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...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | EClinicalMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537023005710 |
| _version_ | 1827374971881521152 |
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| author | Arshad M. Khanani David S. Boyer Charles C. Wykoff Carl D. Regillo Brandon G. Busbee Dante Pieramici Carl J. Danzig Brian C. Joondeph James C. Major, Jr. Adam Turpcu Szilárd Kiss |
| author_facet | Arshad M. Khanani David S. Boyer Charles C. Wykoff Carl D. Regillo Brandon G. Busbee Dante Pieramici Carl J. Danzig Brian C. Joondeph James C. Major, Jr. Adam Turpcu Szilárd Kiss |
| author_sort | Arshad M. Khanani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T11:43:00Z |
| format | Article |
| id | doaj.art-f21f468a439d46d4bc83e3be29994dce |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-03-08T11:43:00Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-f21f468a439d46d4bc83e3be29994dce2024-01-25T05:23:35ZengElsevierEClinicalMedicine2589-53702024-01-0167102394Safety 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 contextArshad M. Khanani0David S. Boyer1Charles C. Wykoff2Carl D. Regillo3Brandon G. Busbee4Dante Pieramici5Carl J. Danzig6Brian C. Joondeph7James C. Major, Jr.8Adam Turpcu9Szilárd Kiss10Sierra Eye Associates, Reno, NV, USA; The University of Nevada, Reno School of Medicine, Reno, NV, USARetina Vitreous Associates Medical Group, Beverly Hills, CA, USARetina Consultants of Texas, Retina Consultants of America, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USAMid Atlantic Retina, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USATennessee Retina, Nashville, TN, USACalifornia Retina Consultants, Bakersfield, CA, USARand Eye Institute, Deerfield Beach, FL, USA; Florida Atlantic University, Charles E. Schmidt School of Medicine, Boca Raton, FL, USAColorado Retina Associates, Denver, CO, USARetina Consultants of Texas, Retina Consultants of America, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USAAdverum Biotechnologies, Redwood City, CA, USADepartment of Ophthalmology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; Corresponding author. 1305 York Ave, 11th floor, New York, NY, 10021, USA.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.http://www.sciencedirect.com/science/article/pii/S2589537023005710Neovascular age-related macular degenerationGene therapyAnti-VEGFIxoberogene soroparvovec |
| spellingShingle | Arshad M. Khanani David S. Boyer Charles C. Wykoff Carl D. Regillo Brandon G. Busbee Dante Pieramici Carl J. Danzig Brian C. Joondeph James C. Major, Jr. Adam Turpcu Szilárd Kiss 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 EClinicalMedicine Neovascular age-related macular degeneration Gene therapy Anti-VEGF Ixoberogene soroparvovec |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Neovascular age-related macular degeneration Gene therapy Anti-VEGF Ixoberogene soroparvovec |
| url | http://www.sciencedirect.com/science/article/pii/S2589537023005710 |
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