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SUBSPECIALTY NEWS: Adverum readies wet AMD therapy for trial, FDA seeks end of unapproved stem cell procedures, and more.

Adverum Readies Wet AMD Therapy for Trial

ADVM-022 offers continuous anti-VEGF production.

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■ Adverum Biotechnologies, a clinical-stage gene therapy company targeting unmet medical needs in serious ocular diseases, recently presented long-term efficacy data from a preclinical study of its gene therapy ADVM-022 in wet AMD. The company says it is on track to move ADVM-022 into a clinical trial with approximately 15 to 20 patients. The unique appeal of ADVM-022 is that a single intravitreal injection combines gene therapy with long-term, vector-derived expression of the anti-VEGF aflibercept, which has the potential of greatly reducing anti-VEGF treatment burden.

Szilard Kiss, MD, chief of the retina service at Weill Cornell Medical Center, explained to Retinal Physician that the DNA sequence for aflibercept was put into a gene therapy vector to make ADVM-022. The aflibercept made from this sequence is called vector-derived aflibercept. A universal constitutive promotor DNA sequence is put in front of the aflibercept sequence so that the aflibercept is continuously made by any cell that is transfected by ADVM-022, according to Dr. Kiss. “The goal here is to get a one-time gene therapy intravitreal injection and then never need another anti-VEGF injection for the treatment of wet AMD, DME, or macular edema from RVO,” he said.

Mehdi Gasmi, PhD, chief science and technology officer of Adverum Biotechnologies, told Retinal Physician he believes Adverum could have the ability to vary the amount of vector-derived aflibercept produced to treat patients who might require a greater or lesser amount of anti-VEGF medication.

In the preclinical study, after 13 months, a single intravitreal injection of ADVM-022 was found to be safe and statistically significant in preventing the development of grade IV lesions compared to the vehicle control group. The efficacy at 13 months was consistent with earlier reported data, demonstrating that ADVM-022 induced long-term efficacy that was comparable to aflibercept. Additionally, mean choroidal neovascularization complex areas were significantly smaller in the ADVM-022 and aflibercept groups, compared with vehicle, when analyzed by spectral-domain optical coherence tomography. ADVM-022 induced sustained intraocular expression of aflibercept for up to 16 months following a single intravitreal injection.

The data suggest that a single injection of ADVM-022 administered intravitreally can generate stable levels of aflibercept found to be within the therapeutic window of the standard-of-care recombinant protein. The levels of vector-derived aflibercept at 56 days were consistent with those observed in the long-term efficacy study at 16 months. The therapy was well tolerated, with no serious adverse events. Treatment-related side effects were limited to mild inflammatory responses and related transient IOP decrease.

FDA Seeks End of Unapproved Stem Cell Procedures

A Florida clinic had disastrous AMD results.

■ The FDA is asking federal courts to institute permanent injunctions to stop 2 facilities from providing unapproved stem cell procedures, some of which — intended to reverse the effects of macular degeneration — have resulted in blindness. In making the request, the FDA singled out U.S. Stem Cell Clinic of Sunrise, Florida, and the Cell Surgical Network in California. The agency also cautioned other clinics that offer stem cell procedures about exploiting patients desperate for cures and causing some individuals “serious and permanent harm.” The FDA said both companies named “have continued to disregard the law” by marketing unapproved products. The agency also advised that it is considering further steps to deter the proliferation of unapproved stem cell procedures. The companies use as defense the fact that they use cells from the patients’ own bodies, which do not fall under the category of drugs and therefore are not subject to FDA approval.

The most notorious example of ophthalmic stem cell procedures gone wrong involves U.S. Stem Cell and 3 women who mistakenly believed they were participating in a government-authorized clinical trial designed to use stem cells taken from their own body to combat macular degeneration. The women, who each underwent the procedure in both eyes, suffered catastrophic vision loss.

Major Study of Retinal Detachment Outcomes

Equal success for scleral buckle and vitrectomy.

■ A retrospective, nonrandomized analysis of more than 3 years of retinal detachment (RD) cases drawn from the IRIS Registry was recently conducted by Richard S. Kaiser, MD, of Thomas Jefferson University in Philadelphia. Results were presented at the recent American Academy of Ophthalmology meeting. The data encompassed 27,489 unique patients from 2013 to second quarter 2016, of whom 8,643 had a complex or high-risk RD. Success was defined by reattachment at 1 year with only 1 surgical intervention.

“The overall success rate for all detachments was 87.9%. We found that those with complex RD repairs had a similar success rate of 86.8%. When further broken down into giant retinal tears and proliferative vitreoretinopathy, the success rate of primary repair is even lower at 83.4%,” co-investigator Prethy Rao, MD, from Associated Retina Consultants in Royal Oak, Michigan, told Retinal Physician.

Results by procedure showed that both in the overall population and in the subgroup with a complex or high-risk RD, the success rate was nearly identical comparing eyes operated on with a primary scleral buckle vs with primary vitrectomy with or without scleral buckle.

The purpose of the IRIS retinal detachment study was to evaluate the real-world reattachment rate of complex RDs undergoing a primary repair in the IRIS Registry over 1 year, according to Dr. Rao. “The IRIS Registry provides a unique opportunity that other series to date do not have: large scale numbers and a sample that most closely mirrors the US population. As of the study analysis, over 16,503 medical providers are involved in the IRIS Registry - a number that has eclipsed any other specialty in medicine,” she said.

“The implications of these findings are vast,” said Dr. Rao. “The IRIS Registry is one of the largest databases in the US and provides a unique opportunity to sample a more comprehensive population with both public and private insurance. With the numbers, however, also come limitations in certain details, such as coding errors or retinal detachment configuration.” The IRIS Registry data, added Dr. Rao, facilitate a more comprehensive study from larger scale, real-world data that clinical trials cannot provide.

Clearside Study Shows Durable Response in DME

Suprachoroidal CLS-TA effective given quarterly.

■ Clearside Biomedical has announced positive topline results from its phase 2 clinical trial evaluating its suprachoroidal injectable suspension of triamcinolone acetonide (CLS-TA) used with intravitreally administered aflibercept (Eylea; Regeneron) in patients with DME over a 6-month evaluation period. The combination, when dosed quarterly, was almost as effective as aflibercept and sham given monthly. CLS-TA is Clearside’s proprietary suspension of the corticosteroid triamcinolone acetonide formulated to be administered through the suprachoroidal space.

TYBEE, a multicenter, randomized, masked, controlled trial, enrolled 71 patients who were naïve to treatment for DME. Patients were randomized 1:1 to receive either quarterly treatments of suprachoroidal CLS-TA together with intravitreal Eylea (months 0 and 3) or a control arm of 4 monthly treatments of intravitreal aflibercept plus a sham suprachoroidal procedure (months 0, 1, 2, and 3), with patients in either arm receiving intravitreal aflibercept treatment at months 4 and 5 as needed.

The trial met its primary endpoint of mean improvement in BCVA from baseline over 6 months as measured using the ETDRS scale. Patients in the combination arm gained an average of 12.3 ETDRS letters compared to 13.5 ETDRS letters in the control arm.

Suprachoroidal CLS-TA together with intravitreal aflibercept met a key secondary endpoint with a mean reduction from baseline of 208 microns in central subfield thickness (CST) at 6 months, compared to a 177 micron mean reduction in the control arm. Further, 93% of patients in the combination arm had a greater than 50% reduction in excess CST at 6 months, compared to 73% of patients in the control arm. The combination was generally well tolerated, with no treatment-related serious adverse events reported in the TYBEE trial through the 24 week evaluation period.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Iconic Therapeutics Begins New Wet AMD Study

■ Iconic Therapeutics, which translates knowledge of tissue factor (TF) biology into new therapeutics for retinal disease, has enrolled its first patient in its second phase 2 study of ICON-1 administered intravitreally, both in combination with and as treatment after anti-VEGF therapy with aflibercept (Eylea; Regeneron).

The DECO (Dose Exploration and Continuation Option) multicenter study is recruiting patients with CNV secondary to AMD to generate additional clinical data with a higher dose of ICON-1 than previously evaluated. DECO is being conducted at 8 clinical centers in the United States.

“Our first multidose phase 2 EMERGE study showed good safety and tolerability and demonstrated signs of biologic activity of ICON-1 on the CNV lesion when administered in combination with anti-VEGF ranibizumab (Lucentis; Genentech) or as monotherapy. This suggests the potential of our drug to modify the underlying disease process and thereby produce more durable treatment outcomes,” said William Greene, MD, CEO of Iconic Therapeutics.

Next-Generation Retinal Prosthesis Implanted

■ Second Sight Medical Products said it has implanted 4 next-generation Orion retinal prostheses in a pilot feasibility study for the device, which attaches directly to the brain. The implant procedures were performed at the UCLA Medical Center and the Baylor College of Medicine.

“The 5-patient Orion feasibility study in human subjects is proceeding as expected with highly encouraging early results. Four subjects have now been implanted and the fifth surgery should occur later this quarter. The first 2 subjects are repeatedly and reliably seeing light from all 60 electrodes and are currently undergoing more advanced testing. Our goal with these initial subjects is to create artificial vision through real-time video input from the eyewear in the near future. Subjects 3 and 4 were recently implanted and are expected to be activated in the next few weeks. We have made our initial submission to the FDA as part of the Breakthrough Device Program and look forward to discussions with them concerning the path to commercialization for Orion,” said Will McGuire, president and CEO of Second Sight.

Unlike Second Sight’s FDA-approved Argus II retinal prosthesis, which provides a level of functional vision for patients who lose their sight from end-stage retinitis pigmentosa, the cortically connected Orion is designed to provide some vision for patients who have been rendered blind from virtually any cause.

PanOptica Begins Trial for Topical Anti-VEGF

■ PanOptica, Inc., a private biopharmaceutical company focused on developing innovative ophthalmology therapies, said the company has dosed the first patient in a phase 1/2 dose-ranging clinical trial of PAN-90806, a once-daily topical eye-drop formulation of a small-molecule anti-VEGF for the treatment of neovascular eye diseases. The company is investigating its new suspension formulation of PAN-90806 as monotherapy, for up to 3 months, in a masked study involving 60 newly diagnosed patients with wet AMD randomized to 1 of 3 dose strengths at sites in the United States and the European Union.

“This phase 1/2 trial builds on research completed to date and advances PAN-90806 as a potentially safe and effective topical eye drop treatment for back-of-the-eye diseases such as wet AMD and diabetic retinopathy,” said Paul G. Chaney, president and CEO of PanOptica, in a news release.

AdaptDx Testing Will Be Part of AMD Study

■ MacuLogix said its AdaptDx dark adaptometer has been selected as a functional testing device for candidate clinical endpoint development in the MACUSTAR project, a 5-year study aimed at exploring novel outcome measures for future interventional trials in patients with intermediate AMD. The investigation, currently funded with more than 16 million euros from the European Innovative Medicines Initiative, will enroll 750 patients in seven countries across Europe.

Evidence shows that patients with AMD often experience night vision problems early in the disease process, but these functional symptoms cannot be detected or measured using either conventional high-luminance visual acuity testing or the latest high-resolution structural imaging technology. The only commercially available automated dark adaptometer, the AdaptDx, will be used at all 20 MACUSTAR study sites. It works by measuring a patient’s rod intercept time, which is the number of minutes it takes for the eye to adapt from bright light to darkness.

Roche and 4DMT Expand Collaboration

■ 4D Molecular Therapeutics (4DMT), a leader in therapeutic vector evolution for adeno-associated virus (AAV) gene therapy vector discovery and product development, announced the expansion of its research agreement with F. Hoffmann-La Roche Ltd. and Hoffmann-La Roche Inc. into a broad long-term partnership to develop and commercialize multiple ophthalmology products. 4DMT’s intravitreally delivered choroideremia clinical candidate, 4D-110, is the first collaboration program; IND-enabling studies and activities are under way. Additional clinical candidate development programs are under way to treat retinal diseases with high unmet need.