Sustained-Release Ranibizumab Now in Phase 3
ARCHWAY trial aims at 6-month durability.
■ Following the successful phase 2 LADDER trial for the delivery of a special formulation of ranibizumab via a refillable, sustained-release implant called the Port Delivery System (PDS), Roche/Genentech has begun the 360-patient ARCHWAY trial with refills scheduled every 24 weeks. The primary endpoint will be change in BCVA from baseline to the average BCVA of weeks 36 and 40.
The 96-week phase 3 study is a randomized, multicenter, open-label (visual assessor-masked), active-comparator study designed to assess the efficacy, safety, and pharmacokinetics of 100 mg/mL delivered via the PDS, compared with monthly ranibizumab intravitreal injections at 0.5 mg (10 mg/mL) in participants with wet AMD. Participants must be previous responders to anti-VEGF therapy.
In the 243-patient LADDER trial, study patients implanted with the PDS were all responders to previous anti-VEGF treatment. They were randomized to monthly intravitreal injections of ranibizumab or to treatment using the PDS filled with 1 of 3 different concentrations of ranibizumab. For PDS patients receiving the 100 mg/mL dose (n=59), approximately 80% were able to go 6 months or longer until their first refill was required. Of the PDS patients receiving the 40 mg/mL (n=62) or the 10 mg/mL (n=58), 71.3% and 63.5%, respectively, were able to go 6 months or longer before their first required refill.
Adverse events encountered during LADDER included postoperative vitreous hemorrhages in the initial months of study enrollment, which were minimized by modifying the procedure to include laser coagulation of the choroid before incision. This step helped reduce the vitreous hemorrhage rate to about 5%. Most vitreous hemorrhages were mild and all cases were manageable. A very small number of the implant reservoirs were explanted during the trial. Some cases of conjunctival erosion were reported, but Roche/Genentech believes that an additional modification to the surgical technique can minimize that risk.
Regeneron, which developed Eylea (aflibercept; the only other FDA-approved anti-VEGF for retinal disease), also has a sustained-release initiative under way with partner Ocular Therapeutix.
Ranibizumab to Prevent Wet AMD
Trial shows that the verdict is still out.
■ An investigator-sponsored prospective clinical trial of prophylactic ranibizumab being conducted by Southern California Desert Retina shows a trend toward protection based on interim data recently reported at the ASRS and Retina Society meetings. The PREVENT study aims to test if ranibizumab (Lucentis; Genentech) administered every 3 months can prevent the development of wet AMD in patients who already have wet AMD in the fellow eye. Eyes with nonexudative AMD at high risk for wet AMD (wet AMD in one eye diagnosed within 5 years and high-risk features) have been randomized 1:1 to sham injection/observation vs 0.5 mg ranibizumab every 3 months for 2 years. Ophthalmic examination, BCVA, IOP, spectral-domain OCT, fundus photography, autofluorescence, and fluorescein angiography are obtained at baseline and every 3 months for 2 years. Adverse events are monitored. The primary outcome measure is conversion to wet AMD confirmed by masked reading center. One hundred eight eyes have been enrolled, with 54 receiving ranibizumab and 54 undergoing observation. All are white (55 female). Mean age was 78.0. Mean BCVA was (20/28, 78 letters) at baseline, and (20/31, 76 letters) at last follow-up. Regarding follow-up, 37% have completed the 2-year study. Thus far, 5 eyes undergoing observation and 3 receiving ranibizumab have converted to wet AMD. No adverse events have been reported. Interim analysis shows a nonstatistically significant trend towards fewer eyes in the treatment group converting to wet AMD. Further, eyes in the treatment group trended to delayed conversion with fewer letters lost on conversion to wet AMD. The principal investigator, Maziar Lalezary, MD, told Retinal Physician that these results are not statistically significant and thus it is premature to draw conclusions or alter patient care. However, the trend may represent a signal to justify further investigation of the role of anti-VEGF therapy in the prevention of choroidal neovascularization.
Avastin Repackagers Must Meet New Guidance
Stricter rules for particulate matter.
■ Earlier this year, the FDA issued its final guidance on the repackaging of biological products. This has required FDA-registered outsourcing facilities to develop new methods for repackaging Avastin (Genentech), the widely used medication for retinal diseases.
Section 503B of the 2013 Drug Quality and Security Act established outsourcing facilities allowed to compound and repackage medications in the absence of a prescription as long as they complied with the more stringent requirements of current good manufacturing practice (cGMP). The repackaging of Avastin has faced challenges due to the biological nature of its active molecule and the route of administration.
Meeting the requirements of the guidance has been costly and challenging for 503B outsourcers. Avastin was developed for solid tumor indications and is used off label in wet AMD. Not surprisingly, bevacizumab meets the requirements for particulate matter in injections (USP Chapter 788), not the more stringent requirements for particulate matter in ophthalmic solutions (USP Chapter 789). As a result, silicone oil microdroplets and protein aggregates have been a recurring issue. The FDA guidance addresses some of these concerns. Repackaging of Avastin now must comply with the stricter FDA requirements for particulate matter in ophthalmic solutions and other standards for repackaging biologics. Because of costs and significant new testing requirements needed to be in compliance with the new regulations, some repackagers may still not be compliant with the higher standards. In response to FDA guidance, Leiters, a registered 503B outsourcing provider, launched an extensive development process to meet the elevated requirements governing the repackaging of Avastin. The final guidance requires 503B outsourcing facilities to repackage in accordance with cGMP and perform specific stability-indicating tests to establish the beyond-use-date (BUD) of repackaged biological products, as well as conduct specific batch release testing.
“Because repackaged Avastin is used as an ophthalmic solution for injection, our development focused on meeting the more stringent requirements of USP CH 789,” said Chris Zuccarelli, chief operating officer of Leiters. Practices are advised to check with their Avastin provider(s) to determine if they are in compliance with the new regulations.
Mediterranean Diet Effective in Preventing AMD
New research adds weight to previous studies.
■ A new study builds on previous evidence that the Mediterranean diet based upon fish, fruits, vegetables, unrefined grains, and olive oil can play a large role in preventing the development of AMD. European researchers investigating the connection between genes and lifestyle on the development of AMD has found that people who adhered to a Mediterranean diet cut their risk of late-stage AMD by 41%. This research expands on previous studies and suggests that such a diet is beneficial for everyone, whether you already have the disease or are at risk of developing it. The new research was recently reported online in Ophthalmology.
In this study, researchers analyzed food-frequency questionnaires from nearly 5,000 people who participated in 2 previous investigations — the Rotterdam Study, which evaluated disease risk in people age 55 and older, and the Alienor Study, which assessed the association between eye diseases and nutritional factors in people aged 73 and older. Patients in the Rotterdam study were examined and completed food questionnaires every 5 years over a 21-year period, while patients in the Alienor Study were seen every 2 years over a 4-year period. The researchers found that those who closely followed the diet were 41% less likely to develop AMD compared with those who did not follow the diet. They also found that none of the individual components of a Mediterranean diet on their own lowered the risk of AMD. Rather, it was the entire pattern of eating a nutrient-rich diet that significantly reduced the risk of late AMD.
“You are what you eat,” said Emily Chew, MD, a clinical spokesperson for the American Academy of Ophthalmology (AAO), who serves on an advisory board to the research group conducting the study, in an AAO news release. “I believe this is a public health issue on the same scale as smoking.”
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Faricimab Moves Into Phase 3 DME Trials
■ Genentech announced that the identically designed global, multicenter, randomized, double-masked, active comparator-controlled phase 3 YOSEMITE and RHINE studies will evaluate the safety and efficacy of the bispecific faricimab (formerly RG7716) for the treatment of DME compared to aflibercept injection.
In both studies, 1,200 patients around the world will be randomized to 1 of 3 arms: arm A will receive faricimab dosed every 8 weeks or sham injections, arm B will be a personalized treatment interval arm where patients will be dosed according to the study protocol or sham injections, and arm C will receive aflibercept dosed every 8 weeks or sham injections. The primary endpoint of each study is the change in BCVA at 1 year. YOSEMITE and RHINE represent the largest studies of DME to date.
Earlier this year, the results of the phase 2 BOULEVARD study showed that DME patients treated with faricimab experienced clinically meaningful visual acuity (VA) gains from baseline, and statistically significant improvements in VA compared with ranibizumab.
Faricimab is the first bispecific, monoclonal antibody specifically designed for the eye that simultaneously binds to and neutralizes both Angiopoietin-2 (Ang2) and VEGF-A with high potency and specificity. In diabetic retinopathy and DME, Ang2 can cause pericyte apoptosis (a hallmark sign of diabetic retinopathy) and works synergistically with VEGF to drive biological pathways that cause increased vessel permeability, inflammation, and neovascularization. Both VEGF and Ang2 are key drivers of angiogenesis that result in vascular instability, leakage, inflammation, and tissue distortion that result vision loss in patients with DME. Therefore, simultaneous inhibition of both Ang2 and VEGF may lead to improved outcomes, reduced treatment burden, or both.
Intravitreal Steroids More Effective for Uveitic Macular Edema
■ Injections of corticosteroids directly into the eye are superior to those placed adjacent to the eye for treating uveitic macular edema, a Mount Sinai-led research study has found. Researchers say the results, published in a recent online issue of Ophthalmology, can help to improve vision in patients with the disease.
“The results of this study suggest that we should be shifting away from periocular injections and toward intravitreal injections of corticosteroids for uveitic macular edema, which should improve the management of patients with uveitis,” said Douglas A. Jabs, MD, MBA, director of the Eye and Vision Research Institute at the New York Eye and Ear Infirmary of Mount Sinai, and the study chair.
Dr. Jabs chaired an international team of researchers as they compared and examined the effectiveness of 3 treatment corticosteroid approaches for patients with uveitic macular edema: regional therapy with periocular triamcinolone injections, intravitreal triamcinolone injections, and intravitreal dexamethasone implants. The trial, known as POINT, was conducted at 23 centers internationally. It followed patients for 6 months after the initial injection for uveitic macular edema to evaluate the injections’ comparative efficacy and safety.
Patients in the trial were randomly assigned to receive periocular triamcinolone, intravitreal triamcinolone, or the intravitreal dexamethasone implant. Researchers found both intravitreal treatments were superior to the periocular treatment for reducing macular edema and improving VA. The intravitreal injection and dexamethasone implant were shown to have similar efficacy and safety profiles.
RegenxBio Goes to Higher Dose in Gene Therapy Study
■ After the higher dose of gene-therapy-derived anti-VEGF RGX-314 used in its third cohort enabled more patients to go longer without requiring retreatment for wet AMD, RegenxBio has now completed dosing a fourth cohort of 6 patients at an even higher level. The data from the 6-patient third cohort of the phase 1 trial showed great improvement over the first 2 lower-dosed cohorts.
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.
Quantel Medical Introduces New Ultrasound Platform
■ Quantel Medical has introduced its ABSolu ultrasound platform, the next-generation replacement for the company’s flagship Aviso ultrasound system. Quantel says the ABSolu, currently pending FDA approval, combines leading-edge technologies to provide superior image quality with exceptional detail. ABSolu offers a new 5-ring annular technology 20MHz B probe that increases depth of field by 70%, thus offering in a single scan high definition information of the vitreous, retinal wall, and orbit.Motion sensors have been integrated in all B Mode and UBM probes, allowing for an automatic and constant detection of the probe position and ultrasound beam direction. In addition, a new signal processing for the linear 50 MHz UBM offers high image quality of the anterior chamber and lens, and a new, first-ever full HD screen is compliant with section 14 of the DICOM standard.
Sustained-Release Implant Receives FDA Approval for Uveitis
■ EyePoint Pharmaceuticals said the FDA has approved Yutiq (fluocinolone acetonide intravitreal implant) for chronic noninfectious uveitis affecting the posterior segment. Yutiq utilizes the company’s Durasert drug-delivery technology and is a nonbioerodible intravitreal microinsert containing 0.18 mg fluocinolone acetonide, designed to release consistently over 36 months. Yutiq is supplied in a sterile single-dose preloaded applicator that can be administered in the physician’s office.
The FDA approved Yutiq based on clinical data from 2 randomized, sham injection-controlled, double-masked phase 3 clinical trials with patient follow-up continuing for 3 years. After 6 months and 12 months, both clinical trials achieved the primary efficacy endpoint of prevention of recurrent uveitis flares. Although a P value of less than 0.001 was reported in each clinical trial, the company will be using a P value of 0.01, which is reflected in Yutiq’s label. In clinical trials, the most common adverse reactions reported were cataract development and increase in IOP.
Regular Eylea Injections Superior to PRN
■ Patients with wet AMD experience better VA outcomes when given aflibercept (Eylea; Regeneron) at regular injection intervals rather than irregular intervals, according to the 24-month results of the PERSEUS study, presented recently at the 18th Congress of the European Society of Retina Specialists. Overall, 279 patients completed a VA test at month 24. Patients who were treatment-naïve and received regular aflibercept injections experienced the greatest overall VA improvement at 24 months of 8.1 letters. Those who were treatment-naïve and irregularly treated demonstrated a mean improvement of 3.6 letters. Among patients who were previously treated, those who received regular aflibercept injections experienced a mean improvement in VA of 4.2 letters, whereas those who received irregular aflibercept injections experienced a mean improvement in VA of 2.1 letters.
Ophthotech Complement Inhibitor in Dry AMD Trial
■ Ophthotech has completed patient recruitment for its phase 2b clinical trial of Zimura (avacincaptad pegol), the company’s complement factor C5 inhibitor, monotherapy in patients with geographic atrophy secondary to dry AMD. Ophthotech says complement factor C5 is a central component of the complement cascade and is believed to be involved in the development and progression of AMD. A total of 286 patients have been enrolled into this randomized, double-masked, sham-controlled multicenter clinical trial. This clinical trial is designed to assess the safety and efficacy of various Zimura dosing regimens over 12 months. Patients will continue to be treated and monitored until month 18.
Second Sight Gets NIH Grant to Develop Orion
■ Second Sight Medical Products, a developer of implantable visual prosthetics intended to provide some functional vision to blind individuals, said the company has received a $1.6 million grant (with the intent to fund $6.3 million over 5 years subject to annual review and approval) from the National Institutes of Health (NIH) to fund the “Early Feasibility Clinical Trial of a Visual Cortical Prosthesis” that commenced in January 2018. The NIH grant will fund ongoing and planned clinical activities and will be used to conduct and support clinical testing of 5 subjects implanted with the Orion Cortical Visual Prosthesis.
Chiropractic Treatment Can Cause Retina Bleed
■ High-velocity neck manipulation by a chiropractor can result in stress on the eye, retinal bleeding, and spotty vision. The risk is rare, but one that Yannis Paulus, MD, a retina specialist at the Kellogg Eye Center, University of Michigan, reports on in the American Journal of Ophthalmology Case Reports.
The thrusts and rotations sometimes performed in neck manipulation have been linked to damage to the blood vessels in the retina. Resulting abnormal bleeding inside the eye may also cause vision loss. This was the case for a 59-year-old woman who experienced a “tadpole” shaped spot in her vision while driving home from a chiropractor visit, with her sight worsening the next day. She had just received cervical spine manipulation using the high-velocity technique to help with her headaches. The woman’s vision returned to normal in about 2 weeks without treatment. She was referred to Kellogg Eye Center by her optometrist, who coauthored the case report.
Keen Eye and Iris Pharma Collaborate on AI Initiative
■ Keen Eye, a French technology company specialized in image analysis for the life science industry, has formed a strategic partnership agreement with Iris Pharma, a worldwide, ophthalmology-focused contract research organization (CRO) that offers preclinical and clinical drug/device development services. The partnership aims at providing Iris Pharma artificial intelligence (AI) applications to make assays faster, more reliable, and more efficient.
“We are very happy to team up and bring our expertise in computer vision to Iris Pharma,” said Sylvain Berlemont, founder and CEO of Keen Eye, in a news release. “Through this partnership, we are expecting to contribute to the most challenging image-based assays to better fight eye diseases.” RP