Paul Yang, Laura P Pardon, Allen C Ho, Andreas K Lauer, Dan Yoon, Shannon E Boye, Sanford L Boye, Alejandro J Roman, Vivian Wu, Alexandra V Garafalo, Alexander Sumaroka, Malgorzata Swider, Iryna Viarbitskaya, Tomas S Aleman, Mark E Pennesi, Christine N Kay, Kenji P Fujita, Artur V Cideciyan
{"title":"ATSN-101 对 GUCY2D 双重突变导致的 Leber 先天性羊角疯患者的安全性和疗效：1/2 期、多中心、开放标签、单侧剂量递增研究。","authors":"Paul Yang, Laura P Pardon, Allen C Ho, Andreas K Lauer, Dan Yoon, Shannon E Boye, Sanford L Boye, Alejandro J Roman, Vivian Wu, Alexandra V Garafalo, Alexander Sumaroka, Malgorzata Swider, Iryna Viarbitskaya, Tomas S Aleman, Mark E Pennesi, Christine N Kay, Kenji P Fujita, Artur V Cideciyan","doi":"10.1016/S0140-6736(24)01447-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1.</p><p><strong>Methods: </strong>15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were treated with three ascending doses: 1·0 × 10<sup>10</sup> vg/eye (low dose), 3·0 × 10<sup>10</sup> vg/eye (middle dose), and 1·0 × 10<sup>11</sup> vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), and secondary endpoints included full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported.</p><p><strong>Findings: </strong>Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, mean change in dark-adapted FST was 20·3 decibels (dB; 95% CI 6·6 to 34·0) for treated eyes and 1·1 dB (-3·7 to 5·9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0·012). Modest improvements in BCVA were also observed (p=0·10). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye.</p><p><strong>Interpretation: </strong>ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose.</p><p><strong>Funding: </strong>Atsena Therapeutics.</p>","PeriodicalId":18014,"journal":{"name":"The Lancet","volume":"404 10456","pages":"962-970"},"PeriodicalIF":98.4000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study.\",\"authors\":\"Paul Yang, Laura P Pardon, Allen C Ho, Andreas K Lauer, Dan Yoon, Shannon E Boye, Sanford L Boye, Alejandro J Roman, Vivian Wu, Alexandra V Garafalo, Alexander Sumaroka, Malgorzata Swider, Iryna Viarbitskaya, Tomas S Aleman, Mark E Pennesi, Christine N Kay, Kenji P Fujita, Artur V Cideciyan\",\"doi\":\"10.1016/S0140-6736(24)01447-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1.</p><p><strong>Methods: </strong>15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were treated with three ascending doses: 1·0 × 10<sup>10</sup> vg/eye (low dose), 3·0 × 10<sup>10</sup> vg/eye (middle dose), and 1·0 × 10<sup>11</sup> vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), and secondary endpoints included full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported.</p><p><strong>Findings: </strong>Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, mean change in dark-adapted FST was 20·3 decibels (dB; 95% CI 6·6 to 34·0) for treated eyes and 1·1 dB (-3·7 to 5·9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0·012). Modest improvements in BCVA were also observed (p=0·10). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye.</p><p><strong>Interpretation: </strong>ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose.</p><p><strong>Funding: </strong>Atsena Therapeutics.</p>\",\"PeriodicalId\":18014,\"journal\":{\"name\":\"The Lancet\",\"volume\":\"404 10456\",\"pages\":\"962-970\"},\"PeriodicalIF\":98.4000,\"publicationDate\":\"2024-09-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Lancet\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/S0140-6736(24)01447-8\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, GENERAL & INTERNAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Lancet","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/S0140-6736(24)01447-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study.
Background: Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1.
Methods: 15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were treated with three ascending doses: 1·0 × 1010 vg/eye (low dose), 3·0 × 1010 vg/eye (middle dose), and 1·0 × 1011 vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), and secondary endpoints included full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported.
Findings: Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, mean change in dark-adapted FST was 20·3 decibels (dB; 95% CI 6·6 to 34·0) for treated eyes and 1·1 dB (-3·7 to 5·9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0·012). Modest improvements in BCVA were also observed (p=0·10). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye.
Interpretation: ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose.
期刊介绍：
The Lancet is a world-leading source of clinical, public health, and global health knowledge. It was founded in 1823 by Thomas Wakley and has been an independent, international weekly general medical journal since then. The journal has an Impact Factor of 168.9, ranking first among 167 general and internal medicine journals globally. It also has a Scopus CiteScore of 133·2, ranking it second among 830 general medicine journals. The Lancet's mission is to make science widely available to serve and transform society, positively impacting people's lives. Throughout its history, The Lancet has been dedicated to addressing urgent topics, initiating debate, providing context for scientific research, and influencing decision makers worldwide.
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