Company set to advance RP therapeutic to Phase 2/3 trials

ProQR Therapeutics NV this week announced results from a planned analysis of its Phase 1/2 Stellar trial of QR-421a in adults with Usher syndrome and non-syndromic retinitis pigmentosa (nsRP) due to USH2A exon 13 mutations.

In a release, the company noted that the therapy was well tolerated at all doses and there were no adverse events or inflammation.

According to the company, which is involved in developing RNA therapies for inherited retinal diseases (IRDs), in the trial QR-421a demonstrated benefit on multiple measures of vision that moved in concordance, including visual acuity, visual fields, and optical coherence tomography (OCT) retinal imaging, after a single dose.

The company noted that QR-421a was observed to be well tolerated with no serious adverse events reported.

Based on these findings, the company plans to advance QR-421a to two parallel pivotal Phase 2/3 trials by year end 2021 – one in early-moderate patients, one in advanced patients.

Aniz Girach, MD, chief medical officer of ProQR, said the company was pleased it met the objectives it set for the Stellar trial, including determining suitable registration endpoints, the dose, dosing interval, and patient population for the Phase 2/3 pivotal trials.

“With just a single dose, QR-421a demonstrated clinical proof of concept with benefit observed in treated eyes compared to the untreated eyes in multiple concordant measures of vision,” he said in a statement. “As expected, we saw benefits in both advanced and early-moderate patients in this slow progressing, debilitating eye disease, allowing us to advance this important investigational therapy for all patients with Usher syndrome and nsRP due to USH2A exon 13 mutations.”

Girach also noted that, based on preliminary regulatory guidance, the company will submit protocols to advance QR-421a to pivotal testing.

“This is our second program targeting a severe inherited retinal disease that is moving into pivotal trials, which we believe further validates our RNA therapy platform and our capabilities to design and efficiently take these programs through clinical development,” he said.

According to Robert Koenekoop, MD, MSc, PhD, FRCS(C), FARVO, a clinical-scientist from the Montreal Children’s Hospital and Professor of the McGill University Faculty of Medicine and Department of Pediatric Surgery, the safety profile and efficacy findings for QR-421a are very encouraging.

“Usher syndrome and non-syndromic retinitis pigmentosa due to USH2A exon 13 mutations are devastating retinal diseases representing a high unmet medical need, as there are no approved therapies to treat the severe vision loss associated with these diseases,” he explained. “Patients’ biggest hope for a therapy is to stop disease progression and prevent vision loss, and these findings suggest that QR-421a has the potential to stabilize vision. I look forward to this exciting program advancing into pivotal trial development.” 

Trial results

In the Phase 1/2 trial, QR-421a was observed to be well tolerated at all doses. There were no serious adverse events reported and no inflammation was observed. One patient had worsening of pre-existing cataracts in both the treated and untreated eyes; both were deemed not treatment related by the investigator.

According to the company, 1 patient had progression of pre-existing cystoid macular edema (CME) that was managed with standard of care. Both cataracts and CME are associated with a high rate of occurrence in the natural history of this disease.

Efficacy Data

In advanced patients, the primary measure of efficacy is BCVA. In early-moderate patients, the primary measure of efficacy is measurement of visual fields by static perimetry.

QR-421a-treated patients responded on endpoints consistent with their disease stage in both advanced and early-moderate patient populations after a single injection.

All 3 doses studied in the Stellar trial were observed to be active as predicted by the pre-clinical data. No differences were observed based on patients being homozygous or heterozygous, or having Usher syndrome or non-syndromic retinitis pigmentosa. These findings are consistent with the preclinical data for QR-421a. 

Visual acuity

Across all treated patients (n = 14), a mean benefit of 6.0 letters was observed at week 48 in the treated eyes compared to the untreated (contralateral) eyes after a single injection.

According to the company, among advanced disease patients (n = 6), a mean benefit of 9.3 letters was observed at week 48 in the treated eyes as compared to the untreated eyes and the benefit was maintained for >12 months.

All six advanced patients had a benefit in the treatment eye, whereas none of the patients in the sham group had a benefit in the treatment eye.

Static perimetry

Across all treated patients, the mean total retinal sensitivity improvement was up to 40dB higher in the treated eyes compared to the untreated eyes, and the benefit was maintained for up to 6 months after a single injection.

The mean number of retinal locations (loci) that improved by ≥7db in retinal sensitivity demonstrated a benefit in the treated eyes compared to the untreated eyes, with up to a mean of 9 loci in the treated eyes improving by ≥7db .

In early-moderate patients (n = 8), up to a mean of 13 loci in the treated eyes improved by ≥7db compared to 7 loci for the untreated eyes at the same timepoint.

Concordant benefits were noted on OCT-based assessment of the Ellipsoid Zone layer, which is an objective evaluation of photoreceptor viability, and other measures of central visual function, such as microperimetry.

The company reported that sham treated eyes responded similarly to the untreated eyes across all endpoints.

Upcoming trials

ProQR announced that in the wake of the findings, it will initiate two pivotal Phase 2/3 clinical trials, one in advanced patents and another in early-moderate patients.

Each trial could potentially serve as the sole registration trial depending on the findings.

Pending finalization of the study designs with regulatory authorities, the trials are expected to start before year end 2021. Both trials are expected to be conducted at global centers of excellence.

Sirius trial in advanced population
The Sirius trial is a Phase 2/3 study that will focus on advanced patients with baseline BCVA ≤20/40. The preliminary design for Sirius is a double-masked, randomized, sham-controlled, 24-month, multiple-dose study.

The trial is expected to enroll approximately 100 adults with Usher syndrome and nsRP due to USH2A exon 13 mutations, including both homozygous and heterozygous patients. The primary endpoint in this trial will be BCVA at 18 months, with potential for an earlier interim analysis.

In this three-arm study, two different doses will be studied that will be administered every 6 months, and a third arm will receive sham treatment.

Celeste trial in early-moderate population

In parallel to Sirius, the company plans to start the “Celeste” Phase 2/3 trial in early-moderate patients. The preliminary design for Celeste is a double-masked, randomized, sham-controlled, 24-month, multiple-dose study.

The trial is expected to enroll approximately 100 adults with Usher syndrome and nsRP due to USH2A exon 13 mutations. The primary endpoint in this trial will be based on static perimetry at 18 months, with potential for an earlier interim analysis.

In this three-arm study, two different doses will be studied that will be administered every 6 months, and a third arm will receive sham treatment.

Benjamin R. Yerxa, PhD, CEO at the Foundation Fighting Blindness, pointed out that there are currently no available treatments for the more than 16,000 patients with Usher syndrome 2A and nsRP due to USH2A exon 13 mutations.

“We are excited about the potential for QR-421a to address this significant unmet need,” he said. “We are pleased to see QR-421a advancing to pivotal testing and proud to support the work of ProQR as they advance their pipeline of RNA therapies to potentially help children, adults, and families who are affected by blindness caused by USH2A mutations and other rare inherited retinal diseases.”