Phase 1/2 Safety and Efficacy Study of AAV-RPE65 Vector to Treat Leber Congenital Amaurosis

A Multiple-Site, Phase 1/2, Safety and Efficacy Trial of a Recombinant Adeno-associated Virus Vector Expressing RPE65 (rAAV2-CB-hRPE65) in Patients With Leber Congenital Amaurosis Type 2

The purpose of the study is to evaluate the safety and efficacy of an adeno-associated virus vector expressing RPE65 in patients with Leber congenital amaurosis caused by mutations in the RPE65 gene.

Funding Source - FDA OOPD

Study Overview

• Status: Completed
• Conditions: Leber Congenital Amaurosis
• Intervention / Treatment: Biological: rAAV2-CB-hRPE65

Detailed Description

This will be a non-randomized, open label study. A total of 12 participants will be enrolled into two groups of 6 each. Each participant will receive rAAV2 CB hRPE65 by subretinal injection in one eye on a single occasion. Participants in Group 1 will receive 450 µL at a dosage level of 4 x 10^11 vg/mL containing a total of 1.8 x 10^11 vg of rAAV2-CB-hRPE65. Participants in Group 2 will receive 450 µL at a dosage level of 1.33 x 10^12 vg/mL containing a total of 6 x 10^11 vg of rAAV2-CB-hRPE65. A retinal surgeon will administer the vector by subretinal injection.

Enrollment will begin with Group 1 and will proceed to Group 2 after review of safety data by a Data and Safety Monitoring Committee.

Safety will be monitored by evaluation of ocular and non ocular adverse events and hematology and clinical chemistry parameters. Efficacy will be measured by evaluation of visual fields, visual acuity and electroretinography.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts Medical School
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institue, Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Retinal disease consistent with a diagnosis of Leber congenital amaurosis and documented mutations in the RPE65 gene (including null mutations and mutations that code for abnormal RPE65 protein);
• At least 6 years of age;
• Good general health without significant physical examination findings or clinically significant abnormal laboratory results;
• Able to perform tests of visual and retinal function;
• Visual acuity not better than 20/60 and not worse than hand motion in both the treated eye and the fellow eye;
• Visible photoreceptor (outer nuclear) layer on a standard optical coherence tomography (OCT) scan;
• Acceptable hematology, clinical chemistry and urine laboratory parameters;
• For females of childbearing potential, a negative pregnancy test at screening and at baseline, and agreement to use effective contraception for 12 months after administration of rAAV2-CB-hRPE65, for sexual activity that could lead to pregnancy;
• For males of reproductive potential, agreement to use effective contraception for 12 months after administration of rAAV2-CB-hRPE65, for sexual activity that could lead to pregnancy

Exclusion Criteria:

• Pre-existing eye conditions that would preclude the planned surgery or interfere with interpretation of study endpoints or complications of surgery (e.g. glaucoma, corneal or lenticular opacities, or history or retinal detachment);
• Presence of epiretinal membrane on OCT;
• History of immunodeficiency or other medical conditions that might increase the risk of rAAV2-CB-hRPE65 administration;
• Use of anticoagulants or anti-platelet agents within 7 days prior to study agent administration;
• History of allergy or sensitivity to medications planned for use in the peri-operative period;
• For females of childbearing potential, a positive pregnancy test at screening or baseline (within 2 days before rAAV2-CB-hRPE65 administration);
• Females who are breast feeding;
• Use of any investigational agent, or systemic corticosteroids or other immunosuppressive drug(s), within 3 months prior to enrollment;
• Prior receipt of any AAV gene therapy product;
• Any condition which leads the investigator to believe that the participant cannot comply with the protocol requirements or that may place the participant at an unacceptable risk for participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Subjects at least 6 y/o treated with a lower dose of the vector by subretinal injection	Biological: rAAV2-CB-hRPE65; Recombinant adeno-associated virus vector expressing RPE65
Experimental: 2; Subjects at least 6 y/o treated with a higher dose of the vector by subretinal injection	Biological: rAAV2-CB-hRPE65; Recombinant adeno-associated virus vector expressing RPE65

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants Experiencing Ocular or Non-ocular Adverse Events	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Changes in Visual Fields	Improvement in the central 30 degree visual field, measured by static perimetry, at one or more time points after treatment, that was greater than the limit of agreement for baseline values .	2 years
Participants With Changes in Best Corrected Visual Acuity	Increase in BCVA of 7 or more letters at Year 2 visit compared to average baseline value	2 years

Collaborators and Investigators

• Sponsor: Applied Genetic Technologies Corp
• Collaborators: Oregon Health and Science University; University of Massachusetts, Worcester
• Investigators: Principal Investigator: J Timothy Stout, MD, PhD, MBA, Casey Eye Institute, Oregon Health & Science University

Publications and helpful links

General Publications

• Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J, Dejneka NS, Pearce-Kelling SE, Maguire AM, Palczewski K, Hauswirth WW, Jacobson SG. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther. 2005 Dec;12(6):1072-82. doi: 10.1016/j.ymthe.2005.08.008. Epub 2005 Oct 14.
• Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ, Cideciyan AV, Schwartz SB, Komaromy AM, Doobrajh M, Cheung AY, Sumaroka A, Pearce-Kelling SE, Aguirre GD, Kaushal S, Maguire AM, Flotte TR, Hauswirth WW. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther. 2006 Aug;17(8):845-58. doi: 10.1089/hum.2006.17.845.
• Weleber RG, Pennesi ME, Wilson DJ, Kaushal S, Erker LR, Jensen L, McBride MT, Flotte TR, Humphries M, Calcedo R, Hauswirth WW, Chulay JD, Stout JT. Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. Ophthalmology. 2016 Jul;123(7):1606-20. doi: 10.1016/j.ophtha.2016.03.003. Epub 2016 Apr 19.
• Pennesi ME, Weleber RG, Yang P, Whitebirch C, Thean B, Flotte TR, Humphries M, Chegarnov E, Beasley KN, Stout JT, Chulay JD. Results at 5 Years After Gene Therapy for RPE65-Deficient Retinal Dystrophy. Hum Gene Ther. 2018 Dec;29(12):1428-1437. doi: 10.1089/hum.2018.014. Epub 2018 Jul 24.

Helpful Links

• Applied Genetic Technologies Corporation home page

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2009
• Primary Completion (Actual): September 23, 2014
• Study Completion (Actual): September 22, 2017

Study Registration Dates

• First Submitted: September 8, 2008
• First Submitted That Met QC Criteria: September 8, 2008
• First Posted (Estimate): September 10, 2008

Study Record Updates

• Last Update Posted (Actual): December 28, 2017
• Last Update Submitted That Met QC Criteria: December 1, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: gene therapy; AAV; adeno-associated virus; Leber congenital amaurosis; RPE65; LCA; human gene transfer
• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Retinal Diseases; Eye Diseases, Hereditary; Sensation Disorders; Vision Disorders; Blindness; Leber Congenital Amaurosis
• Other Study ID Numbers: AGTC-RPE65-002; R01FD003694 (U.S. FDA Grant/Contract)