In early October, Novartis received FDA approval for the Beovu (brolucizumab) injection, previously known as RTH258, for treating neovascular age-related macular degeneration. Significantly, brolucizumab allows for three-month dosing intervals after a three-month loading phase. Some hope that fewer patients may be lost to follow-up with brolucizumab since fewer doses are required, compared to current anti-VEGF agents which have four-week dosing periods. The frequency of a monthly injection often creates a burden for patients suffering from chronic conditions.
Brolucizumab is a single-strand antibody fragment that works by delivering a high concentration of drug to the target area, explains Pravin U. Dugel, MD, managing partner at Retinal Consultants of Arizona and clinical professor at the Roski Eye Institute, Keck School of Medicine, University of Southern California. Dr. Dugel was the principal investigator in Novartis’ HAWK trial of brolucizumab, and consults for the company. “For a long time, single-strand antibody fragments couldn’t be developed because of aggregation and solubility issues,” Dr. Dugel notes. “But a company in Zurich called Esbatech developed a way to make single-strand antibody fragments that overcame the solubility and aggregation challenges.” Esba-tech was later acquired by Alcon.
The small size of single-strand antibody fragments is the key to brolucizumab’s effectiveness, Novartis says, since it allows for enhanced tissue penetration and drug delivery, and provides more active binding agents than other anti-VEGFs. “Brolucizumab is very small—only 26 kDa—and can be delivered to the target at about 12 times the molar concentration of Eylea,” Dr. Dugel explains. “This means is that there’s much more drug where we need it.”
The Phase III HAWK and HARRIER studies were randomized, double-masked multicenter head-to-head trials for patients with wet AMD; they included more than 1,800 patients across nearly 400 centers around the world. The studies were designed to compare the efficacy and safety of brolucizumab 6 mg (both studies) and 3 mg (HAWK only) versus aflibercept 2 mg in patients with wet AMD. Brolucizumab met its primary endpoint of noninferiority versus aflibercept in mean change in best-corrected visual acuity at year one, despite the fact that more than half of the patients were treated every 12 weeks, compared to every eight weeks with Eylea during the maintenance phase, says Dr. Dugel.
In the Phase III clinical trials, brolucizumab produced a greater reduction in central subfield thickness and subretinal fluid than aflibercept. Looking ahead to how clinicians might employ the new treatment, Dr. Dugel says, “We’ll probably use it the same way we use current drugs, which is mainly the treat-and-extend strategy.”
Dr. Dugel explains that OCT was used as a biomarker in the Phase III studies for measuring retinal thickness and checking for the presence of fluid as a sign of disease activity. “The OCT [scans are] the only objective biomarker for disease activity we have,” he says. “We base our decisions to treat or not to treat mainly on the OCT.”
In the HAWK and HARRIER studies, more fluctuations in the OCT data were observed with Eylea than with brolucizumab, says Dr. Dugel. “Fluctuations seen on OCT may be an indication of disease control,” he adds. “Analyses in two separate level 1 studies (CATT and IVAN) found that in a dose-dependent manner, the more fluctuations you have in the OCT, the worse your vision. Novartis repeated this analysis in the HAWK and HARRIER studies and found the same thing. All of these analyses were agnostic of the drug, so now we’ve got four level-one studies (CATT, IVAN, HAWK and HARRIER) with evidence that, in post hoc analyses, the more fluctuations you have—that is, the less disease control you have—the worse your vision will be.” Observers point out, however, that differences in mean OCT fluctuations are only potentially meaningful if all arms are getting the same, fixed dosing regimen. Because the brolucizumab arm is a blended q8/q12 with patients changing from 12 to eight weeks at various time points over the course of the study, that alone may smooth the mean OCT curve and blunt the fluctuations that may or may not be present, so one can’t really can’t claim fluctuation differences with certainty in HAWK and HARRIER.
Brolucizumab is contraindicated in patients with ocular or periocular infections and active intraocular inflammation, according to Novartis. Dr. Dugel reports that no significant adverse side effects or events turned up in the studies.
The most common adverse events (occurring in 5 percent of patients) included blurred vision, cataract, conjunctival hemorrhage, vitreous floaters and eye pain, but Dr. Dugel notes that “none of these were out of line with other anti-VEGF side effects. There are always some adverse events with any biologic,” he says.
The next step for brolucizumab will likely involve the drug being used to treat wet AMD patients who still have fluid despite their current treatment regimen. Dr. Dugel says the first patients who will get this drug will probably be the ones that physicians have treated for six months or a year without fluid resolution. “We’ll see if brolucizumab can offer better disease control,” he says. “The Phase III studies weren’t done on these types of patients, but we’ll also use brolucizumab in the clinic on treatment-naïve patients, as we did in the studies.”
Dr. Dugel says we can look forward to additional study results for brolucizumab. A head-to-head study versus Eylea for macular degeneration called MERLIN is currently recruiting patients, and a treat-and-extend study called TALON is also recruiting. For its use in diabetes, KITE and KESTREL are ongoing, says Dr. Dugel. “We have more data for brolucizumab than any other drug I know at launch, so we won’t have to guess or extrapolate too much.” REVIEW