the eye that produces medication over time. If proven feasible, it could greatly reduce the retreatment burden for a range of retinal diseases.

“We believe that subretinal administration is the most direct route to get a higher level of anti-VEGF to where it needs to go while avoiding neutralizing antibodies,” says Stephen Yoo, chief medical officer of Regenxbio.

“This is the first reported wet AMD gene therapy study to detect intraocular protein being made in the eyes of all subjects. I am encouraged by the dose-dependent increases in protein and biological effect seen in the study that correlated with signals of efficacy,” said Jeffrey Heier, MD, co-president and director of Retina Research at Ophthalmic Consultants of Boston and primary investigator for the trial.

“We are encouraged by the positive interim data for RGX-314, which shows the potential for one-time treatment in wet AMD,” said Ram Palanki, PharmD, senior vice president of commercial strategy and operations at Regenxbio.

Second Sight to Focus on Next-Generation Orion

Cortical connection opens much larger market.

■ In a strategic decision that the company said has long been planned, Second Sight Medical will now prioritize development of its next-generation Orion Cortical Visual Prosthesis System that connects directly to the brain. The cortical connection is designed to provide some functional vision to individuals with virtually any type of blindness, giving it far greater market potential than the FDA-approved Argus II, whose market consists of patients with profound vision loss from advanced retinitis pigmentosa.

Second Sight CEO Will McGuire said an independent study of US market potential for both the Argus II and the Orion concluded that the Argus was suitable for approximately 1,500 patients, while the Orion could be helpful to about 70,000.

“The Orion candidates tend to be younger and healthier, with many of them being blinded by trauma,” said McGuire. “This constitutes an ideal group of candidates and a multibillion opportunity for Second Sight.”

Five patients have already had Orion implanted in a feasibility study and a sixth has recently been approved to receive the device. So far, all patients have been able to see spots of light from the full array of electrodes in laboratory testing. At least one of the earliest Orion recipients is expected have his camera turned on and be cleared for home use of the device. One of the Orion recipients did have a seizure during lab testing but remained in the program after review by a safety committee.

In other Second Sight news, company chairman Gregg Williams has provided an additional $5 million in funding to add to the $7.5 million the company had on hand at the end of the second quarter. The company is expected to undertake a larger financing effort, with a presentation based on the potential of the Orion device.

New Device Images Individual Photoreceptors

Instrument is seen as an advance in diagnostic tools.

■ Duke University researchers have developed and demonstrated the first handheld ophthalmology instrument with resolution-boosting adaptive optics technology that can image individual photoreceptors in the eye. The study was published in the journal Optica in September. The researchers say the new portable instrument has the potential to allow improved diagnosis of eye diseases and could also enable early detection of brain-related diseases and trauma. They tested the device in children and adults, demonstrating its ability to capture images of even the very small photoreceptors close to the center of the retina that play a key role in vision.

“Our portable handheld system could expand this important imaging technique to children and infants, as well as to adults who may not be able to sit upright and stare straight ahead,” which has been necessary for traditional testing, said research team leader Sina Farsiu from the Departments of Biomedical Engineering and Ophthalmology at Duke. The system could be used on people in a reclined position as they undergo surgery, for example, Farsiu’s team reports. It could also help doctors rapidly assess possible brain trauma, such as in football players coming off the field with head injuries.

To image photoreceptors today, doctors commonly use a device known as an adaptive optics scanning laser ophthalmoscope (AOSLO). Although adaptive optics greatly improves the resolution compared to a standard scanning laser ophthalmoscope, the optical components required also increase the size, weight, and cost of the overall system. To shrink the components within an AOSLO, the researchers developed a new algorithm to perform wavefront sensing. The researchers also incorporated a commercially available MEMS-based deformable mirror measuring just 10.5 mm in diameter. The result was a small and highly stable instrument. They used their new system, called HAOSLO (handheld AOSLO), to image the retinas of 12 healthy adult volunteers and 2 children under anesthesia.

The application of the system on a 31-month-old child represents the first use of adaptive optics to image photoreceptors in children. Before starting large-scale clinical trials with the instrument, the researchers plan to incorporate additional imaging modalities useful for detecting disease.

Faricimab Shows Potential for 16-Week Dosing

Initial data presented from Genentech’s STAIRWAY study.

■ The first data coming from Genentech’s phase 2 STAIRWAY trial using the bispecific anti-VEGF/anti-Ang2 faricimab (formerly called RG7716) in wet AMD show early potential for every 16-week dosing in treatment-naïve patients. At 24 weeks into the study, 36 of 55 patients (65%) had no active disease 12 weeks after their last faricimab loading dose, leading to the study’s conclusion that those patients were in no immediate need of retreatment. The potential of more durable every 16-week dosing is considered important because other investigational drugs for wet AMD have recently shown efficacy at 12-week retreatment intervals, while both Eylea (Regeneron) and Lucentis (Genentech) have been approved for conditional 12-week dosing based on physician assessment.

The data were presented at the recent Retina Society meeting by Pravin U. Dugel, MD, of Retinal Consultants of Arizona, who also reported the first clinical results from Genentech’s AVENUE trial for faricimab, a 273-patient, phase 2 trial comparing faricimab, ranibizumab, and a faricimab/ranibizumab combination in treatment-naïve wet AMD patients. In this 5-arm study, a 1.5 mg dose of faricimab given every 4 weeks demonstrated the best vision gain at +9.1 letters at 36 weeks.

All 5 arms showed significant reductions in central subfield thickness, with the faricimab/ranibizumab combination arm demonstrating the largest reduction at -185 microns. In commenting on the overall data, Dr. Dugel said the bispecific nature of faricimab was a potential benefit, as “there are signs that the Ang-2 suppression has a vascular stabilization effect.”

Data were previously released from a third faricimab phase 2 trial, the 229-patient BOULEVARD study. That trial met its primary endpoint, as faricimab demonstrated statistically significant BCVA gains over ranibizumab at week 24 in anti-VEGF treatment-naïve patients with DME.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

FDA Adds 12-Week Dosing to Eylea Label

■ Regeneron Pharmaceuticals said the FDA has amended the label for Eylea (aflibercept) by adding an approval for every-12-week dosing for wet AMD patients who have had 1 year of effective therapy and who are assessed regularly. The new labelling does assert that a 12-week retreatment schedule is “not as effective as the recommended every 8-week dosing regimen.”

The supplemental Biologics License Application (sBLA) for 12-week Eylea dosing that the FDA acted on was based on second-year data from the VIEW studies, during which patients were treated with a modified 12-week dosing schedule (doses given at least every 12 weeks and additional doses as needed).

In a related development, the FDA has accepted Regeneron’s supplemental Biologics License Application (sBLA) of aflibercept for the treatment of diabetic retinopathy. The target action date for the FDA decision is May 13, 2019. The sBLA submission is based on results from the phase 3 PANORAMA trial of Eylea as a treatment for patients with moderately severe to severe nonproliferative DR without DME.

Endophthalmitis Following Anti-VEGF Injection

■ Researchers led by Szilard Kiss, MD, of Weill Cornell Medical College in New York, conducted a large-scale study of the incidence of infectious and noninfectious endophthalmitis following anti-VEGF injection and found that the overall incidence was very low at 0.061%. The researchers studied 818,558 US claims over an 18-month period from 2011 to 2013 and identified 498 cases of endophthalmitis, with ranibizumab (Lucentis) having the lowest incidence. Within 14 days after endophthalmitis, 38.6% of cases received injectable antibiotics, 15.3% received injectable steroids, and 30.3% underwent vitrectomy.

The authors, who reported their findings in a recent issue of Clinical Ophthalmology, concluded that while rates of endophthalmitis following treatment with intravitreal anti-VEGF agents are very low, ophthalmologists should still be aware of the risk of the complication developing.

Adverum to Start Wet AMD Gene Therapy Trial

■ Adverum Biotechnologies, a clinical-stage gene therapy company targeting unmet medical needs in serious rare and ocular diseases, said its Investigational New Drug application is active for the planned multicenter, open-label, phase 1, dose-escalation study of ADVM-022, a novel gene therapy candidate for the treatment of wet AMD.

One injection of ADVM-022 creates a drug factory in the eye that can continuously produce a gene-derived replicate of aflibercept over the long term, with the potential of significantly reducing the treatment burden of regular anti-VEGF injections.

Six leading retinal centers across the United States are expected to participate in the phase 1 trial. The trial is expected to enroll 18 patients and will evaluate three doses of ADVM-022. Patients will be administered a tapering prophylactic corticosteroid regimen.

The primary endpoint of the trial is the safety and tolerability of ADVM-022 at 24 weeks after a single intravitreal injection. Secondary endpoints include changes in BVCA at 24 weeks, measurement of central retinal thickness, and number of rescue aflibercept injections. Each patient enrolled will be followed for a total of 2 years.

Scleral Depressor Takes “Winning Pitch” Prize

■ Gary Ganiban, MD, of the Eye Institute for Medicine and Surgery, Melbourne, FL, took home the $10,000 first prize in the second annual “Winning Pitch” competition, held in conjunction with the recent ASRS annual meeting. The competition provides a showcase — and the presence of potential investors — for development-stage innovation in ophthalmology.

Dr. Ganiban’s disposable device, the patented hands-free Gani-Hand Scleral Depressor, is the product of 4 years of research and numerous iterations. It is designed as a “third hand” for both clinical and surgical procedures, offering enhanced visualization while also reducing patient discomfort.

Mathew Macumber, MD, PhD, of Illinois Retina Associates, Chicago, took second place with his invention of a fluorescent test for night blindness and the early diagnosis of inherited retinal diseases (IRDs). The invention is particularly timely with the recent advent of gene replacement therapies that can reverse the vision loss from IRDs.

Third place went to Natalia Vila, MD, retina fellow at the University of Montreal, with her Scleral Depression Mechanical Assistant Device that clips onto the speculum. The device, which has two rotating rings that can address 360-degree depression while controlling the amount of depression, comes in both disposable and reusable versions.

The competition was judged by an expert panel that included ophthalmic executives and venture capitalists.

Researchers Win Champalimaud Award for Gene Therapy

■ Vision researcher T. Michael Redmond, PhD, chief of the National Eye Institute (NEI) Laboratory of Retinal Cell and Molecular Biology, is a recipient of the prestigious António Champalimaud Vision Award for foundational science discoveries about the molecular biology of the retina. His work deduced how the RPE65 gene converts dietary vitamin A into a form of the vitamin that is central to the workings of the visual cycle.

The award will be shared by 7 scientists. These researchers, 4 of whom were supported by NEI, are being recognized for contributions that led to the development of Spark Therapeutics’ gene therapy Luxturna for treating Leber congenital amaurosis (LCA). LCA is an inherited genetic disorder in which children with severe RPE65 mutations can be born blind. Those with less severe mutations may have some vision at birth, but often become blind by young adulthood.

“We owe much to Michael Redmond for establishing that defects in the retinal pigment epithelium are among the causes of diseases such as LCA and retinitis pigmentosa, and for setting a course toward an effective gene therapy approach to treat them,” said NEI director Paul A. Sieving, MD, PhD.

FDA Clears Heidelberg OCT Angiography Module

■ Heidelberg Engineering said it has received FDA clearance for its OCT Angiography Module (OCTA). The additional module is now available for new and existing Spectralis upgradeable diagnostic imaging devices.

“The addition of OCT angiography to Heidelberg’s Spectralis multimodal platform allows for the evaluation of retinal and choroidal vascular abnormalities in a noninvasive manner,” said Nadia K. Waheed, MD, MPH, Director of the Boston Image Reading Center and Associate Professor of Ophthalmology, Tufts University School of Medicine, Boston, in a news release. “I believe OCTA will soon become invaluable in our daily clinical routine for screening and diagnosing chorioretinal disorders.”

Bascom Palmer Again Rated First in Ophthalmology

■ For the 15th year in a row, Bascom Palmer Eye Institute in Miami was ranked first in ophthalmology in the U.S. News and World Report annual poll. The rankings are based on voting by a randomly selected group of board-certified ophthalmologists. Wills Eye Hospital in Philadelphia was rated second and Wilmer Eye Institute of Johns Hopkins University was third.

RXi Has Positive Early Data in Retinal Scarring

■ RXi Pharmaceuticals said its 9-patient phase 1/2 clinical trial of its RXI-109 RNA-based therapeutic in advanced wet AMD was safe and well tolerated, with patients in the highest of the 3 dosing groups showing the most positive clinical improvement in both BCVA and central lesion thickness. Each subject received a total of 4 doses of RXI-109 at 1-month intervals. RXI-109 was administered by intravitreal injection in 1 eye only. The dosing period (3 months) was followed by a 4-month observation period.

ThromboGenics Changes Company Name

■ ThromboGenics NV, a biopharmaeutical company focused on developing novel treatments for back of the eye disorders, is changing its name to Oxurion. ThromboGenics developed Jetrea, the only approved medical therapy for vitreomacular traction.

Patrik De Haes, MD, CEO of ThromboGenics, said “the new name, Oxurion, is designed to better reflect our ambition to deliver best-in-class therapies for back of the eye disorders. The renaming comes at a moment when we have reached important clinical milestones and are accelerating the execution of our unique pipeline of disease-modifying compounds for diabetic eye disease. Moreover, we are also looking at expanding our drug-development efforts into additional and new areas of back of the eye disease.”

Iridex Laser Accessory Gets FDA Clearance

■ Iridex Corporation announced the introduction of its updated TruFocus LIO Premiere laser accessory following FDA 510(k) review and clearance. The TruFocus LIO Premiere is a light combination and reflection viewing system used with Iridex retina laser systems and worn on the physician’s head.

The product combines a laser treatment beam from an Iridex laser source with the illumination beam of a binocular indirect ophthalmoscope. This mixed optical beam is used by a physician with a handheld ophthalmic examination lens to enter a patient’s pupil and to view and treat a patient’s retina. It provides a portable alternative to patients who cannot be examined or treated with a fixed slit lamp adapter. The device can be used to evaluate and treat patients of all ages, including infants, in an office, operating room, or ambulatory surgical center setting.

ProQR Has Encouraging Data From LCA10 Trial

■ ProQR released positive results from a planned interim analysis of its phase 1/2 trial of RNA-based QR-110 in patients with Leber congenital amaurosis 10 (LCA10) due to the p.Cys998X mutation in the CEP290 gene. LCA10 typically leads to childhood blindness and has no available treatment options.

In the trial, QR-110 demonstrated rapid and sustained improvement in vision in patients with LCA10, as measured by visual acuity and the mobility course performance, as well as being well tolerated with no serious adverse events recorded. Results were presented at the Retinal Degeneration 2018 meeting in Killarney, Ireland.

Thaddeus P. Dryja, MD, professor of ophthalmology at Harvard Medical School and Massachusetts Eye and Ear, said in a news release, “These results are the first human data to evaluate the clinical utility of RNA-based therapeutics in a human photoreceptor disease, particularly one with a severe unmet medical need. While a confirmatory trial will be required ... these results suggest that therapeutic oligonucleotides have the potential to be broadly applicable to a wide spectrum of inherited retinal disorders.”

Aerpio Raises $41.8 Million From Stock Offering

■ Aerpio Pharmaceuticals expects to receive net proceeds of approximately $41.8 million from the sale of common stock (NASDAQ symbol ARPO) after deducting the underwriting discounts and commissions and estimated offering expenses payable by it.

Aerpio intends to use the net proceeds from the offering for working capital and general corporate and administrative purposes. The company’s lead drug candidate AKB 9778, a small-molecule activator of the TIE2 pathway, is currently in a late-stage clinical trial for nonproliferative DR.

ThromboGenics Starts Plasma Kallikrein Study in DME

■ ThromboGenics NV (now Oxurion) has enrolled the first patient in a phase 1 open-label, multicenter, dose-escalation study evaluating the safety of the plasma kallikrein inhibitor THR-149 in the treatment of DME. THR-149 is a novel PKal inhibitor generated using Bicycle Therapeutics’ Bicycles technology platform, and the kallikrein-kinin system is considered a valid target for the treatment of DME through inhibition of plasma kallikrein.

Preclinical studies have demonstrated the potency and efficacy of bicyclic peptide inhibitors of PKal, such as THR-149, supporting its progression into clinical trials for the potential treatment of DME, via a VEGF-independent mechanism. The phase 1 study will primarily assess the safety of a single intravitreal injection of escalating dose levels of THR-149 in patients with DME. Approximately 18 patients will be enrolled.

Wills Eye to Test Retina Implant on RP Patients

■ Wills Eye Hospital has been given FDA approval to begin an early feasibility study to implant the Retina Implant Alpha AMS subretinal device in patients blind due to retinitis pigmentosa (RP). The device is manufactured by Retina Implant AG, Reutlingen, Germany, and has been designed to replace the non-functioning and absent photoreceptor cells in the eye lost to the RP deterioration.

The surgically implanted Alpha AMS chip stimulates the remaining components of the visual system to restore limited functional vision in blind RP patients. The eye’s own natural focusing system focuses light on a chip made of 1,600 photo diodes.

Allergan to develop Editas CRISPR therapy for LCA10

■ As part of an ongoing collaboration, Allergan has agreed to develop and commercialize Editas’s EDIT-101 globally as a treatment for LCA10. EDIT-101 is based on the Editas CRISPR-based genome-editing platform. Editas has received an upfront payment of $15 million, with an additional $25 million payable after FDA acceptance of an IND for the drug.

Some Plans Can Mandate Avastin as First-Line Therapy

■ The CMS has determined that Medicare Advantage health care plans can now require so-called “step” therapy for treatment of retinal diseases, with lower-cost drugs such as bevacizumab (Avastin; Genentech) mandated as first-line therapy for newly prescribed patients. If the lower-cost drug is not effective, physicians can move on to more expensive drugs.

Researcher Gets $4.8 Million Grant for RP

■ University of California, Irvine stem cell researcher Magdalene J. Seiler, PhD, has received a $4.8 million grant from the California Institute of Regenerative Medicine to continue developing a stem cell-based therapy for retinitis pigmentosa. The therapy may also be applicable to macular degeneration.

“Our goal is a treatment based on transplanting sheets of stem-cell derived retina, called retina organoids, to the back of the eye,” said Dr. Seiler in a news release.

Reflection Biotechnologies Given Orphan Status for Gene Therapy

■ Reflection Biotechnologies said the FDA has granted orphan drug designation to the company’s RBIO-101 program, an AAV-based gene therapy product for treating Bietti’s Crystalline Dystrophy (BCD).

“Receiving orphan drug designation from the FDA is a milestone. It validates our R&D progress and provides us with various incentives in further developing BCD gene therapy,” Richard R. Yang, founder and CEO of ReflectionBio, said in a company news release. “This brings hope to BCD patients and their families because BCD is a devastating blinding disease for which currently there is no approved treatment. ... As the next step, we plan to advance BCD gene therapy into human clinical trial.”

MeiraGTx Given “Rare Disease” Status for IRD

■ The FDA has granted MeiraGTx Holdings Plc, a developer of gene-based therapies for several diseases, the rare pediatric disease designation for the company’s gene therapy product candidate AAV-CNGA3 for the treatment of achromatopsia (ACHM) due to mutations in the CNGA3 gene.

ACHM is an inherited retinal disease that severely limits a person’s sight by preventing cone photoreceptors in the eye from functioning. Individuals with ACHM are often legally blind from birth, have extreme sensitivity to light, and experience involuntary eye movements.

AAV-CNGA3 is an investigational gene therapy treatment designed to restore cone function, delivered to the cone receptors at the back of the eye via subretinal injection.

Light Mask Ineffective for Noncentral DME

■ In the phase 3 CLEOPATRA study, the Noctura 400 Sleep Mask light mask from PolyPhotonix Medical did not help control noncentral DME and was no more effective than a sham mask.

“The analysis of compliance highlighted that wearing these light masks over 24 months might also not be a sustainable option, as compliance decreased over time,” wrote Sobha Sivaprasad of Moorfields Eye Hospital, London, UK, and colleagues, in Lancet Diabetes & Endocrinology. RP