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

• ClinicalTrials.gov Identifier: NCT03780972
• Recruitment Status: Recruiting
• First Posted: December 19, 2018
• Last Update Posted: November 13, 2019
• Sponsor: ONL Therapeutics
• Information provided by (Responsible Party): ONL Therapeutics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Rhegmatogenous Retinal Detachment - Macula Off	Drug: ONL1204; Procedure: Intravitreal Injection; Procedure: Collection of ocular fluids	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 21, 2019
• Estimated Primary Completion Date: August 1, 2020
• Estimated Study Completion Date: December 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Cohort 1, 25 μg ONL1204; Intravitreal injection of 50 μl of ONL1204 liquid formulation to deliver 25 μg of ONL1204 (0.5 mg/ml ONL1204 formulation)	Drug: ONL1204; Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection; Procedure: Intravitreal Injection; Injection of study drug into the eye; Procedure: Collection of ocular fluids; vitreous and aqueous fluid collection by a tap and during vitrectomy
Active Comparator: Cohort 2, 50 μg ONL1204; Intravitreal injection of 100 μl of ONL1204 liquid formulation to deliver 50 μg of ONL1204 (0.5 mg/ml ONL1204 formulation)	Drug: ONL1204; Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection; Procedure: Intravitreal Injection; Injection of study drug into the eye; Procedure: Collection of ocular fluids; vitreous and aqueous fluid collection by a tap and during vitrectomy
Active Comparator: Cohort 3, 100 μg ONL1204; Intravitreal injection of 50 μl of ONL1204 liquid formulation to deliver 100 μg of ONL1204 (2.0 mg/ml ONL1204 formulation)	Drug: ONL1204; Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection; Procedure: Intravitreal Injection; Injection of study drug into the eye; Procedure: Collection of ocular fluids; vitreous and aqueous fluid collection by a tap and during vitrectomy
Active Comparator: Cohort 4, 200 μg ONL1204; Intravitreal injection of 100 μl of ONL1204 liquid formulation to deliver 200 μg of ONL1204 (2.0 mg/ml ONL1204 formulation)	Drug: ONL1204; Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection; Procedure: Intravitreal Injection; Injection of study drug into the eye; Procedure: Collection of ocular fluids; vitreous and aqueous fluid collection by a tap and during vitrectomy

Outcome Measures

Primary Outcome Measures :

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

Other Outcome Measures:

1. Exploratory outcome-ONL1204 concentration [ Time Frame: 24 weeks ]
   Measurement of ONL1204 in plasma and vitreous fluid (ng/ml) after drug administration
2. Exploratory outcome-Analysis of cytokine panel concentration before and after drug administration [ Time Frame: 24 weeks ]
   A panel of cytokines will be measured by a single multiplex assay (in ng/ml) in the vitreous and aqueous samples before and after drug administration (monocyte chemoattractant protein-1 (MCP1), interferon gamma-induced protein 10 (IP10), fractalkine, macrophage inflammatory protein-1a (MIP1a), MIP1b, interleukins (IL2, IL1b, IL18, IL6, IL8, IL1ra, IL12p40, IL10, IL5), vesicular endothelial growth factor A (VEGFA), granulocyte colony stimulating factor (G-CSF), platelet derived growth factor-AB (PDGF-AB), tumor necrosis factor alpha (TNFa), intracellular adhesion molecule 1(ICAM1)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Males and females, ≥ 18 to 80 years old
2. Able to give informed consent and comply with all study visits and procedures

3. Patients who:

   1. 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)
   2. For whom standard retinal reattachment surgery by means of a pars plana vitrectomy (with or without scleral buckle) and gas tamponade is indicated, and
   3. In the opinion of the investigator, can safely undergo all study procedures.
4. Best corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity of 20/100 to hand motion in the study eye
5. Best corrected ETDRS visual acuity in the fellow eye of 20/60 or better

Exclusion Criteria:

1. Presence of giant retinal tear defined as greater than 3 clock hours or other type of complex retinal detachment in the study eye
2. Presence of vitreous hemorrhage in the study eye
3. Presence of ocular or periocular infection or intraocular inflammation in either eye
4. Intraocular Pressure > 22 mmHg in the study eye
5. 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
6. Any other ocular pathology in the study eye requiring treatment with topical ophthalmic drops or intravitreal injection
7. 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)
8. Participation in other clinical trials or use of any other investigational drugs or devices within 3 months prior to study participation
9. 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)
10. 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
11. History of uncontrolled hypertension
12. History of stroke, transient ischemic attack, or major cardiac surgery within 3 months prior to study, or current treatment for systemic infection
13. 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

Contacts and Locations

Contacts

Contact: Jana van de Goor, Ph.D.; 650-303-0094; jvandegoor@onltherapeutics.com

Contact: David Zacks, M.D./Ph.D.; 734-936-0871; dnzacks@onltherapeutics.com

Locations

Australia, New South Wales

Save Sight Institute, Sydney Eye Hospital; Recruiting

Sydney, New South Wales, Australia, 2000

Contact: Matthew Simunovic, M.D. +61 2 9382 7300

Contact: Maria Williams +61 2 9382 7300

Sponsors and Collaborators

ONL Therapeutics

Investigators

• Principal Investigator: Matthew Simunovic, M.D.; Save Sight Institute, Sydney Eye Hospital, Australia

More Information

• Responsible Party: ONL Therapeutics
• ClinicalTrials.gov Identifier: NCT03780972 History of Changes
• Other Study ID Numbers: ONL1204-RRD-001
• First Posted: December 19, 2018
• Last Update Posted: November 13, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Retinal Detachment; Dissociative Disorders; Mental Disorders; Retinal Diseases; Eye Diseases