BEOVU reduces retinal fluid, provides long dosing intervals.

For almost a decade, ophthalmologists have had a choice of two FDA-labeled anti-VEGF drugs to treat patients with neovascular (wet) AMD: ranibizumab (Lucentis, Genentech) or aflibercept (Eylea, Regeneron). With the October 2019 FDA approval of BEOVU (brolucizumab-dbll, Novartis), clinicians now have access to a new option.

BEOVU injection is the first FDA-approved anti-VEGF to provide the ability to maintain wet AMD patients on a 3-month dosing interval immediately after a 3-month loading phase, according to Novartis. The recommended dose is 6 mg (0.05 mL of 120 mg/mL solution) monthly (approximately every 25 to 31 days) for the first three doses, followed by one dose of 6 mg (0.05 mL) every 8 to 12 weeks, according to the prescribing information.

“It’s nice to have another option for our patients to help them control their disease and hopefully extend the interval between their treatments,” says Arshad Khanani, MD, MA, managing partner and director of clinical research, Sierra Eye Associates, Reno, Nev. “This can lead to better compliance due to a decreased treatment burden, as the number of clinic visits will hopefully be fewer.”

Dr. Khanani, who was an investigator for the Phase 3 HAWK clinical trial, notes that the most recent FDA-approved drug for neovascular AMD was Eylea in November 2011.

STUDY RESULTS

Approval of BEOVU, says Novartis, was based on findings from the Phase 3 HAWK and HARRIER clinical trials. HAWK and HARRIER were global, randomized, double-masked Phase 3 clinical trials of 1,459 adults with wet AMD carried out over 2 years. In those trials, the drug demonstrated non-inferiority vs. aflibercept in mean change in BCVA at year 1 and approximately 30% of patients gained at least 15 letters at year 1.

What’s more, in both trials, BEOVU showed greater reduction in central subfield thickness as early as week 16 and at year 1, and fewer patients had intraretinal or subretinal fluid.

“The important thing was that the HAWK and HARRIER studies were designed as non-inferiority studies in terms of visual acuity as the primary outcome,” says Pravin U. Dugel, MD, managing partner, Retinal Consultants of Arizona and clinical professor, Roski Eye Institute, Keck School of Medicine, University of Southern California. Dr. Dugel was principal investigator of the HAWK clinical trial. “Brolucizumab achieved the primary outcome of non-inferiority vs. aflibercept in visual acuity at week 48 in both HAWK and HARRIER, and that was despite the fact that over 50% of patients on brolucizumab were being treated every 12 weeks.”

Two results provide confidence in the validity of the studies, says Dr. Dugel. First, outcomes are consistent not only in HAWK and HARRIER but also in earlier studies on brolucizumab. Second, results occurred in a dose-dependent manner.

A GAME-CHANGING MOLECULE

Structurally, BEOVU is a single-chain antibody fragment. As such, it consists of the “business end” of the antibody that binds to the target, resulting in a very small molecule (26 kilodaltons), allowing for a much larger drug concentration to be delivered to the target. Creating such a molecule has been “extremely challenging,” says Dr. Dugel.

Novartis, he says, has created in BEOVU the first single-strand antibody fragment approved not just for the eye, but in all of medicine. Because of the molecule’s small size and “because it’s a single-strand antibody fragment, there’s a lot more of the drug that can penetrate to the target a lot faster and at a lot higher molar concentration,” explains Dr. Dugel.

Although both Eylea and BEOVU have the same volume, as a smaller molecule with 6 mg of dosing, BEOVU provides about 12 times equivalent molar dosing compared to 2 mg of Eylea, says Dr. Khanani.

ANATOMIC OUTCOMES

Anatomic outcomes, in terms of OCT results, were also consistent across all Phase 2 and 3 studies, says Dr. Dugel. “The anatomic outcomes were superior no matter how you measured them for brolucizumab vs. aflibercept, and that’s even when there were more patients who were on Q12. What this tells us is that brolucizumab will allow for better disease control than the other drugs we currently have.”

“Brolucizumab appears to be better in terms of drying the retina and lasting longer than Eylea based on data from HAWK and HARRIER studies,” adds Dr. Khanani.

REDUCING FLUCTUATION

Besides these results, an additional positive finding for BEOVU involved OCT fluctuations.

“There appears to be much more OCT fluctuation with aflibercept as opposed to brolucizumab,” says Dr. Dugel.

However, no research had shown that fluctuation had any impact on vision, he notes. To determine whether there was an impact, the HAWK and HARRIER researchers began a post-hoc analysis. Prior to completing it, other independent researchers in Ireland found that the greater the OCT fluctuations, the worse the patients did in eventual vision outcomes. Researchers then applied that methodology to HAWK and HARRIER and “quite amazingly we showed exactly the same type of results,” said Dr. Dugel.

GOING LONGER

“I think we’ll use this drug the same way that we use our current drugs,” says Dr. Dugel. “We’ll be able to have more patients have better disease control, so we’ll have more patients who can be extended longer and have better outcomes.” OM