Single Ascending Dose Study in Participants With LCA10

Open-Label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Efficacy of EDIT-101 in Adult and Pediatric Participants With Leber Congenital Amaurosis Type 10 (LCA10), With Centrosomal Protein 290 (CEP290)-Related Retinal Degeneration Caused by a Compound Heterozygous or Homozygous Mutation Involving c.2991+1655A>G in Intron 26 (IVS26) of the CEP290 Gene ("LCA10-IVS26")

The purpose of this study is to evaluate the safety, tolerability and efficacy of a single escalating doses of EDIT-101 administered via subretinal injection in participants with LCA10 caused by a homozygous or compound heterozygous mutation involving c.2991+1655A>G in intron 26 of the CEP290 gene ("LCA10-IVS26").

Study Overview

• Status: Active, not recruiting
• Conditions: Retinal Degeneration; Eye Diseases, Hereditary; Vision Disorders; Leber Congenital Amaurosis 10; Inherited Retinal Dystrophies; Retinal Disease; Eye Disorders Congenital
• Intervention / Treatment: Drug: EDIT-101

Detailed Description

This is an open-label, single ascending dose study of EDIT-101 in adult and pediatric (ie, ages 3 to 17) participants with LCA10-IVS26. Up to 34 participants will be enrolled in up to 5 cohorts to evaluate up to 3 dose levels of EDIT-101 in this study. EDIT-101 is a novel gene editing product designed to eliminate the mutation on the CEP290 gene that results in the retinal degeneration that defines LCA10-IVS26.

• Study Type: Interventional
• Enrollment (Anticipated): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Bascom Palmer Eye Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Eye And Ear Infirmary
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • W.K. Kellogg Eye Center - University of Michigan
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute - OSHU
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female
• At least 3 years of age at screening with CEP290-related retinal degeneration caused by a homozygous or compound heterozygous mutation involving c.2991+1655A>G in IVS26 of the CEP290 gene.

• Visual Acuity:

  • Sentinel participant will have severe vision loss with a logMAR BCVA of ≥1.6 to 3.9 (20/800 or worse to LP) in the study eye
  • Non-sentinel participants must have BCVA between 1.0 - 3.0 logMAR in the study eye

Exclusion Criteria:

• Other known disease-causing mutations
• Achieves a passing score for the mobility course at the most difficult level
• In either eye, active systemic or ocular/intraocular infection or inflammation
• In either eye, history of steroid-responsive intraocular pressure with increases > 25 mm Hg following corticosteroid exposure
• Any vaccination/immunization in the last 28 days before screening
• Inability or unwillingness to take oral prednisone
• Prior gene therapy or oligonucleotide treatment

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: Adults Low Dose; Single dose of EDIT-101 administered by subretinal injection surgery	Drug: EDIT-101; Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.
Experimental: Adults Middle Dose; Single dose of EDIT-101 administered by subretinal injection surgery	Drug: EDIT-101; Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.
Experimental: Adults High Dose; Single dose of EDIT-101 administered by subretinal injection surgery	Drug: EDIT-101; Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.
Experimental: Pediatric Middle Dose; Single dose of EDIT-101 administered by subretinal injection surgery	Drug: EDIT-101; Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.
Experimental: Pediatric High Dose; Single dose of EDIT-101 administered by subretinal injection surgery	Drug: EDIT-101; Participants will receive a single dose of EDIT-101 administered via subretinal injection in the study eye. Up to 5 cohorts across 3 doses will be enrolled in this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Frequency of Adverse Events related to EDIT-101	1 year
Number of participants experiencing procedural related adverse events	1 year
Incidence of dose limiting toxicities	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose as determined by occurrence of dose limiting toxicities		1 year
Change from baseline in Mobility course score	Testing the subjects visual function by having the subject walk through obstacle courses. Courses will have different levels of difficulty depending on the light levels of the room and the contrast of the objects in the room.	1 year
Change from baseline in LogMAR measurement of BCVA	The test will evaluate visual acuity in ranges from light perception to normal vision.	1 year
Change from baseline in pupillary response	Measuring the change in pupil diameter in response to a light stimulus.	1 year
Change from baseline in dark adapted visual sensitivity using Full field light sensitivity threshold (FST)	Flashes of light of varying luminance are presented to the eye and the subject reports is the flash was seen.	1 year
Change from baseline in macula thickness		1 year
Change from baseline in contrast sensitivity	The Lea symbols chart will be used for subjects under age 6 and the Pelli-Robson chart for all other subjects. The images or letters on the charts are in decreasing contrast.	1 year
Change from baseline in macular sensitivity as measured by microperimetry	Visual field test measuring the amount of light perceived in specific parts of the macula.	1 year
Change from baseline in color vision score using the Farnsworth 15 score	The Farnsworth D15 tests for congenital and acquired color vision defects. Fifteen color discs will be arranged by the subject. Scoring is accomplished by recording the sequence selected by the patient on a copy of the score sheet. A patient with a color vision deficiency will arrange the color discs in a different order than a person with normal color vision.	1 year
Change from baseline in QOL score for Age <8 years using the Children's Visual Function Questionnaire		1 year
Change from baseline in QOL score for Age 8 to <18 years using the Impact of Vision Impairment for Children		1 year
Change from baseline in QOL score for Age >18 years if BCVA is worse than 1.0 logMAR in both eyes using the Impact of Vision Impairment for Very Low Vision		1 year
Change from baseline in QOL score for Age >18 years if BCVA is 1.0 logMAR or better in both eyes using the Impact of Vision Impairment		1 year
Change from baseline in visual field using kinetic perimetry	Kinetic perimetry looks as the visual field to identify regions of normal and abnormal sensitivity to light	1 year
Change from baseline in Patient Global Impressions of Change score	This QOL has 5 non-numeric choices for the subject to select how they believe their condition has changed.	1 year
Change from baseline in gaze tracking	Video clips of the eyes are used to measure eye position and stability over time.	1 year

Collaborators and Investigators

• Sponsor: Editas Medicine, Inc.

Publications and helpful links

General Publications

• Harvey JP, Sladen PE, Yu-Wai-Man P, Cheetham ME. Induced Pluripotent Stem Cells for Inherited Optic Neuropathies-Disease Modeling and Therapeutic Development. J Neuroophthalmol. 2022 Mar 1;42(1):35-44. doi: 10.1097/WNO.0000000000001375. Epub 2021 Sep 30.
• Zhang X, Zhang D, Thompson JA, Chen SC, Huang Z, Jennings L, McLaren TL, Lamey TM, De Roach JN, Chen FK, McLenachan S. Gene correction of the CLN3 c.175G>A variant in patient-derived induced pluripotent stem cells prevents pathological changes in retinal organoids. Mol Genet Genomic Med. 2021 Mar;9(3):e1601. doi: 10.1002/mgg3.1601. Epub 2021 Jan 26.

Helpful Links

• Clinical Trial Informational Website

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2019
• Primary Completion (Anticipated): May 23, 2025
• Study Completion (Anticipated): May 23, 2025

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: March 11, 2019
• First Posted (Actual): March 13, 2019

Study Record Updates

• Last Update Posted (Actual): December 5, 2022
• Last Update Submitted That Met QC Criteria: December 2, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Congenital Abnormalities; Genetic Diseases, Inborn; CEP290; LCA10; Retinal degenerative diseases (RDD); Leber congenital amaurosis (LCA); Congenital Retinal Blindness; p.Cys998X; c.2991+1655A>G; CRISPR Treatment; Cas9 Protein; Eye Diseases Signs and Symptoms; Eye Abnormalities; CRISPR-Cas9; CRISPR Associated Protein 9; Cas9 Enzyme
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Congenital Abnormalities; Sensation Disorders; Disease; Retinal Diseases; Eye Diseases; Genetic Diseases, Inborn; Blindness; Vision Disorders; Retinal Degeneration; Leber Congenital Amaurosis; Retinal Dystrophies; Eye Diseases, Hereditary; Eye Abnormalities
• Other Study ID Numbers: 1991-201-008

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