QR-421a / ProQR - LARVOL DELTA

AAV-Mediated Exon Skipping Therapy for Usher Syndrome, Type 2A. (PubMed, Mol Ther) - "An investigational antisense oligonucleotide (ASO) for USH2A c.2299delG, QR-421a, designed to bypass the mutation, has already shown promise in Phase 1/2 clinical trials (Dulla et al., 2021)...Optimized vectors and skippers were evaluated in inner ear and retinal organoids derived from human stem cell lines bearing the USH2A c.2299delG mutation. The data revealed enhanced skipping of the pathogenic exon, offering an alternative strategy for treatment of USH2A patients using a single local injection which may prevent progression of vision and hearing loss."

Journal • Inherited Retinal Dystrophy • Ophthalmology • Otorhinolaryngology • USH2A

Study to Evaluate the Efficacy Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene With Early to Moderate Vision Loss (Celeste) (clinicaltrials.gov) - P2/3 | N=5 | Terminated | Sponsor: ProQR Therapeutics | Trial completion date: Jun 2025 ➔ Aug 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jun 2025 ➔ Aug 2022; Business decision

Trial completion date • Trial primary completion date • Trial termination • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

HELIA: An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa (clinicaltrials.gov) - P2 | N=21 | Terminated | Sponsor: ProQR Therapeutics | Trial completion date: Jul 2026 ➔ Oct 2022 | Enrolling by invitation ➔ Terminated | Trial primary completion date: Jul 2026 ➔ Oct 2022; The sponsor decided to terminate the study early

Trial completion date • Trial primary completion date • Trial termination • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

Scrutinizing pathogenicity of the USH2A c.2276 G > T; p.(Cys759Phe) variant. (PubMed, NPJ Genom Med) - "In conclusion, we confirmed pathogenicity of USH2A c.2276 G > T (p.(Cys759Phe)). Consequently, cases homozygous for c.2276 G > T can now receive a definite genetic diagnosis and can be considered eligible for receiving future QR-421a-mediated exon 13 skipping therapy."

Journal • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

Scrutinizing pathogenicity of the USH2A c.2276G>T; p.(Cys759Phe) variant (ARVO 2022) - "We confirmed pathogenicity of USH2A c.2276G>T (p.(Cys759Phe)). Consequently, persons homozygous for c.2276G>T can now receive a definite genetic diagnosis and can be considered eligible for QR-421a-mediated exon 13 skipping therapy in the future."

Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • EGF • USH2A

Study to Evaluate the Efficacy Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene With Early to Moderate Vision Loss (Celeste) (clinicaltrials.gov) - P2/3 | N=5 | Active, not recruiting | Sponsor: ProQR Therapeutics | Recruiting ➔ Active, not recruiting | N=120 ➔ 5

Enrollment change • Enrollment closed • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

Stellar: Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (clinicaltrials.gov) - P1/2 | N=20 | Completed | Sponsor: ProQR Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

A Phase 2/3 study to evaluate efficacy, safety, and tolerability of QR-421a in subjects with advanced vision loss (clinicaltrialsregister.eu) - P2/3; N=81; Sponsor: ProQR Therapeutics IV B.V.

Clinical • New P2/3 trial • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

A Phase 2/3 study to evaluate efficacy, safety, and tolerability of QR-421a in subjects with with Early to Moderate Vision Loss (clinicaltrialsregister.eu) - P2/3; N=120; Sponsor: ProQR Therapeutics IV B.V.

Clinical • New P2/3 trial • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

Study to Evaluate the Efficacy Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene With Early to Moderate Vision Loss (Celeste) (clinicaltrials.gov) - P2/3; N=120; Recruiting; Sponsor: ProQR Therapeutics

Clinical • New P2/3 trial • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

Study to Evaluate the Efficacy Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene With Advanced Vision Loss (Sirius) (clinicaltrials.gov) - P2/3; N=81; Recruiting; Sponsor: ProQR Therapeutics; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

Study to Evaluate the Efficacy Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene With Advanced Vision Loss (Sirius) (clinicaltrials.gov) - P2/3; N=81; Not yet recruiting; Sponsor: ProQR Therapeutics

Clinical • New P2/3 trial • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

HELIA: An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa (clinicaltrials.gov) - P2; N=20; Enrolling by invitation; Sponsor: ProQR Therapeutics

Clinical • New P2 trial • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

Stellar: Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (clinicaltrials.gov) - P1/2; N=20; Active, not recruiting; Sponsor: ProQR Therapeutics; Recruiting ➔ Active, not recruiting; Trial completion date: Jun 2022 ➔ Oct 2021

Clinical • Enrollment closed • Trial completion date • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

"ViewPoints Interview: Dr. Robert Koenekoop Shares Insights on Stellar Study Evaluating ProQR’s QR-421a @Pharmashot https://t.co/FMZ7QQ29YF" (@Pharmashot)

Interview

Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations. (PubMed, Mol Ther) - "Mouse surrogate mQR-421a reached the retinal outer nuclear layer after a single intravitreal injection, and induced a detectable level of exon skipping until at least 6 months post injection. In conclusion, QR-421a-induced exon skipping proves to be a highly promising treatment option for RP caused by mutations in USH2A exon 13."

Journal • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • USH2A

RNA therapeutics in ophthalmology - translation to clinical trials. (PubMed, Exp Eye Res) - "This review provides a detailed insight into the recent developments and clinical trials that have been conducted for several gene-silencing therapies, including ISTH0036, SYL040012, SYL1001, PF-04523655, Sirna-027, QR-110, QR-1123, QR-421a and IONIS-FB-L in glaucoma, dry eye disease, age-related macular degeneration, diabetic macular oedema and various inherited retinal diseases. Our aim is to explore the potential of these drugs whilst evaluating their associated advantages and disadvantages, and to discuss the future translation of RNA therapeutics in ophthalmology."

Clinical • Journal • Review • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Diabetic Macular Edema • Dry Age-related Macular Degeneration • Dry Eye Disease • Glaucoma • Macular Degeneration • Macular Edema • Ocular Infections • Ophthalmology • Retinal Disorders

Stellar: Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (clinicaltrials.gov) - P1/2; N=18; Recruiting; Sponsor: ProQR Therapeutics; Trial completion date: Jan 2022 ➔ Jun 2022

Clinical • Trial completion date • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Infections • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

ProQR to present findings from phase 1/2 interim analysis of QR-421a for Usher syndrome (GlobeNewswire) - P1/2, N=18; Stellar (NCT03780257); Sponsor: ProQR Therapeutics; "ProQR Therapeutics N.V. (Nasdaq:PRQR), a company dedicated to changing lives through the creation of transformative RNA therapies for severe genetic rare diseases, today announced that Company management will present and discuss findings from a planned three-month interim analysis of its Phase 1/2 Stellar trial of QR-421a in adults with Usher syndrome and non-syndromic retinitis pigmentosa on March 31, 2020."

P1/2 data