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Brolucizumab Gets FDA Approval for Wet AMD

For most patients, 3-month dosing is achievable.

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The FDA has approved Beovu intravitreal injection (brolucizumab-dbll; Novartis), also known as RTH258, for the treatment of wet AMD. Novartis said Beovu is the first FDA-approved anti-VEGF to offer both greater fluid resolution vs aflibercept (Eylea; Regeneron) and the ability to maintain most wet AMD patients on a 3-month dosing interval immediately after a 3-month loading phase with proven efficacy. 

The long-awaited approval in a competitive marketplace represents a step forward in both durability and fluid reduction when compared to the existing approved treatments for wet AMD. Beovu intravitreal injection is an advanced humanized single-chain antibody fragment. Single-chain antibody fragments are highly sought after in drug development due to their small size, enhanced tissue penetration, rapid clearance from systemic circulation, and drug delivery characteristics. The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms.1-3

"With BEOVU, greater fluid reduction was demonstrated through larger decreases in retinal thickness and a higher proportion of patients with drier retinas. Coupled with the potential to treat patients with quarterly injections, this approval may change the way we approach the treatment of wet AMD," said Pravin U. Dugel, MD, of Retinal Consultants of Arizona and principal investigator of the HAWK clinical trial, in a news release.

The Beovu approval was based on findings from the large-scale, phase 3 HAWK and HARRIER clinical trials, in which Beovu demonstrated non-inferiority versus aflibercept in mean change in BCVA at year 1. In both clinical trials, approximately 30% of patients gained at least 15 letters at year 1. In HAWK and HARRIER, Beovu showed greater reduction in central subfield thickness (CST) as early as week 16 and at year 1, and fewer patients had intraretinal and/or subretinal fluid. Retinal fluid is a key marker of disease activity.4

Novartis says the Beovu molecule is engineered to deliver the highest concentration of drug, providing more active binding agents than other anti-VEGFs. By inhibiting VEGF, Beovu suppresses the growth of abnormal blood vessels and the potential for fluid leakage into the retina.

"The product labels of existing treatments state that they are not as effective when dosed every 12 weeks,” said Marie-France Tschudin, President, Novartis Pharmaceuticals, in a news release. “Beovu is the first to offer less-frequent dosing in the first year of therapy while maintaining its effectiveness.”

In HAWK and HARRIER, eligible patients could be maintained on a 3-month dosing interval immediately after the loading phase. At year 1, more than half the patients were maintained on the 3-month dosing interval (56% in HAWK and 51% in HARRIER). The remaining patients in the study were treated on a 2-month dosing schedule.

Beovu exhibited an overall safety profile comparable to aflibercept. Beovu is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to brolucizumab or any of the excipients in Beovu. Hypersensitivity reactions may manifest as rash, pruritus, urticaria, erythema or severe intraocular inflammation.5 The most common adverse events (≥5% of patients) with Beovu were vision blurred, cataract, conjunctival hemorrhage, vitreous floaters, and eye pain.

Novartis recently announced it is initiating the 692-patient, 64-week, phase 3b TALON trial for brolucizumab in wet AMD, matching its investigational drug against aflibercept. TALON will match a 6-mg dose of brolucizumab against a 2 mg dose of aflibercept, with the primary endpoints being average change in BCVA and “distribution of the last interval with no disease activity” (durability).
 
References

  1. Nimz EL, Van’t Land CW, Yáñez JA, Chastain JE. Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates [ARVO abstract 4996]. The Association for Research in Vision and Ophthalmology (ARVO) annual meeting. 2016. 
  2. Escher D, et al. Single-chain antibody fragments in ophthalmology. Presented at EURETINA congress. 2015. Abstract.
  3. Gaudreault J, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration [ARVO meeting abstract]. Invest Ophthalmol Vis Sci. 2012;53:3025.
  4. Arnold J, et al. The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration--a phase IV randomised clinical trial with ranibizumab: the FLUID study. BMC Ophthalmol. 2016;143(4):679-680.
  5. Beovu prescribing information. East Hanover, NJ. Novartis: 2019.