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. 2024 Oct 1;13(10):15.
doi: 10.1167/tvst.13.10.15.

Endpoints and Design for Clinical Trials in USH2A-Related Retinal Degeneration: Results and Recommendations From the RUSH2A Natural History Study

Maureen G Maguire  1 , David G Birch  2 , Jacque L Duncan  3 , Allison R Ayala  1 , Lauren N Ayton  4 , Janet K Cheetham  5 , Peiyao Cheng  1 , Todd A Durham  5 , Frederick L Ferris 3rd  6 , Carel B Hoyng  7 , Rachel M Huckfeldt  8 , Glenn J Jaffe  9 , Christine Kay  10 , Eleonora M Lad  9 , Bart P Leroy  11 , Wendi Liang  1 , Lee S McDaniel  1 , Michele Melia  1 , Michel Michaelides  12 , Mark E Pennesi  2   13 , José-Alain Sahel  14   15   16 , Lassana Samarakoon  1 ; REDI Working Group and the Foundation Fighting Blindness Clinical Consortium Investigator Group
Affiliations

Endpoints and Design for Clinical Trials in USH2A-Related Retinal Degeneration: Results and Recommendations From the RUSH2A Natural History Study

Maureen G Maguire et al. Transl Vis Sci Technol. .

Abstract

Purpose: To evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration.

Methods: People with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated.

Results: Rates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression.

Conclusions: Rate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration.

Translational relevance: Analyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

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Conflict of interest statement

Disclosure: M.G. Maguire, Annexon (C), Janssen Research & Development (C), Regenxbio (C); D.G. Birch, 4D Molecular Therapeutics (C, F), Applied Genetic Technologies Corp./Beacon (F), Aldyra (C), Bluerock Therapeutics (C), Editas Medicine (C), Nacuity Pharma (S), Ocugen (F), ONL Therapeutics (C), PYC Therapeutics (C, F), SepulBio (C); J.L. Duncan, Acucela (F), AGTC X-Linked Retinoschisis Trial (S), Applied Genetic Technologies Corp. (F), Allergan/Abbvie (F), Biogen/Nightstar Therapeutics (F), NEI STEM Trial (S), ProQR (F), PYC Therapeutics (F), Spark Therapeutics Choroideremia Trial (S); A.R. Ayala, None; L.N. Ayton, Apellis (C), Kiora Pharmaceuticals (C), Novartis (F); J.K. Cheetham, Allergan/Abbvie (I); P. Cheng, None; T.A. Durham, None; F.L. Ferris, 4D Molecular Therapeutics (C), Adverum (C), Annexon (C), Apellis (C), Bausch & Lomb (P), Genentech (C), Janssen Research & Development (C), Kodiak (C), Novo Nordisk (C), Roche (C), Regenxbio (C); C.B. Hoyng, None; R.M. Huckfeldt, Beacon Therapeutics (F), Biogen (F), BlueRock Therapeutics (C), Janssen (C, F), MeiraGTx (F), ProQR (F), Sanofi (C), Spark Therapeutics (F), Sunovion (C); G.J. Jaffe, 4D Molecular Therapeutics (C), Adverum (C), Annexon (C), Boehringer Ingelheim (C), Eyepoint (C), Novartis (C), Regeneron (C), Roche/Genentech (C); C. Kay, None; E.M. Lad, 4D Molecular Therapeutics (C), Alexion (C, F), Allegro (C), Annexon (C), Apellis (C, F), Aspen Neuroscience (C), Belite Bio (F), BlueRock Therapeutics (C), Boehringer Ingelheim (C, F), Broadwing Bio (C), Complement Therapeutics (C), Galimedix (C), Gemini Therapeutics (F), IVERIC Bio/Astellas (C, F), Janssen (C, F), Kriya Therapeutics (C), LumiThera (C, F), Lutronic Vision (C), Nanoscope Therapeutics (C), Neurotech (F), NGM Biopharmaceuticals (C), Novartis (C), Ocular Therapeutics (C), Osanni Bio (C, I), Perceive Bio (C), Regeneron (C), Retrotope (C), Roche (C, F), Sanofi (C), Thea Laboratoires (C); B.P. Leroy, 4D Molecular Therapeutics (C), AAVantgardeBio (C), Akouos (C), Alia Therapeutics (C), Atsena Therapeutics (C), Belite Bio (C), Biogen (C), Coave Therapeutics (C), GenSight Biologics (C), Gyroscope (C), IVERIC Bio (C), Jansen Pharmaceuticals–Johnson & Johnson (C), MeiraGTx (C), Novartis (C), Opus Genetics (C), ProQR Therapeutics (C), Ray Therapeutics (C), Regenxbio (C), Santen (C), Sepul Bio (C), SparingVision (C), Spark Therapeutics (C), SpliceBio (C), Stoke Therapeutics (C), Transine Therapeutics (C), Vedere Bio I & II (C), ViGeneron (C); W. Liang, None; L.S. McDaniel, None; M. Melia, None; M. Michaelides, Belite Bio (C), MeiraGTx (C, I, O), Mogrify (C), Saliogen (C); M.E. Pennesi, 4D Molecular Therapeutics (C), Adverum (C), Arrowhead Pharmceuticals (C), Akous (S), Aldebaran (C, I), Applied Genetic Technologies Corp. (C, F), Ascidian (C), Atsena (C, I), Astellas (C), Biogen (I), BlueRock Therapeutics/Opsis (C), Coave (C), ClarisBio (C), Dompe (C), Editas Medicine (C, F), Edigene (C), Endogena (C, I), EnterX (I), Gensight (S), Ingel Therapeutics (C, I), J-Cyte (C), Janssen (C), Kala Therapeutics (C), Kiora (C, I), Nacuity Pharmaceuticals (C, I), Ocugen (C, I), Ora (C), ProQR (C, F), Prime Editing (C), PTC Therapeutics (C), PYC Therapeutics (C), Ray Therapeutics (C), RegenexBio (C), Rejuvitas (C), Reneuron (F), RestoreVision (C), Sanofi (F), Sparing Vision (C), SpliceBio (C), Spotlight Therapeutics (C), Thea (C), Theranexus (C), ZipBio (I); J.-A. Sahel, Avista (C, I), Chronolife (I), Cilensee (I), Gensight (I), Prophesee (I), Sharpeye (I), Sparing Vision (I), Tenpoint (C, I), Tilak (I), UPMC Enterprises (C), Vegavect (I); L. Samarakoon, None

Figures

Figure 1.
Figure 1.
Pathways on the microperimetry testing grid for selecting FTPs. The schematic of the testing grid for microperimetry shows pathways from each point to more peripheral adjacent points. FTPs were identified by comparing each point to the 1 to 4 more peripheral adjacent points on the testing grid. A decrease in sensitivity of ≥7 dB from an inner point to the more peripheral adjacent point qualified the inner point as a candidate FTP. Candidate FTPs were ordered by the percentage of qualifying adjacent points, from 100% to 25%. Candidate points that were qualified by 100% of adjacent points were selected as FTPs. If the selected number of selected points was less than 5, then points with the next highest percentage of qualifying points were included.
Figure 2.
Figure 2.
Participants included in analyses for each measure. Shown are the number of participants in the entire cohort and the preserved cohort for each measure and testing modality. VTOT is the total volume beneath the surface of the hill of vision, V30 is the volume below a central region with radius of 30°, and VPERIPH is VTOT – V30.
See this image and copyright information in PMC

References

    1. Ayala A, Cheetham J, Durham T, Maguire M.. The importance of natural history studies in inherited retinal diseases. Cold Spring Harb Perspect Med. 2023; 13(3): a041297, 10.1101/cshperspect.a041297. - DOI - PMC - PubMed
    1. Durham TA, Duncan JL, Ayala AR, et al. .. Tackling the challenges of product development through a collaborative rare disease network: the Foundation Fighting Blindness Consortium. Transl Vis Sci Technol. 2021; 10(4): 23, 10.1167/tvst.10.4.23. - DOI - PMC - PubMed
    1. Kaiserman N, Obolensky A, Banin E, Sharon D.. Novel USH2A mutations in Israeli patients with retinitis pigmentosa and Usher syndrome type 2. Arch Ophthalmol. 2007; 125(2): 219–224, 10.1001/archopht.125.2.219. - DOI - PubMed
    1. McGee TL, Seyedahmadi BJ, Sweeney MO, Dryja TP, Berson EL.. Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. J Med Genet. 2010; 47(7): 499–506, 10.1136/jmg.2009.075143. - DOI - PMC - PubMed
    1. Le Quesne Stabej P, Saihan Z, Rangesh N, et al. .. Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet. 2012; 49(1): 27–36, 10.1136/jmedgenet-2011-100468. - DOI - PMC - PubMed

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