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SUBSPECIALTY NEWS: Stem-cell therapy for geographic atrophy, artifacts in OCTA, European opinion for Beovu, and more.

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Patient-Specific Stem-Cell Therapy for GA

Converting patients’ blood cells to stem cells.

■ Researchers at the National Eye Institute (NEI) are beginning a clinical trial to test the safety of a novel patient-specific stem-cell–based therapy to treat geographic atrophy (GA), which currently has no approved treatment, although numerous clinical trials are now under way.

“The protocol, which prevented blindness in animal models, is the first clinical trial in the United States to use replacement tissues from patient-derived induced pluripotent stem cells (iPSC),” said Kapil Bharti, PhD, a senior investigator and head of the NEI  Ocular and Stem Cell Translational Research Section, in a news release.

The therapy involves taking a patient’s blood cells and, in a lab, converting them into iPSCs, which have the potential to form any type of cell in the body. The iPSCs are programmed to become retinal pigment epithelial (RPE) cells. The therapy is an attempt to shore up the health of remaining photoreceptors in GA by replacing dying RPE with iPSC-derived RPE.

Before they are transplanted, the iPSC-derived RPE are grown in sheets one cell thick, replicating their natural structure within the eye. This monolayer of iPSC-derived RPE is grown on a biodegradable scaffold designed to promote integration of the cells within the retina. Surgeons position the patch between the RPE and the photoreceptors using a specially designed surgical tool.

Under the phase 1/2a clinical trial protocol, 12 patients with advanced-stage GA will receive the iPSC-derived RPE implant in one of their eyes and be closely monitored for a period of at least 1 year to confirm safety.

A concern with any stem-cell–based therapy is its oncogenic potential. In animal models, the researchers genetically analyzed the iPSC-derived RPE cells and found no mutations linked to potential tumor growth. Moreover, the use of an individual’s autologous blood cells is expected to minimize rejection risk. Should early safety be confirmed, later study phases will include more patients to assess the efficacy of the implant to prevent blindness and restore vision in patients with GA.

An FDA requirement for moving forward with the clinical trial was the establishment of good manufacturing practice (GMP) protocols to ensure that the iPSC-derived RPE are a clinical-grade product. GMP protocols are key to making the therapy reproducible and for scaling up production should the therapy receive FDA approval.

Artifacts Seen Prevalent in OCTA Imaging

Study results could have implications for accurate interpretation.

■ In a cross-sectional study led by Ian C. Holmen, MD, of the University of Wisconsin, Madison, that included 406 optical coherence tomography angiography (OCTA) images of eyes with diabetic retinopathy, the prevalence of artifacts was 53.5%, with shadow, defocus, and movement seen as the most common artifacts. Proprietary quality indices commonly used for identifying unreliable images had a high sensitivity (99%) but low specificity (37% to 41%).

Study results, which were recently reported in JAMA Ophthalmology, suggest that knowledge of OCTA artifacts may be important in accurately interpreting these images for patient care and in clinical trials. This cross-sectional study evaluated baseline OCTA images acquired in multicenter clinical trials and submitted to the Fundus Photograph Reading Center in Madison, Wisconsin, between January 1, 2016, and December 31, 2018. Images were captured using the 3 mm  x  3 mm and/or 6 mm  x  6 mm scan protocol with commercially available OCTA systems. Artifacts, including decentration, segmentation error, movement, blink, refraction shift, defocus, shadow, Z offset, tilt, and projection, were given a severity grade based on involvement of cross-sectional OCT and area of OCT grid affected.

Findings from this study suggest that artifacts associated with quantitative outputs on commercially available OCTA devices are highly prevalent and that identifying common artifacts may require correlation with the angiogram and cross-sectional OCT scans. Knowledge of these artifacts and their implications for OCTA indices appears to be warranted for more accurate interpretation of OCTA images.

Kodiak Sells Future KSI-301 Royalties

Drug may treat a range of retinal diseases.

■ Kodiak Sciences said the company has agreed to sell a capped royalty right on future global net sales of investigational retinal drug KSI-301 to Baker Bros. Advisors (BBA) for $225 million. KSI-301 is Kodiak’s promising, early-stage investigational therapy being developed for the treatment of retinal vascular diseases, including AMD and diabetic eye diseases.

Under the terms of the agreement, BBA purchased a capped 4.5% royalty on net sales of the company’s novel anti-VEGF antibody biopolymer conjugate (ABC), which could amount to more than $1 billion if a number of milestones for the drug are met. The initial upfront payment will be $100 million. Unless terminated earlier or repurchased by the company, the royalty terminates on the date that BBA has received an aggregate amount equal to 4.5 times the funding amount paid to the company.

A recent phase 1b trial for KSI-301 has aroused great interest in the retina community (see the October 2019 Retinal Physician article, “Safety Data on KSI-301 Antibody Biopolymer Conjugate for Retinal Disease”). The interest stems from the drug’s durability and its potential to successfully treat a range of retinal diseases.

KSI-301 is built on Kodiak’s ABC platform and is designed to maintain potent and effective drug levels in ocular tissues for longer than existing agents. Kodiak recently announced positive durability data in patients with wet AMD, DME, RVO, and diabetic retinopathy treated in its phase 1b clinical study of KSI-301.

“The emerging durability data suggest our objective for KSI-301 to be a leading next-generation anti-VEGF therapy with a long-interval durability profile is achievable,” said Jason Ehrlich, MD, PhD, Kodiak’s chief medical officer and chief development officer, in a news release. “In the presented cohort of treatment-naïve wet AMD patients followed for 12 weeks or longer after the loading phase, all achieved a treatment-free interval of 3 months or longer, with the majority reaching a 4- or 5-month interval and continuing to be followed without retreatment to date.”

In related news, Kodiak recently raised $317.4 million in new funds via a common stock offering.

Beovu Gets Favorable European Opinion in Wet AMD

Drug achieves step toward EU approval.

■ Novartis announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for Beovu (brolucizumab 6 mg), also known as RTH258, an investigational product in Europe for the treatment of wet AMD. The move is a key milestone in achieving approval from the European Commission.

“Today’s CHMP opinion brings us another step closer to providing wet AMD patients in Europe with a new treatment option,” said Nikos Tripodis, worldwide franchise head of Novartis Ophthalmology, in a news release.

The positive CHMP opinion is based on findings from the phase 3 global, head-to-head HAWK and HARRIER clinical trials, in which Beovu demonstrated noninferiority vs aflibercept in mean change in best corrected visual acuity from baseline to year 1. In both trials, approximately 30% of patients treated with Beovu gained at least 15 letters at year 1.

In prespecified secondary endpoints, fewer patients treated with Beovu 6 mg vs aflibercept had intraretinal and/or subretinal fluid at week 16 (35% fewer patients in both HAWK and HARRIER) and at year 1 (30% fewer patients in HAWK and 41% fewer patients in HARRIER). Significant reductions in central subfield thickness were also seen with Beovu. More than half (56% in HAWK and 51% in HARRIER) of patients treated with Beovu 6 mg maintained a 3-month dosing interval immediately after the loading phase through year 1. Beovu patients who started on 3-month dosing intervals after the loading phase had an 85% (HAWK) and 82% (HARRIER) probability of remaining on this interval through year 1. In October 2019, Novartis received the first, and so far the only, approval for Beovu from the FDA in the treatment of wet AMD. The European Commission will consider the CHMP opinion as it makes its final decision on the marketing authorization for Beovu. The decision is expected within 3 months.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Paul Tornambe, MD, Retina Innovator, Dies at 73

■ Paul E. Tornambe, MD, FACS, the founder of Retina Consultants San Diego and a noted innovator in both the treatment of retinal detachment and creating new surgical devices, passed away on December 23, after a long battle with pulmonary fibrosis and 2 lung transplants. He was 73.

Dr. Tornambe, a graduate of the Creighton University School of Medicine, completed his residency in ophthalmology at Pacific Presbyterian Medical Center. He then completed a 2-year residency in surgical retina at Washington University in Saint Louis before starting his own practice.

Dr. Tornambe had a passion for retina and was known for his honesty, ethics, and being available to his patients 7 days a week. He was also an accomplished drummer, a skill that he displayed in a performance with several other musician colleagues at the 2014 meeting of the American Society of Retinal Specialists.

FDA Approves Tissueblue for ILM Staining

■ DORC has received notice from the FDA that its New Drug Application for Tissueblue (Brilliant Blue G Ophthalmic Solution) 0.025% has been approved. Tissueblue is the first FDA-approved dye for use as an aid in ophthalmic surgery by selectively staining the internal limiting membrane (ILM). The transparent nature of the ILM makes it difficult to visualize and peel. Tissueblue is injected onto the inner retinal surface, enabling the ILM to be clearly stained and distinguished from unstained retina, thereby facilitating removal.

Researchers to Study History of Gene Mutation in RP

■ The Foundation Fighting Blindness has launched a natural history study for people with retinitis pigmentosa (RP) caused by mutations in the gene EYS. The study is called Pro-EYS. The goals of the international, 4-year study include estimating the rate of disease progression and evaluating the usefulness of various outcome measures for future clinical trials for emerging therapies.

“This is an important study because it is characterizing one of the most common genetic causes of retinitis pigmentosa. Natural history studies, such as this, are critical for understanding the impact any therapy may have on the natural progression of disease. These efforts will help accelerate the development of treatments,” said Mark Pennesi, MD, PhD, Oregon Health & Science University, and study chair for Pro-EYS, in a news release.

“The findings from this natural history study will be published and widely disseminated so that we can share what we learn with therapy developers from around the world,” said Todd Durham, PhD, vice president of clinical development and outcomes research at the foundation. “Our goal is to boost and accelerate EYS therapy development for all commercial and academic researchers.  One way we do this is to make de-identified data from the study accessible to researchers who can use it to design clinical trials.”

Enrollment Complete in All Faricimab Phase 3 Trials

■ Genentech and Roche have completed patient enrollment in the TENAYA and LUCERNE phase 3 clinical trials investigating faricimab for the treatment of wet AMD. The phase 3 YOSEMITE and RHINE diabetic macular edema (DME) clinical trials completed patient enrollment in September 2019. With these milestones, Genentech and Roche ended 2019 having fully recruited the current faricimab phase 3 clinical trial program, including more than 3,000 patients in 2 diseases, ahead of schedule.

Faricimab is the first bispecific antibody designed specifically for the treatment of retinal diseases. This investigational medicine simultaneously binds to and neutralizes angiopoietin-2 (Ang2) and vascular endothelial growth factor A (VEGF-A). By targeting both Ang2 and VEGF-A, faricimab may lead to improved and sustained efficacy at longer treatment intervals, thereby delivering better vision outcomes for patients.

Quantel Launches Vitra 2 Photocoagulator

■ Quantel Medical has received approval from the US FDA for the Vitra 2 photocoagulator with a wide range of improvements and new features. Vitra 2 includes the key elements of reliability, compactness, and versatility that have always been signature features of this device. Vitra 2 also features a new generation of optimized laser cavity with an increased maximum power level. It is also now compatible with SingleSpot and MultiSpot technologies.

Vitra 2 features an easy-to-use, clinically oriented software interface, simplifying the treatment procedures and the physicians’ workflow thanks to printable treatment reports. Vitra 2 is compatible with Haag Streit and Zeiss slit lamps as well as Quantel Medical YAG and YAG/SLT lasers, and it can be connected to a wide range of delivery systems (operating microscopes, laser indirect ophthalmoscopes, and laser probes).

Proxima Studies Show Lesion Growth and Vision Loss in GA

■ Researchers led by Nancy Holekamp, MD, reported recently in the journal Ophthalmology that the large Proxima A and B prospective observational studies demonstrated the severe functional impact of geographic atrophy (GA) and rapid rate of GA lesion progression over 2 years. At 24 months, the adjusted mean (standard error) change in GA lesion area from baseline was 3.87 mm2 in participants with bilateral GA (Proxima A), 3.55 mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 mm2 in the fellow eye intermediate AMD cohort (Proxima B). GA progression was greater in patients with baseline non-subfoveal (vs. subfoveal) GA lesions, and tended to increase as baseline low-luminance deficit increased (Proxima A; Proxima B, all patients). Patients lost about 10 ETDRS letters at 2 years across all subgroups.

“This lies contrary to the perception that GA is a slowly progressive disease,” said Dr. Holekamp in a news release.

ADA Endorses AI Screening for Diabetic Eye Disease

■ The nation’s leading association that fights against diabetes released a new set of clinical standards that for the first time include the use of autonomous artificial intelligence (AI). The American Diabetes Association (ADA)’s 2020 Standards of Medical Care in Diabetes states, “AI systems that detect more than mild diabetic retinopathy and diabetic macular edema authorized for use by the FDA represent an alternative to traditional screening approaches.”

To date, IDx-DR is the first and only FDA-authorized autonomous AI diagnostic system for the detection of diabetic retinopathy and macular edema. It is currently in use at a number of large health systems that each serve tens of thousands of people with diabetes and have struggled to implement diabetic retinopathy eye exams at scale for their large diabetes population.

“The ADA’s inclusion of our technology in its Standards of Care marks a significant move toward mainstream adoption of autonomous AI in clinical care,” said Michael Abramoff, MD, PhD, founder and executive chairman at IDx. “Our early customers are visionary leaders who foresaw that autonomous AI would one day become a standard of care for diabetic retinopathy screening, and taking that leap is paying off for them. Already, health systems that are using IDx-DR have experienced significant improvements in accessibility, efficiency and compliance rates, unleashing massive potential for cost savings and improved patient outcomes.”

ProQR Begins RP Trial With RNA Drug

■ ProQR Therapeutics N.V. said the first patient has been dosed in its phase 1/2 Aurora clinical trial of QR-1123 in patients with autosomal dominant retinitis pigmentosa (adRP). Initial data from the study are expected in 2021.

“From previous clinical trials we have seen that RNA therapies can be a promising approach for patients with inherited retinal diseases, and there is a strong need for novel approaches in diseases that currently have no treatments,” said David G. Birch, PhD, principal investigator of Aurora and scientific director of the Retina Foundation of the Southwest in Dallas, Texas, in a news release. “QR-1123 has shown encouraging results in preclinical models and we hope to see that translated to the clinic in this first-in-human trial in patients with adRP.”

ProQR has also announced that it received orphan drug designation from the FDA for QR-1123, a first-in-class investigational antisense oligonucleotide designed to address the underlying cause of vision loss associated with autosomal dominant RP.

Quantel and Ellex to Combine Businesses

■ Lumibird Group, the parent company of Quantel Medical, has signed an agreement with the Australian company Ellex Medical Lasers to acquire Ellex’s laser and ultrasound business for $100 million AUD (approximately $69.4 million USD). The company says the acquisition, if approved, will create a world leader for laser and ultrasound technologies for the diagnosis and treatment of ocular diseases.

“The future success of both companies depends on sharing R&D capability and manufacturing structures, and on strengthening our approach to clinical research in order to meet the current and future needs of the ophthalmologists,” said Jean-Marc Gendre, Quantel Medical’s CEO, in a news release. He added that Quantel Medical and Ellex have complementary strengths and that coming together enables the combined businesses to offer a broader range of products at all price points to better meet diverse client needs.

Lineage Cell Therapeutics Updates Dry AMD Trial

■ Lineage Cell Therapeutics has announced additional patient data from its ongoing phase 1/2a clinical study of OpRegen, the company’s retinal pigment epithelium (RPE) transplant therapy, for the treatment of dry AMD. The first cohort 4 patient treated using both a new subretinal delivery system and the company’s new thaw-and-inject formulation of OpRegen has continued to demonstrate notable improvements in vision, having gained 25 readable letters (or 5 lines) 6 months following administration of OpRegen RPE cells, as assessed by the Early Treatment Diabetic Retinopathy Scale (ETDRS). This represents an improvement in visual acuity from a baseline of 20/250 to 20/100 in the treated eye.

A second cohort 4 patient has also been similarly dosed, and though early, the patient has shown a small improvement in visual acuity in the treated eye at just 14 days following treatment. To date, improvements have become most evident approximately 3 to 6 months after treatment. Both patients had rapid healing at the surgical site with no unexpected complications or any serious adverse events. RP

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by REGENXBIO.