The Residency Report: Study provides new insights into USH2A target end points

The Residency Report is a partnership between the Department of Ophthalmology at the New York University (NYU) Grossman School of Medicine and Ophthalmology Times, featuring NYU faculty, residents, and a visiting professor. This installment focuses on clinical trial end points in patients with Usher syndrome type 2 (USH2A)–related retinal degeneration.

USH2A-related retinal degeneration, although rare, is one of the most common causes of rod-cone degeneration and is inherited in an autosomal recessive manner. It classically is associated with congenital hearing loss. When hearing loss is not present, the entity is termed nonsyndromic autosomal recessive retinitis pigmentosa.¹ USH2A-related retinal degeneration generally begins in the second decade of life, often starting with nyctalopia and then midperipheral vision loss, with slow progression of central and peripheral visual field deficits.^2,3

Given these clinical characteristics, and the fact that USH2A mutations are a common cause of rod-cone degeneration (yet overall, the disorder is quite rare), selecting appropriate end points for possible clinical trials aiming at slowing, halting, or reversing the disease is paramount.

Shifting trends in ophthalmology clinical trial end points

Over the past few years, end points for clinical trials in ophthalmology in general, and especially retina, have shifted from acuity-based outcomes to other parameters. For example, in the GATHER1 (NCT02686658), OAKS (NCT03525613), and DERBY (NCT03525600) studies, changes in fundus autofluorescence were the primary end point when evaluating avacincaptad pegol and pegcetacoplan, respectively, on slowing the progression of geographic atrophy; pegcetacoplan is now FDA-approved.^4,5 Indeed, phase 3 trials for a ciliary neurotrophic factor–releasing encapsulated cell therapy implant to treat macular telangiectasia type 2 have concluded, and the treatment is undergoing final FDA review—with the rate of ellipsoid zone (EZ) area loss on optical coherence tomography (OCT) serving as the primary clinical end point.⁶

A study on USH2A target end points was recently published in Translational Vision Science & Technology.⁷ In the study, 105 patients across 16 clinical sites in North America and Europe were included for meeting the following inclusion criteria: 2 pathologic variants in USH2A, ETDRS letter score of at least 54 (20/80 or greater), and stable fixation with a central visual field of at least 10° in diameter. These patients were followed over 4 years; 1 study eye was included per patient, which was the eye with the better best-corrected visual acuity (BCVA).

Key findings from the study

All subjects were evaluated periodically, and the following potential end points were collected and assessed: static perimetry, mesopic microperimetry, BCVA, full-field stimulus testing (FST), and EZ area on OCT. Interestingly, electroretinography (ERG) was not evaluated as a possible end point because the ERG response was undetectable for a large proportion of patients and therefore had no ability to discriminate ongoing changes and differences between treatment groups.⁸

As an end point paradigm, rates of change of the above parameters were generally found to be more sensitive than changes in the proportion of eyes meeting a certain threshold (such as the coefficient of repeatability). Because USH2A-related retinal degeneration is so rare, end points that allow for smaller required sample sizes during clinical trials are preferred. This corresponds to continuous measures that are most sensitive to changes in disease severity and measures that change similarly across eyes with different levels of baseline damage for a given decrement in function.

Now, to the possible end points: Baseline EZ area of at least 3 mm² was required to detect any further change in this metric. Thus, although EZ area has many desirable features as an end point (objectivity, ease of procuring in clinic, high clinical relevance, correlation with duration of symptoms), it may be a subpar primary end point for USH2A because it excludes a swath of patients with more advanced disease.

Furthermore, the standardized rate of change for EZ area loss was lower than the rates for every other parameter evaluated except for BCVA. Worsening of disease was detectable regardless of patient baseline in the metrics of BCVA (which had the lowest standardized rate of change) and FST with white stimuli. FST remained sensitive over time, and there was no floor effect in the data (another favorable attribute). Indeed, the European Medicines Agency cited FST results in support for the approval of voretigene neparvovec for RPE65-associated inherited retinal dystrophy—although it should be noted that the relationship between FST changes and functional vision in patients with preserved central vision (as can be seen earlier in USH2A-related disease) is uncertain.

Regulatory considerations and future directions

Finally, microperimetry and static perimetry both were evaluated according to FDA-guided definitions of clinically meaningful change (mean change of at least 7 dB in at least 5 prespecified points). According to BCVA and perimetric changes, a very small percentage of eyes at 2 and 4 years (less than 3% and less than 10%, respectively) met this criteria. The use of specific perimetric loci as functional transition points resulted in an increase in the percentage of eyes with worsening to 40%. However, this was offset by lower reliability (and, due to the inherent polarized nature of these points on a perimetric field, the area of treatment of a potential gene therapy would potentially affect some points more than others).

Joseph Colcombe, MD

Colcombe is a resident physician with the Department of Ophthalmology at New York University Grossman School of Medicine in New York, New York.

Nitish Mehta, MD

E: nmehta252@gmail.com

Mehta is an assistant professor and a vitreoretinal surgeon at New York University Grossman School of Medicine.

Abigail T. Fahim, MD, PhD

E: ahteich@med.umich.edu

Fahim is an assistant professor of ophthalmology and visual sciences at the University of Michigan Kellogg Eye Center in Ann Arbor, Michigan.

References

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. doi:10.1001/archopht.125.2.219

2. Toualbi L, Toms M, Moosajee M. USH2A-retinopathy: from genetics to therapeutics. Exp Eye Res. 2020;201:108330. doi:10.1016/j.exer.2020.108330

3. Sandberg MA, Rosner B, Weigel-DiFranco C, McGee TL, Dryja TP, Berson EL. Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene. Invest Ophthalmol Vis Sci. 2008;49(12):5532-5539. doi:10.1167/iovs.08-2009

4. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128(4):576-586. doi:10.1016/j.ophtha.2020.08.027

5. Heier JS, Lad EM, Holz FG, et al; AKS and DERBY study investigators. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023;402(10411):1434-1448. doi:10.1016/S0140-6736(23)01520-9

6. Neurotech Pharmaceuticals, Inc. announces positive phase 3 topline results for NT-501 implant in macular telangiectasia type 2. News release. Neurotech Pharmaceuticals. November 2, 2022. Accessed December 3, 2024. https://www.neurotechpharmaceuticals.com/wp-content/uploads/Neurotech-Topline-PR__FINAL_11022022.pdf

7. Maguire MG, Birch DG, Duncan JL, et al; REDI Working Group and the Foundation Fighting Blindness Clinical Consortium Investigator Group. Endpoints and design for clinical trials in USH2A-related retinal degeneration: results and recommendations from the RUSH2A natural history study. Transl Vis Sci Technol. 2024;13(10):15. doi:10.1167/tvst.13.10.15

8. Birch DG, Cheng P, Duncan JL, et al; Foundation Fighting Blindness Consortium Investigator Group. The RUSH2A study: best-corrected visual acuity, full-field electroretinography amplitudes, and full-field stimulus thresholds at baseline. Transl Vis Sci Technol. 2020;9(11):9. doi:10.1167/tvst.9.11.9