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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

eyeDNA Therapeutics

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Eye Diseases [C11]

Trial duration

12 Oct 2017 → 30 Jun 2025

Decision date (initial)

2024-05-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

eyeDNA therapeutics

External identifiers

EU CT number

2024-511687-90-00

EudraCT number

2016-001429-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response, Pharmacodynamic, Therapy

To assess the safety of a unilateral subretinal administration of HORA-PDE6B

Secondary objectives 1

1. to assess putative humoral and cellular immune responses, shedding of viral vector and the efficacy of a unilateral subretinal administration of HORA-PDE6B. The overall safety and efficacy assessment aims to select the most optimal dose for further clinical investigations

Conditions and MedDRA coding

retinitis pigmentosa

Study design 1 period

Regulatory references

Scientific advice from competent authorities

National Agency For The Safety Of Medicine And Health Products

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Patients (male or female) having retinitis pigmentosa (RP) caused by defect in rod cGMP phosphodiesterase 6 (PDE6B) gene without other syndromic manifestations, referred to thereafter as PDE6B RP
2. 2. Patients having a phenotypic clinical status established by: a. Disease history; b. Presence of characteristic features of retinitis pigmentosa in fundus; c. Reduction of both rod and cone ERG responses in full-field ERG, with predominance of rod involvement, and with the exception of Cohort #4 (multifocal ERG not done) relative preservation of ERG responses of the fovea in multifocal ERG; d. Best-corrected visual acuity (BCVA) score of ≤60 ETDRS letters (corresponding to ≤0.32 or 20/63 Snellen equivalent) for Cohort #1, ≤ 75 ETDRS letters (corresponding to ≤0.63 or 20/32 Snellen equivalent) for Cohort #2 and a conserved central visual field of at least 10 degrees in every meridian using a V4 stimulus in the study eye for Cohort #3 and ≤75 ETDRS letters (corresponding to ≤0.63 or 20/32 Snellen equivalent). For Cohort #4, an unlimited BCVA score and with a conserved central visual field of at least 10 degrees for the two first adult patients and of at least 20 degrees for all other patients in every meridian using a V4 stimulus in the study eye
3. 3. Patients with at least one pathogenic mutant PDE6B allele on each chromosome confirmed by direct sequencing and co-segregation analysis within the patient's family in a certified laboratory
4. 4. Adult patients who have given informed consent, and patients under the age of 18 years who have given their assent, and whose both parents/legally designated representatives have provided their informed consent, after having been counselled by the investigator, particularly on the high number of visits and on the requirement of a short hospitalisation
5. 5. Patients having a RP aged ≥18 years old for Cohorts #1 to #3; ≥13 years old for Cohort #4
6. 6. Patients still having a residual central retinal function that allows ambulation.
7. 7. For females (including minors) with childbearing potential, a negative urine pregnancy test at screening (Visit 1/Day -120 to Day -7) and at visit 2 (Day -1). Females (including minors) with childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile) must be using a highly and effective method of contraception (e.g., hormonal birth control, IUD, double barrier [male condom, female condom, diaphragm]) plus a spermicidal agent [contraceptive foam, jelly, or cream], bilateral tubal occlusion, vasectomised partner, sexual abstinence). The patient will be requested to continue the contraception for six months after surgery (Visit 9/Day 180)
8. 8. For males of reproductive potential, agreement to use effective contraception for 6 months after administration of the IMP, for sexual activity that could lead to pregnancy
9. 9. Patients affiliated to the health security system or covered by national healthcare insurance system as required if non-French citizens

Exclusion criteria 4

1. Non-inclusion criteria related to co-morbidities 1. Patients with chronic conditions such as haematological, cardiac, renal diseases. 2. Patients with a clinically significant cardiac disease on routine clinical examination (history, physical examination), or known congestive heart failure, myocardial infarction, clinically significant valvular heart disease, clinically significant cardiac rhythm or conduction abnormalities, uncontrolled or unstable hypertension within 6 months prior to Day 0. 3. Patients with pulmonary dysfunction or severe obstructive pulmonary disease that, in the investigator's judgment, could interfere with the study participation and completion. 4. Patients with suspected rheumatoid arthritis or any other systemic autoimmune disease. 5. Patients with active cancer or patients currently undergoing therapy for cancer. 6. Patients with unstable endocrine disease, including unstable diabetes or thyroid disease. 7. Patients with alanine transaminase (ALAT), aspartate transaminase (ASAT), or gamma glutamyl transferase (GGT) >3x upper limit of normal. 8. Patients with severe anaemia (haemoglobin <9 g/dL), leukopenia (while blood cell count (WBC) <2,500/mm3), thrombocytopenia (platelet count <80,000/mm3), polycytemia (haematocrit >54% [male] or haematocrit >49% [female]) or clinically significant coagulopathy
2. Non-inclusion criteria related to infections or immune suppression 9. Patients with known history or clinical diagnosis of herpes zoster or varicella infection within 6 weeks before treatment or chicken pox exposure within 21 days before treatment. 10. Patients with current systemic infection. 11. Patients with active, extraocular infection requiring the prolonged or chronic use of antimicrobial agents. 12. Patients with seropositivity for human immunodeficiency virus (HIV), hepatitis B surface antigen (Ag-HBs) >0, polymerase chain reaction (PCR) test for hepatitis C virus (HCV) >0. 13. Patients using a therapy that would likely affect immune responses or interfere with trial logistics (steroidal, non-steroidal anti inflammatory, immunosuppressive and immune modulatory drugs) within 3 months before treatment. 14. Patients receiving an anti-viral drug treatment within 3 months before treatment (except topical labial herpes treatment). 15. Patients receiving a treatment based on a non-specific phosphodiesterase inhibitor within 3 months before treatment. 16. Patients with any non-ocular, medically significant co-morbid conditions that impair normal activities, require immunosuppression, or any medical condition that would likely have an impact on the participant's ability to comply with the study schedule. 17. Recipients of a solid organ transplant.
3. Ophthalmology-related non-inclusion criteria 18. Patients with "monophthalm" (monovisual capacity). 19. Patients with previous ocular surgery or thermal laser within 6 months before the surgery. 20. Patients with other ocular pathology, glaucoma, high myopia (>6 diopters), previous retinal detachment, diabetic retinopathy. 21. Patients with chronic ocular hypotony (less than 6 mmHg). 22. Patients with lens opacities or obscured ocular media upon recruitment such reliable evaluation or grading of the posterior segment cannot be performed. 23. For Cohort #4 only: Presence of any of the following lens opacities/cataracts in either eye: cortical opacity ≥ +2, posterior subcapsular opacity ≥ +2, nuclear opalescence ≥ +2 or nuclear colour ≥ +2. 24. Patients with known serious allergies to the fluorescein or indocyanine green dye used in angiography, to the mydriatic, steroidal and non-steroidal eye drops.
4. Other non-inclusion criteria 25. Patients who received a vaccination during the month before treatment and patients who will receive a vaccination within 6 months after treatment. For Cohort #4 only: Patients who have received an AAV-based vaccination within 3 months before treatment. 26. Patients who received an anti-acneic medication containing retinoid within 3 months before treatment. 27. Adult patients under guardianship, curatorship or legal safeguard or deprived of liberty. 28. Patients participating in another clinical trial with an investigational agent in the 30 days or within 5 half-lives (whichever is longer) of the investigational agent previously tested prior to the study participation and/or has not recovered from any reversible effects or side effects prior investigational agent. 29. Patients enrolled or being enrolled in another gene therapy clinical trial. 30. Patients currently pregnant or lactating. 31. Patients with any current or history of substance abuse, psychiatric disorder or a condition that, in the opinion of the investigator, would jeopardize the safety of the patient or impact the validity of the study results. 32. For Cohort #4 only: known contraindication to any medication likely to be given during the course of the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoints will be the assessment of safety parameters: routine ophthalmic examination, intraocular inflammation, chorioretinal tolerance, questionnaire, vital signs, laboratory measurements

Secondary endpoints 3

1. Functional tests: •distance and near visual acuity and refraction (near visual acuity not applicable for Cohort #4 patients); •colour vision; •visual fields; •global or full-field ERG; multifocal ERG*; •pupillometry (not applicable for the Cohort #3 & Cohort #4 patients); •microperimetry; •mobility test; •dark adaptation test; •full-field sensitivity threshold for the Cohort #3 & Cohort #4 patients; •evaluation of quality of life in adult patients
2. Morphologic tests: •fundus autofluorescence; •spectral domain optical coherence tomography (SD-OCT)
3. Exploratory assessment: functional magnetic resonance imaging (fMRI)* * Not to be performed in Cohort #4

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

eyeDNA Therapeutics

Sponsor organisation

eyeDNA Therapeutics

Address

63 B Avenue Ledru Rollin

City

Paris

Postcode

75012

Country

France

Scientific contact point

Organisation

eyeDNA Therapeutics

Contact name

Chief Development Officer

Public contact point

Organisation

eyeDNA Therapeutics

Contact name

Chief Development Officer

Third parties 12

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications