PMID- 38152412
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231229
IS  - 2589-5370 (Electronic)
IS  - 2589-5370 (Linking)
VI  - 67
DP  - 2024 Jan
TI  - 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.
PG  - 102394
LID - 10.1016/j.eclinm.2023.102394 [doi]
LID - 102394
AB  - 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 x 10(11) vs 6 x 10(11) 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 x 10(11) dose group and in 7 participants in the 2 x 10(11) dose group; 
      intraocular inflammation was responsive to topical corticosteroids, with no 
      anterior chamber cells or vitreous cells observed in 2 x 10(11) 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 x 10(11) vg/eye and 98% (9.8 mean annualised anti-VEGF 
      injections to 0.2) in 6 x 10(11) 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.
CI  - (c) 2023 The Author(s).
FAU - Khanani, Arshad M
AU  - Khanani AM
AD  - Sierra Eye Associates, Reno, NV, USA.
AD  - The University of Nevada, Reno School of Medicine, Reno, NV, USA.
FAU - Boyer, David S
AU  - Boyer DS
AD  - Retina Vitreous Associates Medical Group, Beverly Hills, CA, USA.
FAU - Wykoff, Charles C
AU  - Wykoff CC
AD  - Retina Consultants of Texas, Retina Consultants of America, Blanton Eye 
      Institute, Houston Methodist Hospital, Houston, TX, USA.
FAU - Regillo, Carl D
AU  - Regillo CD
AD  - Mid Atlantic Retina, Wills Eye Hospital, Thomas Jefferson University, 
      Philadelphia, PA, USA.
FAU - Busbee, Brandon G
AU  - Busbee BG
AD  - Tennessee Retina, Nashville, TN, USA.
FAU - Pieramici, Dante
AU  - Pieramici D
AD  - California Retina Consultants, Bakersfield, CA, USA.
FAU - Danzig, Carl J
AU  - Danzig CJ
AD  - Rand Eye Institute, Deerfield Beach, FL, USA.
AD  - Florida Atlantic University, Charles E. Schmidt School of Medicine, Boca Raton, 
      FL, USA.
FAU - Joondeph, Brian C
AU  - Joondeph BC
AD  - Colorado Retina Associates, Denver, CO, USA.
FAU - Major, James C Jr
AU  - Major JC Jr
AD  - Retina Consultants of Texas, Retina Consultants of America, Blanton Eye 
      Institute, Houston Methodist Hospital, Houston, TX, USA.
FAU - Turpcu, Adam
AU  - Turpcu A
AD  - Adverum Biotechnologies, Redwood City, CA, USA.
FAU - Kiss, Szilard
AU  - Kiss S
AD  - Department of Ophthalmology, Weill Cornell Medical College, New York-Presbyterian 
      Hospital, New York, NY, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03748784
PT  - Journal Article
DEP - 20231222
PL  - England
TA  - EClinicalMedicine
JT  - EClinicalMedicine
JID - 101733727
PMC - PMC10751837
OTO - NOTNLM
OT  - Anti-VEGF
OT  - Gene therapy
OT  - Ixoberogene soroparvovec
OT  - Neovascular age-related macular degeneration
COIS- Arshad M Khanani, M.D., M.A.: *Support of present manuscript: Adverum 
      Biotechnologies.*Consultant: Adverum Biotechnologies, 4D Molecular Therapeutics, 
      Genentech, Novartis, Regeneron Pharmaceuticals, Regenxbio,*Research Support: 
      Adverum Biotechnologies, 4D Molecular Therapeutics, Genentech, Novartis, 
      Regenxbio. David S Boyer, M.D.:*4D Molecular Therapeutics, Achillion, Adverum 
      Biotechnologies, Alcon, Aldeyra Therapeutics, Alimera Sciences, Alkahest, 
      Allegro, Allergan, Allgenesis, Amydis, Annexon Biosciences, Apellis 
      Pharmaceuticals, Applied Genetec Technologies Crop (AGTC), Ashvattha, AsclepiX 
      Therapeutics, Aviceda Therapeutics, Bausch & Lomb, Bayer, Biovisics Medical, 
      Boehringer-Ingelheim, Cell Care Therapeutics, Chengdu Kanghong Biotechnology, 
      Clearside Biomedical, Curacle Co LTD, Delsitech, Eyepoint Pharmaceuticals, 
      Genentech, Glaukos, Iveric Bio, jCyte, Kriya Therapeutics, Kyowa Kirin, Lineage 
      Cell, Lumithera, Inc, Nanoscope, NGM Biotherapeutics, Novartis, Ocular 
      Therapeutix, Ocular Therapeutix, Ocugen, Oculis, Ocuphire, OcuTerra, Ocutrx 
      Vision Technologies, Opthea, Optigo Biotechnology, Optos, Oxurion, Palatin, 
      Pfizer, Regeneron Pharmaceuticals, RetinAI Medical AG, Ripple Therapeutics, 
      Roche, Sanofi, Santen, Shenyang XingQi Pharma, Smilebiotek Zhuhai Limited, 
      Stealth Biotherapeutics, Surrozen, Inc, Syneos, Thea Laboratories, UNITY 
      Biotechnology, Vanotech, Verseon Corporation, Vitranu, Virto Biopharma, Viva 
      Vision Biotech. Charles C Wykoff, M.D., Ph.D.:*Consulting fees/honoraria paid to 
      me for ongoing services provided as a Consultant for: 4DMT, AbbVie, Adverum, 
      Aerie, AGTC, Alcon, Alimera, Allergan, Allgenesis, Alnylam, Annexon, Apellis, 
      Arrowhead, Bausch + Lomb, Bayer, Bionic Vision Technologies, Boehringer 
      Ingelheim, Cholgene, Clearside, Curacle, Eyebiotech, EyePoint, Foresite, 
      Frontera, Genentech, Gyroscope, IACTA, IVERIC Bio, Janssen, Kato, Kiora, Kodiak, 
      Kriya, Merck, Nanoscope, Neurotech, NGM, Notal Vision, Novartis, OccuRx, Ocular 
      Therapeutix, Ocuphire, Ocuterra, OliX, ONL, Opthea, Oxular, Palatin, PerceiveBio, 
      Perfuse, PolyPhotonix, Ray, RecensMedical, Regeneron, RegenXBio, Resonance, 
      Roche, Sandoz, Sanofi, SciNeuro, Stealth, Surrozen, Suzhou Raymon, Takeda, THEA, 
      Therini, TissueGen, Valo, Verana.*Grants paid to my institution for ongoing 
      Research support as a Principal Investigator for trials sponsored by: 4DMT, 
      Adverum, AffaMed, Alexion, Alimera, Alkahest, Allergan, Aldeyra, Allgenesis, 
      Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu 
      Kanghong, Clearside, Curacle, Eyebiotech, EyePoint, Gemini, Genentech, 
      GlaxoSmithKline, Graybug, Gyroscope, IONIS, iRENIX, IVERIC bio, Janssen, Kodiak, 
      LMRI, McMaster University, Nanoscope, Neurotech, NGM, Novartis, Ocular 
      Therapeutix, Ocuphire, OcuTerra, OliX, Ophthotech, Opthea, Oxurion, Oxular, 
      Oyster Point, PerceiveBio, RecensMedical, Regeneron, RegenXBio, Rezolute, Roche, 
      SamChunDang Pharm, Sandoz, Senju, Taiwain Liposome Co., UNITY, Verily, 
      Xbrane.*Participation on a Data Safety Monitoring Board or Advisory Board: Kato, 
      Aerie.*Leadership or fiduciary role in other board, society, committee or 
      advocacy group, paid or unpaid: ASRS, Vit-Buckle Society.*Stock Options (not 
      owner) from Private For-Profit Entities: ONL, PolyPhotonix, RecensMedical, 
      TissueGen, Visgenx, Vitranu. Carl D Regillo, M.D.:*Consulting: 4DMT, Adverum, 
      Allergan, Annexon, Apellis, Aviceda, Bausch and Lomb, Clearside, Cognition, 
      Eyepoint, Genentech, Iveric, Janssen, Kodiak, Lineage, Merck, NGM, Novartis, 
      Ocugen, Ocular Therapeutics, Ocuterra, Ray, RegenXBio, Stealth, Thea, 
      Zeiss.*Research Support: Adverum, Allergan, Annexon, Apellis, Astellas, Eyepoint, 
      Genentech, Gyroscope, Iveric, Janssen, Kodiak, Lineage, NGM, Notal, Novartis, 
      Ocugen, Ocuterra, Opthea, Regeneron, RegenXBio.*Participation on a Data Safety 
      Monitoring Board or Advisory Board: Cognition, Iveric. Brandon G Busbee, 
      M.D.:*Consultant: Genentech.*Speaker: Apellis.*Royalties: Thea. Dante Pieramici, 
      M.D.:*Medical writing support for present manuscript: Adverum 
      Biotechnologies.*Consultant: Genentech, Regeneron, RegenXBio, Adverum, Eyepoint, 
      Unity, Clearside, Gyroscope, Opthea.*Research Funding paid to institution: 
      Regeneron, RegenXBio, Adverum, Ocular Therapeutix, Eyepoint, Clearside, 4DMT, 
      Janssen, Helios, Valo.*Participation on a Data Safety Monitoring Board or 
      Advisory Board: PERCEIVE*Leadership or fiduciary role in other board, society, 
      committee or advocacy group, paid or unpaid: Genentech. Carl J Danzig, 
      M.D.:*Research Grant: Adverum, Genentech/Roche, Regeneron/Bayer, Kodiak, Unity, 
      IvericBio, Gyroscope, Novartis, Curacle, Rezolute, 4DMT.*Consultant: Adverum, 
      Genentech/Roche, Regeneron/Bayer, Novartis, Kodiak, IvericBio.*Speaker: 
      Genentech, IvericBio, Novartis, Regeneron.*Advisory Board or Data Safety 
      Monitoring Board: Abbvie/RegenexBio, Genentech, Adverum. Brian C Joondeph, 
      M.D.:*Payment for expert testimony: Contegrity Expert Group.*Leadership or 
      fiduciary role in other board, society, committee or advocacy group, paid or 
      unpaid: Colorado Retina Executive Committee, unpaid. James C Major, M.D., 
      Ph.D.:*Research Support: Adverum Biotechnologies, Inc.*Leadership or fiduciary 
      role in other board, society, committee or advocacy group, paid or unpaid: ASRS 
      Board of Directors (unpaid). Adam Turpcu, Ph.D.:*Employee and stockholder of 
      Adverum Biotechnologies, Inc. Szilard Kiss, M.D.:*Consultant/Advisor, Equity: 
      Adverum Biotechnologies*Consulting: Regeneron, Optos, Novartis, Gyroscope, 
      Apellis.*Advisory Board or Data Safety Monitoring Board: Novartis.*Intellectual 
      Property related to gene and cellular therapy: Assigned to Weill Cornell/Cornell 
      University.
EDAT- 2023/12/28 06:42
MHDA- 2023/12/28 06:43
PMCR- 2023/12/22
CRDT- 2023/12/28 04:09
PHST- 2023/08/07 00:00 [received]
PHST- 2023/12/01 00:00 [revised]
PHST- 2023/12/08 00:00 [accepted]
PHST- 2023/12/28 06:43 [medline]
PHST- 2023/12/28 06:42 [pubmed]
PHST- 2023/12/28 04:09 [entrez]
PHST- 2023/12/22 00:00 [pmc-release]
AID - S2589-5370(23)00571-0 [pii]
AID - 102394 [pii]
AID - 10.1016/j.eclinm.2023.102394 [doi]
PST - epublish
SO  - EClinicalMedicine. 2023 Dec 22;67:102394. doi: 10.1016/j.eclinm.2023.102394. 
      eCollection 2024 Jan.