Pravin U. Dugel, MD: Conversations in Age-Related Macular Degeneration

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Neovascular AMD

Pravin U. Dugel, MD

What up-and-coming therapies for wet AMD are you most excited about and why?

The therapies currently being investigated for neovascular age-related macular degeneration (nvAMD) can be stratified into 3 silos: better short-term efficacy, better long-term efficacy, and increased durability. The majority of drugs in the pipeline have focused on the latter.

Several next-generation anti-VEGF-A drugs are either recently approved or in phase 3 clinical trials. Brolucizumab (Beovu) is the first single strand antibody fragment approved in ophthalmology. The HAWK and HARRIER studies met their primary endpoint of non-inferiority at week 48 with a majority of patients dosed q12 weeks, compared to aflibercept on label (q8 on maintenance). However, and most importantly, brolucizumab demonstrated superior results in OCT analyses, suggesting better disease control. This drug was FDA approved last month. Abicipar pegol is a DARPin derivative that has demonstrated long durability in early clinical trials. Importantly, this is the only drug that showed effective q12 week dosing for all patients with a shortened loading phase in its phase 3 Cedar and Sequoia trials. However, an intraocular inflammation rate of 15% was also noted. Thereafter, the MAPLE study was done to specifically examine the intraocular inflammation rate after a manufacturing modification. The rate of intraocular inflammation in the MAPLE study was 9% and most patients were said to have mild inflammation without loss of vision. Conbercept will likely be the first FDA approved drug manufactured in China. In preclinical studies it has the most favorable binding characteristics of all the drugs mentioned. Whether this translates into improved clinical efficacy will be determined by the ongoing PANDA phase 3 trials. Interestingly, this drug has already been approved by the Chinese FDA and is being prescribed in China. Finally, faricimab is a bi-specific drug capable of simultaneously inhibiting VEGF-A and Ang2. There is evidence to show that Ang2 interacts with VEGF-A and causes vascular leakage, inflammation, and angiogenesis. Therefore, the simultaneous inhibition of both targets makes sense in achieving immediate and long-term effects. The phase 2 AVENUE and STAIRWAY studies demonstrated the possibility of greater durability. This is being evaluated in ongoing phase 3 studies.

In addition to the next generation anti-VEGF drugs described above, an existing anti-VEGF drug, ranibizumab, is being placed in a passive drug delivery device in the phase 3 ARCHWAY trial. This consists of a surgical procedure to place the drug in a bladder-like passive elution device that can be refilled in the office. The phase 2 trial (LADDER) demonstrated a median duration to a refill of 15 months.

Many exciting early phase studies look promising. Opthea, OPT-302, is a VEGF-C and VEGF-D inhibitor which, when combined with a VEGF-A inhibitor, will allow for pan-VEGF inhibition. Studies in oncology and ophthalmology have shown that suppression of VEGF-A may upregulate VEGF-C and VEGF-D which may account for sub-optimal outcomes. The recent phase 2 study of Opthea shows encouraging results. Hopefully, this drug will soon be in phase 3 trials. Additionally, Kodiak, KSI-301, is developing an anti-VEGF compound embedded in an optically clear phosphoryl choline infrastructure that allows for increased durability. Graybug, GB-102, has modified its manufacturing and demonstrated encouraging results for its tyrosine kinase inhibitor, sunitinib, in PLGA microparticles giving long-term durability. Panoptica, PAN 01-102, is a topical tyrosine kinase inhibitor in phase 2 clinical trial. Alkahest, AKST-4290, has recently completed trials for an oral CCR3 inhibitor that shows a good safety profile and biologic signal. Asclepix, ATX-107, is an integrin inhibitor in pre-clinical studies that will simultaneously inhibit VEGF-A and activate Tie-2, while forming a gel that may last for more than 1 year.

Finally, gene therapy for nvAMD may be in our not-too-distant future. Regenxbio, RGX-314, has demonstrated excellent results using a specific AAV-8 vector that produces an anti-VEGF protein delivered surgically into the sub-retinal space. The company has recently announced that it is investigating a supra-choroidal delivery of the same product as well. Adverum, ADVM-022, also produces an anti-VEGF-A protein akin to aflibercept which can be injected intravitreally in the office. The recent results suggest encouraging long-term effects with a reduction in OCT thickness.

Clearly, we are in an exciting time with regard to the development of new treatment options for nvAMD.