Ophthalmologists face challenges of drug delivery for retinal diseases.
Reviewed by Albert J. Augustin, MD
During a recent roundtable, experts in retinal disease discussed the challenges of drug delivery for retinal diseases and investigational strategies for improving patient care and outcomes by overcoming existing issues.
Moderated by Albert J. Augustin, MD, the international panel included Jean-François Korobelnik, MD; Mariya Moosajee, MBBS, PhD, BSc, FRCOphth; and Tunde Peto, MD, PhD.
After reviewing approaches to diagnosis, which establish the indication for treatment, and patient-specific factors that may factor into therapeutic decision-making, the group reviewed the current therapeutic landscape for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, macular edema secondary to retinal vein occlusion (RVO), and inherited retinal dystrophies.
The physicians’ summaries highlighted the risks of the available modalities and their burdens for patients, caregivers, and providers.
To provide a foundation for understanding solutions to overcome the drawbacks of existing approaches, the discussion turned to barriers and unmet needs related to achieving effective drug delivery to the retina. Finally, the participants shared their perspectives on investigational therapeutics, including novel compounds and delivery systems.
The ability to prolong the treatment interval is a main goal for the development of new therapeutics for retinal diseases.
Discussing brolucizumab, which is approved in both the United States and Europe for treating exudative AMD, Korobelnik noted that clinical trial data suggest that the benefit of this anti-VEGF agent may last longer than previously available VEGF inhibitors.
However, clinical studies investigating brolucizumab were not designed to fully explore response durability, and inflammatory reactions have emerged as a potential concern in postmarketing experience, said Korobelnik, a professor and chief of ophthalmology at the University Hospital of Bordeaux in France.
He noted that despite some initial encouraging data, development has stalled for conbercept, DARPin molecules (Designed Ankyrin Repeat Proteins), and abicipar pegol because of efficacy and/or safety issues.
New agents still in development include ripasudil (Glanatec), a rho-kinase inhibitor being investigated as a treatment for diabetic retinopathy, and CLS-AX, a suspension of axitinib for suprachoroidal injection. Axitinib is a VEGF receptor tyrosine kinase inhibitor that provides pan-VEGF inhibition. This formulation is being studied for its potential to be a long-acting treatment for wet AMD.
Discussing faricimab, a bispecific antibody targeting angiopoietin-2 and VEGF-A, Peto said that it has shown promise for allowing less frequent injections in clinical trials investigating its use to treat both DME and wet AMD.
“During the first year, about one-half of patients needed repeat injections just every 4 months. We will have to wait to see if this prolonged activity holds up in the real world,” said Peto, a professor of clinical ophthalmology at Queen’s University Belfast in Northern Ireland, United Kingdom.
Korobelnik noted that phase 3 studies have been completed investigating triamcinolone acetonide suprachoroidal injectable suspension (CLS-TA) to treat macular edema associated with uveitis and RVO. Compared with intravitreal administration, this approach offers easier administration and reduced risk of intraocular infection. However, it also carries a concern for causing increased IOP, he said.
Peto discussed the refillable port delivery system with ranibizumab. The panel members noted that the agent has a practical limitation of requiring placement by a vitreoretinal surgeon and that more research is needed to understand whether there are downsides from continuous exposure to VEGF blockade.
Sustained-release systems under investigation include a microparticle depot formulation of sunitinib (Sutent), GB-102. Sunitinib is a pan-VEGF inhibitor, and GB-102 is designed to be administered by intravitreal injection twice per year.
“GB-102 has been evaluated for treatment of macular edema secondary to RVO in a phase 2A trial, and it continues to appear promising based on interim results from a phase 2B study,” said Augustin, professor and chairman of the Department of Ophthalmology at Klinikum Karlsruhe in Germany.
Patients with DME or exudative AMD are being recruited for enrollment in a safety study of an intravitreal implant providing sustained release of AR-13503, an inhibitor of rho kinase and protein kinase C. In addition, a sustained-release intravitreal implant of axitinib (OTX-TKI) is being developed as a treatment for wet AMD, DME, and RVO.
KSI-301, an intravitreal anti-VEGF biopolymer conjugate, was associated with some positive results in a phase 2 trial of DME; a phase 3 study is investigating an injection interval of up to 24 weeks.
“Of course, there is the potential for inflammation and induction of immunogenicity with the devices and compounds used for sustained release, and safety is something that everybody is looking at very carefully,” Korobelnik said.
Numerous trials are investigating gene therapy for hereditary retinal disorders, Moosajee said. Most are using adeno-associated viral (AAV) vectors, but these vectors have a packaging limit. Therefore, ongoing research aims to develop alternative approaches for delivering larger genes that include the use of dual AAV vectors and nonviral vectors.
Although the latter option has potential safety advantages compared with viral vectors, it may need to be used with microneedles, microelectroporation systems, or nanoparticles to achieve adequate transduction into target cells, said Moosajee, a professor of molecular ophthalmology at UCL Institute of Ophthalmology and a consultant ophthalmologist in genetic eye disease at Moorfields Eye Hospital in London, United Kingdom.
Investigators in gene therapy are also looking at intravitreal injection using novel AAV capsids that may provide more efficient transduction into target cells. A phase 1 clinical trial is under way using this technology to deliver the CHM gene for choroideremia, Moosajee said. Gene therapy for RPE65 retinopathy with voretigene neparvovec is now an approved treatment worldwide.
“The hope is that work being done with delivery systems in AMD and diabetic eye disease can be applied to our field and allow gene delivery through intravitreal injection that would have fewer risks and reach more parts of the retina,” she concluded.