This article is reviewed by Allen C. Ho, MD.

RGX-314 subretinal gene therapy (RE­GENXBIO Inc) is being tested in the first pivotal gene therapy trial for exu­dative age-related macular degenera­tion (AMD). Interim results indicate the treatment is generally well toler­ated with stable to improved visual acuity (VA) and reductions in anti-vascular endo­thelial growth factor (VEGF) injection burden of up to 1.5 to 3 years, depending on the cohort. Allen C. Ho, MD, a professor of ophthalmology at Wills Eye Hospital in Philadelphia, and Thomas Jeffer­son University in Plymouth Meeting, Pennsylva­nia, reported the findings.

RGX-314 uses an adeno-associated viral 8 vector to deliver a gene encoding for a therapeutic anti-VEGF Fab protein, and is designed to produce con­tinuous anti-VEGF therapy, he explained.

A total of 42 patients have been enrolled in the RGX- 314-001 study (NCT03066258) with up to 3 years of follow-up. The drug continues to be well tolerated with stable to improved vision and has resulted in clinically meaningful decreases in anti-VEGF injec­tions in cohorts 3, 4, and 5 of the 5 dosing cohorts, all of which were well balanced demographically.

The patients with neovascular AMD have been treated previously with an average of 10 injections annually for 4 to 5 years, and were required to respond to a baseline injection of ranibizumab (Lucentis; Genentech, Inc) before receiving RGX-314. These patients do not receive systemic steroids during the study; anti-VEGF rescue injections were permitted beginning 4 weeks into the study if needed.

Subretinal gene therapy for neovascular AMD showing efficacy and safety

The primary outcome was determination of the safety and tolerability of RGX-314 through 6 months. Secondary outcomes included determination of trans­gene protein production, effect on vision and ocular anatomy, and need for additional injections. The retreatment criteria included the presence of any fluid, visual loss of 5 or more letters associated with fluid, and presence of hemorrhages.

“RGX-314 continues to be generally well tolerated across all doses,” Ho said. “Importantly, no clini­cally determined immune responses, drug-related ocular inflammation, or postsurgical inflamma­tion were seen beyond what is expected following routine vitrectomy.”

Surgical incision conjunctival hemorrhages and pigmentary changes in the retinal pigment epithe­lium (RPE) occurred, both of which were mostly mild events. One patient had RPE changes through the macula that were associated with visual loss.

Ho presented interim data for cohorts 4 and 5 at 1.5 years and cohort 3 at up to 2 years. An additional year of follow-up for cohort 3 is described below. Changes in best-corrected VA (BCVA) showed improved vision over 2 years for cohort 3, and this patient group had a significant reduction in the need for rescue therapy over the 2 years; in cohorts 4 and 5, the vision was stable or improved and the patients needed fewer rescue injections over a period of 1.5 years. For cohorts 3, 4, and 5, retinal thickness was stable on opti­cal coherence tomography images over time, and VA was stable or improved, including in those who did not need rescue therapy.

Evaluation of the protein levels in cohorts 3, 4, and 5 showed durable and dose-depen­dent increases in protein production over 2 years for cohort 3, and over 1 year for cohorts 4 and 5.

This study will follow patients for an additional 3 years beyond the phase 1/2a trial, for a total of 5 years of follow-up after receiving RGX-314. Ho also presented the third year of data for cohort 3. Thus far, investigators have reported no new drug-related ocular adverse events. In cohort 3, patients continue to show stable to improved VA, and have shown a mean of 12 letters of improvement and a reduc­tion in the need for rescue injections out to 3 years.

How gene therapy clinical trials are addressing retinal diseases at the core

Based on these findings, REGENXBIO has begun ATMOSPHERE, a subretinal pivotal trial in neo­vascular AMD. Investigators will evaluate 2 doses of RGX-314 compared with monthly injections of ranibizumab in pseudophakic patients with a base­line VA of 20/32 to 20/160. The study will enroll about 300 patients at 60 clinical sites. The primary end point is the mean change in BCVA relative to ranibizumab at week 54.

REGENXBIO is also conducting studies using the in-office SCS Microinjector to deliver RGX- 314 to the suprachoroidal space in patients with neovascular AMD and diabetic retinopathy. Upcom­ing results from these suprachoroidal programs will be announced for the phase 2 AAVIATE (neovascu­lar AMD; NCT04514653) and ALTITUDE (diabetic retinopathy; NCT04567550) trials.

This article is adapted from Ho’s presentation at the Bascom Palmer Eye Institute Angiogenesis, Exudation and Degeneration 2021 virtual meeting. Ho reported receiving research grants from REGENXBIO Inc, and he serves as a scientific advisor to the company.

Articles

Angiogenesis

RGX-314 eyed by investigators as a therapeutic option for exudative AMD.

Pivotal subretinal gene therapy trial begins

This article was reviewed by Thomas Albini, MD.

reported highly promising findings regarding the drug’s safety and efficacy, including noninferiority to aflibercept (Eylea, Regeneron Pharmaceuticals), reduced injection frequencies, and improved secondary imaging outcomes. In addition, the overall safety data were good and the drug was subsequently approved by the FDA.

However, shortly after physicians began using brolucizumab in clinical settings, cases of intravitreal inflammation associated with occlusive retinal vasculitis and severe visual acuity loss in a few patients were being reported in early 2020. The American Society of Retina Specialists reported 26 cases and closer evaluations showed arterial, venous, choroidal, optic nerve, and anterior segment inflammation, and vitritis.

Baumal et al reported on 15 eyes of 12 patients treated with intraocular brolucizumab injections; the mean vision decreased in these patients from 20/53 to 20/200

 and the findings included vitreous and anterior chamber cells, nongranulomatous granular precipitates, retinal artery changes, vascular leakage, occlusion, ischemia, dilated retinal veins, and optic nerve leakage, according to Thomas Albini, MD, professor of ophthalmology at Bascom Palmer Eye Institute in Miami, Florida.

Novartis assembled an expert committee to review all ocular imaging and cases of inflammation from the HAWK and HARRIER studies. A rate of intraocular inflammation of about 4.6% was ascertained in the patients in the HAWK and HARRIER studies; 3.3% had intraocular inflammation and retinal vasculitis; 2.1% had intraocular inflammation with retinal vasculitis and occlusion; and 0.5% had these findings associated with severe vision loss, Albini said.

Q&A: The increasing potential of ERG in diagnosing a wide range of eye conditions

“This resulted in about a 1 in 200 chance of retinal vasculitis with occlusion and severe vision loss,” according to the HAWK and HARRIER data, Albini said.

Every aspect of the drug and its administration were examined, including patient risk factors. Aggressive treatment was recommended in patients with ocular inflammation, especially vasculitis, with systemic or local steroids.

Further studies by Michael Ip, MD, and Marco Zarbin, MD, using data from the IRIS Registry and Komodo claims registry, identified an association between female gender and retinal vasculitis and with a history of previous inflammation.

“Any previous inflammation seemed to predispose these patients to retinal vascular events,” he advised. “When using brolucizumab, patients must be asked about, for example, prior HLA B27-associated uveitis.”

Managing uveitis with a multidisciplinary treatment approach

Albini explained that it is not unusual for treatment-naïve patients to have pre-existing antibodies to anti-VEGF agents. However, the numbers are generally low. When the HAWK and HARRIER data were evaluated, investigators found higher values than those typically seen, about 40%. There was a risk of either having preexisting antidrug antibodies, specifically neutralizing antibodies, or a having a boost in the antibodies during the trial that would be associated with an inflammatory vascular event, indicating that this could be an immunologic phenomenon.

“The finding was that 86% of patients with retinal vasculitis and retinal occlusion had neutralizing antibody positivity either at baseline or were boosted during the study,” he said.

Baumal and colleagues also reported a 24-week study

 of 172 eyes treated with brolucizumab injections. The investigators found that 8.1% of patients had intraocular inflammation and 1 patient had severe VA loss associated with retinal vasculitis. The study also showed an inflammation rate of 1 in 200 patients and a correlation with female gender. However, no association was found between the injections and previous inflammation.

1. Dugel P, Koh A, Ogura Y, et al; HAWK and HARRIER Study Investigators. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127(1):72-84. doi:10.1016.j.opht ha.2019.04.017

2. Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. 

 2020;127(10):1345-1359. doi:10.1016/j.ophtha.2020.04.017

3. Baumal CR, Bodaghi B, Singer M, et al. Expert opinion on management of intraocular inflammation, retinal vasculitis, and vascular occlusion after brolucizumab treatment. 

. Published online September 19, 2020. 2020;S2468-6530(20)30400-0. doi:10.1016/j. oret.2020.09.020

This article is adapted from Albini’s presentation at the Bascom Palmer Angiogenesis, Exudation, and Degeneration 2021 virtual meeting. Albini is a consultant to Novartis and is on the company’s data monitoring committee and safety review committee.

Preexisting neutralizing antibodies associated with the inflammatory changes.

Investigating inflammation caused by intravitreal brolucizumab

This article was reviewed by Dilsher Dhoot, MD.

In the Phase 3, double-masked PANORAMA study, retinal nonperfusion and leakage were associated with increased incidence of center-involved diabetic macular edema (DME) and vision-threatening complications in patients with nonproliferative diabetic retinopathy (NPDR), according to Dilsher Dhoot, MD, of Retina Consultants of America/California Retina Consultants in Santa Barbara, who reported the results on behalf of the study investigators.

The PANORAMA study comprised 402 participants with moderately severe to severe NPDR rated 47 to 53 on the Diabetic Retinopathy Severity Scale (DRSS) who did not have baseline DME. The participants were randomized to intravitreal aflibercept injection (IAI) (Eylea, Regeneron Pharmaceuticals) every 16 weeks following 3 monthly doses and one 8-week interval (n = 135), IAI 2 mg every 8 weeks following 5 initial monthly doses with as-needed dosing after week 52 (n = 134), or sham (n = 133). Dhoot noted that the patients were assessed through the 100 weeks of the study.

The topline data from PANORAMA showed that a significantly greater proportion of patients in both aflibercept arms achieved a 2-step or greater reduction (improvement) from baseline DRSS level at weeks 24, 52, and 100 versus the sham arm. Primary end point was the proportion of patients improving 2 or more steps on the DRSS at weeks 24 and 52. The secondary end points were the proportion of patients who developed PDR or anterior-segment neovascularization and the proportion of patients developing center-involved DME at week 100.

The post hoc analysis under discussion evaluated the impact of angiographic variables, specifically baseline retinal nonperfusion and leakage area, on the potential incidence of vision-threatening complications or center-involved DME in patients with moderately severe to severe NPDR, Dhoot explained.

Images obtained from the participants in the PANORAMA trial were graded at the Wisconsin Reading Center for baseline nonperfusion and baseline leakage: 45 had nongradable baseline nonperfusion area and 13 had nongradable baseline leakage area.

According to Dhoot, patients were stratified into no baseline nonperfusion (group 1) and 3 tertiles of increasing degrees of baseline nonperfusion area (groups 2, 3, and 4) for the retinal nonperfusion analysis and into four quartiles (1-4) based on the leakage area.

Dhoot noted that, at baseline, a greater number of patients with a DRSS score of 53 had increased nonperfusion. In addition, race, eg, African American, was associated with increasing nonperfusion area. The mean hemoglobin A1C trended upward slightly from 8.38 in group 1 to 8.95 in group 4. The mean duration of diabetes trended down from 15.6 years in group 1 to 12.8 years in group 4.

Regarding the cumulative incidence rate of any center-involved DME or vision-threatening complications through week 100, Dhoot reported an upward trend in the sham group as baseline nonperfusion area increased, but no differences were seen in the combined aflibercept groups. The hazard ratios for any center-involved DME or vision-threatening complications were 1.32 and 1.06 in the sham and combined aflibercept groups, respectively.

“Aflibercept was favored in terms of the vision-complication rates or center-involved DME, and the complication rates increased in the sham groups,” Dhoot said.

An evaluation of center-involved DME based on the baseline nonperfusion also favored aflibercept over sham, with hazard ratios for the sham and aflibercept groups being 1.32 and 0.95, respectively.

Finally, evaluation of only vision-threatening complications based on baseline nonperfusion showed respective hazard ratios of 1.44 and 1.10 for sham and aflibercept, respectively.

“The risk of developing center-involving DME and/or vision-threatening complications increased with increasing base-line nonperfusion area in sham-treated but not in aflibercept-treated patients,” Dhoot said. “Aflibercept reduced the incidence of vision-threatening complications or center-involving DME compared with sham regardless of the extent of the baseline area of nonperfusion.”

Of the 402 participants, 13 had nongradable leakage area at baseline. As with the nonperfusion groups, the number of participants with DRSS 53 increased with increasing leakage area (across, quartiles 1-4).

“With increasing leakage there is increasing numbers of patients with level 53 disease. The baseline level of nonperfusion also trended up moving from quartiles 1 to 4,” Dhoot said.

Regarding the mean hemoglobin A1C, there was also an upward trend from 8.18 in quartile 1 to 8.70 in quartile 4. The mean diabetes duration showed a downward trend from 16.9 years in quartile 1 to 12.7 years in quartile 4.

Through week 100, the cumulative incidence of any vision-threatening complications or center-involved DME trended to increase as the increase of base-line leakage area with sham but no difference was observed among patients in the combined aflibercept arm, Dhoot said.

Regarding the incidence of center-involved DME, the sham group had an upward trend; in the aflibercept group, the incidence rate was blunted.

An increasing rate of center-involved DME was seen with increased baseline leakage in the sham and aflibercept groups. The hazard ratios favored aflibercept over sham, respectively, 1.03 and 1.02. When considering only vision-threatening complications, the sham group showed an upward trend, whereas the aflibercept group did not; the respective hazard ratios were 1.08 and 1.00.

“The risk of developing center-involved DME and/or vision-threatening complications increased with increasing baseline leakage in the sham-treated patients but not in the aflibercept-treated patients,” Dhoot said. “Aflibercept reduced the incidence of center-involved DME and/or vision-threatening complications.”

Dhoot concluded that the increasing retinal non-perfusion and leakage areas were associated with increased rates of center-involved DME and vision-threatening complications in the sham group.

“These associations were not seen in the aflibercept group,” he said. “It appears that it may be helpful to first identify those patients who are at risk in levels 47 and 53 and that retinal nonperfusion and the area of leakage are important considerations when managing patients with NPDR and deciding whether to treat these often well-sighted patients.”

In analyses of data from week 52 and week 100, there were no treatment-by-subgroup interactions for any baseline factors. In addition, both dosing regimens of aflibercept maintained statistical superiority over sham in all baseline factor subgroups.

The PANORAMA data are expected to be reported soon.

This article was adapted from Dhoot’s presentation at the Bascom Palmer Angiogenesis, Exudation, and Degeneration 2021 virtual meeting in February. He is a consultant for Regeneron Pharmaceuticals.

Study results show that aflibercept-treated eyes are protected.

Retinal leakage and nonperfusion linked with center-involved DME

This article was reviewed by Hans W. Andrews, MD.

Results from a real-world study of the FDA-approved fluocinolone acetonide 0.18 mg in­travitreal implant (Yutiq, EyePoint Pharmaceuti­cals Inc.) showed that the device was effective for treating 

 over the long term, according to Hans W. Andrews, MD, a resident at the Vanderbilt Eye In­stitute, in Nashville, Tennessee.

Uveitis is an important cause of visual loss, and corticosteroids remain the standard of care for patients. When the MUST trial [NCT00132691] compared the use of systemic and regional corticoste­roids to treat intermediate uveitis, posterior uveitis, and panuveitis, the best-corrected visual acuities (BCVAs) were very similar throughout the 5-year study.

The implant group had better control of intraocular inflammation, but that group had sig­nificantly higher incidence rates of cataract and glaucoma. Based on these results, the investiga­tors concluded that regional therapy was a reason­able approach for treating unilateral uveitis when systemic therapy was ineffective or not feasible.

Noninfectious uveitis: Meeting the challenge

The POINT trial (NCT00991029) also evaluated regional steroid (periocular and intravitreal) therapy for uveitic macular edema (ME), and investiga­tors reported significantly reduced ME with intravitreal steroids (triam­cinolone and dexamethasone) com­pared with periocular triamcinolone. Results also showed improved BCVA by more than 5 letters in the intravit­real groups, but a risk of intraocular pressure (IOP) exceeding 24 mm Hg with intravitreal treatment.

 Andrews noted that about 40% of patients in all groups required IOP-lowering medication.

The Yutiq implant, which is inserted by an in-office procedure, delivers a low dose (0.2 μg) of fluocinolone acetonide for up to 3 years, lasts sig­nificantly longer than the dexamethasone implant (Ozurdex, Allergan), which requires replacement every 2 to 3 months. 

The Yutiq implant was evalu­ated in 2 multicenter, randomized, phase 3 clini­cal studies in which it was compared with sham therapy.

 Study results reported that the device provided a significant reduction in the recurrence rate of uveitis at 6 and 12 months compared with sham (P < .001 for both comparisons). Andrews reported that in the Yutiq group, significantly (P < .01) more frequent cataract development and a trend toward higher IOP (P = .19).

Andrews and colleagues conducted a retrospec­tive chart review that included 103 consecutive eyes (68 patients; median age, 59 years) treated with the implant. Posterior uveitis was the most frequent uveitic type. The patients were evaluated at 1-, 3-, and 6-month intervals for improved vi­sual acuities (VAs) by 2 or more lines, recurrent intraocular inflammation, recurrent or improved ME, and the steroid-sparing effect.

Andrews pointed out that this is the largest study of the implant outside of a clinical trial.

“The VA remained stable after injection of the implant with a trend toward improvement by 6 months,” Andrews said. “The baseline VA was 20/50 that improved to about 20/32. Fifteen eyes had active uveitis at baseline, which resolved in all but 1 patient at 6 months. At baseline, 77% of eyes had no ME, which improved to 88% at 1 month and 89% at 3 months, and was stable at 87% at 6 months. The ME resolved within the first month of treatment in 50% and 62.5% at 3 months.”

Confirming uveitis treatment efficacy in study

Twenty-four patients studied were taking more than 10 mg of oral pred­nisone daily and/or immunotherapy at baseline. One month after the Yutiq implant was inserted, 40% of patients decreased the oral prednisolone dose under 10 mg or decreased or discontinued immunotherapy. At the 3-month time point, that percentage was 57%, and remained stable at 53% at 6 months.

Why uveitis is a leading and underestimated cause of visual morbidity in patients

Andrews concluded that the review of the results of the long-term Yutiq implant in 103 eyes showed that the fluocinolone acetonide injectable intravit­real implant is a convenient and effective adjunc­tive treatment for chronic uveitis.

“The results showed improved vision and ME, suppressed disease activity, and decreased sys­temic sys­temic steroid use and need for immunotherapy,” Andrews said.

The investigators are continuing to study the short- and long-term efficacy and adverse effects of this novel therapy.

1. Kempen JH, Altaweek MM, Drye LT, et al. Benefits of systemic anti-inflammatory therapy versus fluocinolone acetonide intraocular implant for intermediate uveitis, posterior uveitis, and panuveitis: fifty-four-month results of the multicenter uveitis steroid treatment (MUST) Trial and follow-up study. 

 2015;122(10):1967- 1975. doi:10.1016/j/ophtha.2015.06.042

2. Thorne JE, Sugar EA, Holbrook JT, et al. Periocular triamcinolone vs. intravitreal triamcinolone vs. intravitreal dexamethasone implant for the treatment of uveitic macular edema: the PeriOcular vs. INTravitreal corticosteroids for uveitic macular edema (POINT) trial. 

 2019;126(2):283-295. doi:10.1016/j. ophtha.2018.08.021

3. Jaffe GH, Forster CS, Pavesio CE, et al. Effect of an injectable fluocinolone acetonide insert on recurrence rates in chronic noninfectious uveitis affecting the posterior segment: twelve-month results. 

. 2019;126(4);601-610. doi:10.1016/j. ophtha.2018.10.033

This article is adapted from Andrews’ presentation at the American Academy of Ophthalmology’s 2020 virtual annual meeting. Andrews has no financial interest in this subject matter.

Study results show the device offers an effective long-term option for patients.

Treating chronic uveitis with fluocinolone acetonide implants

The preliminary results of 2 ongoing phase 1/2 clinical trials evaluating the effects of subretinal gene therapies for achromatopsia (ACHM) indicate that both drugs, AGTC-401 and AGTC-402 (Applied Genetic Technologies Corp. [AGTC]), seem safe and well tolerated in patients with ACHM.

It is noteworthy that data from both studies are showing encouraging signs of biologic activity, according to Mark E. Pennesi, MD, PhD, associate professor of ophthalmology and Molecular and Medical Genetics Kenneth C. Swan Endowed Professor, division chief, Ophthalmic Genetics, Oregon Health and Science University Casey Eye Institute, Portland, OR.

ACHM is an autosomal recessive disease that causes a cone dysfunction syndrome, with the bulk of the mutations in 2 genes, 

. Two clinical trials of the affected genes are underway, one is a long-term follow-up gene therapy study for achromatopsia CNGB3 and CNGA3, at the Moorfields Eye Hospital, London, and Kellogg Eye Center, Ann Arbor, MI, and the other is a natural history study of achromatopsia CNGB3 and CNGA3, at Moorfields Eye Hospital.

Patients with ACHM have poor central vision in the range of 20/100 to 20/200, nystagmus, color vision defects, photophobia, and high myopia. The disorder is nonprogressive in contrast to cone-rod dystrophy. Electroretinography (ERG) shows severely decreased cone function but normal rod function, Pennesi explained.

Both trials are phase 1/2, open-label, dose-escalation studies using recombinant adeno-associated virus (rAAV) viral vectors.

The enrolled patients were treated with 1 subretinal injection of either AGTC-401 (rAAV2tYF-PR1.7-hCNGB3; 26 patients) or AGTC-402 (rAAV2tYF-PR1.7-hCNGA3; 19 patients) into the macular region on 1 eye (study eye). All patients were 14 years or older.

Participants were sequentially assigned to 1 of 4 dosing groups in both studies. The primary study endpoints were changes in the best-corrected visual acuity, light discomfort testing by ocular photosensitivity analyzer, ERG and multifocal ERG, retinal sensitivity by static perimetry and microperimetry, color vision testing using the Farnsworth D15 and color assessment and diagnosis tests, and patient-reported outcomes using the quality-of-life Visual Light Sensitivity 

Most of the ocular adverse events noted in the study were mild to moderate in nature. Of those that occurred in more than 20% of eyes, the most common were conjunctival hemorrhages and likely were related to the surgical procedure. Vitreous and anterior chamber cells were seen more frequently in the ACHM-CNGB3 group.

In the CNGA3 group, 2 patients had a serious adverse event, one was a macular hole that was related to the study surgery and the other was ocular hypertension that was related to the steroids prescribed and was controlled with modification of the steroids.

One patient in the CNGB3 group had increased intraocular pressure that was steroid-related and controlled with modification of the steroids.

Both patients with elevated pressures underwent a glaucoma filtering surgery.

Pennesi summarized that the preliminary results showed that the study agents, AGTC-401 and AGTC-402, administered via subretinal injection in the ongoing phase 1/2 CNGA3 and CNGB3 clinical trials are safe and well tolerated. No significant immunologic responses to the vector or capsid occurred. The preliminary results also showed improvements in photosensitivity and 2-color dark light-adapted perimetry in 3 of the 16 patients in the CNGA3 study and 7 of the 16 patients in the CNGB3 study in the higher dose groups. Enrollment of young patients aged 4 to 8 years is ongoing.

This article is adapted from Pennesi’s presentation at the Association for Research in Vision and Ophthalmology virtual annual meeting. He is a consultant to Applied Genetic Therapies Co.

ARVO

Mark Pennesi, MD, PhD, reports during ARVO 2021 that preliminary results have shown that AGTC-401 and AGTC-402 seem safe and well tolerated in patients with ACHM.

Gene therapy offers first steps in treatment of achromatopsia

An AOO montage image of the central fundus before treatment. (Image courtesy of Friederike Kortuem, MD, MSc)

Reviewed by Friederike C. Kortuem, MD, MSc

Treatment with voretigene neparvovec-rzyl (Luxturna, Novartis) resulted in a short-term change in the foveal morphology in a 15-year-old girl with visual impairment that included nyctalopia and decreased visual acuity (VA) in early childhood, according to Friederike Kortuem, MD, MSc, from Eye Clinic Tübingen, University of Tübingen, Tübingen, Baden-Württemberg, Germany.

Speaking at the Association for Research in Vision and Ophthalmology’s virtual 2021 annual meeting, Kortuem pointed out that visual deterioration generally occurs early in Leber’s congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD), as soon as birth to 5 years of age.

Characteristically, rapid degeneration of the rods and cones, visual field reduction, sluggish or near-absent pupillary responses, photophobia, nystagmus, and nyctalopia can occur. By the 4th decade of life, patients usually are legally blind. 

Subretinal administration of voretigene naparvovec-rzyl in an adeno-associated viral vector was FDA-approved in the US in 2017 and in Germany in 2019 to treat retinal dystrophies caused by bi-allelic RPE65 mutations; RPE65 is involved in the vitamin A restoration cycle in the eye.

The current patient had an RPE65 homozygous mutation. The VA in the right eye at examination was 20/63, and the anterior segment was unremarkable. The retinal examination in that eye showed central macular atrophy, narrowed vessels, and diffuse peripheral atrophy.

Kortuem demonstrated the overall decreased retinal thickness in the right eye.

Clinical examinations included measurement of the best-corrected VA (BCVA), spectral-domain optical coherence tomography (OCT), and adaptive optics retinal imaging.

At baseline, the patient was injected with the gene therapy vector that was successfully positioned between the neural retina and the retinal pigment epithelium. She was evaluated at baseline and then 2 and 5 weeks and 3 months following treatment.

At baseline, compared with healthy individuals of the same age, this patient’s retina was thinner. Kortuem showed that the central fovea had alterations in its layers and the retinal structures were not well demarcated, in contrast to the parafoveal layer with a preserved outer retina and photoreceptors.

As soon as 2 weeks after treatment, the foveal layer started to change. The external limiting membrane was visualized in the fovea.

“The overall disrupted appearance improved,” she pointed out.

After 5 weeks, the layering of the central fovea improved more out to 3 months.

The adaptive optics images obtained at baseline showed a mosaic of disrupted photoreceptor cells, that according to Kortuem, is characteristic of inherited retinal diseases. Following treatment, the superior nasal area appeared partly clear and the cones were identifiable. In the first 5 weeks following treatment, the initially patchy areas seemed to be decreasing over time. These morphologic rescue parameters changed gradually over time and were correlated partly with the improvement in the foveal-mediated vision after the treatment.

Regarding the safety of the treatment, no signs of inflammation were observed.

The cone functionality improved a bit and the patient reported “brighter” vision, which she also reported 5 weeks after surgery. At 3 months after surgery, the objective changes persisted.

The VA remained stable from baseline to week 5 and then improved by 1 line to 20/50. The contrast sensitivity also remained stable over time.

Chromatic pupil campimetry showed a dramatic increase in the central 10 degrees of the pupil from week 2 to week 5 and this improvement persisted to month 3.

“Rapid changes in the photoreceptor morphology seen on OCT and adaptive optics imaging after successful gene therapy in patients with LCA and EORD can be quantifiable at the individual level,” Kortuem concluded.

This article is adapted from Kortuem’s presentation at the Association for Research in Vision and Ophthalmology virtual annual meeting. She has no financial interest in this subject matter.

In a presentation at ARVO, Friederike Kortuem, MD, MSc, explains that treatment with voretigene neparvovec-rzyl led to a short-term change in the foveal morphology in a patient with visual impairment that included nyctalopia and decreased visual acuity in early childhood. 


Foveal morphologic changes in LCA sparked by gene therapy

Michael A. Singer, MD, of the Medical Center Ophthalmology Associates in San Antonio, Texas, speaks on the highlights of his presentation focusing on intraocular pressure (IOP) in the PALADIN 24-month data intravitreal steroid (ILUVIEN), presented during ARVO 2021. 

Videos

Michael A. Singer, MD, speaks on the highlights of his presentation focusing on IOP in the PALADIN 24-month data intravitreal steroid (ILUVIEN).

Analysis of 24-month data from the PALADIN study

Theodore Leng, MD, medical advisor at Verana Health and director of clinical translational research, Byers Eye Institute, Stanford University School of Medicine, discusses the highlights from his presentation on "AAO IRIS Registry Data Replicates VIEW 1 and VIEW 2 Clinical Trial Outcome Data," in which the first replications using real-world data of a phase 3 trial was utilized, during the virtual 2021 ARVO meeting. 

Theodore Leng, MD, discusses the highlights from his presentation on "AAO IRIS Registry Data Replicates VIEW 1 and VIEW 2 Clinical Trial Outcome Data," during the virtual 2021 ARVO meeting. 

A look at real-world trial data replication outcomes from IRIS Registry data 

Michael Mbagwu, MD, of the VA Palo Alto Health Care System; Byers Ophthalmic Innovations Fellow, Byers Eye Institute, Stanford University Medical School, speaks on the highlights of his virtual 2021 ARVO presentation regarding the development of an algorithm tool that links patient imaging to their clinical data, specifically within the American Academy of Ophthalmology's (AAO) IRIS Registry. 

Michael Mbagwu, MD, speaks on the highlights of his virtual 2021 ARVO presentation regarding the development of an algorithm tool that links patient imaging to their clinical data, specifically within the AAO IRIS Registry.  

Linking patient imaging data to AAO IRIS Registry

Daniel F. Kiernan, MD, a vitreoretinal surgeon at The Eye Associates, Sarasota, Florida, discusses the highlights of his 2021 ARVO virtual presentation on the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on optical coherence tomography (OCT) testing following vitreoretinal surgery.

Daniel F. Kiernan, MD, discusses key findings of a clinical study analyzing the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on OCT testing following vitreoretinal surgery.

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