Gene therapy now on two separate paths

Drug production in the eye is a new goal.

Until recently, efforts to employ gene therapy in the retina subspecialty focused on inherited retinal diseases and the replacement of defective genes with healthy ones.

“This concept has best been exemplified by Spark Therapeutics and its one-time therapy Luxturna to replace mutated RPE65 genes, which was approved by the FDA late last year,” says Pravin Dugel, MD, of Retinal Consultants of Arizona. “Now, we have a second effort in gene therapy that has moved into clinical trials in the past year. This is a totally different concept and essentially an attempt to create a miniature drug factory in the eye to continuously produce gene-derived anti-VEGF medication to combat retinal disease.”

Dr. Dugel says the idea of continuous drug production in the eye through gene-derived drug therapies delivered via a single injection has potential, but it also faces major challenges and a number of unknowns that will only be resolved as clinical trials progress. Among the challenges he cites are disease variability in individual patients that could result in undertreatment or overtreatment, controlling the effects of a long-term drug production process that cannot be reversed and possible side effects that could lead to atrophy, fibrosis and possible upregulation of damaging VEGF-C and VEGF-D. Also unknown are the effects, good or bad, of constant anti-VEGF elution vs. our current pulsatile injection strategies. However, Dr. Dugel feels strongly that these challenges will be met with more scientific data in the near future, and he remains enthusiastic about gene therapy as a potential “game changer.”


Recently, RegenxBio released new data on its 18-patient Phase 1 clinical trial of RGX-314, a gene-driven, one-time treatment designed to continuously produce anti-VEGF to combat wet AMD for many years — and possibly for life. RegenxBio reported that its highest-dosed cohort (six patients) in this dose-escalation trial had an encouraging response that included a mean 8-letter gain in BCVA and a mean reduction of -14 µm in central retinal thickness. Three of the six patients were in what the company called a “difficult to treat” study group and had previously required frequent retreatment; these patients required no anti-VEGF injections at six months following a single injection of RGX-314.

The data from the highest-dosed cohort showed great improvement over the two lower-dosed cohorts. The company has recently completed dosing a fourth cohort with an even higher dose of RGX-314.

“This is the first reported wet AMD gene therapy study to detect intraocular protein being made in the eyes of all subjects. I am encouraged by the dose-dependent increases in protein and biological effect seen in the study that correlated with signals of efficacy,” said Jeffrey Heier, MD, co-president and director of Retina Research at Ophthalmic Consultants of Boston and primary investigator for the trial.

Gene therapy-derived anti-VEGF, if proven feasible, could greatly reduce the retreatment burden for a range of retinal diseases.

If the concept is eventually approved — and it’s a long route to approval — this new form of one-time drug delivery could play a huge role in reducing the treatment burden of regular injections and examinations that impacts both every patients and retina practices. RegenxBio uses its proven NAV AAV8 gene vector to encode an antibody fragment that inhibits VEGF, modifying the pathway that would have formed new leaky blood vessels and caused vision loss.


But RegenxBio is not the only company pursuing the concept of continuous, gene-derived anti-VEGF therapy for wet AMD. Adverum has recently begun its first clinical trial using a slightly different approach with its vector-derived ADVM-022. Adverum uses intravitreal delivery of replicated aflibercept, while RegenxBio employs a subretinal administration of a replicate of gene-derived ranibizumab.

“We believe that subretinal administration is the most direct route to get a higher level of anti-VEGF to where it needs to go while avoiding neutralizing antibodies,” says Stephen Yoo, chief medical officer of RegenxBio. “One of the major issues in anti-VEGF therapy has been undertreatment. The people we have in the clinical trial are individuals who have responded to anti-VEGF and who have had at least four injections in the past eight months. We want to make sure that they get a dose that will prove effective.”

Adverum has chosen intravitreal delivery because the company believes that retina specialists are more comfortable with that form of drug administration.

“We recently announced an active Investigational New Drug (IND) for ADVM-022 and a Fast Track designation,” says Leone Patterson, BS, MBA, Adverum CEO and president. “We are excited to be moving this program toward clinical development in patients.”

Ms. Patterson commented that ADVM-022 therapy induced long-term efficacy at 13 months that was comparable or identical to aflibercept. The intraocular expression of aflibercept was sustained for up to 16 months; robust levels of aflibercept protein were likewise detected up to 16 months in aqueous and vitreous humor and, more importantly, in retina and choroid tissues where neovascularization occurs in wet AMD. For safety, ADVM-022 was well tolerated with no serious adverse events.


One of the major challenges of gene-derived continuous drug production is that individuals respond differently to anti-VEGF therapy, with some needing more frequent retreatment and others requiring less medication.

Because the drug production cannot be turned off once started, not everyone with wet AMD may be a candidate for this form of drug delivery. But it may be possible to vary the amount of drug production to meet the needs of different patient cohorts, the companies say.

Paul A. Yates, MD, PhD, associate professor of ophthalmology at the University of Virginia, agrees that many challenges lay ahead.

“There are some big issues here,” he asserts. “One, what’s the transduction efficiency in human eyes; two, what’s the sustained expression level over time and is it therapeutically efficacious; and three, are there any concerns about use of an anti-VEGF switch you can’t turn off. This is the Goldilocks problem. Does a constitutive expression approach get us to ‘just right?’ With the treat-and-extend approach, we essentially personalize the therapy to the patients’ needs.”

Dr. Yates says monthly treatment patients (RVO and recalcitrant wet AMD) could benefit most from long-term inhibition of VEGF. In addition, it may also prevent proliferative disease progression for severe NPDR patients.

But there is still the question of whether constitutive anti-VEGF may precipitate retinal atrophy.

“I suspect the FDA will want to know the answer to that question from any clinical trials forthcoming,” he notes. “We are a long, long way from an actual new therapeutic here.”

“Reducing the treatment burden is a real unmet need,” concludes Dr. Yoo. “And that’s our main goal is pursuing this concept.” OM