Safety and Efficacy of Ixoberogene Soroparvovec in Neovascular Age-Related Macular Degeneration in the United States (OPTIC): A Prospective, Two-Year, Multicentre Phase 1 Study

Background Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD. Methods In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to antiVEGF were assigned to four cohorts differing by ixo-vec dose (2 × 1011 vs 6 × 1011 vector genomes (vg/eye)) and prophylactic steroids (oral prednisone vs topical difluprednate). The primary outcome was the type, severity, and incidence of ocular and systemic adverse events (AEs); secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. This study was registered with ClinicalTrials.gov, NCT03748784. Findings Thirty patients with nAMD were enrolled between November 14, 2018 and June 30, 2020 at nine study sites in the United States. No systemic ixo-vec related AEs were noted. Across both dose groups the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6 × 1011 dose group and in 7 participants in the 2 × 1011 dose group; intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2 × 1011 vg/eye patients at the end of the study. Vision and CST remained stable throughout two years with annualised anti-VEGF injections reduced by 80% (10.0 mean annualised anti-VEGF injections to 1.9) in 2 × 1011 vg/eye and 98% (9.8 mean annualised anti-VEGF injections to 0.2) in 6 × 1011 vg/eye cohorts. Interpretation Ixo-vec was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. A single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionise the management of common ocular disorders requiring ongoing, frequent therapeutic interventions

Dilated Eye Exam Compliance for Persons With Diabetes Mellitus in a Managed Care Setting

Background/Aims: National practice guidelines recommend regular dilated eye examinations for persons with diabetes mellitus (DM). Regular exams can identify the presence of diabetic eye diseases leading to early detection and treatment along with vision preservation. We aimed to: 1) assess compliance with guideline-recommended dilated eye exams among persons with DM, and 2) determine the factors associated with noncompliance. Methods: Kaiser Permanente Southern California members aged ≥ 18 years with DM identified from January 2009 to December 2010 were followed until disenrollment or study end date (December 2013). Dilated eye exams were identified from CPT-4, ICD-9 procedure codes and retinal photographs. Compliance with guidelines over the entire duration of follow-up was the binary outcome of interest. A patient was defined as compliant when having at least one exam in each 12-month period if there was evidence of retinopathy, or at least one exam in each 24-month period if there was no evidence of retinopathy. Multivariate logistic regressions were used to investigate patient demographics and other baseline characteristics associated with noncompliance. Results: Among the 204,073 eligible patients, mean age ± standard deviation was 61 ± 13 years and 48% were female. The median follow up was 4.8 years, and overall, 71.1% of patients were compliant with dilated eye exams, including 27.7% who received an eye exam every year and 4.4% who never received a dilated eye exam. At baseline 13% of patients had retinopathy, while an additional 20% of patients developed retinopathy during follow-up time. Noncompliant patients were more likely to be younger, black, male, smokers, and have a Medicare plan, a lower income, a lower education and a higher specialist co-payment plan. In addition, these patients were less likely to be adherent to antidiabetes medications, on statin medications, take a diabetes education class and have other eye diseases; however, they were more likely to use insulin, have retinopathy, have nephropathy, and have a lower comorbidity index. Discussion: During nearly 5 years of follow-up, 28.9% of person’s with DM were noncompliant with dilated eye exam guidelines. Future research should focus on eye disease outcomes associated with noncompliance and the development of interventions to address modifiable factors associated with noncompliance

Visual Impairment and Blindness Avoided with Ranibizumab in Hispanic and Non-Hispanic Whites with Diabetic Macular Edema in the United States

ObjectiveTo estimate visual impairment (VI) and blindness avoided with intravitreal ranibizumab 0.3 mg treatment for central-involved diabetic macular edema (DME) among Hispanic and non-Hispanic white individuals in the United States.DesignPopulation-based model simulating visual acuity (VA) outcomes over 2 years after diagnosis and treatment of DME.ParticipantsVisual acuity changes with and without ranibizumab were based on data from the RISE, RIDE, and DRCR Network trials.MethodsFor the better-seeing eye, VA outcomes included VI, defined as worse than 20/40 in the better-seeing eye, and blindness, defined as VA of 20/200 or worse in the better-seeing eye. Incidence of 1 or both eyes with central-involved DME in 2010 were estimated based on the 2010 United States population, prevalence of diabetes mellitus, and 1-year central-involved DME incidence rate. Sixty-one percent of incident individuals had bilateral DME and 39% had unilateral DME, but DME could develop in the fellow eye.Main Outcomes MeasuresCases of VI and blindness avoided with ranibizumab treatment.ResultsAmong approximately 102 million Hispanic and non-Hispanic white individuals in the United States 45 years of age and older in 2010, an estimated 37 274 had central-involved DME and VI eligible for ranibizumab treatment. Compared with no ranibizumab treatment, the model predicted that ranibizumab 0.3 mg every 4 weeks would reduce the number of individuals with VI from 11 438 (95% simulation interval [SI], 7249–16 077) to 6304 (95% SI, 3921–8981), a 45% (95% SI, 36%–53%) reduction at 2 years. Ranibizumab would reduce the number of incident eyes with VA worse than 20/40 from 16 910 (95% SI, 10 729–23 577) to 9361 (95% SI, 5839–13 245), a 45% (95% SI, 38%–51%) reduction. Ranibizumab was estimated to reduce the number of individuals with legal blindness by 75% (95% SI, 58%–88%) and the number of incident eyes with VA of 20/200 or worse by 76% (95% SI, 63%–87%).ConclusionsThis model suggests that ranibizumab 0.3 mg every 4 weeks substantially reduces prevalence of VI and legal blindness 2 years after initiating treatment among Hispanic and non-Hispanic white individuals in the United States with central-involved DME that has caused vision loss

Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 studyResearch in context

Summary: Background: Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD. Methods: In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to anti-VEGF were assigned to four cohorts differing by ixo-vec dose (2 × 1011 vs 6 × 1011 vector genomes (vg/eye)) and prophylactic steroids (oral prednisone vs topical difluprednate). The primary outcome was the type, severity, and incidence of ocular and systemic adverse events (AEs); secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. This study was registered with ClinicalTrials.gov, NCT03748784. Findings: Thirty patients with nAMD were enrolled between November 14, 2018 and June 30, 2020 at nine study sites in the United States. No systemic ixo-vec related AEs were noted. Across both dose groups the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6 × 1011 dose group and in 7 participants in the 2 × 1011 dose group; intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2 × 1011 vg/eye patients at the end of the study. Vision and CST remained stable throughout two years with annualised anti-VEGF injections reduced by 80% (10.0 mean annualised anti-VEGF injections to 1.9) in 2 × 1011 vg/eye and 98% (9.8 mean annualised anti-VEGF injections to 0.2) in 6 × 1011 vg/eye cohorts. Interpretation: Ixo-vec was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. A single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionise the management of common ocular disorders requiring ongoing, frequent therapeutic interventions. Funding: Adverum Biotechnologies