Novartis' Brolucizumab Nears FDA Approval, Poised to Disrupt the VEGF Inhibitor Market

Original: Dopine

In April this year, Novartis used a priority review voucher to accelerate the Biologics License Application (BLA) for brolucizumab in the treatment of wet age-related macular degeneration (wet-AMD), shortening the review cycle from the standard 10 months to 6 months. An FDA response is expected in October. If brolucizumab is successfully approved, it will become the fourth VEGF inhibitor drug approved by the FDA for the treatment of wet-AMD, following Pegaptanib, Lucentis, and aflibercept, and is expected to enter the market by the end of this year. Evaluate Pharma previously predicted that its global sales could reach $1.32 billion in 2024.

Brolucizumab is a humanized single-chain antibody fragment (scFv) with a molecular weight of 26 kDa. Its small fragment size and strong penetrability confer potent inhibitory activity and high affinity against vascular endothelial growth factor A (VEGF-A) isoforms. Novartis’s submission of the Biologics License Application (BLA) for brolucizumab was primarily based on two Phase 3, prospective, randomized, double-blind, multicenter clinical trials named HAWK and HARRIER. These studies enrolled 1,800 patients with wet age-related macular degeneration (wet AMD) from 400 centers worldwide and aimed to compare the efficacy and safety of intravitreal injections of brolucizumab (6 mg and 3 mg [the 3 mg dose only in the HAWK trial]) versus aflibercept (2 mg) in patients with neovascular AMD (nAMD). Patients were randomly assigned to either the brolucizumab group or the aflibercept group. Following a 3-month loading phase, patients in the brolucizumab group received dosing every 12 weeks or every 8 weeks depending on disease activity, whereas patients in the aflibercept group received dosing every 8 weeks (every 2 months). The primary endpoint of both studies was the non-inferiority of brolucizumab to aflibercept, as measured by the mean change in best-corrected visual acuity (BCVA) from baseline to Week 48.

These two trials prospectively demonstrated the efficacy of an innovative q12w/q8w dosing regimen at 48 weeks, with most patients initiating the q12w regimen immediately after the loading doses. In the HAWK and HARRIER studies, 57% and 52% of patients, respectively, who initiated the q12w regimen immediately after the loading period maintained this regimen through week 48. Data from both studies at 48 weeks indicated that brolucizumab met the primary efficacy endpoint of non-inferiority to aflibercept in terms of the mean change in best-corrected visual acuity (BCVA) from baseline to week 48. Furthermore, brolucizumab demonstrated superiority over aflibercept in three secondary endpoints related to key indicators of nAMD disease progression: central retinal thickness, retinal fluid (intraretinal and/or subretinal fluid), and disease activity. Specifically, a lower proportion of patients in the brolucizumab (6 mg) group exhibited disease activity compared to the aflibercept group, and there was a significant reduction in key markers of retinal fluid in the brolucizumab (6 mg) group. At 96 weeks, patients in the brolucizumab 6 mg group continued to show reductions in retinal fluid and central retinal thickness, while maintaining non-inferiority to aflibercept in BCVA, thereby reaffirming the treatment outcomes observed at 48 weeks (see table below for specific data).

The HAWK and HARRIER studies are the first and only global head-to-head clinical trials to prospectively demonstrate the significant efficacy of brolucizumab initiated with a dosing regimen of once every 12 weeks (once every 3 months) in patients with wet AMD. Given its advantages in the treatment of wet AMD, brolucizumab is expected to rapidly capture market share and compete with other VEGF inhibitors.

On Wet AMD and Other VEGF Inhibitor Drugs Approved by the FDA

Wet AMD, or wet age-related macular degeneration, also known as neovascular AMD (nAMD), is a leading cause of severe vision loss and blindness in the elderly, affecting approximately 20–25 million people worldwide. Without timely treatment, it can lead to significant visual impairment within two years. Traditional treatments, such as laser photocoagulation and photodynamic therapy, can slow disease progression but inevitably damage healthy tissue. With continuous breakthroughs in fundus treatment methods, vascular endothelial growth factor (VEGF) inhibitors have emerged, opening new avenues for the treatment of wet AMD and becoming the first-line therapy preferred by most ophthalmologists.

Prior to this, the VEGF inhibitor drugs approved by the FDA for the treatment of wet AMD included pegaptanib sodium, co-developed by Eyetech Pharmaceuticals and Pfizer; Lucentis, developed through a collaboration between Genentech (a Roche subsidiary) and Novartis; and aflibercept from Regeneron (see table below).

Pegaptanib is the first VEGF inhibitor approved for the treatment of neovascular eye diseases. As a chemically synthesized oligonucleotide sequence, it exhibits high affinity for vascular endothelial growth factor (VEGF), thereby inhibiting angiogenesis and suppressing the formation of new blood vessels. The drug is administered via intravitreal injection at a dose of 300 μg every six weeks. However, if there is no significant therapeutic response after two consecutive injections, discontinuation of treatment should be considered. Although pegaptanib sodium was the first to be marketed, its market performance has been suboptimal due to limited efficacy. To enhance its competitiveness, clinical studies are currently underway to evaluate its adjunctive use in the treatment of diabetic retinopathy.

Lucentis is a humanized therapeutic antibody fragment co-developed by Genentech, a member of the Roche Group, and Novartis. It was approved for marketing in the United States in 2006. Lucentis shares the same mechanism of action as Avastin (bevacizumab), differing only by the absence of the Fc region. Avastin was the first approved anti-VEGFA monoclonal antibody and is used off-label for ophthalmic diseases. Through more than a decade of innovation, Lucentis has demonstrated excellent clinical performance, not only halting disease progression but also improving or restoring patients’ vision. It is now marketed in over 110 countries worldwide for the treatment of up to seven indications: wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), choroidal neovascularization secondary to pathologic myopia (mCNV), choroidal neovascularization (CNV) due to other causes, and retinopathy of prematurity (ROP). Moreover, Novartis and Roche continue to explore the potential of Lucentis for treating the youngest and most vulnerable patient populations. Lucentis was approved for marketing in China in 2011. In 2017, global sales of Lucentis reached USD 3.407 billion, ranking it 27th among global pharmaceutical products by sales revenue. In 2018, its global sales amounted to USD 3.719 billion, moving its rank up to 23rd.

Eylea was co-developed by Regeneron and Bayer. Regeneron holds exclusive rights to Eylea in the United States, while Bayer holds exclusive marketing rights in countries and regions outside the United States. Eylea is a recombinant fusion protein composed of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc fragment of human immunoglobulin G1. It neutralizes VEGF-A, VEGF-B, and PlGF, whereas Lucentis is solely an anti-VEGF-A antibody. Currently, Eylea has four approved indications in the United States: wet age-related macular degeneration (wet AMD), macular edema (ME) secondary to retinal vein occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR). Furthermore, Eylea was approved in China in 2018 for the treatment of DME in adults. Due to its convenience of administration, Eylea outperformed Lucentis, surpassing it in market share within four years of launch and firmly securing the leading position in the treatment of fundus diseases via inhibition of angiogenesis. As one of the best-selling products globally, Eylea achieved global sales of $5.856 billion in 2017, ranking 10th among global pharmaceutical products by sales revenue. In 2018, its global sales reached $6.746 billion, ranking 9th globally.

As evident from the above sales data, Eylea holds a dominant position in the VEGF inhibitor market. However, brolucizumab is expected to gain approval smoothly and rapidly capture market share in the ophthalmic disease sector, leveraging advantages such as prolonged duration of action, superior efficacy, and less frequent dosing, thereby challenging Eylea’s leading status in the VEGF inhibitor market. Furthermore, Roche is developing a novel intraocular drug delivery system, ranibizumab PDS (ranibizumab port delivery system), to address the limitations of Lucentis. These developments will further intensify competition in the wet AMD segment of the VEGF inhibitor market.

References:

[1] Regeneron Scores New Approval for Eylea Four Days After an FDA Rejection

[2] Novartis announces FDA filing acceptance and Priority Review of brolucizumab (RTH258) for patients with wet AMD