ProQR Announces Additional Sepofarsen Illuminate Trial Analyses and Provides Update on Company Strategy

ProQR Therapeutics provided an update on its sepofarsen program following a comprehensive post-hoc analysis of the data from the phase 2/3 Illuminate trial in people with CEP290-mediated Lebercongenital amaurosis 10, or LCA10, a severe inherited retinal disease. The company also announced the completion of an in-depth strategic review designed to extend the company’s runway and deliver on its commitment to advance RNA therapies for diseases with high unmet need.

Strategy update

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

• Genetic eye diseases – Explore development path for selected ophthalmology programs based on comparing active treatment and sham eyes to their corresponding contralateral eyes, subject to regulatory feedback from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA)
• RNA editing technology – Accelerate development of the Axiomer RNA base-editing technology platform, including an initial focus on liver, central nervous system (CNS), and the eye.

The company ended 2021 with €187.5 million of cash and cash equivalents on its balance sheet and expects these resources, together with anticipated expense reductions resulting from a corporate restructuring and the strategic update announced today, will fund currently planned operations into 2025, and through several milestones, including the potential readout of the modified Phase 2/3 Sirius trial of ultevursen.

New findings from sepofarsen Illuminate analysis

Following the topline announcement in February 2022 that Illuminate, ProQR’s pivotal Phase 2/3 trial of sepofarsen in CEP290-mediated LCA10, did not meet the primary endpoint of Best Corrected Visual Acuity (BCVA) at Month 12 compared to a shamprocedure control group, comprehensive post-hoc analyses of the trial wereundertaken which revealed:

• No technical errors in the trial conduct, data handling, or the drug product used.
• The overall safety profile of sepofarsen was consistent with earlier trials.
• When the effect in the treatment eye was compared to the untreated contralateral eye in the same patient, at Month 12, a benefit in vision was observed as a mean change from baseline in BCVA of -0.12 logMAR (n=23) in the sepofarsen treated groups. This effect was not observed in the sham treated group (n=12) with the same comparison (treated vs. contralateral eye). 
• 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 (PRO) analyses, 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 active treatment and sham eyes to their corresponding contralateral eyes across BCVA, FST, and other endpoints, including PROs, was more consistent with the results seen in earlier findings, where the contralateral eye was used as the control, according to ProQR. Based on these results, ProQR will focus on the following core activitiesrelated to sepofarsen:

• In Q3, the company 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, depending on timing of regulatory meetings.
• Based on the recommendation of the Data Safety and Monitoring Committee (DSMC), the company currently plans to continue Illuminate, which is a 2-year study, the Brighten pediatric study, and Insight, until further regulatory guidance, after which next steps will be determined. No further investments are planned at this time for new trials of sepofarsen or commercial preparations.

“These post-hoc analyses show an encouraging efficacy signal when comparing the active treatment and sham eyes to their corresponding contralateral eyes acrossmultiple 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.” 

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.

Operational updates

The Company will implement the following portfolio prioritization and restructuring initiatives with the aim to reduce expenses:

• 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 sham control will be provided after alignment with regulatory authorities;
• Suspend development of QR-1123 for autosomal dominant retinitis pigmentosaand 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 ofour Chief Scientific Officer Naveed Shams, MD, PhD, expected to be effective in Q2.

These efforts are expected to extend ProQR’s cash runway into 2025.

Axiomer RNA editing platform technology

The company will accelerate the development of its Axiomer RNA editing platform and pipeline activities and expand into areas beyond the eye, including initially liver and CNS, which have strong alignment with ProQR’s oligonucleotide delivery approaches. 

In parallel, ProQR will continue to execute on its partnership with Lilly and selectively enter into additional partnerships designed to advance and capture the full potential value of the platform. Since the company discovered its RNA editing technology in 2014, it has established a leading IP estate in the ADAR editing space, a first industry partnership, and with its broad applicability the platform has significant further potential. 

ProQR will present further non-clinical data for Axiomer and announce its internal development targets in H2 2022.

“We are focusing our strategy on accelerating our Axiomer RNA-base editing platform technology, and a select pipeline of RNA therapies for inherited retinal diseases as we remain committed to developing RNA therapies for patients with high unmet need,” said Daniel A. de Boer, Founder and CEO of ProQR Therapeutics. “ProQR has a strong cash position with runway into 2025, and we look forward to continued progress with the business, including providing an update following our discussions in Q3 with the EMA and FDA, and sharing details of our development plans for Axiomer in the second half of 2022.”

Mr. De Boer continued, “These have been extremely difficult decisions to make as we position the business to drive long-term growth and value. 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."