News update ProQR update and additional sepofarsen Illuminate trial analyses

Based on the outcomes of this strategic review, ProQR will prioritize the following strategic objectives:

1. Genetic eye diseases – explore development path for selected ophthalmology programs subject to Regulatory feedback from European Medicines Agency (EMA) and US Food & Drug Administration (FDA).
2. RNA editing technology – accelerate development of the Axiomer^® RNA base-editing technology platform, including initial focus on liver, the Central Nervous System (CNS) and the eye.

ProQR ended 2021 in a strong position and expects this, together with expense reductions resulting from a corporate restructuring and the strategic update announced today, will fund operations into 2025, and through several milestones, including the potential readout of the modified Phase 2/3 Sirius trial of ultevursen.

For a full update, please read our community statement.

ProQR will reduce expenses through the following portfolio prioritization and restructuring initiatives:

• Focus the ultevursen (QR-421a) program for USH2A-mediated Usher syndrome and retinitis pigmentosa on a single Phase 2/3 Sirius trial with the potential addition of an interim/futility analysis in 2023. Updates on planned adjustments to the Sirius trial in light of the findings related to the sham control group will be provided after alignment with regulatory authorities.
• Suspend development of QR-1123 for autosomal dominant retinitis pigmentosa and QR-504a for Fuchs endothelial corneal dystrophy.
• Suspend all other IRD-related research activities; and
• Reduce the workforce by approximately 30%, which will include the departure of our Chief Scientific Officer Naveed Shams, MD, PhD, expected to be effective in Q2.

“We believe deeply in the promise of RNA therapies, the Company’s pioneering efforts in this field, and ProQR employees,” said Dinko Valerio, co-founder and Chairman of ProQR’s Supervisory Board. “These are the right steps to take to offer the best opportunity to create long-term value for all of our stakeholders, including our shareholders whom we thank for their support, and the communities we aim to serve.”

“These have been extremely difficult decisions to make as we position the business to drive long-term growth and value," said Daniel A. de Boer, Founder and CEO of ProQR. "I want to thank the employees separating from ProQR for their significant contributions toward our mission. I also want to acknowledge the disappointment that many in the eye disease community may feel today, particularly individuals and families living with autosomal dominant retinitis pigmentosa and Fuchs endothelial corneal dystrophy as we wind down our programs for these indications."

Following the top-line data announcement in February 2022 that Illuminate, ProQR’s pivotal Phase 2/3 trial of sepofarsen in CEP290-mediated Leber congenital amaurosis 10, or LCA10, did not meet the primary endpoint of Best Corrected Visual Acuity (BCVA) at month 12 compared to a sham procedure control group, comprehensive post-hoc analyses of the trial and trial conduct were undertaken which revealed:

• No technical errors in the trial conduct, data handling, or the medicine product used.
• The overall safety profile of sepofarsen was consistent with earlier trials.
• When the effect in the sepofarsen treated, eye was compared to the untreated eye in the same patient, at month 12, a benefit in vision was observed. This effect was not observed in the control group that received a sham treatment.
• Other endpoints showed similar effect when comparing treatment to contralateral eye, including Full Field Stimulus Testing (FST).  
• These findings were supported by the patient reported outcomes analysis, based on the Patient Global Impressions-Change (PGI-C) that demonstrated that 61% of patients in the treatment groups reported an improvement in vision, as well as by Visual Function Questionnaire 25 (VFQ-25). 

Overall, the post-hoc analyses showed that the efficacy signal seen with sepofarsen when comparing the active treatment and sham eyes to their corresponding contralateral eyes across BCVA, FST, and other endpoints, including PROs, is more consistent with the results seen in earlier trials, where the contralateral eye was used as the control.

Based on these results, ProQR will focus on the following core activities related to sepofarsen:

• In Q3, ProQR plans to meet with the EMA and FDA to discuss these data from the Illuminate trial. Following this discussion, ProQR will share an update in Q3 or early Q4.

ProQR currently plans to continue Illuminate, which is a 2-year study, the Brighten pediatric study, and the Insight open-label extension study, until further Regulatory guidance, after post which next steps will be determined.

“These post-hoc analyses show an encouraging efficacy signal when comparing the active treatment and sham eyes to their corresponding contralateral eyes across multiple endpoints and are consistent with feedback received from the investigators. In prior interactions, EMA preferred the use of the contralateral eye as a control, however the protocol was ultimately harmonized globally to use a parallel sham group based on US regulatory requirements,” said Aniz Girach, MD, Chief Medical Officer of ProQR Therapeutics. “While we were disappointed by the outcome of the primary analysis, we believe that these post-hoc analyses and the observation that approximately a third of the patients benefited across multiple concordant endpoints in this trial, in combination with the high unmet need in LCA10, warrants a discussion with the regulators.”

As announced in February, data from the Illuminate trial will be presented at the upcoming Seventh Annual Retinal Cell and Gene Therapy Innovation Summit, April 29, 2022, and the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, May 1-4, 2022.