Safety and Efficacy Study in Patients With Retinitis Pigmentosa Due to Mutations in PDE6B Gene

Safety and Efficacy of a Unilateral Subretinal Administration of HORA-PDE6B in Patients With Retinitis Pigmentosa Harbouring Mutations in the PDE6B Gene Leading to a Defect in PDE6ß Expression

The study is a Phase I/II, monocentric, open-label, dose-ranging safety and efficacy gene therapy intervention by subretinal administration of AAV2/5-hPDE6B.

At least twelve patients 18 years of age or older, within four consecutive cohorts of patients, will be recruited.

Then at least four patients 13 years of age or older, within a fifth cohort, will be recruited.

Study Overview

• Status: Recruiting
• Conditions: Retinitis Pigmentosa
• Intervention / Treatment: Biological: AAV2/5-hPDE6B

Detailed Description

Retinitis pigmentosa (RP) is a disease where part of the eye (the retina) is degenerating over time. Patients initially present with night blindness, and later in life experience loss of central vision which leads to blindness. RP is a highly variable disorder with some patients developing symptomatic visual loss in childhood whereas others remain asymptomatic until mid-adulthood. There are no treatments available.

This study focuses on the form of RP caused by mutations (modifications) in the genetic information necessary to make the protein called rod cGMP phosphodiesterase 6 β subunit (or PDE6β). Clinical diagnosis is made by function tests of the eye and confirmed using a specific method called molecular testing to verify that the PDE6B gene is not correct.

This study uses a gene therapy vector inspired from an adeno-associated virus (AAV) called AAV2/5-hPDE6B. This vector intends to supply to the target cells the PDE6B therapeutic gene that is not functioning properly in the cell. The AAV parts of the gene therapy vector work as a vehicle to deliver the normal human PDE6B gene into the cells of the retina.

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Medical Director / Chief Development Officer, MD; Phone Number: 01 81 69 87 70; Email: contact@eyednatx.com

Study Locations

• France
  • Nantes, France, 44093
    • Recruiting
    • Clinique Ophtalmologique, CHU de Nantes
    • Contact: Pierre Lebranchu; Email: pierre.lebranchu@chu-nantes.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Clinical and molecular diagnosis of retinitis pigmentosa caused by defect in PDE6B gene without other syndromic manifestations
• Aged above 13 years
• Ability to give informed consent

Key Exclusion Criteria:

• Previous ocular surgery or thermal laser within 6 months before the surgery
• Lens opacities or obscured ocular media upon recruitment such reliable evaluation or grading of the posterior segment cannot be performed
• Known serious allergies to the fluorescein dye used in angiography, to the mydriatic, steroidal and non-steroidal eye drops
• Participation in another clinical trial with an investigational agent
• Enrolled or being enrolled in another gene therapy clinical trial
• Active, extraocular infection requiring the prolonged or chronic use of antimicrobial agents
• Chronic medical conditions, cancer
• Abnormal laboratory values
• On immunosuppressive therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 - Low Dose; Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the lowest dose. Dose-escalation will be performed after DSMC assessment.	Biological: AAV2/5-hPDE6B; Subretinal administration in one eye
Experimental: Cohort 2a - Medium Dose; Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the medium dose. Confirmatory dose will be determined after DSMC assessment.	Biological: AAV2/5-hPDE6B; Subretinal administration in one eye
Experimental: Cohort 2b - High Dose; Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the highest dose. Confirmatory dose will be determined after DSMC assessment.	Biological: AAV2/5-hPDE6B; Subretinal administration in one eye
Experimental: Cohort 3 - High Dose (confirmatory cohort); Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the confirmatory dose.	Biological: AAV2/5-hPDE6B; Subretinal administration in one eye
Experimental: Cohort 4 - High Dose - 13 years old or older population; Biological: AAV2/5-hPDE6B Unilateral (one eye), subretinal, administration of the confirmatory dose.	Biological: AAV2/5-hPDE6B; Subretinal administration in one eye

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of ocular and non-ocular adverse events	1 year + 4 years follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in visual function	Improvement in visual function as assessed by mobility test	1 year + 4 years follow-up
Improvement in visual fields	Improvement in visual fields as assessed by visual fields measurements	1 year + 4 years follow-up
Improvement in visual function	Improvement in visual function as assessed by reading speed	1 year + 4 years follow-up
Improvement in Quality of Life	Quality of life will be measured by Quality of Life questionnaire National Eye Institute Visual Function Questionnaire (NEI VFQ-25)	1 year + 4 years follow-up

Collaborators and Investigators

• Sponsor: eyeDNA Therapeutics

Publications and helpful links

General Publications

• Petit L, Lheriteau E, Weber M, Le Meur G, Deschamps JY, Provost N, Mendes-Madeira A, Libeau L, Guihal C, Colle MA, Moullier P, Rolling F. Restoration of vision in the pde6beta-deficient dog, a large animal model of rod-cone dystrophy. Mol Ther. 2012 Nov;20(11):2019-30. doi: 10.1038/mt.2012.134. Epub 2012 Jul 24.
• Pichard V, Provost N, Mendes-Madeira A, Libeau L, Hulin P, Tshilenge KT, Biget M, Ameline B, Deschamps JY, Weber M, Le Meur G, Colle MA, Moullier P, Rolling F. AAV-mediated Gene Therapy Halts Retinal Degeneration in PDE6beta-deficient Dogs. Mol Ther. 2016 May;24(5):867-76. doi: 10.1038/mt.2016.37. Epub 2016 Feb 9.
• Palmowski-Wolfe A, Stingl K, Habibi I, Schorderet D, Tran HV. Novel PDE6B Mutation Presenting with Retinitis Pigmentosa - A Case Series of Three Patients. Klin Monbl Augenheilkd. 2019 Apr;236(4):562-567. doi: 10.1055/a-0811-5480. Epub 2019 Jan 15.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2017
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: October 5, 2017
• First Submitted That Met QC Criteria: October 31, 2017
• First Posted (Actual): November 1, 2017

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Gene Therapy; Eye Diseases; AAV; Retinitis Pigmentosa; Eye Diseases, Hereditary; Retinal Diseases; Adeno-associated virus; Retinal Dystrophy; Retinal Degeneration; Gene Transfer; Vision Disorders; PDE6B
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Genetic Diseases, Inborn; Eye Diseases, Hereditary; Retinal Dystrophies; Retinitis; Retinitis Pigmentosa
• Other Study ID Numbers: HORA-PDE6B-001; 2016-001429-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No