Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10 : a phase 1b/2 trial
CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multic...
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| creator | Russell, Stephen R Drack, Arlene V Cideciyan, Artur V Jacobson, Samuel G Leroy, Bart Van Cauwenbergh, Caroline Ho, Allen C Dumitrescu, Alina V Han, Ian C Martin, Mitchell Pfeifer, Wanda L Sohn, Elliott H Walshire, Jean Garafalo, Alexandra V Krishnan, Arun K Powers, Christian A Sumaroka, Alexander Roman, Alejandro J Vanhonsebrouck, Eva Jones, Eltanara Nerinckx, Fanny De Zaeytijd, Julie Collin, Rob W. J Hoyng, Carel Adamson, Peter Cheetham, Michael E Schwartz, Michael R den Hollander, Wilhelmina Asmus, Friedrich Platenburg, Gerard Rodman, David Girach, Aniz |
| description | CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received |
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J ; Hoyng, Carel ; Adamson, Peter ; Cheetham, Michael E ; Schwartz, Michael R ; den Hollander, Wilhelmina ; Asmus, Friedrich ; Platenburg, Gerard ; Rodman, David ; Girach, Aniz</creator><creatorcontrib>Russell, Stephen R ; Drack, Arlene V ; Cideciyan, Artur V ; Jacobson, Samuel G ; Leroy, Bart ; Van Cauwenbergh, Caroline ; Ho, Allen C ; Dumitrescu, Alina V ; Han, Ian C ; Martin, Mitchell ; Pfeifer, Wanda L ; Sohn, Elliott H ; Walshire, Jean ; Garafalo, Alexandra V ; Krishnan, Arun K ; Powers, Christian A ; Sumaroka, Alexander ; Roman, Alejandro J ; Vanhonsebrouck, Eva ; Jones, Eltanara ; Nerinckx, Fanny ; De Zaeytijd, Julie ; Collin, Rob W. J ; Hoyng, Carel ; Adamson, Peter ; Cheetham, Michael E ; Schwartz, Michael R ; den Hollander, Wilhelmina ; Asmus, Friedrich ; Platenburg, Gerard ; Rodman, David ; Girach, Aniz</creatorcontrib><description>CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received <= 4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 mu g/80 mu g, and five patients received sepofarsen 320 mu g/160 mu g. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 mu g/80 mu g; 5/5 with 320 mu g/160 mu g) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 mu g/80 mu g; 4/5 with 320 mu g/160 mu g), as lens replacement was required. As the 160-mu g/80-mu g group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.</description><identifier>ISSN: 1078-8956</identifier><identifier>ISSN: 1546-170X</identifier><language>eng</language><publisher>Springer Science and Business Media LLC</publisher><subject>General Biochemistry, Genetics and Molecular Biology ; General Medicine ; Medicine and Health Sciences</subject><creationdate>2022</creationdate><rights>Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) info:eu-repo/semantics/openAccess</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,315,780,784,4024,27860</link.rule.ids></links><search><creatorcontrib>Russell, Stephen R</creatorcontrib><creatorcontrib>Drack, Arlene V</creatorcontrib><creatorcontrib>Cideciyan, Artur V</creatorcontrib><creatorcontrib>Jacobson, Samuel G</creatorcontrib><creatorcontrib>Leroy, Bart</creatorcontrib><creatorcontrib>Van Cauwenbergh, Caroline</creatorcontrib><creatorcontrib>Ho, Allen C</creatorcontrib><creatorcontrib>Dumitrescu, Alina V</creatorcontrib><creatorcontrib>Han, Ian C</creatorcontrib><creatorcontrib>Martin, Mitchell</creatorcontrib><creatorcontrib>Pfeifer, Wanda L</creatorcontrib><creatorcontrib>Sohn, Elliott H</creatorcontrib><creatorcontrib>Walshire, Jean</creatorcontrib><creatorcontrib>Garafalo, Alexandra V</creatorcontrib><creatorcontrib>Krishnan, Arun K</creatorcontrib><creatorcontrib>Powers, Christian A</creatorcontrib><creatorcontrib>Sumaroka, Alexander</creatorcontrib><creatorcontrib>Roman, Alejandro J</creatorcontrib><creatorcontrib>Vanhonsebrouck, Eva</creatorcontrib><creatorcontrib>Jones, Eltanara</creatorcontrib><creatorcontrib>Nerinckx, Fanny</creatorcontrib><creatorcontrib>De Zaeytijd, Julie</creatorcontrib><creatorcontrib>Collin, Rob W. J</creatorcontrib><creatorcontrib>Hoyng, Carel</creatorcontrib><creatorcontrib>Adamson, Peter</creatorcontrib><creatorcontrib>Cheetham, Michael E</creatorcontrib><creatorcontrib>Schwartz, Michael R</creatorcontrib><creatorcontrib>den Hollander, Wilhelmina</creatorcontrib><creatorcontrib>Asmus, Friedrich</creatorcontrib><creatorcontrib>Platenburg, Gerard</creatorcontrib><creatorcontrib>Rodman, David</creatorcontrib><creatorcontrib>Girach, Aniz</creatorcontrib><title>Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10 : a phase 1b/2 trial</title><description>CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received <= 4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 mu g/80 mu g, and five patients received sepofarsen 320 mu g/160 mu g. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 mu g/80 mu g; 5/5 with 320 mu g/160 mu g) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 mu g/80 mu g; 4/5 with 320 mu g/160 mu g), as lens replacement was required. As the 160-mu g/80-mu g group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.</description><subject>General Biochemistry, Genetics and Molecular Biology</subject><subject>General Medicine</subject><subject>Medicine and Health Sciences</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>ADGLB</sourceid><recordid>eNqtjMtuwjAQAH0oUinwD_sDqDaIV68oD6QeQPRQ5WJt0iXZyrUje4PE3xekfkJPcxjNPKmx0ZvtfLtbrZ_VS0rfWuulXu3Gyh28RLyyREIH6IUT-UQQHLfBD42jIPxFkKgPF4x3CezhnWqK0ATfkmd5hD84xJA4gdx6AqPhDRD6Du8rU78uQCKjm6rRBV2i2R8nKsuzj305bzvyYh3XkRoUG5AtxqbjK9mhfaiarDbFqazKkzHn4jMvjll1rLLzIt_r5X99fgFrxWC3</recordid><startdate>2022</startdate><enddate>2022</enddate><creator>Russell, Stephen R</creator><creator>Drack, Arlene V</creator><creator>Cideciyan, Artur V</creator><creator>Jacobson, Samuel G</creator><creator>Leroy, Bart</creator><creator>Van Cauwenbergh, Caroline</creator><creator>Ho, Allen C</creator><creator>Dumitrescu, Alina V</creator><creator>Han, Ian C</creator><creator>Martin, Mitchell</creator><creator>Pfeifer, Wanda L</creator><creator>Sohn, Elliott H</creator><creator>Walshire, Jean</creator><creator>Garafalo, Alexandra V</creator><creator>Krishnan, Arun K</creator><creator>Powers, Christian A</creator><creator>Sumaroka, Alexander</creator><creator>Roman, Alejandro J</creator><creator>Vanhonsebrouck, Eva</creator><creator>Jones, Eltanara</creator><creator>Nerinckx, Fanny</creator><creator>De Zaeytijd, Julie</creator><creator>Collin, Rob W. 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J</au><au>Hoyng, Carel</au><au>Adamson, Peter</au><au>Cheetham, Michael E</au><au>Schwartz, Michael R</au><au>den Hollander, Wilhelmina</au><au>Asmus, Friedrich</au><au>Platenburg, Gerard</au><au>Rodman, David</au><au>Girach, Aniz</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10 : a phase 1b/2 trial</atitle><date>2022</date><risdate>2022</risdate><issn>1078-8956</issn><issn>1546-170X</issn><abstract>CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received <= 4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 mu g/80 mu g, and five patients received sepofarsen 320 mu g/160 mu g. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 mu g/80 mu g; 5/5 with 320 mu g/160 mu g) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 mu g/80 mu g; 4/5 with 320 mu g/160 mu g), as lens replacement was required. As the 160-mu g/80-mu g group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.</abstract><pub>Springer Science and Business Media LLC</pub><oa>free_for_read</oa></addata></record> |
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| source | Ghent University Academic Bibliography; Nature Journals Online; Alma/SFX Local Collection |
| subjects | General Biochemistry, Genetics and Molecular Biology General Medicine Medicine and Health Sciences |
| title | Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10 : a phase 1b/2 trial |
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