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SUBSPECIALTY NEWS: Gene therapy, stem-cell therapy, DR screening rates for the uninsured, and more.

Regenxbio Reports 9-Month Gene Therapy Data

Some wet AMD patients needed no retreatment.

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■ Regenxbio said 3 of the 6 patients in cohort 3 receiving its single-injection RGX-314 gene therapy for wet AMD had gone 9 months without the need for any anti-VEGF rescue injections. These 3 patients had gained a mean of 13 letters at 9 months with a mean reduction of 37 microns in central retinal thickness. Prior to being treated with RGX-314, the 3 patients had an average of 35 anti-VEGF injections.

No report was given on the other 3 patients in the third cohort. Regenxbio has now completed dosing a fourth cohort of 6 patients at an even higher dose of RGX-314, which expresses DNA-coded ranibizumab over a long period of time in the eye. The company noted strong anti-VEGF expression in the fourth cohort.

The 9-month data were presented by clinical investigator Jeffrey Heier, MD, of Ophthalmic Consultants of Boston, at a special event hosted by Regenxbio to discuss current treatments for retinal disease and the potential for gene therapy to greatly ease the treatment burden.

In related news, Regenxbio plans to develop RGX-314 for the treatment of additional chronic retinal conditions that respond to anti-VEGF therapy but would benefit from improved, long-term treatment solutions. In the second half of 2019, the company plans to file the first such IND for an additional phase 2 clinical trial designed to further evaluate the potential benefit of RGX-314 as a one-time anti-VEGF treatment in such conditions.

ReNeuron RP Therapy Effective in Initial Trial

Significant vision gains reported.

■ ReNeuron Group plc, a U.K-based developer of cell-based therapeutics, said that patients in a small early-stage phase 1/2 trial for retinitis pigmentosa have initially responded well to the company’s hRPC stem cell therapy. The company reported that all 3 of the first cohort of subjects in the phase 2 part of the trial have reported a significant improvement in vision, on average equivalent to reading an additional 3 lines of 5 letters on the ETDRS eye chart.

The phase 2 part of the trial, which uses a cryopreserved, commercially ready hRPC (human retinal progenitor cell) formulation, enrolled subjects with some retinal functionality, in contrast to the very poor vision and lack of potential for improvement of the subjects in the phase 1 trial.

In the latest observations of the first phase 2 cohort, at 2 months follow-up for 1 subject, and at 18 days for the other 2, all 3 subjects have reported improved vision, with standardized eye chart testing showing objective improvement in visual acuity compared with their pretreatment baseline vision and compared with the patients’ untreated control eye.

For the first subject in the cohort, visual acuity improved in the treated eye from 9 letters at baseline to 29 letters at 2 months follow-up; for the second subject, visual acuity improved from 9 letters at baseline to 24 letters at 18 days follow-up; for the third subject, visual acuity improved from 32 letters at baseline to 46 letters at 18 days follow-up. The mean change from baseline in visual acuity for these first 3 subjects is +16 letters in the study eye, compared with a mean change from baseline of -1 letters in the untreated control eye. All 3 subjects have noted a subjective improvement in vision in their treated eye.

The company notes that these data are early and it will continue to generate further data, including regular ongoing monitoring of the 3 treated subjects, to assess durability of effect and efficacy over a longer period of time and in a larger number of patients.

DR Screening Very Low for Insured Patients

Only 15% have regular eye exams.

■ Although screening for diabetic retinopathy (DR) with eye exams is effective, screening rates for even insured individuals is currently at a troublingly low level, a new study shows. Researchers led by Steven Benoit, MD, of the Centers for Disease Control and Prevention, evaluated eye exam visits over a 5-year period in a large population of insured patients with diabetes from 10 to 64 years of age. They recently reported their findings in the journal Diabetes Care.

The researchers used claims data from IBM Watson Health to identify patients with diabetes and continuous insurance coverage from 2010 to 2014. Among the 298,383 insured patients with type 2 diabetes and no diagnosed DR, almost half had no eye exam visits over the 5-year period and only 15.3% met the American Diabetes Association (ADA) recommendations for annual or biennial eye exams. For the 2,949 patients with type 1 diabetes, one-third had no eye exam visits and 26.3% met ADA recommendations. The 5-year period prevalence of DR was 24.4% and cumulative incidence of DR was 15.8% for patients with type 2 diabetes; prevalence was 54.0% and incidence was 33.4% for patients with type 1 diabetes. The researchers concluded that the frequency of eye exams was alarmingly low, adding to the abundant literature that systemic changes in health care may be needed to detect and prevent vision-threatening eye disease among people with diabetes.

One recent step in that direction is the recent FDA clearance of the IDx-DR (IDx), the first medical device to use artificial intelligence to detect greater than a mild level of diabetic retinopathy in adults. IDx provides a screening decision without the need for a clinician to also interpret the image or results.

The FDA evaluated data from a clinical study of retinal images obtained from 900 patients with diabetes at 10 primary care sites. The study was designed to evaluate how often IDx-DR could accurately detect patients with more than mild diabetic retinopathy. In the study, IDx-DR was able to correctly identify the presence of more than mild diabetic retinopathy 87.4% of the time and was able to correctly identify those patients who did not have more than mild diabetic retinopathy 89.5% of the time.

Gene Therapy Surgery to Correct Dry AMD

A UK company targets the complement system.

■ Gyroscope Therapeutics, a UK biotechnology company, hopes to pioneer the first gene-therapy surgical procedure to correct dry AMD. The first such procedure was carried out at the John Radcliffe Hospital by Dr. Robert MacLaren, professor of ophthalmology at the University of Oxford in a clinical trial (FOCUS) sponsored by Gyroscope Therapeutics.

The surgery involves detaching the retina and injecting a solution containing a virus underneath. The virus contains a modified DNA sequence, which infects the retinal pigment epithelium and corrects a genetic defect that causes AMD. Ideally, if successful, gene therapy would only need to be performed once, as the effects are thought to be long lasting.

A potentially key target in AMD is the complement system, a system of proteins in the immune system that fights bacteria. In macular degeneration, these proteins are overactive and attack retinal cells.

Professor MacLaren explains: “We’re harnessing the power of the virus, a naturally occurring organism, to deliver the DNA into the patient’s cells. When the virus opens up inside the retinal cell it releases the DNA of the gene we have cloned, and the cell starts making a protein that we think can modify the disease, correcting the imbalance of the inflammation caused by the complement system. The idea of this gene therapy is to ‘deactivate’ the complement system, but at a very specific point at the back of the eye, so the patient would otherwise be unaffected by it, and we hope that in future it will slow down the progression of macular degeneration.”

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Regeneron Plans Study of High-Dose Eylea

■ In a one-line statement accompanying its earnings release, Regeneron said it plans to initiate a study of high-dose Eylea (aflibercept) in 2019. The company provided no further details.

A similar study was conducted in 2015 by William R. Freeman, MD, and colleagues at the Shiley Eye Center of the University of California San Diego. In that study of difficult-to-treat wet AMD patients, a 4 mg dose of aflibercept was effective in significantly reducing central retinal thickness in both nonvitrectomized (13) and vitrectomized (19) eyes, but it did not produce additional vision gains.

“Though we did not see statistical vision gains with the 4 mg dose, patients who received the high-dose Eylea said their vision was sharper and had better contrast than before,” Dr. Freeman told Retinal Physician. “We continue to use high-dose Eylea in specific patients who can benefit from the additional potency, including those who have undergone vitrectomies.”

Dr. Freeman and colleagues have published 3 papers on their use of high-dose Eylea at 4-week and 8-week intervals that can be accessed in PubMed.

FDA Accepts Clearside’s Xipere for Approval Review

■ The FDA has notified Clearside Biomedical that it has accepted for review Clearside’s New Drug Application (NDA) for Xipere (triamcinolone acetonide ophthalmic suspension) for suprachoroidal injection for the treatment of macular edema associated with uveitis. The FDA has determined that the application is sufficiently complete to permit a substantive review. The PDUFA goal date has been assigned for October 19, 2019. This date reflects a standard review period and is consistent with management’s expectations for the 505(b)(2) filing.

“We are delighted with this positive news on our Xipere NDA. If Xipere is approved, Clearside will have the first therapy indicated for patients suffering from macular edema associated with uveitis,” said Daniel H. White, Clearside president and CEO. “Macular edema is the leading cause of vision loss, and even blindness, in uveitis patients, and we are now one step closer to treating this underserved patient population.”

The NDA filing is supported by data from the phase 3 PEACHTREE clinical trial that demonstrated significant and clinically meaningful improvement in vision for patients with macular edema associated with noninfectious uveitis. The results also showed that improvement was achieved across all anatomical locations of uveitis. Also, in patients with active inflammation at baseline, resolution was achieved in more than two-thirds of those treated with Xipere across 3 commonly used measures of inflammation: vitreous haze, anterior chamber cells, and anterior chamber flare.

Faricimab Now in Phase 3 Studies for Wet AMD

■ Following positive efficacy and durability results from the phase 2 STAIRWAY study, Roche and Genentech have initiated 2 large, global phase 3 clinical trials in wet AMD investigating the bispecific molecule faricimab. Faricimab is the first bispecific antibody designed specifically for the treatment of retinal eye diseases that simultaneously binds to and inactivates angiopoietin-2 (Ang2) and VEGF-A. By targeting both Ang2 and VEGF-A, the company believes faricimab may lead to sustained efficacy at longer treatment intervals, thereby improving vision outcomes for patients.

The identically designed multicenter, randomized, double-masked, active comparator-controlled phase 3 TENAYA and LUCERNE studies will evaluate the efficacy, safety, and durability of faricimab compared to aflibercept for the treatment of wet AMD. In total, nearly 1,300 patients with wet AMD will be randomized to receive either faricimab dosed every 16 weeks (with an option to drop to every 12 or 8 weeks), or aflibercept dosed every 8 weeks. The primary endpoint of each study is the change in BCVA at week 48 from baseline.

Faricimab is also being studied in patients with DME. The global phase 3 YOSEMITE and RHINE studies, announced in September 2018, aim to confirm the significant vision gains and durability results in the phase 2 BOULEVARD study.

Dr. Stanley Chang Keynotes Retina Fellows Forum

■ Seventy-five retina second-year fellows from around the United States recently attended the 19th annual Retina Fellows Forum in Chicago for a weekend of learning and socializing. The Distinguished Guest Speaker was Stanley Chang, MD, professor of ophthalmology at the Columbia University Medical Center, who spoke on the topic of “Back to Basics.” Among his many achievements, Dr. Chang is primarily noted for being a pioneer in developing new and improved methods of repairing retinal detachments.

Retina Fellows Forum faculty Dean Eliott, MD; Tarek S. Hassan, MD; Carl C. Awh, MD; Stanley Chang, MD; Judy E. Kim, MD; Thomas A. Albini, MD; Amy D. Schefler, MD, FACS; Rishi P. Singh, MD; and David R. Chow, MD, FRCS(C) (not pictured: John W. Kitchens, MD).

A highlight of the weekend was the “Real World” session, discussing aspects of retina practice that aren’t typically covered during fellowship, such as building a practice, managing staff, and life balance issues.

The faculty of 10 leading retina specialists was headed by course director Tarek Hassan, MD, and co-course directors Carl Awh, MD, and David Chow, MD. The hotly contested annual bowling tournament was won by Dr. Chow’s team.

Blindness From Retinal Disease Projected to Double

■ Bilateral blindness from retinal disease, which now affects almost a quarter of a million people in the United States, is projected to afflict more than half a million people by 2050, with the total direct and indirect costs to society more than tripling to almost $64 billion per year. Most of these costs will be attributed to a growing need for caregivers.

These projections were presented by Andrew Moshfeghi, MD, at the recent Angiogenesis meeting hosted by Bascom Palmer Eye Institute, to highlight the need for sustained and less burdensome treatment strategies for retinal disease that help patients preserve their vision.

Ocular Therapeutix Studies Implant for Wet AMD

■ Ocular Therapeutix has dosed the first patient in a phase 1 trial of OTX-TKI (tyrosine kinase inhibitor implant) in patients with wet AMD. The first patient was dosed with the sustained-release implant at the Sydney Retina Clinic in Sydney, Australia.

“Our trial is primarily intended to demonstrate safety, but we will also evaluate biological activity in patients with increased retinal thickness and measure whether there are decreases over time, said Michael Goldstein, MD, chief medical officer at Ocular Therapeutix. “Given that TKIs act upstream of VEGF inhibitors, we believe this phase 1 trial may bring us one step closer to understanding whether TKIs may represent a next-generation treatment for wet AMD and diabetic macular edema.”

The trial is a multicenter, open-label study testing the safety, durability, and tolerability of OTX-TKI, a bioresorbable hydrogel fiber implant formulated with a tyrosine kinase inhibitor delivered by intravitreal injection to patients with wet AMD. The study will evaluate biological activity by measuring retinal thickness using standard optical coherence tomography and following visual acuity over time.

OTX-TKI can be delivered through a small-gauge, sterile injection needle to the back of the eye. It is designed to deliver drug to the target tissues for a period of up to 9 months, thereby potentially extending the dosing interval from the 1-month to 2-month frequency needed with the current standard of care.

Biogen to Acquire Nightstar in Gene Therapy Move

■ The biotechnology company Biogen has agreed to acquire Nightstar Therapeutics, a UK-based clinical-stage gene-therapy company focused on adeno-associated virus (AAV) treatments for inherited retinal disorders.

“Ophthalmology is an emerging growth area for Biogen, and we are excited about the opportunity to work with the talented employees at Nightstar to advance potentially transformative gene therapy programs for rare retinal diseases,” said Michel Vounatsos, Biogen’s CEO. “Nightstar would accelerate our entry into ophthalmology by contributing two mid- to late-stage gene therapy assets, with the potential to create long-term shareholder value.”

Nightstar’s lead asset is NSR-REP1 for the treatment of choroideremia (CHM), a rare, degenerative, X-linked inherited retinal disorder, which leads to blindness and has no approved treatments. CHM primarily affects males and is caused by loss of function in the CHM gene, which encodes the Rab escort protein-1 (REP-1). The REP-1 protein plays a role in intracellular protein trafficking, and loss of function in the CHM gene leads to abnormal intracellular protein trafficking and impaired elimination of waste products from the retinal pigment epithelium and photoreceptors. Initially, patients with CHM experience poor night vision, and over time progressive visual loss ultimately leads to complete blindness.

New Funding Advances AI Effort to Screen Newborns

■ Pr3vent, Inc., a healthcare AI company developing machine vision for detecting eye disease in newborns, has closed a Series A financing led by InFocus Capital Partners, a venture capital fund specializing in disruptive opportunities in the ophthalmic space.

As many as 9% of newborns have pathology related to eyes, which, if left untreated, can have a life-long negative impact on vision. To date, scalable technology capable of examining millions of newborns has not been available. Pr3vent’s screening tool is the first AI-based system designed to protect against vision loss in infants. The company says its breakthrough technology detects abnormality from noninvasive images of the infant’s retina with an algorithm that instantly identifies pathology and can trigger examination and treatment when it is most effective.

According to market research firm Frost & Sullivan, healthcare leaders believe artificial intelligence will be a game changer this year. By the end of 2019, the firm predicts the market for healthcare IT applications using AI is likely to reach $1.7 billion, a 68.5% increase of compound annual growth rate through 2022.

Second Sight Raises $34.6 Million in New Funding

■ Second Sight Medical, developer of the Argus and Orion retinal prostheses that are designed to provide some functional sight for individuals who are blind or have profound vision loss, has raised $34.6 million in a stock offering.

“The proceeds from this offering will enable us to continue gathering safety and efficacy data to advance the development of our proprietary Orion cortical visual prosthesis, and seek regulatory approval and ultimately commercialize Argus 2s,” said Will McGuire, president and CEO of Second Sight, in a news release. “This financing allows us to progress toward our goal of making the dream of sight a reality for blind individuals around the world by developing commercially successful products that provide useful artificial vision.”

Roche Gains Foothold in Gene Therapy With Acquisition of Spark Therapeutics

■ Roche will gain a major position in gene therapy with its move to purchase Philadelphia-based Spark Therapeutics in what has been reported as a $4.8 billion deal. Although Spark is best known in the retina community for receiving FDA approval for Luxturna, the first approved gene therapy in the United States for a genetic disease (a gene defect that causes Leber congenital amaurosis), the company has a strong pipeline of investigational drugs for conditions ranging from hemophilia to Huntington disease.

“As the only biotechnology company that has successfully commercialized a gene therapy for a genetic disease in the US, we have built unmatched competencies in the discovery, development, and delivery of genetic medicines. But the needs of patients and families living with genetic diseases are immediate and their needs vast,” said Jeffrey D. Marrazzo, CEO of Spark Therapeutics, in a news release. “With its worldwide reach and extensive resources, Roche will help us accelerate the development of more gene therapies for more patients for more diseases and further expedite our vision of a world where no life is limited by genetic disease.”

“Spark Therapeutics’ proven expertise in the entire gene therapy value chain may offer important new opportunities for the treatment of serious diseases,” Roche Chief Executive Severin Schwan said.

Avoiding IOP Spikes After Anti-VEGF

■ A recent study shows that prophylaxis with brimonidine prevents the common incidence of sharp increases in IOP in patients following intravitreal injections with anti-VEGF. In a study of 58 eyes conducted by Efrem Mandelcorn, MD, and colleagues at the University of Toronto, mean IOP was significantly lower with brimonidine prophylaxis immediately after anti-VEGF injection and at 10 and 20 minutes after injection compared to no prophylaxis.

IOP immediately following injection was 41.6 mmHg without prophylaxis and 34.2 mmHg with prophylaxis. Significantly fewer eyes receiving prophylaxis had an elevation of 20 mmHg from baseline or an IOP higher than 55 mmHg immediately after injection. The researchers concluded that brimonidine plays a protective role by reducing the risk of eyes reaching very elevated IOPs in the range of 70-80 mmHg, and thus it reduces the need for postinjection anterior-chamber paracentesis.

Aldeyra Acquisition Adds Phase 3 PVR Candidate

■ Aldeyra Therapeutics has acquired Helio Vision, a privately held biotechnology company. The acquisition adds to Aldeyra’s pipeline a phase 3 ready product candidate (ADX-2191, intravitreal methotrexate) for the treatment of proliferative vitreoretinopathy (PVR), the leading cause of failure of retinal reattachment surgery, which has no approved treatment. ADX-2191 has received Orphan Drug Designation from the FDA.

PVR, a serious inflammatory condition that can cause permanent vision loss, affects up to 10% of patients undergoing surgery for retinal detachment, and 50% or more of patients undergoing retinal surgery following open-globe injury. ADX-2191 was co-developed by Dean Eliott, MD, and Tomasz Stryjewski, MD, both retina specialists at Massachusetts Eye and Ear Infirmary in Boston.

“The acquisition of Helio Vision is highly complementary to Aldeyra’s focus on novel therapeutic approaches for immune-mediated diseases and broadens our late-stage pipeline,” said Todd C. Brady, MD, PhD, president and CEO of Aldeyra, in a news release. “Helio Vision’s unique approach is at the crosshairs of our areas of expertise, leveraging an immunological mechanism that diminishes inflammation and cell proliferation, an orphan indication addressing a significant unmet medical need, the potential applicability to a variety of other diseases, and a phase 3 ready retinal program that represents another important catalyst in our development pipeline.”

An adaptive phase 3 clinical program for ADX-2191 in PVR is expected to initiate in 2019, with results expected in 2020.

Study: AI Accurate in Assessing DME Severity

■ In a Roche/Genentech study, scientists used nearly 18,000 color fundus photos (CFPs) and their associated OCT images captured during Genentech’s past phase 3 DME studies to develop and assess the performance of deep-learning algorithms. Results of the study showed that the best deep-learning algorithm was up to 97% accurate in detecting DME severity using CFP images alone.

Roche/Genentech says such groundbreaking results underscore the promising potential of AI in increasing screening capacity via telemedicine with appropriate triage to assist ophthalmologists in improving vision outcomes for a large population of patients that may not be getting comprehensive eye exams. Study data were recently published in the journal Investigative Ophthalmology and Visual Science. RP