Cheryl Guttman Krader, BS, Pharm

Two anti-VEGF gene therapies are being investigated in clinical trials of patients with exudative age-related macular degeneration. Initial efficacy and safety results are encouraging.

 has transformative potential for reducing treatment burden and improving patient outcomes, according to 

Two investigational anti-VEGF gene therapies are currently being investigated in clinical trials-

. Dr. Kiss described the two technologies and reviewed some preliminary clinical trial results that support their promise for providing sustained benefit with a single injection.

“Considering the treatment burden of anti-VEGF therapy for other ocular diseases, we can imagine that exudative AMD is just the first indication that will be targeted for anti-VEGF gene therapy,” said Dr. Kiss, chief, Retina Service, associate professor of ophthalmology, and associate dean at 

RGX-314 delivers a gene for an anti-VEGF fab protein that is similar to ranibizumab. It uses adeno-associated virus-8 (AAV8) as a vector and is administered in the operating room as a subretinal injection.

“AAV is the most common viral vector carrier used for gene therapy. Different AAV serotypes have different tissue selectivity,” Dr. Kiss explained. “AAV8 is a wild type AAV that has the propensity for greater transfection of retinal cells compared with AAV2 following subretinal gene therapy delivery.” 

AAO 2019: Encouraging results revealed from early trial of subretinal gene therapy for wet AMD

The phase I study of RGX-314 has a dose-escalating design and is enrolling previously treated patients requiring frequent injections for exudative AMD.

Results have been reported for 42 subjects enrolled across five cohorts who completed at least six months of follow-up, which is the primary endpoint.

On average, the patients had been diagnosed 56 months previously and had received an average of 33 anti-VEGF injections (9.6/year). Mean baseline BCVA was 55.7 ETDRS letters and mean OCT-measured central retinal thickness (CRT) was 399 Î¼m.

The treatment has been well-tolerated in all dose cohorts. Most adverse events have been rated mild in severity, and there have been no serious drug-related adverse events.

“Fifteen serious adverse events were recorded in nine subjects and there were two deaths, but none were related to the treatment,” Dr. Kiss said.

There has been no observed clinically determined immune responses, drug-related ocular inflammation, or post-surgical inflammation exceeding that expected following routine vitrectomy. Two ocular procedure-related serious adverse events occurred, including a peripheral retinal detachment that was repaired and a case of endophthalmitis following collection of an aqueous humor sample.

In the fourth dose cohort, which included 12 patients, BCVA remained stable through six months and mean CRT improved. Five (42%) patients were injection-free through the six months, requiring no rescue anti-VEGF therapy.

The fifth dose cohort includes 12 patients who have five to six months of available follow-up. This group also had stable BCVA and improved CRT, and nine of the patients (75%) remained injection-free.

“Standardization, automation, and surgeon skill are critical for the success and safety of subretinal gene therapy,” Dr. Kiss noted. “Surgeons need extensive training that begins in the wet lab and then moves into a virtual reality environment.”

ADVM-022 is an AAV vector encoding aflibercept. It uses a novel AAV.7m8 capsid for gene delivery, which is an engineered vector optimized for strong retinal transfection following in-office intravitreal injection.

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OPTIC, the phase I clinical trial investigating ADVM-022 in exudative AMD, is evaluating two dose levels of the gene therapy. Eligible subjects must demonstrate a meaningful response to anti-VEGF therapy and are receiving an injection of aflibercept seven to 14 days prior to ADVM-022 injection.

Data from median follow-up of eight months was available for six patients enrolled in OPTIC. This first cohort had received an average of 6.2 anti-VEGF injections in the eight months prior to study screening and a mean of 35.3 injections since being diagnosed with exudative AMD.

There were some other interesting findings, and patients were requiring few, if any, injections. Dr. Kiss pointed out that one patient had received 109 previous injections.

“Of the 52 rescue injection opportunities during the eight-month follow-up period, zero rescue injections were needed in any of the first six subjects,” he said.

In this small group there have been no serious adverse events nor any adverse events meeting criteria for dose-limiting toxicity.

According to the research, there were 19 ocular adverse events potentially related to the investigational agent, of which 14 were mild and five rated as moderate in severity.

Mild anterior inflammation and vitreous cells were the most common adverse events, and all were well controlled with topical corticosteroids. The research team reported that there were no cases of vasculitis, retinitis, or choroiditis.

Evaluations for efficacy showed BCVA remained stable and CRT improved while all patients remained injection-free.

Anti-VEGF injections and glaucoma: Surgeons must watch IOP elevation

Gene therapy approaches represent three basic categories, the choice of which depends on the underlying pathology. Both RGX-314 and ADVM-022 are gene augmentation approaches as they are designed to deliver a gene for a functioning protein that is not naturally produced.

Gene augmentation can also be utilized to replace a non-functioning gene, as represented by voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) the FDA-approved gene therapy that replaces the non-functioning RPE65 gene in those patients with biallelic RPE65 mutation-associated retinal dystrophy.

As another approach, gene therapy can aim to edit existing genes. This approach is applicable to diseases caused by a single-nucleotide, gain-of-function/dominant-negative mutation. Or, in the case of pathologies caused by a dominant mutation, gene therapy can be designed to inactivate the causative gene.


	This article was adapted from Dr. Kiss’ presentation at the 2019 meeting of the American Academy of Ophthalmology. Dr. Kiss is a consultant to RegenxBio and Spark Therapeutics and is a consultant and equity owner in Adverum.

Articles

Research targets gene therapy for exudative AMD patients

In an era when pharmacological therapy has become the mainstay for treatment of diabetic macular edema (DME), pars plana vitrectomy (PPV) deserves consideration as a reasonable alternative for early DME in appropriate patients, according to Maurice B. Landers III, MD.

“Anti-VEGF therapy has become the current standard of care for treatment of DME in the United States,” said Dr. Landers, professor of ophthalmology, University of North Carolina Medical School, Chapel Hill. “But it is extremely expensive and outcomes with its use in the real world are nowhere near as good as the results obtained in clinical trials.”

Dr. Landers pointed out that modern PPV is safe, effective for reducing DME, less expensive, and the only affordable option for treating DME in most countries of the world.”

An analysis conducted by the DRCR.net demonstrates that anti-VEGF therapy for DME with either of the two drugs that have an indication for this use (ranibizumab [Lucentis, Genentech]; aflibercept [Eylea, Regeneron]) is not a cost-effective treatment using a liberal standard of $100,000 per quality-adjusted life-year.

Bevacizumab (Avastin, Genentech) is a less expensive alternative. Its use, however, is accompanied by issues relating to the need for compounding and potential for counterfeiting. It also may be prohibited by regulatory agencies in some countries, Dr. Landers added.

Furthermore, the DRCR.net cost-effectiveness calculations are based on results of its comparative effectiveness in clinical trials. However, research using Medicare data shows that in the real-world, patients are receiving anti-VEGF injections less frequently and achieving less improvement than has been reported in clinical trials.

“In clinical trials, there is a lot more effort devoted to ensure patients attend follow-up visits,” said Dr. Landers. “Compliance in the real world is simply not as good.”

Dr. Landers said there is considerable evidence that PPV reduces macular edema in patients with DME. In the DRCR.net Vitrectomy for DME study, central subfield thickness (CST) decreased in more than 90% of patients and was reduced 33% overall, from 412 µm to 278 µm.

Figure 1: The top graph shows the results of the meta-analysis of 1,800+ cases of vitrectomy for DME in the literature, showing the resulting decreased macular thickness after vitrectomy. The bottom graph outlines the duration of follow-up in these studies, showing the long term, beneficial effect of vitrectomy on macular thickness, up to 30 months in some cases (Images courtesy of Maurice Landers III, MD)

Furthermore, in a 2013 publication that reviewed data from more than 1,800 patients with DME, Dr. Landers and colleagues found the vast majority of patients achieved a durable decrease in macular thickness, showing persistence through follow-up periods that extended up to 30 months.

Doubt that PPV has benefit for treating DME may exist because in the DRCR.net Vitrectomy for DME study, it was not associated with improvement in visual acuity. Dr. Landers suggested, however, that selection bias may explain that study’s outcome.

“We know from other studies that vision of patients with DME never improves without an associated decrease in CST,” Dr. Landers said. “The DRCR.net study, however, recruited patients who had failed all other treatments and they likely had irreversible retinal damage that limited their potential for vision improvement even after successful reduction of their macular edema.”

He suggested that with the availability of spectral-domain optical coherence tomography (SD-OCT), which enables preoperative determination of the integrity of the outer retina, patients with potential to gain visual acuity can be selected for PPV.

Figure 2. These images show the different visual results obtained after thinning the retina with vitrectomy. The top (before and after) images of the retina show good visual result if patients start with intact outer retina (by SD-OCT). The bottom (before and after) images of retina show poor visual results (20/200 only improved to 20/160, in spite of good anatomical result) if patients start with damaged outer retina by SD-OCT (Images courtesy of Maurice Landers III, MD)

“We now have evidence that the integrity of the outer retinal layers correlates with visual acuity in patients with DME,” Dr. Landers explained. “There is a correlation between the previtrectomy integrity of the external limiting membrane and ellipsoid zone and the potential for functional improvement with improvement in DME.”

Dr. Landers noted that the techniques and instrumentation for PPV have advanced significantly since the procedure was first introduced almost 50 years ago. It has an acceptable risk profile compared with anti-VEGF therapy, considering rates of major complications.

“There is an about 1% incidence of sight-threatening retinal detachment with PPV and an about 1% cumulative three-year incidence of endophthalmitis with intravitreal injections,” Dr. Landers said.

Dr. Landers has no relevant financial interests to disclose.

When vitrectomy offers a viable therapeutic option for DME

Intravitreal faricimab (previously known as RG7716, Genentech/Roche) shows promise for improving outcomes and reducing the treatment burden for diabetic macular edema (DME), according to results of a phase II study.

Faricimab is a first-in-kind bispecific antibody that simultaneously binds and neutralizes VEGF-A and angiopoietin-2, said Arshad M. Khanani, MD, MA, BOULEVARD Investigator, managing partner and director of clinical research at Sierra Eye Associates and clinical associate professor, University of Nevada, Reno, NV. The agent is also optimized for fast systemic clearance and to avoid effector function.

Known as BOULEVARD, the phase II study compared faricimab at doses of 1.5 mg and 6.0 mg against ranibizumab 0.3 mg (Lucentis, Genentech).

Patients received six monthly injections (up to week 20), after which they were followed monthly (off treatment), up to week 36 to evaluate the durability potential of the drug. The primary endpoint analyzed adjusted mean change in BCVA letter score from baseline to week 24 in treatment-naÃ¯ve patients, which showed a statistically significant difference favoring faricimab 6.0 mg against ranibizumab (13.9 vs. 10.3 letters; P=.03).

Analyses looking at percentages of patients achieving ≥2-line or ≥3-line improvements in BCVA and improvements in Diabetic Retinopathy Severity Score (DRSS) (DRSS simplified conversion table (

http://www.icoph.org/dynamic/attachments/resources/diabetic-retinopathy-detail.pdf

)) also favored faricimab over ranibizumab. In addition, the investigational agent showed a benefit for better control of disease activity during the 16-week observation period, following the last study injection, Dr. Khanani said.

“Angiopoietin-2 levels are elevated in the vitreous of patients with diabetic retinopathy (DR) and DME. The results from this phase II study confirm the role of blocking angiopoietin-2 to stabilize the vasculature and decrease leakage and inflammation in these patients,” Dr. Khanani said. “Two large global phase III pivotal studies, YOSEMITE and RHINE, have been initiated and are currently enrolling patients (clinicaltrials.gov id: NCT03622580).”

BOULEVARD is a U.S. multicenter, randomized, double-masked study that enrolled 229 patients (168 treatment-naÃ¯ve and 61 previously treated) with diabetic macular edema and decreased visual acuity (20/320 to 20/40).

Highlighting some results from secondary outcome measures in the treatment-naÃ¯ve patients, Dr. Khanani reported that a ≥2-line gain in BCVA from baseline to week 24 was achieved by 57.0% of patients in the ranibizumab group, 61.2% of patients treated with faricimab 1.5 mg, and 70.5% of those receiving faricimab 6.0 mg. Rates of patients with a ≥3-line improvement in BCVA in the three treatment groups were 32.7%, 36.7%, and 43.2%, respectively.

“These data show that compared with ranibizumab, faricimab 6.0 mg was associated with impressive relative increases of 24% in the percentage of 2-line gainers and 32% in the percentage of 3-line gainers in treatment-naÃ¯ve patients,” Dr. Khanani said.

Data on central subfield thickness changes from baseline to week 24 supported the primary efficacy outcome, showing a dose-dependent effect with faricimab and more improvement with the investigational agent compared with ranibizumab.

In the treatment-naÃ¯ve study population, 39% of patients treated with faricimab 6.0 mg and 12% of ranibizumab-treated patients had a ≥2-step improvement in DRSS at week 24. Among the high-risk population with a baseline DRSS ≥53 (i.e., ≥ severe nonproliferative diabetic retinopathy), 25% of ranibizumab-treated patients versus 88% of those treated with faricimab 6.0 mg showed an improvement of at least 2 steps in their diabetic retinopathy severity.

In the off-treatment observation period, patients treated with faricimab 6.0 mg showed potential for extended durability with a higher proportion of patients maintaining disease stability over time after the last dose.

Faricimab was well-tolerated and showed no new or unexpected safety signals.

This article is based on a presentation given by Dr. Khanani at the 2018 World Ophthalmology Congress in Barcelona, Spain. Dr. Khanani is a consultant for Genentech and Roche.

Targeting angiopoietin-2 + VEGF-A to treat DME

Nanotechnology-based approaches for restoring sight in patients with retinal degenerative diseases hold great interest because they offer potential advantages compared with a retinal prosthesis, said Marco A. Zarbin, MD, PhD.

Dr. Zarbin described three nanoscale technologies that are currently in development. He explained that they represent an exciting approach for several reasons.

“In principle, the nanotechnology approaches may be safer than a retinal prosthesis and give better spatial resolution,” said Dr. Zarbin, professor and chair, Institute of Ophthalmology and Visual Science, Rutgers-New Jersey Medical School Rutgers University, Newark, NJ.

“In addition, some of the approaches that are being developed offer reversibility, and that is an important feature because it means patients will have the opportunity to take advantage of new and better approaches if they come along,” Dr. Zarbin said.

Compared with a retinal prosthesis, nanoscale technology approaches offer the potential for providing higher spatial resolution because they can deploy far more cells as photoreceptors, ie., about 1 million ganglion cells or 10 million bipolar cells. Their safety advantage relates to the fact that they are delivered using intravitreal or subretinal injections rather than requiring major intraocular surgery.

Optogenetics is the first nanotechnology-based approach Dr. Zarbin discussed. It involves transfecting neurons to express light-activated molecules linked to ion channels, which allows the neurons to initiate a synaptic signal when exposed to light.

“A potential disadvantage of this approach is that it is probably not reversible,” Dr. Zarbin said.

Two companies, Allergan and GenSight Biologics, have clinical trials underway investigating an optogenetics approach to restore sight in patients with advanced retinitis pigmentosa (RP). Both companies are using a recombinant adeno-associated viral vector to transfect retinal ganglion cells with a channelrhodopsin-2 gene. Because activation of synaptic transmission with channelrhodopsin-2 requires exposure to very bright light, patients in the GenSight study are being given special glasses to amplify the external visual stimulus to the optogenetically engineered retina.

“Development of this technology using alternative light sensing molecules such as rhodopsin is moving forward,” Dr. Zarbin said.

The second nanotechnology-based approach is known as the photoswitch. It is based on using light to induce a change in molecular configuration that leads to light-induced activation of voltage-gated ion channels and, subsequently, synaptic transmission.

Dr. Zarbin described an in vitro study done in tissue culture that provided proof of principle for the photoswitch approach using the photochromic ligand, DAD. In addition, studies in animal models showed that intravitreal injection of DAD led to a positive change in visual-guided behavior.

“A remarkable feature of the photoswitch approach using DAD is that it changes retina sensitivity to light only in areas lacking photoreceptors, but it has no effect in areas of the retina where the photoreceptors are still viable, even if the cells are not functional,” Dr. Zarbin said.

Based on this selective activity, Dr. Zarbin envisioned that the photoswitch approach could be used as an early intervention to improve peripheral vision in patients with RP when they still retain 20/20 visual acuity.

Unlike the optogenetics approach, DAD-induced light sensitivity has a relatively short half-life. Therefore, it offers reversibility and the opportunity to do dose titration.

“The amount of DAD needed may be different in different patients. The reversible nature of the treatment would permit experimenting with the dose to find the one that might work best for an individual patient,” Dr. Zarbin said. “It also allows patients to retain the option to switch to an alternative treatment should a better one become available.”

Another advantage of the photoswitch approach compared with optogenetics is that the pathway for regulatory approval of the photoswitch is probably less complex. Downsides of the current photoswitch approach using DAD are that the molecule stains the lens and vitreous, and it has relatively low light sensitivity.

The third nanoscale technology Dr. Zarbin described involves quantum dots, which are nanoparticles made of semiconductor material. When exposed to light, quantum dots can generate an electric current or a dipole moment that causes voltage-gated ion channel activation in adjacent retinal neurons and therefore synaptic transmission. Dr. Zarbin noted that quantum dots are generally toxic. They are rendered safe by applying a coating, but the coating also limits the strength of the electric current or dipole moment that can be generated.

“Coated quantum dots only generate pico amps of current, which is only one-millionth of the level thought to be needed to stimulate degenerated retina. Our concept about the amount of current that may be needed may be wrong, however, considering that results were observed using quantum dots in an animal model of an uncommon form of RP,” Dr. Zarbin said.

In the preclinical study, animals receiving ten trillion cadmium-selenium zinc oxide-biotin quantum dots by intravitreal injection demonstrated a transient increase in the scotopic ERG. Retinal histology was also found to be improved, and there were no safety signals.

The quantum dot approach also seemed to have acceptable safety in an early phase clinical trial conducted in Mexico that enrolled 20 patients with advanced RP. A clinical trial is now being planned in the United States, Dr. Zarbin said. Advantages of the quantum dot approach include reversibility-the quantum dots are rapidly cleared from the retina-and the action wavelength is tunable.

Dr. Zarbin has no financial interests relevant to the topics discussed in this article.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Research targets gene therapy for exudative AMD patients

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