Usher update

LEIDEN, the Netherlands & CAMBRIDGE, Mass.—ProQR Therapeutics N.V., which is working on RNA therapies for severe, rare genetic diseases, recently announced positive findings from a planned three-month interim 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.

“The goal of the interim analysis of this 24-month STELLAR trial of QR-421a was to assess safety and early signs of efficacy for the purpose of informing next steps in development and future trial strategy,” said Dr. David Rodman, executive vice president of research and development of ProQR. “We are pleased with the current safety profile and are very encouraged by early signals of target engagement and clinical activity supported by concordant benefit observed across multiple outcome measures for 25 percent of QR-421a-treated patients thus far in this trial.

“The findings support continuing the trial as planned, with both cohort expansion and dose escalation in order to identify a potential development path to registration. Importantly, these data represent the second program from our ophthalmology pipeline that is supported by preclinical predictions from human retinal organoids, providing further validation of our translational approach and platform technology.”

Key initial findings include the following:

• Across both cohorts thus far, QR-421a was observed to be generally well tolerated with no serious adverse events noted.
• In the six sham treated subjects (two followed for nine months and four for three months), outcome measures demonstrated no consistent pattern of response above the “noise” level.  In contrast, two of eight QR-421a-treated patients (one each in the 50 µg and 100 µg dose cohorts) demonstrated benefit across multiple concordant outcome measures.
• One of four treated patients in the low-dose group was classified as a responder, with onset of action observed by the 3 month visit. Benefit was maintained for six months or longer, which is consistent with the expected half-life of QR-421a in photoreceptors. This Usher syndrome patient was homozygous for USH2A exon 13 mutations and had moderate visual impairment at baseline (peripheral vision affected).
• One of four treated patients in the mid-dose group was classified as a responder with onset of action observed by three months. This non-syndromic RP patient was heterozygous for USH2A exon 13 mutations and had severe visual impairment at baseline (peripheral and central vision affected) with baseline best corrected visual acuity (BCVA) of 33 and 36 letters (approximate Snellen equivalent: 20/250 and 20/200) in the treated and untreated eye, respectively.

Based on the safety profile and early evidence of efficacy observed to date, ProQR plans to take advantage of the adaptive design, and expand the 100 µg cohort with additional subjects who are homozygous for exon 13 mutations. Dose escalation to 200 µg (“high dose”) is planned to occur in parallel. An interim analysis of dose- and gene copy-dependent safety and efficacy will be planned once all additional subjects have reached at least three months of treatment.