LCA, LCA1, Leber Congenital Amaurosis
Conditions
Keywords
GUCY2D
Brief summary
Primary Objective: To evaluate the safety and tolerability of ascending doses of ATSN-101 administered as a unilateral subretinal injection in patients with Leber Congenital Amaurosis (LCA) caused by autosomal recessive guanylate cyclase 2D (GUCY2D) mutations (GUCY2D-LCA). Secondary Objective: To evaluate the efficacy of ascending doses of ATSN-101 administered as a unilateral subretinal injection in patients with GUCY2D-LCA.
Detailed description
Study duration per participant is approximately 112 weeks including: an approximately 56-day screening/baseline period, an approximately 52-week study observation period including 1 treatment day, and an approximately 52-week safety follow-up period. The end of study visit will be approximately 260 weeks after the Investigational Medicinal Product (IMP) administration. The study is separated into 2 parts including a dose escalation phase (Part A) and a dose expansion phase (Part B). In Part B participants will be treated at the maximum tolerated dose (MTD) or maximum administered dose (MAD) determined from Part A.
Interventions
DRUGATSN-101
Pharmaceutical form:Solution for intraocular administration Route of administration: Subretinal injection
DRUGATSN-101 Diluent Solution
Pharmaceutical form:Solution for parenteral use Route of administration: Subretinal injection
DRUGPrednisone
Pharmaceutical form:Tablet Route of administration: Oral
DRUGTriamcinalone Acetonide
Pharmaceutical form:Suspension Route of administration: Peri-ocular injection
DRUG1% Prednisolone
Pharmaceutical form:Suspension Route of administration: Drops
DRUGTrimethoprim/polymyxin B
Pharmaceutical form:Solution Route of administration: Topical
Sponsors
Atsena Therapeutics Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Male or female participant with clinical diagnosis of Leber congenital amaurosis caused by biallelic mutations in the GUCY2D (retinal guanylate cyclase) gene with all of the following: a) Documented mutations in both alleles of the GUCY2D gene per testing in a CLIA-approved laboratory, b) For Cohort 1-3, best corrected visual acuity (BCVA) of 20/200 or worse in the eye to be injected; subsequent cohorts may include BCVA of 20/80 or worse in the eye to be injected, c) Photoreceptor (outer nuclear) layer structure identifiable on an optical coherence tomography (OCT) scan across the central retina. * Age ≥18 years for Cohorts 1 through 4, and age ≥ 6 years and \<18 years for Cohort 5. * Male and female participants must follow the contraception requirements of the trial. * Participants must agree to not donate blood, organs, tissues, cells or sperm for at least three months following ATSN-101 administration.
Exclusion criteria
* Complicating systemic diseases (such as medical conditions causing immunosuppression) that would preclude the gene transfer, ocular surgery or planned study procedures. * History of human immunodeficiency virus (HIV) infection. * Pre-existing eye conditions in the study eye that would preclude the planned surgery or interfere with the assessment and interpretation of study endpoints: for example, glaucoma or optic neuropathy that has resulted in significant visual loss, corneal or lenticular abnormalities or opacities that would preclude view of the fundus or performance of the outcome measures, uveitis, retinopathy and maculopathy that in the opinion of the Investigator are causing significant visual loss. * Presence of significant ocular abnormalities in the study eye that in the opinion of the Investigator would preclude the planned surgery, effective safety follow-up, or interfere with the interpretation of study endpoints (eg, glaucoma, corneal or significant lens abnormalities or opacities, pre-existing uveitis, intraocular infection, choroidal neovascularization). * Any contraindication to the planned surgical procedure, such as contraindications to the use of anaesthesia or allergy to medications planned in the peri-operative period. * Known allergy or hypersensitivity to any component of the investigational medicinal product (IMP), diagnostic agents used during the study or medications planned for use in the peri-operative period, particularly corticosteroids. * Women who are pregnant (defined as positive beta-Human Chorionic Gonadotropin (HCG) blood or urine test), lactating or breastfeeding. * Any ocular procedure, either planned or performed within 6 months of Day 1, which would interfere with the planned surgery or the interpretation of study endpoints in the opinion of the Principal Investigator (PI). * Laboratory test abnormalities or abnormalities in electrocardiogram that in the opinion of the PI would make the participant unsuitable for participation in the study. * Significant intercurrent illness or infection during the 28 days prior to enrollment. * Current substance use disorder. * Use of any investigational agent administered within 5 times the elimination half-life of that investigational agent prior to ATSN-101 administration. * Enrollment in any other clinical treatment study, for any condition, including those relating to GUCY2D-LCA, throughout the duration of the ATSN-101 study participation. * Use of anticoagulation therapy within two weeks prior to surgery. * Use of immunosuppressive medications. * Current, planned during the course of this trial, or past (within 5 times the elimination half-life of that therapy prior to ATSN-101 administration) use of anti-viral therapy that would inactivate the investigational agent. * Received gene therapy within the last 15 years. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) From Baseline up to the End of the Observation Period | From Baseline to Week 52 | Number of participants with treatment-emergent AEs will be summarized in each cohort (this includes cohorts 1 - 5) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Best-Corrected Visual Acuity (BCVA) Between the Treated and Untreated Eyes | Baseline to Week 52 | Mean change from Baseline to Week 52 in BCVA (LogMAR) in the treated eye and untreated eye (control). In logMAR notation (logarithm of the minimum angle of resolution) is interpreted as follows: Lower LogMAR values indicates better vision. Higher LogMAR values indicates worse vision. |
| Change From Baseline of Sensitivity Between the Treated and Untreated Eye - Light Adapted | Baseline to Week 52 | Mean change from Baseline to Week 52 in sensitivity as measured by the full-field stimulus testing - Light Adapted in the treated eye and untreated eye. Full-field stimulus testing was performed for three stimulus colors - blue, red, and white. |
| Mean Change From Baseline of Sensitivity Between the Treated and Untreated Eye - Dark Adapted | Baseline to Week 52 | Mean change from Baseline to Week 52 in sensitivity as measured by the full-field stimulus testing - Dark Adapted in the treated eye and untreated eye. Full-field stimulus testing was performed for three stimulus colors - blue, red, and white. |
| Number of Participants With Adverse Events (AEs) From Baseline up to the End of the Observation Period | From Baseline to Week 260 | Number of participants with treatment-emergent AEs will be summarized in each cohort (this includes cohorts 1 - 5) |
Countries
United States
Participant flow
Recruitment details
Study screening and enrollment occurred between October 2019 through May 2022. A total of 23 patients were screened, resulting in 2 enrollments at the Casey Eye Institute - Oregon Health and Science University and 13 enrollments at the Scheie Eye Institute - University of Pennsylvania to reach the study's goal of 15 enrolled patients across all cohorts.
Pre-assignment details
Of the 23 screened patients, 15 had a signed ICF and were not identified as screen failures and were assigned to single dose of ATSN-101 in the dose escalation and dose expansion phases of the study (Cohorts 1-5). Participants are still ongoing in the study From Week 52 to Week 260. The record will be updated upon study completion.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 33.7 Years STANDARD_DEVIATION 11.06 |
| Baseline BMI (kg/m^2) | 28.0 kg/m^2 STANDARD_DEVIATION 5.44 |
| Baseline Height (cm) | 158.0 cm STANDARD_DEVIATION 10.15 |
| Baseline Weight (kg) | 77.9 kg STANDARD_DEVIATION 26.29 |
| Ethnicity Hispanic or Latino | 0 Participants |
| Ethnicity Not Hispanic or Latino | 3 Participants |
| Ethnicity Not Reported | 0 Participants |
| Ethnicity Unknown | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race Not Reported | 2 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants |
| Race/Ethnicity, Customized Race White | 10 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 3 | 1 / 3 |
Outcome results
None listed