IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Alcon Hosts Fellow Training Event

BY FRANK BRODIE, MD, VITREORETINAL FELLOW, DUKE UNIVERSITY EYE CENTER

■ The weekend before Thanksgiving, 40 first-year retina fellows from across the country converged on Fort Worth, Texas, for the second annual Alcon Retina Fellows Institute. Now 6 months into fellowship, fellows benefited from a course perfectly timed to review vitrectomy fundamentals and provide tips and tricks from experienced hands. The wealth of experience in instructors was formidable, from the advice of Kirk Packo, MD, on customization and fine tuning of Alcon’s Constellation to pearls from both Maria Berrocal, MD, and Audina Berrocal, MD, on complex detachment. Highlights included a discussion with Steve Charles, MD, on fluid dynamics in vitrectomy and the evolution of the myriad devices he has developed, a vitrectomy wet lab station, and tips from Dean Elliot, MD, on management of proliferative vitreoretinopathy.

The opportunity to learn from attendings across institutions facilitated discussion and hands-on experience with techniques that fellows would not normally have the opportunity to try. Training on optimization of the Ngenuity visualization system was informed by the growing number of procedures that have been performed using it. Attendees can use the theory and practical tips they learn on day 1 back in the operating room. The course is offered at no cost to retina fellows.

Gene Vectors Can Overcome Anti-AAV Antibodies

■ Applied Genetic Technologies Corporation (AGTC) reported new data from nonclinical studies evaluating the effect of pre-existing anti-AAV antibodies on the transduction and expression efficiency of AAV vectors. Results presented in a poster at the European Society of Gene and Cell Therapy conference showed that the presence of neutralizing antibodies (NAbs) to AAV in the serum or in the eye did not affect gene delivery, gene expression, or inflammation following ocular administration of AAV vectors.

“Pre-existing immunity to AAV remains a challenge for many AAV gene therapies due to the high prevalence of AAV in the general population,” said Mark Shearman, PhD, chief scientific officer of AGTC and lead author on the poster in a news release. “While the eye has partial immune privilege and appears less affected by NAbs, fully understanding the degree of vector neutralization that occurs following ocular administration of AAV-based gene therapies is important for the approval of our clinical-stage product candidates and for their safe and effective use in patients. The data support the safety and efficiency of our AAV vectors independent of NAb levels, which should allow use of these vectors in larger patient populations.”

Self-Prescribed Niacin Can Cause Damage to Retina

■ Retina specialists at the New York Eye and Ear Infirmary of Mount Sinai (NYEE) have shown that severe vision loss from a self-prescribed high dose of over-the-counter niacin is linked to injury of a specific cell type in a patient’s eye. The researchers report that discontinuing the vitamin led to reversal of the condition and have published their findings in the fall issue of the Journal of VitreoRetinal Diseases.

Niacin, also known as vitamin B3, is used to lower cholesterol and comes in prescription and over-the-counter forms. It can produce a rare toxic reaction called niacin-induced cystoid maculopathy, a form of retinal swelling.

“People often live by the philosophy that if a little bit is good, more should be better. This study shows how dangerous large doses of a commonly used over-the-counter medication can be,” said lead investigator Richard Rosen, MD, chief of the retina service at NYEE and the Mount Sinai Health System, in a news release. “People who depend on vision for their livelihood need to realize there could be long-lasting consequences from inadvertent overdosing on this vitamin.”

Clearside to Study Axitinib as Anti-VEGF

■ Clearside Biomedical said it has done significant preclinical testing of the anti-VEGF axitinib and plans to begin a clinical trial in 2020. Axitinib is already approved as a treatment for renal cell carcinoma with the trade name Inlyta (Pfizer).

Thomas A. Ciulla, MD, MBA, chief medical officer of Clearside, commented, “With a renewed focus on research and development, our team has spent the last several months performing additional analysis on our proprietary suspension of axitinib (CLS-AX) for suprachoroidal injection and we are now planning to advance this as our next internal development program.” Dr. Ciulla added that axitinib directly inhibits receptor tyrosine kinases, including VEGF receptors-1, -2, and -3 with high potency and specificity, and pan-VEGF inhibition may benefit patients who sub-optimally respond to current anti-VEGF therapy. “Further, our preclinical testing of CLS-AX using our proprietary microinjector demonstrated reduced growth of experimental neovascularization with decreased fluorescein leakage, and delivered the compound directly to affected tissues with durable drug levels, suggesting the potential to maintain visual gains and reduce clinical treatment burden in patients with angiogenic retinal diseases.”

Wet AMD Treatments Create Significant Economic Value

■ A new economic study, published in JAMA Ophthalmology and conducted by researchers representing several disciplines at the University of Southern California, quantified the benefits of treatment for wet AMD with anti-VEGF therapy. They found improvements in vision from these innovative treatments generated $5.1 billion to $8.2 billion in patient benefits over 3 years. This translates to $0.9 billion to $3.0 billion in societal value (patient benefits minus treatment costs) over 3 years. Future innovative treatments that lead to improved adherence would generate an additional $7.3 billion to $15.0 billion in patient benefits over 3 years, they estimate.

“We already know these drugs are effective based on clinical data. Our economic model helps translate clinical outcomes into dollar terms so payers and practitioners can quantify the value of treatment to patients rather than focusing on the treatment cost alone,” said Karen Mulligan, lead author on the study and a professor at the USC Price School of Public Policy and the USC Schaeffer Center.

To build the economic model, Mulligan and her team collected data from published literature on wet AMD patients treated with anti-VEGF therapy, translating average documented changes in visual acuity and treatment usage to quality-adjusted life years.

“Our model scenarios suggest that even though anti-VEGFs provide substantial benefits, a lot is left on the table due to low adherence,” said Mulligan. “One limitation in these types of modeling exercises is we often have access to vision data or treatment patterns, but not both for the same set of patients. Generating more comprehensive and long-run real world data on vision outcomes and treatment patterns would improve our ability to understand the impact of things like adherence on value.”

Roche to Acquire Company Studying Antifibrotics

■ Promedior has entered into a definitive merger agreement for Roche to acquire the company for an upfront payment of $390 million and conditional payments that could amount to $1.4 billion. With this acquisition, Roche will obtain full rights to Promedior’s entire portfolio of molecules for serious fibrotic diseases. One of the molecules, PRM-151, has successfully completed a phase 2 trial for idiopathic pulmonary fibrosis. Promedior, based in Lexington, Massachusetts, is developing PRM-167, the company’s preclinical ocular product candidate, to assess its potential in AMD. PRM-167 is a variant of human pentraxin-2 that is being developed specifically for intravitreal injection.

Fibrosis — along with angiogenesis and inflammation — is a progressive pathological process that leads to vision loss and is associated with a number of retinal fibrovascular diseases, including AMD and diabetic retinopathy.

Oral Drug Studied for Stargardt and Dry AMD

■ Belite Bio, a drug-development company targeting currently untreatable conditions in ophthalmology and metabolic diseases, has announced positive phase 1 data for LBS-008, a first-in-class oral therapy for the treatment of dry AMD and Stargardt disease. The LBS-008 therapy will be one of the first drugs to graduate from the US National Institute of Health’s (NIH) Blueprint Program, which has funded LBS-008’s discovery and development.

LBS-008 is an oral therapy that prevents the buildup of toxins (A2E) in the eye that cause Stargardt disease and contribute to dry AMD. The toxins are byproducts of the eye’s visual cycle, which are produced from vitamin A. It works by reducing and modulating a carrier protein, retinol-binding protein 4 (RBP4), that transports vitamin A to the eye. It does not directly interfere with the visual cycle, and therefore is unlikely to affect the visual cycle rate.

In a news release, Konstantin Petrukhin, PhD, who developed the concept for this oral therapy, said the drug was well tolerated systemically in this ascending-dose study, with a good safety profile. He added that the effect on the serum biomarker, and the reduction in RBP4, was promising for future studies.

OpRegen RPE Cell Therapy Effective for Dry AMD

■ Lineage Cell Therapeutics (formerly BioTime) announced positive results from an ongoing phase 1/2a study of its lead product candidate, OpRegen, a retinal pigment epithelium (RPE) cell transplant therapy currently in development for the treatment of dry AMD.

Data from the study demonstrate that treatment with OpRegen continues to be well tolerated and, at the furthest time point collected, all 4 cohort 4 patients treated have better visual acuity on an Early Treatment Diabetic Retinopathy Scale (ETDRS) in the treated eye (range +8 to +19 letters) than in the untreated eye (range -2 to +7 letters). The largest increase recorded at any single timepoint in a cohort 4 patient was +22 letters. Cohort 4 patients have better baseline vision and less advanced disease than patients in cohorts 1 to 3, who were legally blind at baseline.

Previously reported structural improvements in the retina and decreases in drusen density observed in some patients have been maintained and there is evidence of the continued presence of transplanted OpRegen cells in patients treated in the first 3 cohorts, some over 3 years following administration.

Of note, the first patient successfully dosed using the Orbit Subretinal Delivery System (Orbit SDS) as well as a new Thaw-and-Inject (TAI) formulation of OpRegen is also demonstrating signs of improved visual acuity having gained 13 letters in the 3 months following administration as assessed by ETDRS.

Sleep Apnea Can Exacerbate DME

■ New research from Taiwan presented at the recent AAO meeting shows that evidence is mounting that sleep apnea is a risk factor in the development of DME in diabetics and can also make DME more difficult to treat. Researcher Juifan Chiang, MD, and colleagues looked at 8-year data on all patients diagnosed with diabetic retinopathy at Chang Gung Memorial Hospital in Taiwan. They found that the rate of severe sleep apnea was much higher in those patients with DME (80.6%) than in those patients without DME (45.5%). They also found that the worse the sleep apnea was, the worse the DME and the more difficult to treat, often requiring 3 or more treatments of medical or laser therapy.

Researchers Discover a Cause of MacTel

■ Scientists at the Lowy Medical Research Institute (LMRI) have discovered one cause of a progressive, debilitating eye disease called macular telangiectasia type 2 (MacTel). The work, using genetic, clinical, and biochemical studies has implications for other retinal eye diseases, as well as peripheral neuropathies. The research was published recently in the New England Journal of Medicine.

MacTel causes a gradual deterioration of central vision, interfering with such critical tasks as reading and driving. There is currently no approved treatment for the disease.

However, a unique, multifaceted approach that involved networks of patients and scientists, using not only genetics but also metabolomics, suggested the disease was associated with low blood levels of serine. Serine is an amino acid involved in many pathways in the body but not previously known to affect macular health.

In their paper, the LMRI researchers show that low serine levels in MacTel patients lead to an accumulation of toxic lipids called deoxysphingolipids, which causes photoreceptor cell death.

Second Sight Gets Grant to Improve Orion Prosthesis

■ Second Sight Medical Products, a developer of retinal prosthetics that allow those with profound vision loss to achieve a level of functional vision, has received a $2.4 million, 4-year grant from the National Institutes of Health (NIH) to develop spatial localization and mapping technology (SLAM).

A joint collaboration with the Johns Hopkins University Applied Physics Laboratory (APL), the initiative is intended to speed the integration of SLAM into next-generation versions of the company’s Orion Visual Cortical Prosthesis System.

Second Sight and APL will use the NIH grant to capitalize on recent advances in computer vision, including object recognition, depth sensing, and SLAM, to augment the existing capabilities of Orion. The goal is to give Orion users the ability to localize objects and navigate salient landmarks in unfamiliar surroundings in real time. RP