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Association for Research in Vision and Ophthalmology (ARVO)

Findings from the ongoing PERCEIVE study demonstrate continued safety and efficacy of voretigene neparvovec (Luxturna; Spark Therapeutics) in patients with 

-mediated inherited retinal dystrophy in the real-world setting.

The findings, which included up to 2 years of data and were presented at the Association for Research in Vision and Ophthalmology (ARVO) 2022 Annual Meeting, also shed light on a new treatment-related adverse reaction.

 and the European Commission in 2018, voretigene neparvovec was the first directly administered adeno-associated virus gene therapy to gain approval and the first approved ocular gene therapy. Intended to treat children and adults with confirmed biallelic 

 mutation-associated retinal dystrophy that leads to vision loss and blindness, the therapy delivers a functional copy of the 

 gene directly to retinal cells to restore normal protein production, ultimately restoring a patient’s vision.

The therapy’s safety and efficacy was established in 2 phase 1 clinical trials and an open-label, randomized phase 3 trial,

 in which a statistically significant and clinically meaningful difference was observed in the primary end point, mean bilateral multi-luminance mobility testing score change, between the intervention group (n=21) and control group (n=10) at 1 year (difference of 1.6; 95% CI, 0.72, 2.41; 

 = .001). In addition, a statistically significant difference in 2 key secondary end points were observed, including full-field light sensitivity threshold testing averaged over both eyes (

 = .001) and the mobility test score change for the first injected eye (

 = .001). A third secondary endpoint, change in visual acuity averaged over both eyes, was not statistically significant between the groups.

Launched in 2019, the post-marketing PERCEIVE trial follows patients for up to 5 years. As of the August 2021 data cutoff, 106 patients were enrolled and 103 received treatment with the gene therapy (mean age, 19.5 years; 50.5% female; mean duration of follow-up, 0.8 years [max, 2.3 years]). Among the group, 35% experienced at least 1 ocular adverse event (AE), including 13 instances of chorioretinal atrophic changes at the injection site or elsewhere, which were the most common AE.

Ocular AEs of special interest included foveal degeneration (n = 4), vitritis (n = 4), eye inflammation (n = 3), retinal tear (n = 2), and increased intraocular pressure (n = 5). Two serious AEs, eye inflammation and increased intraocular pressure, were reported by 1 patient each. The most frequent nonocular AE was headache. Notably, 1 patient with no prior history of mental illness, reported 3 instances of a psychiatric disorder.

In terms of efficacy, visual function improved in terms of full-field light sensitivity threshold,and best-corrected visual acuity (LogMAR) at year 2 with a mean change from baseline of −13.67 decibels and −0.03, respectively.

“Overall, the safety and effectiveness of [voretigeneneparvovec] observed in the PERCEIVE study, with up to 2-years data, are consistent with the findings of [voretigeneneparvovec] clinical trials,” the investigators concluded.

1. Fischer MD, Maier R, Suhner A, et al. PERCEIVE study report: Real-world safety and effectiveness of voretigeneneparvovec. Presented at: Association for Research in Vision and Ophthalmology (ARVO) 2022 Annual Meeting. May 1-4, 2022; Denver, CO.

2. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. News release. US FDA. December 17, 2018. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss#:~:text=The%20U.S.%20Food%20and%20Drug,that%20may%20result%20in%20blindness

3. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigeneneparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. 

2017;390(10097):849-860. doi:10.1016/S0140-6736(17)31868-8

Investigators presented up to 2 years of post-marketing data on the first-ever gene therapy.

Real-World Luxturna Data Shows Good Efficacy, New Adverse Reaction in Retinal Dystrophy 

 gene-delivering rAAV-based therapy AGTC-501 (rAAV2tYF-GRK1-RPGR) demonstrated sustained efficacy and safety after 18 months of follow-up for patients with X-linked retinitis pigmentosa (XLRP), which is caused by 

 mutations, according to findings from an ongoing, phase 1/2, open-label, dose escalation trial presented at the Association for Research in Vision and Ophthalmology (ARVO) 2022 Annual Meeting.

The efficacy of the subretinal AGTC-501 injection was assessed by optical coherence tomography (OCT) measurement of the foveal ellipsoid zone (EZ), which is a predictor of visual function and a common marker of disease progression in XLRP. The study enrolled 21 patients age ≥6 years with XLRP, 13 had visible foveal EZ at baseline and 8 did not have visible AZ at study entry. Following injection of AGTC-501 for those with visible EZ at baseline, 69% experienced EZ recovery 3 to 6 months following treatment (9 of 13). Of these patients, 67% had signs of EZ improvement (6 of 9) at 12 months that was sustained at 18 months. Those with no prior EZ did not experience a change following treatment with AGTC-501.

“These results indicate sustained durability of improved visual function over 18 months and suggest evidence of biological activity for this XLRP gene therapy,” principal investigator Paul Yang, MD, assistant professor of Ophthalmology at Oregon Health & Science University's Casey Eye Institute, said in a statement. “Because there are currently no approved treatment options for patients with XLRP, this data provides an important step toward a potential treatment for patients with vision loss due to XLRP.”

The study enrolled a total of 29 patients across 5 dose levels ranging from 4.0 x 10

 vg/ml that were administered in the central or peripheral regions. Those who received a central dose of the treatment were analyzed for efficacy (n = 21) while those who were injected outside of the macula were not eligible for the macular structure and function-based end points (n = 8). The primary end point of the study was safety, with secondary end points focused on macular structure by OCT and function by macular integrity assessment (MAIA) microperimetry and best-corrected visual acuity (BCVA) by ETDRS.

There were 3 OCT case studies presented in the poster at the ARVO meeting of patients who responded to treatment with AGTC-501. In the first, an 18-year-old patient received AGTC-501 at 3.6 x 10

 vg/ml and showed signs of EZ thickening and expansion, which led to improvements in macular autofluorescence. There were 24 months of follow up for this individual. In another example, a 45-year-old patient experienced EZ thickening with a 1.1 x 10

 vg/ml dose and in the final case study a 26-year-old had expansion in visible EZ at 3.2 x 10

 vg/ml, demonstrating EZ improvement across dose levels.

For secondary end points, there was a significant association observed between EZ and MAIA microperimetry improvement (

 = .0212). Moreover, treated eyes with EZ improvement also had a higher incidence of stabilization in central foveal thickness (CFT) compared with eyes that did to have an EZ improvement, wherein CFT thinning was observed. "Significant association between EZ and MAIA improvement suggest that macular EZ may be a useful objective biomarker of the biological signal in gene therapy," the authors of the study wrote in their poster. "More stable CFT MIN thickness after surgery may be predictive of EZ recovery and improvement."

Most adverse events (AEs) observed in the study were mild to moderate in severity. The most frequently observed AEs were related to the subretinal injection and required vitrectomy procedures. Additionally, AEs were seen that were related to concomitant prophylactic steroid administration, which was intended to mitigation inflammation.

“We continue to be enthusiastic about our lead candidate AGTC-501. The data presented today combined with the prior 12-month data from this trial are a strong indicator of the potential of both AGTC-501 and our gene therapy platform,” Sue Washer, president and chief executive officer of AGTC, the company developing the gene therapy, said in a statement. “These data, coupled with other data from our ongoing clinical trials, reassure us that we are on the right path to bringing life-changing therapies for rare retinal diseases to patients and we look forward to sharing the three-month interim data from the SKYLINE phase 2 expansion portion of this trial in the second quarter of calendar 2022 and 24-month results from this phase 1/2 trial in the third quarter of calendar year 2022.”

In January 2022, AGTC announced that the phase 2 expansion of the phase 1/2 study, which is known as SKYLINE, had exceeded its enrollment goal, with 14 patients with XLRP receiving the treatment compared with the intended 12. Initial 3-month interim study results, including visual acuity, visual sensitivity, mobility, and safety are anticipated in the coming months (NCT03316560).

Updated data at ARVO show that AGTC-501 had sustained efficacy and safety at 18 months for patients with X-linked retinitis pigmentosa caused by RPGR mutations. 


AGTC-501 Efficacy Maintained in 18-Month Follow Up Data for X-linked Retinitis Pigmentosa

This video originally appeared on our sister site, 

Much research has been presented at the Association for Research in Vision and Ophthalmology (ARVO) 2022 Meeting that demonstrates the significant advancements being made in the treatment of retinal diseases, namely with gene and cell therapy approaches. 

In an interview, Veeral S. Sheth, MD, MBA, Director of Clinical Research at the University of Retina and Macula Associates, discussed the state of landmark research into complement factor inhibitors for geographic atrophy (GA) and gene therapies for a litany of ophthalmic conditions.

“I think there’s exciting things in the pipeline if you look at some of these gene therapies for GA—and I think a lot of these are related to complement factor inhibition, but there’s a lot of other avenues as well.”

Regarding gene therapies, Sheth discussed later-stage advances from REGENXBIO with agents that could potentially reverse the effect of wet AMD in key patients, as well as Gyroscope Therapeutics—recently acquired by Novartis—in GA reversal.

“I think for us, anything that’s a little further along is exciting,” Sheth explained.
“Because I think gene therapy is still in that period of strong development—every quarter, we’re getting a new milestone from one of these companies. You’re seeing a really good uptick in their studies, and hopefully that all pans out. Because in the GA study, for example, it’s an unmet need—but also an opportunity to reduce treatment burden right off the bat.”

Sheth also discussed come of the parameters that would go into implementing novel gene therapies into ophthalmic care, such as the level of regulation that would go into conducting procedures—or what to expect in follow-up care with long-term patients.

“From the front end: are surgeons going to be able to do these procedures from their surgical centers?,” Sheth suggested. “And on the back end: what happens year 3, year 4, year 5? I think we’re still so early in the process we don’t know exactly yet. We’re starting to get data that gives us a better idea, but that’s always going to be something (clinicians) think about.”

Veeral S. Sheth, MD, MBA, Director of Clinical Research at the University of Retina and Macula Associates, discusses advanced therapies for retinal diseases.

Advancements in Gene Therapy for Retinal Diseases

New data from the phase 1 clinical trial examining OpRegen in patients with dry age-related macular degeneration (AMD) show that the subretinal cell therapy may help improve or maintain visual acuity in this patient population, according to a presentation made at the 

2022 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting

, taking place in Denver, Colorado May 1-4, 2022 and virtually May 11-12, 2022.

The findings, presented by Allen C. Ho, MD, director of retina research and attending surgeon at Wills Eye Hospital, also demonstrated good persistence of OpRegen transplanted cells via alterations in drusen appearance, subretinal pigmentation, and hyper-reflective areas. In addition, in patients whose atrophic areas were extensively covered by the cell suspension (4/12), signs of outer retinal restoration and reduction in geographic atrophy were observed compared with baseline imaging. 

OpRegen has been generally well-tolerated with no unexpected adverse events. 

In an interview with CGTLive, lead investigator Ho details the findings from this latest analysis and extrapolates the potential of this therapy in dry AMD. 

Ho A, Banin E, Barak A, et al. Safety and Efficacy of a Phase 1/2a Clinical Trial of Transplanted Allogeneic Retinal Pigmented Epithelium (RPE, OpRegen) Cells in Advanced Dry Age-Related Macular Degeneration (AMD). Presented at: 2022 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; May 1-4, 2022, Denver, CO; May 11-12, 2022, virtual.

New data from cohort 4 showed outer retinal restoration following treatment with OpRegen. 

Treatment With OpRegen Shows Improvement in Visual Acuity, Cell Persistence in Dry AMD

Findings from a post-hoc analysis of the phase 1 OPTIC trial show that patients with neovascular age-related macular degeneration (nAMD) with high levels of neutralizing antibodies (NAbs) to the adeno-associated viral vector used in the gene therapy ADVM-002 were more likely to have robust protein expression and sustained improvements in central subfield thickness, among other benefits.

"These new data give us important insight into the high levels of efficacy that wet AMD patients experience following treatment with ADVM-022, particularly among those whose baseline levels of NAbs are below 1:125," said Szilárd Kiss, MD, Bob and Dolores Hope – Robert M. Ellsworth, MD Distinguished Associate Professor in Ophthalmology and lead author of the study, in a statement.

 "We continue to seek ways to address critical areas of unmet needs in wet AMD patients and caregivers by decreasing the treatment burden from frequent anti-VEGF injections, which are the current standard of care.”

The phase 1 OPTIC trial assessed safety, tolerability, and efficacy of a single intravitreal injection of Adverum Bio’s ADVM-002 (AAV.7m8-aflibercept gene therapy) in patients with nAMD. The open-label, dose-ranging study included 30 participants assigned to 2 dose levels, 6x10

 vg of ADVM-022 (n=15), with NAbs inclusion criteria of <1:5 within 6 months prior to ADVM-002 treatment for cohort C1 (n=6) or <1:125 for cohorts C2-C4 (n=24).

As of the data cutoff, median follow-up ranged from 60 to 104 weeks for cohorts C4 through C1, respectively. Of those who received the first or second dose level, 89% and 67% had baseline NAbs of <1:125. At follow-up, 12/15 and 8/15 patients who received 6x10

 vg of ADVM-022 remained anti-vascular endothelial growth factor (VEGF) injection-free, with mean annualized injection frequency reduced by 97% and 81% in each dose group, respectively. In those with NAbs <1:125, reductions in mean annualized anti-VEGF injection frequency were 97% and 93% in the 6x10

Among those with baseline NAbs <1:125, more robust aflibercept protein expression levels were observed as well as sustained improvements in central subfield thickness compared with those with a baseline NAbs of >1:125. No correlations with safety were observed based on baseline NAbs levels.

Although both doses were well-tolerated, patients in the 2x10

 vg/eye dose required less topical corticosteroid therapy to alleviate inflammation, and NAbs levels were generally not associated with occurrence or duration of inflammation.

Based on the previously presented findings from the OPTIC trial, Adverum plans to initiate a phase 2 clinical trial further examining the 2x10

 vg/eye dose of ADVM-002 as well as a new lower 6x10

 vg/eye dose, with new local and systemic steroid regimens. With a target enrollment of 70 patients with wet AMD, Adverum hopes to dose its first participant in Q3 of 2022.

Szilard K, Turpcu A, Bender K, et al. Phase 1 Study of Intravitreal (IVT) Gene Therapy with ADVM-022 for neovascular AMD (OPTIC Trial): the role of neutralizing antibodies (NAbs). Presented at: 2022 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; May 1-4, 2022, Denver, CO; May 11-12, 2022, virtual.

Adverum Biotechnologies Presents Additional Efficacy and Safety Data from the OPTIC Trial of ADVM-022 in Wet AMD at the ARVO 2022 Annual Meeting. News release. Adverum Bio. May 1, 2022. 

https://www.benzinga.com/pressreleases/22/05/g26921752/adverum-biotechnologi

The post-hoc analysis of the OPTIC trial explored the effects of neutralizing antibodies on patients treated with ADVM-002.  

Neutralizing Antibodies to AAV Vector for AMD Gene Therapy May Boost Therapeutic Effect 

Association for Research in Vision and Ophthalmology (ARVO) Virtual Meeting

 demonstrates safety and efficacy of gene therapy ADVM-022 in patients with 

neovascular age-related macular degeneration (nAMD)

These findings are from the Phase 1 OPTIC trial, an open-label, multicenter, dose-ranging study designed to evaluate the safety, efficacy, and tolerability in patients who have previously received and shown response to anti-VEGF therapy.

“Intravitreal gene therapy has the potential to significantly reduce treatment burden and improve vision outcomes in patients with neovascular AMD,” noted the study investigators.

Led by Brandon Busbee, MD, of Tennessee Retina, the investigative team administered 2 different intravitreal doses of the gene therapy across 4 cohorts. Furthermore, they measured incidence and severity of adverse events, change in visual acuity (BCVA), change in central retinal thickness (CST), as well as need for and number of supplemental aflibercept injections.

In the study, cohorts 1 (n = 6) and 4 (n = 9) received 6x10

 vg/eye while cohorts 2 (n = 6) and 3 (n = 9) received 2x10

 vg/eye. Patients in cohort 1 were followed up for a median of 86 weeks, patients in cohort 2 for a median of 64 weeks, cohort 3 for a median of 48 weeks, and cohort 4 for a median of 16 weeks.

All patient across cohorts received mean 7.1-9.2 injections of anti-VEGF in the 12 months prior to the study. Notably, such injections led to decent baseline BCVA (mean, 65.0-65.9 letters) before commencing ADVM-022 treatment.

Thus, Busbee and team reported that the gene therapy was well-tolerated across cohorts; it further demonstrated a favorable safety profile.

Reported ocular events related to the therapy were rated as mild in 78% of cases and moderate in 22% of cases. Any ocular inflammation was shown to subside with steroid eye drops. The investigators also reported no cases of retinal involvement.

As for general efficacy, both doses of gene therapy were linked with a significant reduction in anti-VEGF injection burden. Of the 15 who received the higher dose and 15 who received the lower dose, 14 and 10, respectively, did not require anti-VEGF supplementation.

Even more, mean annualized anti-VEGF injection frequency was reduced by 99% in the higher dose cohorts and 85% in the lower dose cohorts after treatment.

In cohorts 1-3, BCVA was maintained with an overall mean age change from -2.5 to 0.5 ETDRS letters. Patients demonstrated a CST mean change from -19.7 to -132.7 µm. Data from cohort 4 is currently pending.

“Over 80% of patients with nAMD treated with a single injection of ADVM-022 in OPTIC have not needed any supplemental anti-VEGF injections up to 92 weeks follow-up,” Busbee and colleagues emphasized. “ADVM-022 has the potential to reduce treatment burden and improve patient vision outcomes.”

Phase 1 Study of Intravitreal Gene Therapy with ADVM-022 for neovascular AMD (OPTIC Trial)

Despite these promising results, the future for ADVM-022 remains unclear. In late April, Adverum, the company developing the gene therapy, 

announced the discovery of a suspected unexpected serious adverse reaction

 of hypotony with panuveitis and loss of vision in a patient with diabetic macular edema treated in the phase 2 INFINITY trial. This adverse event is currently under exploration to uncover a potential cause.

The single-injection investigative gene therapy may help with providing continuous expression of aflibercept. 

ADVM-022 Gene Therapy for nAMD May Reduce Anti-VEGF Injection Burden 

Investigative gene therapy BIIB112 was shown to lead to durable improvements in patients with 

, a group of rare diseases marked by progressive vision loss leading to blindness.

“BIIB112 (NSR-RPGR) is an AAV8 vector–based gene therapy that uses codon optimization to express the full-length, correctly sequenced retinitis pigmentosa GTPase regulator (RPGR) protein in the photoreceptors of individuals with XLRP caused by mutations in RPGR,” noted the University of Oxford investigators, led by Robert MacLaren, FMedSci, FRCOphth.

The estimated prevalence of retinitis pigmentosa in the United States is between 1 in 3500 or 1 in 4000 individuals. Currently, the US Food and Drug Administration (FDA) has approved only 1 therapy — an adeno-associated virus vector-based gene therapy, which is indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Therefore, newer therapeutic options—particularly investigative, efficacious, and safe gene therapies—are warranted.

, MacLaren's team presented their findings from 2 ongoing trials — the Phase 1 dose-escalation Xirius study and Xolaris, a natural disease progression study.

As such, the team evaluated 18 patients from the Xirius study who were treated with BIIB112. All patients were ≥18 years of age. They also looked at a subgroup of patients from Xolaris (N = 69) who met the inclusion criteria for Part I of Xirius and completed 12 months of follow-up.

For the purposes of their analysis, they defined retinal sensitivity responder as an achievement of ≥7 dB improvement from baseline at ≥5 loci.

MacLaren and colleagues reported that treatment with the 4 highest doses (n = 12) resulted in early and durable improvements in central retinal sensitivity. As such, 6 participants showed response at month 1, and 4 maintained response through month 12.

Furthermore, none of the selected participants from Xolaris (untreated eyes) achieved central retinal sensitivity response at any point through month 12.

The team also assessed low-luminance visual acuity (LLVA), defining improvements as gain of ≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Thus, they observed improvements in treated eyes as early as Month 1 as well as maintenance through 12 months of follow-up (3/11 participants). There were no untreated eyes that achieved improvements.

Most of the associated reported adverse events were considered mild and resolved. Additionally, there were no dose-limiting toxicities that occurred at any of the studied doses. Inflammation mostly occurred at higher doses, but treatment with oral corticosteroids was considered efficacious and useful.

"Treatment with BIIB112 was well tolerated and, in cohorts 3-6, led to early and durable improvements in 2 measures of visual function," the investigators concluded.

Visual function improvements with BIIB112 (NSR-RPGR) in X-linked retinitis pigmentosa: XIRIUS (dose-expansion) and XOLARIS (natural disease progression) studies

The AAV8 vector–based gene therapy was associated with improvements in 2 measures of visual function. 

Gene Therapy BIIB112 Promising for X-Linked Retinitis Pigmentosa

A phase 2B study was conducted on the efficacy of regenerative medicine advanced therapy (RMAT)-designated intravitreal injection of allogeneic human retinal progenitor cells (hRPCs) (jCell, jCyte Inc.) to treat 

The study showed that in the high-dose patient group, there was a significant correlation between all visual function changes measured over the 12-month study and the optical coherence tomography (OCT) measurement of the central foveal thickness (CFT). A similar correlation was seen between most study end points and the mid-subfield mean ellipsoidal zone (EZ) thickness, according to Sunil Srivastava, MD, a staff physician at Cleveland Clinic Cole Eye Institute in Ohio.

EZ recession and more generally the thinning of the EZ outer zone are structural retinal changes that occur as RP progresses and could serve as important objective anatomic surrogates for RP severity and response to jCell treatment.

This work was initiated after the principal investigators in the phase 2B study identified a subgroup of patients without extremely advanced forms of the disease that could be much more reliably measured across the visual function endpoints within the study. The readable SD-OCT volumetric data from this subgroup were analyzed and included 29 eyes of 29 patients (sham treatment, n=10; low-dose treatment, n=9; high-dose treatment n=10).

For more of the latest news on gene and cell therapies for eye disorders, 

The investigators analyzed the SD-OCT using automated segmentation followed by EZ mapping with manual correction. The correlational analysis explored the relationship between each baseline OCT parameter and the change in each of the visual function measurements at the final 12-month time point versus baseline. The end points included the best-corrected visual acuity, kinetic visual fields, low-luminance mobility test, contrast sensitivity, and a visual function questionnaire.

The study showed moderate to strong correlations between all clinical trial end points and the mean CFT and mid-subfield mean EZ thickness in the high-dose treatment group that received one 6-million cell injection of jCell, Srivastava reported. Importantly, strong and significant correlations were seen between all 5 visual function end points and the mean CFT. The sham group and the low-dose treatment (3 x 106 cells) group did not demonstrate a significant relationship.

The results of this work are informative for the future study of jCell. The identification of these important structural predictors of response aligns nicely with the patients with RP who would be expected to respond to this RMAT-designated therapy based on its paracrine mechanism of action.

In conclusion, the authors noted that identifying and selecting patients with adequate CFT and mid-subfield mean EZ thickness will, given the known neurotrophic effects of jCell, facilitate the selection of an RP population with the greatest chance of a treatment response in a phase 3 study.

Optical coherence tomography characteristics may be predictive of the efficacy of intravitreal injection of allogeneic human retinal progenitor cells, according to research presented at ARVO 2021. 

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