QR‐421a RNA therapy in retinitis pigmentosa due to mutations in USH2A: Stellar trial Phase[AP1] 1b/2 interim results
Isabelle Audo, David G. Birch, Thiran Jayasundera, Isabelle Meunier, Rachel M. Huckfeldt, Robert K. Koenekoop, Paul Yang, Edouard P. M. de Cock, Ellen C. Dahler, John Taylor, Naveed Shams, Aniz Girach
Abstract
Abstract Purpose To report Phase 1b/2 interim results of QR‐421a RNA therapy promoting USH2A exon 13 skipping. USH2A exon 13 mutations lead to non‐syndromic Retinitis Pigmentosa & Usher syndrome type 2. Methods Stellar ( NCT03780257 ) is a 24‐month, multicenter Phase 1b/2 single‐dose trial assessing 3 dose levels (50, 100, 200 μg) of QR‐421a in patients aged ≥18 years with biallelic USH2A pathogenic mutations with at least one in exon 13. Cohorts 1 & 2 included subjects randomized to sham‐procedure or QR‐421a. Primary endpoints: frequency & severity of adverse events (AEs). Secondary endpoints: change in best‐corrected visual acuity (BCVA), static perimetry & ellipsoid zone [EZ] area. Results 20 subjects were enrolled, 14 received QR‐421a & 6 received sham. Response to QR‐421a was similar for all doses. No serious AE or inflammation was observed. Two subjects had worsening of pre‐existing conditions: one with cataracts (not treatment‐related) & one with cystoid macular edema (being managed with standard care). BCVA stabilization was observed in QR‐421a‐treated eyes (TE), versus a decline in untreated eyes (UE). At week 48, mean BCVA benefit was 6.0 & 9.3 letters in all QR‐421a‐treated & advanced subjects ( n = 6; baseline BCVA of <70 letters) respectively. No BCVA benefit was observed in sham‐treated eyes (SE). Mean change from baseline of the EZ‐area was +15.0% in TE, –26.4% in UE, & –12.5% in SE at week 24. For static perimetry at week 12, the mean number of locations (loci) that improved by ≥7 dB compared to baseline was 9.2 loci versus 6.1 loci in TE versus UE in all QR‐421a‐treated subjects & 12.9 loci versus 6.9 loci in early moderate‐stage subjects ( n = 8; baseline BCVA of ≥70 letters). SE responded similarly to UE. Conclusions QR‐421a was well tolerated & demonstrated evidence of disease stabilization in visual acuity, & improvements in retinal sensitivity & retinal structural imaging data. An open‐label extension trial & 2 Phase 2/3 trials are planned.