Lynda Charters

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Reviewed by Elise Orhan, PhD, and Thierry Bordet, PhD

A non-viral gene therapy sustained drug-delivery product (EYS809, Eyevensys) that delivers anti-vascular endothelial growth factor (VEGF) to the eye may replace the need for repeated intravitreal anti-VEGF injections and improve vision in patients diagnosed with wet age-related macular degeneration (AMD).

This real-world approach would both address the tremendous treatment burden imposed on patients with wet AMD by providing an effective longer acting treatment and a non-VEGF-based therapy for patients who need a more convenient treatment approach to control disease progression long term and to achieve improved vision.

This platform is based on the electrotransfection of DNA plasmids that turns the ciliary muscle into a production site for the intraocular expression and secretion of therapeutic proteins, according to Elise Orhan, PhD, the preclinical project leader at Eyevensys.

EYS809 is a dual-gene plasmid designed to deliver sustained concentrations of both the anti-VEGF inhibitor aflibercept (Eylea, Regeneron Pharmaceuticals) and decorin, an endogenous transforming growth factor-beta inhibitor with known anti-angiogenic and anti-fibrotic properties, that has been demonstrated to reduce choroidal neovascularization (CNV) in the rat laser CNV model.

According to Thierry Bordet, PhD, senior author and chief scientific officer of Eyevensys, Decorin has the potential to enhance the efficacy of anti-VEGF therapy by reducing CNV leakage and scarring via non-VEGF dependent pathways.

During the study, aflibercept or decorin-coding plasmids (30 µg/eye) were electrotransfered in the rat ciliary muscle 3 days before laser was applied to induce CNV. Intravitreal injection of a human equivalent dose of aflibercept (15 µg/eye) or recombinant decorin (1 µg/eye) at the CNV induction served as positive controls. Fluorescein angiography (FA) was performed on day 14 to assess the CNV leakage. Different dual gene expression cassettes were compared in rats to deliver optimal intraocular concentrations of the 2 treatments.

“Electrotransfection of plasmids resulted in sustained intravitreal production of aflibercept or decorin in the vitreous during the 2-week study compared with rapid elimination of the 2 therapies after intravitreal injections,” investigators said.

Both plasmid and intravitreal aflibercept reduced the incidence of grade 3 CNV lesions to 11% and 29%, respectively, compared with 59% in untreated rats. The percentage of eyes with at least 1 clinically relevant lesion also decreased in both treatment groups (39% and 63%, respectively compared to 97% in untreated).

In a like manner, plasmid- or intravitreally administered decorin reduced the incidence of grade 3 CNV lesions to 36% and 24%, respectively, compared to 59% in untreated rats with 60% and 66% of eyes having at least one clinically relevant lesion compared to 75% in untreated rats.

Eyevensys previously demonstrated the safety of its platform with a plasmid coding for an anti-tumor necrosis factor protein tested in 18 patients with non-infectious uveitis. The most common adverse event was mild subconjunctival hemorrhage that last for a short period.

Compared with viral gene therapy, the advantages of EYS809 for treating wet AMD include no need for subretinal surgery, easy delivery, the lack of immunogenicity related to the vector, the possibility of repeated dosing to extend treatment effect if needed, and no limited cargo capacity allowing for the delivery of 2 therapeutic proteins. Moreover, EYS809 only transfects the ciliary muscle cells in contrast to potentially any cell in the eye being transfected following intravitreal injection of viral vectors offering a limited risk of retinal damage.

“This non-viral gene therapy sustained drug delivery approach to deliver anti-VEGF proteins to the eye could be a viable alternative to repeated intravitreal injections that have been associated with poor visual outcomes in patients with wet AMD,” investigators concluded. “The combined effect of aflibercept and decorin, expressed from the EYS809 dual-gene plasmid, is expected to provide benefits over aflibercept alone by also reducing CNV and subretinal fibrosis.”

This article is adapted from Orhan’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. Orhan is an employee of Eyevensys.

Articles

EYS809, a non-viral gene therapy sustained drug-delivery product that delivers anti-vascular endothelial growth factor to the eye, may replace the need for repeated intravitreal anti-VEGF injections and improve vision in patients diagnosed with wet age-related macular degeneration. 


Non-viral gene therapy eases treatment burden in wet AMD

This treatment fills a gap for patients who are unresponsive and/or intolerant to the standard treatments for noninfectious keratitis, such as lubricants, corticosteroids, and immunosuppressants. 

Few treatments are available for this patient population with advanced disease, according to Joseph Grieco, PhD, director of Clinical Development at Mallinckrodt Pharmaceuticals in Bedminster, New Jersey.

Grieco explained that RCI works via its anti-inflammatory and immunomodulatory effects through interaction with melanocortin receptors.


Grieco and his colleagues conducted a multicenter, open-label, phase 4 study to evaluate the efficacy and safety of RCI in patients with refractory severe non-infectious keratitis. 

The primary efficacy endpoint was the proportion of patients with improvements in the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire score by 12 or more points. 

The Visual Analogue Scale (VAS) for burning/stinging and eye discomfort, and corneal fluorescein staining were exploratory endpoints for the study. 

The safety endpoints were the proportion of patients with treatment-emergent or serious adverse effects during the study.

The study included 36 patients (mean age, 63.3 years; 71.4% women; 80% Caucasian). All patients had bilateral keratitis (mean duration, 4.4 years). Patients administered 80 units of RCI twice a week for 12 weeks followed by tapering for 4 weeks.

Grieco explained that the IDEEL symptom bother score at week 12 after the start of treatment showed that 50% of patients had greater than a 12-point improvement, and 52.9% achieved that level of improvement as early as week 2 after treatment initiation.

“The mean changes from baseline in the symptom bother score exceeded the minimal clinically important difference threshold at every evaluation point,” he said.

At the 12-week evaluation, the VAS score indicated that all symptoms improved from baseline, with the most pronounced improvements seen in ocular dryness and discomfort.

Improvements in corneal and conjunctival staining also were seen as soon as 4 weeks after treatment started and were sustained through week 12. 

The mean change went from 5.3 at baseline to -1.0 at week 4 and was sustained to week 12 at -1.1.

A third of patients had an adverse effect during the study, most of which occurred once. The intraocular pressure did not increase.

“The results of this open-label study showed that 80 units of RCI twice weekly for 12 weeks was associated with rapid and sustained improvements in the symptoms of persistent severe noninfectious keratitis that had previously not responded to standard-of-care therapies,” Grieco concluded. 


This article is adapted from Grieco’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual conference. He is an employee of Mallinckrodt Pharmaceuticals. RCI is approved by the FDA for severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, including keratitis.


1. Huang YJ, Galen K, Zweifel B, et al. Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists. J

Joseph Grieco, PhD, notes that treatment fills a gap for patients who are unresponsive to the standard treatments for noninfectious keratitis. 

Injections offer relief for refractory severe noninfectious keratitis

An experimental study of hemorrhagic shock conducted in rabbits found that during progression of and recovery from shock, the blood flow in the eye shows decreases and increases similar to those seen in the kidney and intestines. 

Noninvasive measurement of the blood flow in the eye may be a new indicator of shock-related organ damage, reported Kento Watanabe, MD, from the Department of Ophthalmology, Toho University School of Medicine, Tokyo, and Tomoaki Shiba, MD, from the Department of Ophthalmology, International University of Health and Welfare Narita Hospital, Funabashi, Chiba, Japan.

While shock is defined as the progression of organ disorders, it is difficult to evaluate using only parameters such as blood pressure. 

Fundus examination is the only examination that facilitates direct observation of an organ’s blood supply, which reflects the true nature of shock. 

Evaluation of the retinal vessels is a valuable resource because they have the same function and structure as the coronary and renal arteries, Watanabe explained.

Watanabe and his colleagues used laser speckle flowgraphy (LSFG) to study the relationship between whole body and ocular blood flow in small- and medium-sized animals and they found previously that the ocular blood flow index obtained using LSFG accurately reflects the blood pressure and cardiac output during shock, and that the ocular blood flow is larger than the rate of decrease in cardiac output (unpublished data).

In the study, shock was induced in 10 New Zealand white rabbits by removing blood at the rate of 1 mL/minute for 30 minutes; the animals were observed for 20 minutes and the blood returned. 

During the period of shock, the mean arterial blood pressure (MAP) was measured in the brachial artery. 

The blood flow in the intestines and kidneys was measured using an ultrasonic blood flow meter at the mesenteric artery and renal artery. LSFG was used to measure the ocular blood flow. 

The mean blur rate (MBR), a blood flow index specific to LSFG, was measured in the retinal vessels and choroid. The rate of change of each parameter was compared with the baseline value before the blood was removed.

The investigators found that the MBR in the retinal vessels and choroid, the intestinal and renal blood flow, and the MAP decreased significantly as the blood was removed and recovered nearly to the baseline value when the blood was returned. 

The rates of change at the end of the period of blood removal were as follows: MAP, 69.4%; kidney, 43.5%; intestine, 54.8%; MBR of the retinal vessels, 42.3%; and MBR of the choroid, 55.5%.

The rates of change between the MBR of the retinal vessels and kidney and between the MBR of the choroid and intestine were similar, and no significant difference was observed. 

The MBR of the retinal vessels and MBR of the choroid were significantly positively correlated with the MAP (r = 0.87, 0.73), renal blood flow (r = 0.66, 0.59), and intestinal blood flow(r = 0.84, 0.61).

“In this study, the ocular blood flow reflected the blood flow in the kidneys and intestines,” the authors concluded. “The key takeaway point is that non-invasive ocular blood flow measurement using LSFG may be a new indicator of shock-related organ damage.”

This article is adapted from Watanabe’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interest in this subject matter.

Non-invasive ocular blood flow measurement using laser speckle flowgraphy may be a new indicator of shock-related organ damage, investigators report. 

Researchers target ocular blood flow, systemic organ blood flow in hemorrhagic shock

The 6-month results of a phase 1/2 clinical trial of the subretinal gene therapy drug AGTC-501 for X-linked retinitis pigmentosa (XLRP) indicated that the drug was well tolerated out to month 12 in patients treated in the central retinal area.

Meaningful improvements were achieved in the macular sensitivity and significant changes in the best-corrected visual acuity (BCVA), according to Paul Yang, MD, PhD, assistant professor, Oregon Retinal Degeneration Center, Casey Eye Institute, Oregon Health and Science University, Portland.

This is good news for affected patients, because no other treatment is currently available for patients with XLRP. Luxturna (Spark Therapeutics) is the only FDA-approved treatment for RP due biallelic pathogenic variations in 

, which represents only 1% of cases of RP. In contrast, XLRP accounts for 10% of patients with RP, and 80% of cases of XLRP have a mutation in the 

In the ongoing phase 1/2, open label, dose-escalation clinical trial under discussion, investigators used an adeno-associated viral vector to deliver a normal functioning copy of the 

A total of 29 male patients were assigned sequentially to 1 of 5 dosing groups (lowest to highest, 4.0 x 1010 vg/ml to 3.2 x 1012 vg/ml) and underwent injection of AGTC-501 into the central or peripheral macular region in 1 eye. The primary outcome was safety, and the secondary outcome was the efficacy of the treatment based on assessments that included BCVA and microperimetry from 6 to 12 months after treatment. All patients were age 6 years and older.

The central macula was treated in 21 patients and the peripheral retina in 8 patients.

Yang reported that the treatment was generally well tolerated across all doses. Six serious adverse events have been documented thus far, all of which were unrelated to the study drug; these included retinal detachment, concussion, and uncontrolled secondary glaucoma due to prophylactic corticosteroids. Most adverse events were mild and resolved without sequelae; the most frequent were anterior and/or posterior chamber inflammation, blurred vision, conjunctival hemorrhages and hyperemia, and vitreal cells.

Intraocular pressure elevations were related to coriticosteroid use and were well controlled medications with the exception of the severe adverse event that required an Ahmed valve.

Ocular adverse events that were related to the study drug occurred infrequently; these included anterior chamber cells in 4 eyes, retinal pigment epitheliopathy in 2 eyes, and vitreal cells in 2 eyes, he reported. The untreated eye was reported to be affected by adverse events in 3 cases; xanthopsia in 1 fellow eye, and bilateral iritis and photopsia involving 2 fellow eyes.

Yang reported the results from the 20 patients who were treated centrally. At the 6-month time point, the results showed improved BCVA across all the centrally dosed groups. The results were significant (p≤0.001) when compared to the untreated fellow eyes.

“Eleven patients had improvements in the BCVA of 5 or more letters in the treated eyes compared to the fellow untreated eyes,” he said.

Nine of the centrally treated patients with a complete data set were evaluated at 12 months. Among these patients, there was a significant (p ≤ 0.005) difference in the proportion of treated compared with untreated eyes with a gain of 5 letters or more that started as early as 1 month after treatment that was sustained out to 12 months, Yang described.

Among the centrally treated patients, 18 patients had microperimetry data that could be evaluated. Of these patients, 8 were responders; responders were defined as those with 7 decibels or more improvement in the retinal sensitivity at 5 or more retinal loci in the central 36 loci of the perimetry grid at 6 months. At the 6-month evaluation, the responders had an improvement in mean sensitivity across the central 36 loci in the treated eye that was significantly greater (p ≤ 0.05) than that in the untreated eye.

Eight of the patients had microperimetry data that could be evaluated at 12 months. Of these, 4 patients were responders.

“Among those 4, the change in the mean sensitivity within the centrally treated area was greater in the treated eye compared with the untreated eye at 6 and 12 months, although the difference did not reach significance at 12 months,” he explained.

The doses that resulted in the best responses were the high, higher, and highest doses (respective doses, 3.6 x 1011mg/ml, 1.1 x 1012 vg/ml, and 3.2 x 1012 mg/ml) with respective response rates of 29%, 43%, and 50%.

“Subretinal gene therapy in this cohort of XLRP patients was well tolerated with a favorable safety profile to month 12,” Yang concluded. “There was evidence of responses to the treatment using the criteria of a 7-decibel or more improvement at 5 or more retinal loci in the treated eye. The patients treated peripherally will require long-term follow-up to determine the treatment efficacy. A significant improvement in the BCVA of 5 or more letters was seen through month 12, which is supportive of a biological signal.”

The patients will be followed over the long term. The next study, the Skyline clinical expansion trial, is underway and will enroll another 12 patients and randomized to either a group 2 low dose or a group 5 high dose, and a mobility maze will be added. At 12 months, the fellow eyes will also be dosed. A phase 2/3 study, the Vista trial, also is planned that will enroll 60 patients and randomized to the same high- and low-dose treatment arms and an untreated control arm. All eligible control eyes will receive dosing at 12 months.

This article is adapted from Yang’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. He is a consultant to and receives clinical trial support from AGTC.

During an ARVO presentation, Paul Yang, MD, PhD, explained that in a clinical trial, investigators used an adeno-associated viral vector to deliver a normal functioning copy of the RPGR gene via subretinal injection.

Author | Lynda Charters

Articles

Injections offer relief for refractory severe noninfectious keratitis

Researchers target ocular blood flow, systemic organ blood flow in hemorrhagic shock

Initial data from AGTC-501 subretinal gene therapy for X-linked RP demonstrates safety, efficacy

Non-viral gene therapy eases treatment burden in wet AMD