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There is subset of patients with resistant or persistent DME that forms the impetus for new treatment strategies, including next-generation anti-VEGF-A and new classes of drugs. Pravin U. Dugel, MD, outlines a list of potential treatment candidates that may lead that paradigm shift.
By Michelle Dalton, ELS;Reviewed by Pravin U. Dugel, MD
There is no denying that the anti-vascular endothelial growth factor A (anti-VEGF-A) monotherapy has “absolutely revolutionized our treatment of diabetic macular edema (DME).” However, there is a subset of patients in whom the anti-VEGFs are not an optimal treatment, according to Pravin U. Dugel, MD.
That subset of patients “with resistant or persistent disease” form the impetus for new treatment strategies, including next-generation anti-VEGF-A and new classes of drugs, said Dr. Dugel, managing partner, Retinal Consultants of Arizona, Phoenix, and clinical professor, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles.
Here is a list of potential treatment candidates that may lead that paradigm shift:
Brolucizumab (Alcon Laboratories/Novartis) represents “the smallest active unit of antibody that allows for concentrated molar dosing: 22 times that of ranibizumab (Lucentis, Genentech) and more than 11 times that of aflibercept (Eylea, Regeneron Pharmaceuticals),” Dr. Dugel said.
Two phase III studies compared brolucizumab to aflibercept in patients with neovascular age-related macular degeneration (AMD), with non-inferiority found for the primary endpoint and superiority in key retinal health outcomes.
“DME trials with brolucizumab are currently being planned,” Dr. Dugel said.
Abicipar pegol (Allergan) belongs to a new class of genetically engineered antibody mimetic proteins (designed ankyrin repeat proteins, or DARPins). Its small size and high potency, coupled with stability and solubility, makes this protein a viable potential treatment for both AMD and DME. Results from the phase IIb PALM trial (n = 151) showed that abicipar pegol injected every 8 or 12 weeks for DME offered comparable functional and anatomical effects to ranibizumab injected monthly.
Conbercept (Khanghong Biotech) is a soluble receptor decoy that blocks all isoforms of VEGF-A, VEGF-B, VEGF-C, and placental growth factor (PlGF), which has a high-binding affinity for VEGF-A and a long half-life in vitreous. DME studies have been initiated, and the drug is approved for the treatment of wet AMD in China.
In both the Frontier study and the Sailing study, conbercept has shown “an improvement in visual acuity with a concomitant decrease as measured by optical coherence tomography (OCT),” Dr. Dugel said. Additional DME trials are currently being planned.
Dr. Dugel stressed the importance of understanding the mechanism of action in these compounds.
“In times of health, angiopoietin-1 (Ang1) is secreted at a basal rate,” Dr. Dugel explained. “This maintains a stable vasculature by activating the Tie2 receptor (TEK receptor tyrosine kinase). In times of ill health, an angiogenic switch occurs and Ang2 is up regulated.”
Ang2 is a weak agonist that effectively functions as an antagonist “that attracts pro-angiogenic and inflammatory cytokines and is oftentimes coupled with the up regulation of VEGF-A that causes increased permeability and angiogenesis,” he added.
RG7716 (Genentech/Roche) is a bi-specific molecule that “will simultaneously inhibit Ang2 as well as VEGF-A,” Dr. Dugel said. This compound features “two important genetic engineering feats,” one to increase systemic clearance and the other to decrease inflammation.
The BOULEVARD phase II study is evaluating 2 different doses of RG7716 with ranibizumab 0.3 mg. It has a 20-week treatment period followed by up to 16 weeks of observation.
(Editor’s note: A second Ang2 compound (nesvacumab) was being developed by Regeneron/Bayer. However, since Dr. Dugel’s presentation, the companies noted the antibody failed to meet primary endpoints in 2 phase II trials and will not move forward.)
OPT-302 (Opthea) blocks both VEGF-C and VEGF-D. Phase I/IIa studies for wet AMD have already been completed. The company is enrolling patients in a phase IIb trial for AMD and a phase Ib/IIa trial for patients with DME.
Allegro Ophthalmics is developing Luminate, an integrin antagonist.
“Luminate is a first-in-class molecule for ophthalmology that binds to specific integrin receptor sites and effects multiple angiogenic pathways and inflammation,” Dr. Dugel said. “The Del Mar Phase IIb study has recently been read-out, looking for signs of increased durability as well as efficacy.”
In that study, patients who did the best were patients who had been treated sequentially first with an anti-VEGF-A agent followed by Luminate, he said.
“But perhaps what was most impressive is that the patients who really drove the study were patients who were previously resistant to anti-VEGF-A mono-therapy,” Dr. Dugel said. “This suggests that such patients may benefit most from this drug.”
KVD001 (KalVista Pharmaceuticals) is a plasma kallikrein inhibitor “as a VEGF-independent mediator of DME,” Dr. Dugel said. A phase I open-label study looked specifically at patients who were treatment-resistant to anti-VEGF A monotherapy and showed improvement with a single injection. The phase II study is expected to be underway shortly.
KalVista has granted Merck an option to acquire KVD001 after the phase II proof-of-concept study is completed. Merck also has a similar option to acquire investigational orally delivered molecules for DME that KalVista also is developing.
Clearside Biomedical is developing triamcinolone acetonide injection in the suprachoroidal space. The company is investigating a single injection of CLS-TA alone and in combination with aflibercept in 10 treatment-naïve subjects and in 10 non-treatment-naïve subjects.
The HULK open-label, multicenter, phase I/II study showed a visual benefit for patients receiving CLS-TA “with a greater benefit in the treatment-naïve eyes,” Dr. Dugel said.
According to the company, anatomic improvement was observed in all treated eyes, with more than 66% of those eyes achieving >50% reduction in excess central retinal thickness based on monthly measurements through 6 months after initial treatment. Of the treatment-naïve eyes, 40% did not need re-treatment during the 6-month study, and 20% needed one re-treatment.
Aerpio Pharmaceuticals has taken “an entirely different approach of pre-empting the development of DME with AKB-9778,” Dr. Dugel said. AKB-9778 is a Tie-2 activator that is self-administered via the subcutaneous route. The TIME-2 proof-of-concept study showed AKB-9778 as a monotherapy improved diabetic retinopathy (DR) by 2 or more steps in the DR severity scale.
“More than 10% of patients had a regression in both eyes–not just one eye–with the subcutaneous injection,” he said.
Although the anti-VEGF drugs “have revolutionized the treatment of DME, a large unmet need remains,” Dr. Dugel said. There is “great opportunity to change our treatment paradigm by the next generation of anti-VEGF A drugs and combination drugs currently in development.”
Pravin U. Dugel, MD
This article was adapted from a presentation Dr. Dugel delivered at Retina Subspecialty Day held prior to the 2017 American Academy of Ophthalmology meeting.