Novel brolucizumab fosters as real-world alternative for nAMD

October 23, 2017

Topline results from phase III studies investigating intravitreal brolucizumab (Novartis) for treatment of neovascular age-related macular degeneration (nAMD) support the potential of this novel anti-VEGF antibody to meet the real-world need for an alternative agent with a sustainable therapeutic regimen.

Topline results from phase III studies investigating intravitreal brolucizumab (Novartis) for treatment of neovascular age-related macular degeneration (nAMD) support the potential of this novel anti-VEGF antibody to meet the real-world need for an alternative agent with a sustainable therapeutic regimen.

Known as HAWK and HARRIER, the two pivotal studies enrolled more than 1,800 patients and compared brolucizumab head-to-head with aflibercept (Eylea, Regeneron). HAWK randomized patients equally into 3 groups to receive brolucizumab 3 mg, brolucizumab 6 mg, or aflibercept 2 mg, and HARRIER compared brolucizumab 6 mg and aflibercept 2 mg. All treatment arms featured an initial loading phase of 3 injections given at 1-month intervals.

Thereafter, patients continued with monthly follow-up visits, but aflibercept injections were given every 8 weeks per the product labeling, while brolucizumab dosing was extended to every 12 weeks with an option to adjust to every 8 weeks if patients exhibited disease activity based on pre-specified criteria.

More than half of the patients in the brolucizumab 6-mg groups continued to receive injections every 12 weeks through week 48. In the primary efficacy analysis that looked at mean change in best-corrected visual acuity (BCVA) from baseline to week 48, both brolucizumab 3 mg and 6 mg met the primary efficacy endpoint, demonstrating non-inferiority to aflibercept.

All arms met endpoint

All brolucizumab treatment arms also met a key secondary efficacy endpoint, demonstrating non-inferiority to aflibercept for average mean change in BCVA from baseline over the period week 36 to 48.

“Real-life experience shows that anti-VEGF injection frequency for patients with nAMD falls far below the level received by patients in clinical trials,” explained Pravin U. Dugel, MD, a HAWK investigator and chairperson of the Steering Committee. “This delta between how patients should be and are being managed suggests that there are undertreated patients who may not be doing as well in real life as those in clinical trials. This is the basis for needing a sustainable treatment strategy that reduces injection burden.

“We now have evidence from clinical trials demonstrating that brolucizumab has long-lasting efficacy versus aflibercept dosed every 8 weeks,” Dr Dugel added. “Therefore, brolucizumab holds potential as a true advance for narrowing the gap between what is occurring in real-world practice versus in the setting of clinical trials.”

Results from the 2 trials demonstrate that brolucizumab delivered robust visual gains in nAMD patients with a majority of patients on a 12-week injection interval.

“This is good news for patients,” said Fred Guerard, worldwide business franchise head, ophthalmology, Novartis, Ft. Worth, TX. “If approved, brolucizumab has the potential to address the needs of patients, by providing an efficacious treatment with a less-frequent dosing regimen. As the global leader in ophthalmology, we look forward to bringing this pioneering treatment to patients.”

Unique technology

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.”

 

Pravin U. Dugel, MD

E: pdugel@gmail.com

Dr. Dugel is a consultant for Alcon Laboratories, Novartis, Ophthotech, Genentech, and Roche.