A Study to Evaluate the Safety and Tolerability of ONL1204 in Patients With Macula-off, Rhegmatogenous Retinal Detachment

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of ONL1204 in participants with Macula-off, Rhegmatogenous Retinal Detachment (RRD). RRD is an acute and serious vision threatening condition in which a tear in the retina, typically resulting from a vitreous detachment, allows liquid to accumulate under the retina, detaching the photoreceptor (PR) layer of the retina from the retinal pigment epithelium (RPE). As the RPE is the principal source of nutritional support for the PR layer, the photoreceptors begin a cascade of inflammation and cell death. Photoreceptor cell death is the primary mechanism of vision loss after retinal detachment. ONL1204 is a first-in-class inhibitor of Fragment Apoptosis Stimulator receptor (Fas)-mediated cell death. ONL1204 has demonstrated protection of multiple retinal cell types in numerous preclinical models of acute ocular injury. This will be a first-in-human (FIH) study to evaluate safety and tolerability of a single-dose of ONL1204 in participants with macula-off RRD. The standard of care for surgical repair of macula-off RRD is reattachment surgery within 7 days of the macula detaching. Participants in this study will receive a single intravitreal injection upon diagnosis and enrollment in the study, followed by standard of care surgery. The surgery includes vitrectomy, a procedure that removes the bulk of drug remaining in the vitreous.

Official Title
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A Phase 1 Open-Label, Dose Escalation Study to Assess the Safety and Tolerability of Intravitreal ONL1204 in Patients With Macula-off, Rhegmatogenous Retinal Detachment

Conditions
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Rhegmatogenous Retinal Detachment - Macula Off

Intervention / Treatment
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* Drug: ONL1204
* Procedure: Intravitreal Injection
* Procedure: Collection of ocular fluids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, ≥ 18 to 80 years old Able to give informed consent and comply with all study visits and procedures Patients who: Present between 1 week (7 days) and 4 weeks (28 days) of a macula-off RRD (based on patient-reported history of loss of central vision) For whom standard retinal reattachment surgery by means of a pars plana vitrectomy (with or without scleral buckle) and gas tamponade is indicated, and In the opinion of the investigator, can safely undergo all study procedures. Best corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity of 20/100 to hand motion in the study eye Best corrected ETDRS visual acuity in the fellow eye of 20/60 or better Exclusion Criteria: Presence of giant retinal tear defined as greater than 3 clock hours or other type of complex retinal detachment in the study eye Presence of vitreous hemorrhage in the study eye Presence of ocular or periocular infection or intraocular inflammation in either eye Intraocular Pressure > 22 mmHg in the study eye Any other significant ocular disease in the study eye including media opacity that, in the opinion of the investigator, would preclude a visual acuity of at least 20/25 following successful vitrectomy or limit adequate visibility of the retina Any other ocular pathology in the study eye requiring treatment with topical ophthalmic drops or intravitreal injection History of previous ocular surgery in the study eye other than uncomplicated cataract surgery with posterior chamber intraocular lens and intact posterior capsule (which must have occurred at least 6 months prior to the baseline visit) Participation in other clinical trials or use of any other investigational drugs or devices within 3 months prior to study participation Females who are pregnant or lactating and women of childbearing potential who are not using adequate contraceptive precautions (e.g., intrauterine device, oral contraceptives, barrier method, or other contraception deemed adequate by the investigator) Known retinopathy, known hepatic disease (or history of significant chronic liver disease), or known renal disease. Patients with diabetes and no known retinopathy may be enrolled History of uncontrolled hypertension History of stroke, transient ischemic attack, or major cardiac surgery within 3 months prior to study, or current treatment for systemic infection Any ocular or systemic condition that in the opinion of the investigator could compromise the safety of the patient, or may interfere with the safety and tolerability assessments or study procedures of the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1 Dose A<br>Intravitreal injection of 50 μl of ONL1204 liquid formulation to deliver dose 1 | Drug: ONL1204<br>* Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection<br>Procedure: Intravitreal Injection<br>* Injection of study drug into the eye<br>Procedure: Collection of ocular fluids<br>* vitreous and aqueous fluid collection by a tap and during vitrectomy<br>|
| Active Comparator: Cohort 2 Dose B<br>Intravitreal injection of 100 μl of ONL1204 liquid formulation to deliver dose 2 | Drug: ONL1204<br>* Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection<br>Procedure: Intravitreal Injection<br>* Injection of study drug into the eye<br>Procedure: Collection of ocular fluids<br>* vitreous and aqueous fluid collection by a tap and during vitrectomy<br>|
| Active Comparator: Cohort 3 Dose C<br>Intravitreal injection of 50 μl of ONL1204 liquid formulation to deliver dose 3 | Drug: ONL1204<br>* Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection<br>Procedure: Intravitreal Injection<br>* Injection of study drug into the eye<br>Procedure: Collection of ocular fluids<br>* vitreous and aqueous fluid collection by a tap and during vitrectomy<br>|
| Active Comparator: Cohort 4 Dose D<br>Intravitreal injection of 100 μl of ONL1204 liquid formulation to deliver dose 4 | Drug: ONL1204<br>* Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection<br>Procedure: Intravitreal Injection<br>* Injection of study drug into the eye<br>Procedure: Collection of ocular fluids<br>* vitreous and aqueous fluid collection by a tap and during vitrectomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital sign-systolic and diastolic blood pressure | Systolic and diastolic blood pressure in mmHg | 24 weeks | 
| Vital sign-heart rate | Heart rate in beats per minute | 24 weeks | 
| Best corrected visual acuity | ETDRS chart (number of letters read) | 24 weeks | 
| Intraocular pressure | Intraocular pressure in mmHg | 24 weeks | 
| Slit lamp biomicroscopy | Slit lamp biomicroscopy (using US FDA clinical grading scale 0-4; 0=normal, 4=very severe changes) | 24 weeks | 
| Complete blood count | White blood cells with differential, hemoglobin, hematocrit and platelet count | 24 weeks |