Brolucizumab Overview

Introduction of Brolucizumab

Brolucizumab (RTH258) is the first and only single-chain variable fragment (scFv) targeting vascular endothelial growth factor (VEGF)-A. It has a smaller molecular weight (26 kDa). The mAb is undergoing evaluation as a treatment for neovascular age-related macular degeneration (nAMD). In June 2017, Novartis announced that the primary efficacy endpoint of non-inferiority to aflibercept (EYLEA®) in mean change in best-corrected visual acuity from baseline to week 48 was met in the Phase 3 HAWK (NCT02307682) and HARRIER (NCT02434328) studies, which included more than 1,800 patients. The two studies compared the efficacy and safety of intravitreal injections of 6 mg brolucizumab or 3 mg brolucizumab (HAWK study only) versus 2 mg aflibercept in patients with nAMD. Of patients receiving 6 mg brolucizumab, 57% (HAWK) and 52% (HARRIER) were maintained exclusively on an every 12 week dosing interval immediately following the loading phase and continuing through week 48.54 Key secondary endpoints were also met. Novartis is developing a competitive, low cost of goods formulation, and expects to complete the PK study with antibody derived from the final manufacturing process to enable filing in 2018.

Mechanism of Action of Brolucizumab

Angiogenesis is the process by which new vessels are created from pre-existing vasculature. Increased rates of angiogenesis are associated with several disease states, including cancer, age-related macular degeneration (AMD), psoriasis, rheumatoid arthritis, and diabetic retinopathy. AMD is a multifaceted disease characterized by early subclinical changes at the choroidea-retinal pigment epithelium interface. Vascular endothelial growth factor (VEGF) is an important modulator of angiogenesis, and has been implicated in the pathology of a number of conditions, including AMD, diabetic retinopathy, and cancer. VEGF belongs to a family of dimeric glycoproteins within the superfamily of PDGFs. While VEGF, also known as VEGF-A, is the most comprehensively studied, other members of this family include VEGF-B, VEGF-C, VEGF-D, and PLGF. VEGF-A has several isoforms that arise from alternative splicing. All VEGF ligands bind to tyrosine kinase receptors, causing the receptors to dimerize and autophosphorylate. Upon binding to its receptor, VEGF initiates a cascade of signaling events that begins with auto-phosphorylation of both receptor kinases, followed by activation of numerous downstream proteins, including phosphoinositide-3-kinase (PI3K), the Ras GTPase activating protein, Ras, mitogen-activated protein kinase (MAPK), and others. VEGF-A binds to VEGF receptor (VEGFR)-1 and VEGFR-2. VEGF promotes the growth, migration, and proliferation of endothelial cells. In addition, VEGF induces vasodilatation and enhances endothelial cell survival. These biologic activities occur in few physiologic processes outside wound healing and ovulation, making VEGF an attractive target for therapy. Brolucizumab binds to VEGF-A, and thereby inhibits the binding of VEGF-A to its receptors, neutralizing the biological activity of VEGF-A and regressing the vascularization, thereby inhibiting the AMD process.

Fig.1 Mechanism of action of brolucizumab

Table 1. Clinical Projects of Brolucizumab*

What We Provide

Therapeutic Antibody

Brolucizumab

We provide high-quality Brolucizumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

Reference
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Brolucizumab

For research use only. Not intended for any clinical use.