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Rachel M Huckfeldt, Jason Comander, Mark E Pennesi, Paul Yang, Andreas Lauer, Robert Sisk, Edward Averbukh, Eyal Banin, Ninel Z Gregori, Janet L Davis, Byron L Lam, Christine Nichols Kay, Jessica Ijams Wolfing Morgan, Joseph Carroll, Bright Senyo Ashimatey, Matthew Feinsod; Findings on visual photosensitivity in two phase 1/2 clinical trials of subretinal gene therapy with AGTC-401 and AGTC-402 for CNGB3 and CNGA3 achromatopsia. Invest. Ophthalmol. Vis. Sci. 2022;63(7):450.
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© ARVO (1962-2015); The Authors (2016-present)
Achromatopsia (ACHM) is an autosomal recessive retinal disorder associated with photosensitivity, absent color discrimination, and decreased visual acuity. We describe the effects of the subretinal gene therapies AGTC-401 and AGTC-402 on photosensitivity at Month(M) 12 and M24 post-treatment.
Participants with ACHM due to biallelic mutations in either CNGA3 (n=15; 2<18y) or CNGB3 (n=25; 4<18y) were sequentially assigned to one of 5 (CNGA3) or 6 (CNGB3) dose levels before receiving a single subretinal injection of AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) or AGTC-401 (rAAV2tYF-PR1.7-hCNGB3) involving the macula of the study eye (SE). Safety and efficacy assessments included best-corrected visual acuity (BCVA; ETDRS letter score) and photosensitivity, which was measured as the light discomfort threshold (LDT). Two tests assessed LDT: LDT-1 using a full-field light stimulus generated by the Diagnosys ColorDome and LDT-2 using the Ocular Photosensitivity Analyzer. A meaningful post-treatment response in LDT was defined as an increase from baseline >1 loglux.
In these participants with at least 12 months of follow-up, AGTC-401 and AGTC-402 were generally well-tolerated; serious adverse events were related to the surgical procedure (n=1) and steroid-associated elevated intraocular pressure (n=2). Mean BCVA changed by < 3 letters in both trials. Mean LDT at M12 was higher on LDT-1 in the CNGB3 trial (p=0.002) but unchanged on LDT-1 in the CNGA3 trial and on LDT-2 in both trials. The CNGB3 trial had 4 LDT-1 and 9 LDT-2 responders with the greatest number (LDT-1, n=3; LDT-2, n=6) in the pediatric and highest dose groups (1.1e12 and 3.2e12 vg/ml). All LDT-1 responders were also LDT-2 responders. Improved LDT was sustained in 3 of 4 LDT-2 responders with M24 data. Untreated fellow eyes showed >1 loglux change in 75% of LDT-1 and 67% of LDT-2 responders. The CNGA3 trial had 2 LDT-1 and 2 LDT-2 responders among 3 participants with sustained improvement at M24 for the 2 responders for whom data was available.
Subretinal gene therapy with AGTC-401 resulted in clinically-meaningful and sustained improvement in light discomfort in some participants with CNGB3 ACHM. Fewer individuals showed a response after treatment with AGTC-402 in the CNGA3 trial. Further study is needed to understand the bilateral nature of the LDT improvement.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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