AGN-151587 / Editas Medicine, AbbVie - LARVOL DELTA

Optimal SpCas9- and SaCas9-mediated gene editing by enhancing gRNA transcript levels through scaffold poly-T tract reduction. (PubMed, BMC Genomics) - "This modification was applied to the EDIT-101 therapeutic strategy, where it demonstrated marked improvements in performance. This study highlights the importance of shortening the 4T sequences in the gRNA scaffold to optimize gRNA transcript expression for enhanced CRISPR-Cas9 gene editing efficiency. This optimization is particularly important for therapeutic applications, where the quantity of vector is often limited, ensuring more effective and optimal outcomes."

Journal

Gene Editing for CEP290-Associated Retinal Degeneration. (PubMed, N Engl J Med) - P1/2 | "The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.)."

Journal • Ophthalmology • CEP290

Safety and Efficacy of EDIT-101 for Treatment of CEP290-associated Retinal Degeneration (ARVO 2023) - P=N/A, P1/2 | "Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Clinical • Ophthalmology • CEP290

Prime Editing for the Installation and Correction of Mutations Causing Inherited Retinal Disease: A Brief Methodology. (PubMed, Methods Mol Biol) - "Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems represent a promising avenue for the treatment of IRDs, as exemplified by FDA clinical trial approval of EDIT-101 (AGN-151587), which removes a deep intronic variant in the CEP290 gene that causes Leber congenital amaurosis (LCA) type 10. Prime editing is a novel double-strand break (DSB) independent CRISPR/Cas system which has the potential to correct all 12 possible transition and transversion mutations in addition to small deletions and insertions. Here, as a proof-of-concept study, we describe a methodology using prime editing for the in vitro installation and correction of the classical Pde6b c.1678C > T (p.Arg560Cys) mutation which causes autosomal recessive retinitis pigmentosa (RP) in mice."

Journal • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • CEP290

Single Ascending Dose Study in Participants With LCA10 (clinicaltrials.gov) - P1/2 | N=34 | Active, not recruiting | Sponsor: Editas Medicine, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2024 ➔ May 2025 | Trial primary completion date: Mar 2024 ➔ May 2025

Enrollment closed • Trial completion date • Trial primary completion date • Inherited Retinal Dystrophy • Ophthalmology • Pediatrics • Retinal Disorders • CEP290

Exploratory Immuno-Safety Profile of EDIT-101, a First-in-Human In Vivo CRISPR Gene Editing Therapy for CEP290-Related Retinal Degeneration (ASGCT 2022) - P1/2 | "Pre-existing humoral or cell-mediated immunity in subjects did not lead to immune-related adverse events, which is encouraging for subsequent treatment of the contralateral eye. Our data suggests that EDIT-101 has a favorable immunogenic profile and no adverse events have been attributable to immunogenic responses in subjects treated in the BRILLIANCE trial."

P1 data • Preclinical • Ophthalmology • CEP290 • IFNG

Using CRISPR to treat inherited retinal degenerations (ARVO 2022) - "Presentation Description:Results from the Phase 1/2 Brilliance using Edit101 to treat patients with CEP290-related retinopathy will be presented."

Ophthalmology • Retinal Disorders • CEP290

Exploratory Safety Profile of EDIT-101, a First-in-Human in vivo CRISPR Gene Editing Therapy for CEP290-related Retinal Degeneration (ARVO 2022) - P1/2 | "We developed a SaCas9-specific qPCR assay to evaluate viral shedding in the BRILLIANCE trial. Our data suggests observed EDIT-101 shedding is transient and at low levels of detection, with no risk of systemic viral persistence."

P1 data • Preclinical • Inherited Retinal Dystrophy • Ophthalmology • CEP290

Single Ascending Dose Study in Participants With LCA10 (clinicaltrials.gov) - P1/2 | N=34 | Recruiting | Sponsor: Editas Medicine, Inc. | N=18 ➔ 34

Enrollment change • Inherited Retinal Dystrophy • Ophthalmology • Pediatrics • Retinal Disorders • CEP290

Prime Editing for Inherited Retinal Diseases. (PubMed, Front Genome Ed) - "However, there is currently only one FDA-approved gene augmentation therapy, Luxturna (voretigene neparvovec-rzyl), available to patients with RPE65-mediated retinitis pigmentosa (RP)...EDIT-101, a CRISPR-based therapy that is currently in clinical trials, uses double-strand breaks and nonhomologous end joining to remove the IVS26 mutation in the CEP290 gene...Instead, PE uses reverse transcriptase and Cas9 nickase to repair mutations in the genome. While this technique is still developing, with several challenges yet to be addressed, it offers promising implications for the future of IRD treatment."

Journal • Review • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • CEP290

[VIRTUAL] BRILLIANCE: A Phase 1/2 Single Ascending Dose Study of EDIT101, an in vivo CRISPR Gene Editing Therapy, in CEP290 Related Retinal Degeneration (ESGCT 2021) - P1/2 | "No doselimiting toxicities or serious adverse events have been reported in these patients to date. Efficacy and safety evaluations are ongoing."

P1/2 data • Preclinical • Genetic Disorders • Ophthalmology • CEP290

open - label trial with ascending dose to evaluate safety, tolerability and efficacy of EDIT-101 in adult and children with Leber Congenital Amaurosis Type 10 (LCA10) (clinicaltrialsregister.eu) - P2; N=18; Sponsor: Editas Medicine, Inc.

New P2 trial • Inherited Retinal Dystrophy • Ophthalmology • Pediatrics • CEP290

Single Ascending Dose Study in Participants With LCA10 (clinicaltrials.gov) - P1/2; N=18; Not yet recruiting; Sponsor: Allergan

Clinical • New P1/2 trial • Inherited Retinal Dystrophy • Ocular Infections • Ophthalmology • Pediatrics • CEP290

Single Ascending Dose Study in Participants With LCA10 (clinicaltrials.gov) - P1/2; N=18; Recruiting; Sponsor: Allergan; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Inherited Retinal Dystrophy • Ocular Infections • Ophthalmology • Pediatrics • CEP290

Single Ascending Dose Study in Participants With LCA10 (clinicaltrials.gov) - P1/2; N=18; Recruiting; Sponsor: Allergan; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open • Inherited Retinal Dystrophy • Ocular Infections • Ophthalmology • Pediatrics • Retinal Disorders • CEP290

Single Ascending Dose Study in Participants With LCA10 (clinicaltrials.gov) - P1/2; N=18; Active, not recruiting; Sponsor: Allergan; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Inherited Retinal Dystrophy • Ocular Infections • Ophthalmology • Pediatrics • Retinal Disorders • CEP290

Genome editing strategies for treating human retinal degenerations. (PubMed, Hum Gene Ther) - "Progress in this rapidly-evolving field has been highlighted by recent FDA clinical trial approval for EDIT-101 (Editas Medicine Inc, Cambridge, MA, USA) which has demonstrated efficacious genome editing in a mouse model of CEP290-associated Leber congenital amaurosis and safety in non-human primates...In particular, the heterogeneity of IRD-causing mutations in more than 200 known genes and long-term safety concerns relating to Cas9 expression in vivo. This review highlights (i) the technological advances in gene editing technology, (ii) major safety concerns associated retinal genome editing, and (iii) potential strategies for overcoming these challenges to develop clinical therapies."

Journal • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Genetic variations in a Natural History Study for Leber CEP290-Associated Retinal Degeneration (ARVO 2020) - P=N/A; "The purpose is to determine the genetic variation and explore phenotypic differences among patients enrolled in the Allergan/Editas sponsored Natural History Study of CEP290 associated retinal degeneration (NCT03396042), which will inform a therapeutic study for AGN-151587, a CRISPR/Cas9 gene editing therapy designed to remove CEP290 c.2991+1655A>G mutation.Methods Genetic testing using a vision panel test modified for this study consisting of 254 genes associated with IRDs was performed by Molecular Vision Laboratory...Homozygous patients, along with patients in Category 4 and 5, had the worst visual acuity, while patients in Category 2 and 3 had better vision.Conclusions This study demonstrates the spectrum of mutations present with the c.2991+1655A>G mutation in CEP290. Further study of the phenotypes of the patients in the CEP290 Natural History Study will help define potential genotype–phenotype correlations as well as potential for therapeutic interventions."

Editas Medicine Announces Fourth Quarter and Full Year 2019 Results and Update (GlobeNewswire, Editas Medicine, Inc.) - "Announcement of first patient dosing with EDIT-101 (AGN-151587) expected in 1Q20....EDIT-301 for Sickle Cell Disease and Beta-Thalassemia: IND filing for Sickle Cell Disease targeted by end of 2020."

IND • Trial status

Newly added product (GlobeNewswire) - P2, Ophthalmology

Pipeline update