Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration

Elizabeth P. Rakoczy, Aaron L. Magno, Chooi May Lai, Cora M. Pierce, Mariapia A. Degli-Esposti, Mark S. Blumenkranz, Ian J. Constable

Research output: Contribution to journalArticle

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Abstract

Purpose: To assess the safety and the 3-year results of combined phase 1 and 2a randomized controlled trials of rAAV.sFLT-1 gene therapy (GT) for wet age-related macular degeneration. Design: Phase 1/2a clinical trial. Methods: Patients were prospectively randomized into control (n = 13) and GT (n = 24) groups. GT patients received 1X1011vg rAAV.sFLT-1 and were seen every month for 1 year then as needed every 1 to 2 months. They were given retreatment anti–vascular endothelial growth factor injections according to predetermined criteria. At 12 months, GT patients were divided into 2 groups: HD-1 (n = 14), requiring <2, and HD-2 (n = 10), requiring >2 retreatments. Results: Between 1 year and 3 years there were 3 adverse events (AEs) and 33 serious AEs reported. Of these, 15 occurred in the 13 control subjects and 21 in the 24 GT patients. Except for 1 case of transient choroiditis in a control patient, serious AEs were deemed to be unrelated to the study. Control patients received a median of 7.0 retreatments and lost a median of 7.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, HD-1 patients received a median of 2.5 retreatments and lost a median of 4.0 ETDRS letters, and HD-2 patients received a median of 11.0 retreatments and lost a median of 7.0 ETDRS letters over 3 years. Center point thickness fluctuated. Thirty-three percent of control subjects, 44% of HD-2 patients, and 51% of HD-1 patients showed maintenance of baseline visual acuity. Four HD-1 patients (34%) maintained significant visual improvement at 3 years. None of these observations were statistically significant. Conclusions: Given the small number of patients, this study was unable to unequivocally confirm the existence of a biologic efficacy signal; however, it confirmed that rAAV.sFLT-1 gene delivery was well tolerated among the elderly.

Original languageEnglish
Pages (from-to)113-123
Number of pages11
JournalAmerican Journal of Ophthalmology
Volume204
DOIs
Publication statusPublished - 1 Aug 2019

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Macular Degeneration
Genetic Therapy
Retreatment
Diabetic Retinopathy
Choroiditis
Endothelial Growth Factors
Clinical Trials, Phase I
Visual Acuity
Therapeutics
Randomized Controlled Trials
Maintenance
Safety

Cite this

Rakoczy, Elizabeth P. ; Magno, Aaron L. ; Lai, Chooi May ; Pierce, Cora M. ; Degli-Esposti, Mariapia A. ; Blumenkranz, Mark S. ; Constable, Ian J. / Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. In: American Journal of Ophthalmology. 2019 ; Vol. 204. pp. 113-123.
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abstract = "Purpose: To assess the safety and the 3-year results of combined phase 1 and 2a randomized controlled trials of rAAV.sFLT-1 gene therapy (GT) for wet age-related macular degeneration. Design: Phase 1/2a clinical trial. Methods: Patients were prospectively randomized into control (n = 13) and GT (n = 24) groups. GT patients received 1X1011vg rAAV.sFLT-1 and were seen every month for 1 year then as needed every 1 to 2 months. They were given retreatment anti–vascular endothelial growth factor injections according to predetermined criteria. At 12 months, GT patients were divided into 2 groups: HD-1 (n = 14), requiring <2, and HD-2 (n = 10), requiring >2 retreatments. Results: Between 1 year and 3 years there were 3 adverse events (AEs) and 33 serious AEs reported. Of these, 15 occurred in the 13 control subjects and 21 in the 24 GT patients. Except for 1 case of transient choroiditis in a control patient, serious AEs were deemed to be unrelated to the study. Control patients received a median of 7.0 retreatments and lost a median of 7.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, HD-1 patients received a median of 2.5 retreatments and lost a median of 4.0 ETDRS letters, and HD-2 patients received a median of 11.0 retreatments and lost a median of 7.0 ETDRS letters over 3 years. Center point thickness fluctuated. Thirty-three percent of control subjects, 44{\%} of HD-2 patients, and 51{\%} of HD-1 patients showed maintenance of baseline visual acuity. Four HD-1 patients (34{\%}) maintained significant visual improvement at 3 years. None of these observations were statistically significant. Conclusions: Given the small number of patients, this study was unable to unequivocally confirm the existence of a biologic efficacy signal; however, it confirmed that rAAV.sFLT-1 gene delivery was well tolerated among the elderly.",
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Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. / Rakoczy, Elizabeth P.; Magno, Aaron L.; Lai, Chooi May; Pierce, Cora M.; Degli-Esposti, Mariapia A.; Blumenkranz, Mark S.; Constable, Ian J.

In: American Journal of Ophthalmology, Vol. 204, 01.08.2019, p. 113-123.

Research output: Contribution to journalArticle

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T1 - Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration

AU - Rakoczy, Elizabeth P.

AU - Magno, Aaron L.

AU - Lai, Chooi May

AU - Pierce, Cora M.

AU - Degli-Esposti, Mariapia A.

AU - Blumenkranz, Mark S.

AU - Constable, Ian J.

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N2 - Purpose: To assess the safety and the 3-year results of combined phase 1 and 2a randomized controlled trials of rAAV.sFLT-1 gene therapy (GT) for wet age-related macular degeneration. Design: Phase 1/2a clinical trial. Methods: Patients were prospectively randomized into control (n = 13) and GT (n = 24) groups. GT patients received 1X1011vg rAAV.sFLT-1 and were seen every month for 1 year then as needed every 1 to 2 months. They were given retreatment anti–vascular endothelial growth factor injections according to predetermined criteria. At 12 months, GT patients were divided into 2 groups: HD-1 (n = 14), requiring <2, and HD-2 (n = 10), requiring >2 retreatments. Results: Between 1 year and 3 years there were 3 adverse events (AEs) and 33 serious AEs reported. Of these, 15 occurred in the 13 control subjects and 21 in the 24 GT patients. Except for 1 case of transient choroiditis in a control patient, serious AEs were deemed to be unrelated to the study. Control patients received a median of 7.0 retreatments and lost a median of 7.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, HD-1 patients received a median of 2.5 retreatments and lost a median of 4.0 ETDRS letters, and HD-2 patients received a median of 11.0 retreatments and lost a median of 7.0 ETDRS letters over 3 years. Center point thickness fluctuated. Thirty-three percent of control subjects, 44% of HD-2 patients, and 51% of HD-1 patients showed maintenance of baseline visual acuity. Four HD-1 patients (34%) maintained significant visual improvement at 3 years. None of these observations were statistically significant. Conclusions: Given the small number of patients, this study was unable to unequivocally confirm the existence of a biologic efficacy signal; however, it confirmed that rAAV.sFLT-1 gene delivery was well tolerated among the elderly.

AB - Purpose: To assess the safety and the 3-year results of combined phase 1 and 2a randomized controlled trials of rAAV.sFLT-1 gene therapy (GT) for wet age-related macular degeneration. Design: Phase 1/2a clinical trial. Methods: Patients were prospectively randomized into control (n = 13) and GT (n = 24) groups. GT patients received 1X1011vg rAAV.sFLT-1 and were seen every month for 1 year then as needed every 1 to 2 months. They were given retreatment anti–vascular endothelial growth factor injections according to predetermined criteria. At 12 months, GT patients were divided into 2 groups: HD-1 (n = 14), requiring <2, and HD-2 (n = 10), requiring >2 retreatments. Results: Between 1 year and 3 years there were 3 adverse events (AEs) and 33 serious AEs reported. Of these, 15 occurred in the 13 control subjects and 21 in the 24 GT patients. Except for 1 case of transient choroiditis in a control patient, serious AEs were deemed to be unrelated to the study. Control patients received a median of 7.0 retreatments and lost a median of 7.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, HD-1 patients received a median of 2.5 retreatments and lost a median of 4.0 ETDRS letters, and HD-2 patients received a median of 11.0 retreatments and lost a median of 7.0 ETDRS letters over 3 years. Center point thickness fluctuated. Thirty-three percent of control subjects, 44% of HD-2 patients, and 51% of HD-1 patients showed maintenance of baseline visual acuity. Four HD-1 patients (34%) maintained significant visual improvement at 3 years. None of these observations were statistically significant. Conclusions: Given the small number of patients, this study was unable to unequivocally confirm the existence of a biologic efficacy signal; however, it confirmed that rAAV.sFLT-1 gene delivery was well tolerated among the elderly.

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