ProQR Announces Positive Top-Line Results from the Phase 1/2 Study of Sepofarsen in LCA10 Patients

ProQR Therapeutics, a company dedicated to changing lives through the creation of transformative RNA medicines for severe genetic rare diseases, today 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.

“We reported today that patients receiving sepofarsen had a clinically meaningful improvement in vision, and in some cases the patient’s vision improved to a level that could be deemed life changing. This is very encouraging for the LCA10 community and the Inherited Retinal Disease community as a whole,” said Stephen R. Russell, MD, Schrage Professor of Ophthalmology and Visual Sciences and Principal Investigator at the University of Iowa. “LCA10 is a severe inherited retinal disease that leads to blindness, and for which there is currently no treatment.”

David Rodman, M.D., Executive Vice President of Research & Development of ProQR, said, “We are very pleased with the data reported from the Phase 1/2 study, in which LCA10 patients treated with sepofarsen experienced a rapid and durable improvement in vision. The top-line data from this study strengthen our confidence in the design of the ongoing Phase 2/3 trial, which could be the sole registration trial for the sepofarsen program. We appreciate the patients’ and medical communities’ ongoing support for the sepofarsen clinical studies, and we will continue to work with the regulators to advance this program as efficiently as possible.”

Top-line results from the Phase 1/2 trial

Based on positive 3-month interim results from the Phase 1/2 trial (Nature Medicine 2018) the Phase 2/3 Illuminate trial was initiated earlier this year. The 12-month top-line results from the Phase 1/2 trial that will be presented today confirm durable activity of sepofarsen for up to one year in patients with LCA10. Furthermore, the results support the assumptions used in the design and powering of Illuminate, including:

• 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, as used in Illuminate, 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,
• and subjects with better vision than light perception (BCVA> LogMAR 3.0) at baseline, the study population in Illuminate, were more likely to respond to treatment with sepofarsen.

Table: Change from baseline in treated eye

Analysis: Pooled analysis: Unpaired t-test, between group change from baseline versus untreated. Target registration dose group: MMRM with repeated measures, within group change from baseline versus baseline

Visual acuity

Statistically significant improvement from baseline in best corrected visual acuity (BCVA) was observed as assessed by the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart and the Berkeley Rudimentary Vision Test (BRVT). In the pooled analysis with all patients after twelve months of treatment, the mean improvement (and standard error of mean, SEM) was -0.55 LogMAR (SEM 0.26). The mean change in the untreated contralateral eye was -0.11 LogMAR (SEM 0.07).

In the target registration dose group, the mean change from baseline at twelve months was -0.93 LogMAR (SEM 0.43) with four of six subjects showing an improvement of more than -0.3 LogMAR from baseline equivalent to 3 lines, or 15 letters, on ETDRS chart (generally considered clinically meaningful by US regulators). Five of six subjects showed an improvement greater than -0.2 LogMAR (generally considered clinically meaningful by EU regulators). The mean change in the untreated contralateral eye in this group was -0.22 LogMAR (SEM 0.11). In all five subjects in this group, in which a six-month dosing frequency was explored, the observed benefit in visual acuity was maintained during the twelve-month follow up.

Full field stimulus threshold test (FST)

Improvements in visual function were supported by a meaningful increase in the ability to detect flashes of red or blue light as determined by the FST test. In the pooled analysis after twelve months, mean improvement in red light sensitivity was -0.92 log Cd/m² (SEM 0.18) and improvement in blue light sensitivity was -0.79 log Cd/m² (SEM 0.23). The mean change in the untreated contralateral eye was -0.16 log Cd/m² (SEM 0.16) for red light and 0.02 log Cd/m² (SEM 0.11) for blue light.

In the target registration dose group, the mean change from baseline at twelve months in red light sensitivity was -0.66 log Cd/m² (SEM 0.14) and improvement in blue light sensitivity was -0.63 log Cd/m² (SEM 0.31). Three of six subjects showed an improvement of greater than -0.5 log Cd/m² for blue light, which can be regarded as clinically meaningful. Five of six showed a clinically meaningful improvement for red light. The mean change in the untreated contralateral eye in this group was 0.05 log Cd/m² (SEM 0.17) for red light and -0.12 log Cd/m² (SEM 0.16) for blue light.

Mobility course

Most patients demonstrated improvement in functional vision, as assessed using a series of mobility courses at increasing difficulty and multiple light intensities. In the pooled analysis the mean improvement for patients navigating the mobility course after twelve months of treatment was 2.5 levels (SEM 0.99). The mean change in the untreated contralateral eye was 1.75 (SEM 0.75). This increase was likely due to a training effect. An adjusted mobility course endpoint is being validated in parallel with the Illuminate trial.

In the target registration dose group, the mean change at twelve months of treatment was 4.0 levels (SEM 1.27) with five of six subjects improving by more than 2.0 levels, which can be regarded as clinically meaningful. The mean change in the untreated contralateral eye was 2.7 levels (SEM 1.11).

SafetySubjects received up to four doses of sepofarsen (range 1-4), and all eleven subjects in the study completed twelve months of follow up. This represents data equivalent to over 4,000 treatment days. Sepofarsen was observed to be well-tolerated with manageable safety findings. In total, eight cases of lens opacities (cataract) were observed (three in the target registration dose cohort and five in high dose cohort). All six of the subjects that had lens replacement surgery regained their pre-cataract vision. Four cases (in three subjects) of retinal findings were observed in the now retired 320/160 µg dose group: Two incidences of mild cystoid macular edema were resolved with topical treatment and two incidences of subclinical retinal thinning stabilized within two months of last dose without additional treatment.

Source ProQR (press release)