Eyeing Gene Therapy’s Ocular Future

CHICAGO—The first gene therapy approved in the United States happened to be for an inherited eye disease, with an agent that is administered subretinally. But investigators are actively examining therapies for other eye-related genetic diseases and other routes of delivery. Investors, of course, are closely following the progress.

In a panel discussion here at OIS@ASRS 2019, moderator John Pollack, MD, began by asking participants to discuss the respective pros and cons of subretinal versus intravitreal and suprachoroidal injections.

Mehdi Gasmi, PhD, President and Chief Scientific Officer, Adverum Biotechnologies, said the preferred approach is usually related to the indication and the target tissues involved. For retinal structures, for example, entering through the vitreous might not be the most efficacious due to the eye’s inner limiting membrane (ILM). The ILM can impede the progress of available vectors to their target cells.
“Currently available vectors, which are largely naturally occurring adeno-associated viruses [AAVs],” he said, “were evolutionarily evolved to transduce airway epithelia and the gut; not so much retinal cells and not to cross the retinal membrane. So they [would] need to be administered subretinally.”

For some proteins produced in the vitreous, like trophic factor or antivascular endothelial growth factor (anti-VEGF), Dr. Gasmi noted, the type of cell involved is less important than the number of cells that can be stimulated to produce the desired protein.

“This is what we’ve been doing at Adverum,” Dr. Gasmi said. “We have this new vector … a chimeric vector not found in nature, which has been engineered to transduce a lot of cells in the intraocular space and the retina.” In this case, he noted, an intravitreal approach could be effective.

Steve Pakola, MD, Senior Vice President and Chief Medical Officer, Regenxbio, said the company’s AAV gene delivery platform has more than 100 novel AAV vectors. One lead program uses a new-generation AAV that has “very high tropism for the retinal layers you want to transfect such as the [retinal pigment epithelium] and the photoreceptors.”

“From our perspective,” Dr. Pakola continued, the “gold standard” delivery approach is subretinal, citing Luxturna’s approval in December 2017. Voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) is indicated for inherited vision loss due to mutations in the RPE65 gene, which can only be confirmed through genetic testing. “Now we have the benefit of actual clinical data with prolonged protein expression correlating with functional and anatomical outcomes.”

Glenn Yiu, MD, PhD, Associate Professor, University of California, Davis, discussed the differences between the three routes of injection in terms of inflammatory or immune response. “We do know in general that when you give intravitreal AAV, there’s often significant intraocular inflammation that has to be suppressed with immunosuppression. And we also noted in our experiments that for suprachoroidal [injection], there’s actually very little systemic increase in neutralizing antibodies, but a little bit more local inflammation,” he said.

From the Patient’s Perspective

Dr. Pollack, a Partner in Illinois Retina Associates, asked the panel to describe how their patients perceive gene and stem cell therapies.

Thomas Ciulla, MD, MBA, Chief Medical Officer, Clearside Biomedical, was Medical Strategy Lead-Ophthalmology for Spark. He discussed findings from Spark’s market research before the launch of Luxturna. “Some of my retina colleagues are surprised by this,” he said, “but there is a small but distinct percentage of patients with retinitis pigmentosa who were very successful and well adjusted as adults, and they did not want genetic testing nor did they want treatment. Their blindness was sort of incorporated into their life.”

Mark Humayun, MD, PhD, Professor of Ophthalmology, University of Southern California, said his experience was just the opposite. Patients are “very, very interested in getting it back. Stem cell therapy seems very intuitive to them.” He cited the 7 million Californians who voted to fund Proposition 71 in 2004, which ultimately funded research into stem-cell therapy.

Factors Impacting Physician Decisions

Dr. Pollack asked the panel to consider factors that might impact the physician’s decision to recommend gene therapy to patients, including agents that may have a longer-lasting effect or require a less frequent need for intervention.

Dr. Pakola described less-frequent injections as an “incremental benefit” that has already shown great impact. He noted how the field has moved to Eylea (anti-VEGF, Regeneron/Bayer), which requires less-frequent injections than previously available anti-VEGF therapies. He added that a similar pattern may emerge with Novartis’ Beovu (brolucizumab-Dbll). This new anti-VEGF injection for wet age-related macular degeneration received FDA approval Oct. 8. In clinical trials, Beovu was shown to sustain qualified patients with wet AMD for a dosing interval of 3 months immediately after a 3-month dosing phase.

According to Dr. Ciulla, the situation is complicated by the economics of medical practice. Although anti-VEGF treatment can be “repetitive, and a lot of doctors complain about it, it’s a huge part of their business model,” he said. “Doctors are now building new buildings, redesigning their offices, and establishing injection lanes. If you [develop] a one-and-done therapy to replace that, it’s going to disrupt their business model enormously.”

But, said Dr. Pakola: A safe and effective “one-and-done” therapy yet to be discovered may be the best possible outcome.