Author: David Birch (United States)
Co-authors: Isabelle Audo, Thiran Jayasundera, Isabelle Meunier, Rachel Huckfeldt, Robert Koenekoop, Paul Yang
Purpose
Retinitis Pigmentosa (RP) is a group of inherited retinal diseases causing progressive blindness. USH2A mutations are the most common cause of autosomal recessive RP (arRP). Exon 13 mutations in USH2A are present in non-syndromic (nsRP) and syndromic forms of RP called Usher syndrome type 2, the leading cause of deaf-blindness; neither has an approved treatment. The Stellar trial evaluates the safety and tolerability of QR 421a, an RNA antisense oligonucleotide, in subjects with biallelic mutations in exon 13 of USH2A.
Setting/Venue
The Stellar trial (NCT03780257) is a 24-month, multicenter Phase 1b/2 dose- escalation single-dose study in arRP patients aged ≥18 years that are homozygous or compound heterozygous for exon 13 mutations in USH2A. The study enrolled subjects at 7 sites (USA, Canada, and Europe).
Methods
The population varied in disease characteristics (Usher syndrome or nsRP), genetic background (homozygous or compound heterozygous USH2A exon 13 mutations), and disease stage (advanced stage defined as participants with baseline best-corrected visual acuity [BCVA] of less than 70 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] chart, or early moderate stage with a baseline BCVA of ≥70 ETDRS letters). Three cohorts were assessed where participants received a single intravitreal QR-421a injection at dose levels of 50, 100, or 200 μg administered unilaterally. The first subjects in dose cohort 1 and 2 were treated with active treatment; further recruitment to at least 6 subjects per dose cohort was double-masked using a 2:1 ratio of randomization (QR-421a : Sham). Dose cohort 2 was expanded to recruit 3 additional subjects in an open-label fashion. Dose cohort 3, also open label, included 3 subjects. The maximum follow-up duration was 24 months. Primary endpoints were frequency and severity of ocular adverse events (AEs) and non-ocular AEs. Secondary endpoints included change in functional (BCVA; static perimetry) and structural (ellipsoid zone [EZ] area by optical coherence tomography) outcome measures in QR-421a-treated eyes (TE), untreated eyes (UE), and sham-treated eyes (SE), and serum pharmacokinetics.
Results
20 subjects were enrolled, 14 participants received QR-421a (50-μg dose: 4, 100-μg dose: 7, 200-μg dose: 3) and 6 received sham. No serious AE or inflammation was observed. One participant had worsening of pre-existing cataracts (deemed not treatment-related by treating physician). One participant had progression of pre-existing cystoid macular edema, being managed with standard care. BCVA stabilization (no decline compared with baseline) was observed in QR-421a-TE, versus a decline in UE, in keeping with the natural history of the disease. At week 48, mean BCVA benefit was 6.0 letters and 9.3 letters in all QR-421a-treated and advanced participants (n=6) respectively. No BCVA benefit was observed in SE (2.2 letters difference between both eyes). Mean change from baseline of the EZ-area was +15.0% in QR-421a-TE, –26.4% in UE, and –12.5% in SE at week 24. For static perimetry, mean change from baseline of number of locations (loci) that improved by ≥7 dB in QR-421a-TE versus UE was up to 9.2 loci versus 6.1 loci in all QR-421a-treated participants and up to 12.9 loci versus 6.9 loci in early moderate-stage participants (n=8; week 12). SE responded similarly to QR-421a-UE. Response to QR-421a was similar in all cohorts.
Conlusions
QR-421a was observed to be well tolerated at all doses in participants with exon 13 mutations in USH2A. QR-421a demonstrated encouraging evidence of disease stabilization in visual acuity and clinically significant improvements in retinal sensitivity, supported by objective retinal structural imaging data, after a single dose compared with UE and SE. An open-label extension trial is planned to follow up the Stellar trial participants, and 2 Phase 2/3 trials are planned.
Financial Disclosure
DGB reports grant funding from ProQR Therapeutics during the course of the study.
Comments
Additional Co-authors: 7. Eduard P. M. de Cock - ProQR Therapeutics, Leiden, Netherlands 8. Ellen C. Dahler - ProQR Therapeutics, Leiden, Netherlands 9. John Taylor - ProQR Therapeutics, Leiden, Netherlands 10. Naveed K. Shams - ProQR Therapeutics, Leiden, Netherlands 11. Aniz Girach - ProQR Therapeutics, Leiden, Netherlands
