ProQR Therapeutics announced positive top-line results from the PQ-110-001 study, a Phase 1/2 dose range finding, first-in-human trial of sepofarsen (QR-110) in patients with Leber’s congenital amaurosis 10 (LCA10) due to the p.Cys998X mutation in the CEP290 gene. Treatment with sepofarsen resulted in rapid, significant and durable improvements in vision at twelve months and was well tolerated.
PQ-110-001 was an was an open-label trial designed to enroll children (over six years of age) and adults who have LCA10 due to one or two copies of the p.Cys998X mutation in the CEP290 gene. Eleven patients were enrolled in either the 80 μg dose cohort (160 μg loading dose) or 160 μg dose cohort (320 μg loading dose) and received one to four intravitreal injections with sepofarsen in the treated eye at varying dosing intervals, with the other (contralateral) eye remaining untreated. The treatment duration was 12 months. The trial was conducted at the University of Iowa, the Scheie Eye Institute at the University of Pennsylvania and the Ghent University Hospital, Ghent, Belgium.
Safety and efficacy endpoints were reached. Sepofarsen was observed to be well-tolerated with manageable safety findings. The target registration dose (80 µg with a 160 µg loading dose) was associated with a clinically meaningful and statistically significant improvement in vision and had a favorable benefit/risk profile, A six-month dosing frequency was associated with durable improvements in vision. The response observed at 12 months in the target registration dose was equal to or greater than the response at the 3-month interim analysis. Results also indicated that subjects with better vision than light perception (BCVA> LogMAR 3.0) at baseline were more likely to respond to treatment with sepofarsen.
A phase 2/3 study, lluminate, or PQ-110-003, is currently underway. The randomized, prospective, double-masked, sham-controlled 24-month trial is planned to initially enroll 30 adults and children (eight years of age and over) who have LCA10 due to one or two copies of the p.Cys998X mutation in the CEP290 gene and a baseline best corrected visual acuity (BCVA) of 3.0 LogMAR or better. The trial is designed as the sole registration trial for the program. Top-line data are expected in the first half of 2021.
About Leber’s congenital amaurosis 10
Leber’s congenital amaurosis (LCA) is the most common cause of blindness due to genetic disease in children. It consists of a group of diseases of which LCA10 is the most frequent and one of the most severe forms. LCA10 is caused by mutations in the CEP290 gene, of which the p.Cys998X mutation has the highest prevalence. LCA10 leads to early loss of vision causing most people to lose their sight in the first few years of life. To date, there are no treatments approved or other products in clinical development that treat the underlying cause of the disease. Approximately 2,000 people in the Western world have LCA10 because of this mutation.
Sepofarsen (QR-110) is a first-in-class investigational RNA-based oligonucleotide designed to address the underlying cause of Leber’s congenital amaurosis 10 due to the p.Cys998X mutation (also known as the c.2991+1655A>G mutation) in the CEP290 gene. The p.Cys998X mutation is a substitution of one nucleotide in the pre-mRNA that leads to aberrant splicing of the mRNA and non-functional CEP290 protein.
Sepofarsen is designed to bind to the mutated location in the pre-mRNA and enable normal splicing, resulting in restoration of normal (wild type) CEP290 mRNA and subsequent production of functional CEP290 protein.
Sepofarsen is intended to be administered through intravitreal injections in the eye and has been granted orphan drug designation in the United States and the European Union and received fast-track designation from the FDA as well as access to the PRIME scheme by the EMA.