The molecular structure of brolucizumab explains its prolonged activity, and the technology itself merits notice, said Dr. Dugel, managing partner, Retinal Consultants of Arizona, Phoenix; clinical professor, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles; and physician executive director, Banner Eye Institute, Phoenix.
“Brolucizumab represents the first single-chain antibody fragment that has been successfully used therapeutically in humans,” he said.
“It has high affinity to all VEGF-A isoforms and a molecular weight of 26 kDa, which is much smaller than what has previously been studied,” Dr. Dugel outlined. “Brolucizumab can be formulated at a higher concentration. On a molar basis, a 6-mg dose of brolucizumab is about equal to 12 times the 2-mg dose of aflibercept. The smaller molecular size of brolucizumab and ability to deliver a higher molar dose should translate into advantages of better target-tissue penetration and slower clearance from the eye, resulting in longer duration of action.”
When it comes to systemic clearance, however, brolucizumab is eliminated from the systemic circulation faster than aflibercept.
“Theoretically, faster systemic clearance of an anti-VEGF agent should have a positive impact on systemic safety,” Dr. Dugel said. “Whether brolucizumab offers any advantage in this regard remains to be seen, but so far, it has had an excellent safety profile throughout its clinical development.”
Study design decisions
HAWK and HARRIER have a planned duration of 96 weeks and are being carried out at a total of 400 centers around the world. Only HAWK, which is evaluating both the 3-mg and 6-mg doses of brolucizumab, includes study sites in the United States.
“In the phase I and II brolucizumab clinical trials, both the 3-mg and 6-mg doses demonstrated biological activity and were safe and well-tolerated,” Dr. Dugel pointed out. “HAWK is investigating the 2 doses of brolucizumab to satisfy regulatory requirements in the United States.”
Dr. Dugel noted that the design of HAWK and HARRIER incorporated a treatment strategy that is consistent with real-life practice. Whereas OSPREY, the phase II study investigating brolucizumab for the treatment of nAMD, featured a fixed, 12-week dosing interval after the loading phase, the treatment frequency in HAWK and HARRIER is being adjusted based on patient response.
“I was involved with protocol development for the phase III trials,” Dugel said. “In discussions about extending the dosing interval, I voiced the importance of designing the study in a way that reflects clinical practice. That means individualizing treatment regimens based on patient monitoring and extending the injection interval only in patients whose disease activity is controlled.
“Because HAWK and HARRIER were designed in this way, their results are extremely relevant to patient care in the real world.”