Lucentis Gains New Indications as Billion-Dollar Anti-VEGF Biosimilars Gear Up for Market Entry

Recently, Novartis' ranibizumab was approved for new indications, including retinopathy of prematurity (ROP) and diabetic retinopathy (DR). Previously approved indications include wet age-related macular degeneration (wAMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), and choroidal neovascularization (CNV).

Ranibizumab is classified as a VEGF receptor inhibitor. VEGF inhibitors function by binding to and blocking VEGF receptors, thereby suppressing vascular endothelial cell proliferation, vascular permeability, and neovascularization. Ranibizumab, conbercept, and aflibercept are three classic VEGF inhibitors for the treatment of retinal diseases, establishing a stable tripartite competitive landscape. Data indicates that China's anti-VEGF monoclonal antibody biosimilar market is projected to reach RMB 9.9 billion by 2030. Looking ahead, as biosimilars, innovative drugs, and novel bispecific antibodies sequentially enter the market, what competitive landscape will these three drugs face, and how will the therapeutic track evolve?

Ranibizumab Patents Set to Expire

Generics Gear Up

Ranibizumab, marketed under the brand name Lucentis, was co-developed by Roche and Novartis. Roche holds the commercialization rights for ranibizumab in the United States, while Novartis holds exclusive rights in countries and regions outside the United States. As a novel vascular endothelial growth factor (VEGF) inhibitor, ranibizumab inhibits neovascularization via antagonism, reduces vascular permeability, and thereby promotes the rapid absorption of intraretinal fluid and improves patients' visual quality.

Ranibizumab is approaching its patent cliff, with biosimilar developers gearing up and poised to enter the market. Approved by the FDA in 2006, ranibizumab has since gained global approval for multiple indications, including wet age-related macular degeneration (wAMD), retinal vein occlusion (RVO), diabetic macular edema (DME), and myopic choroidal neovascularization (mCNV). In 2020, ranibizumab generated $3.377 billion in sales, marking a 13.67% year-on-year decline. Specifically, sales dropped by 16% in the U.S. market and 7% in markets outside the U.S. According to Roche's financial reports, the primary reason for the 2020 decline was the impact of the COVID-19 pandemic, which caused some patients to delay or cancel their treatments. However, a more pressing concern is the impending patent expiration; ranibizumab's patents are set to expire in the second half of 2021. SB11, a ranibizumab biosimilar co-developed by Biogen and Samsung, submitted a Biologics License Application (BLA) to the FDA in late 2020 and is expected to officially challenge Lucentis in 2022.

It is worth noting that ranibizumab and bevacizumab share a highly similar molecular structure and were both developed by Genentech, yet there is a substantial price disparity between them. Bevacizumab was launched in 2005 at a price of just $460, whereas ranibizumab, which reached the market a year later, carried a steep price tag of $1,600—nearly four times that of bevacizumab. Given this stark price difference, some ophthalmologists and patients overseas have opted to use bevacizumab for the treatment of ocular diseases, including age-related macular degeneration (AMD). Notably, a study sponsored by the U.S. National Institutes of Health and published in *The New England Journal of Medicine* also indicated that ranibizumab and bevacizumab demonstrate comparable efficacy in preserving vision for AMD patients. Naturally, Roche has never initiated clinical trials for the ophthalmic indications of bevacizumab. Since both agents share the same origin, and ranibizumab clearly offers greater profitability, Roche has had little strategic incentive to develop bevacizumab for eye conditions, thereby avoiding internal market cannibalization.

Figure: Global Sales of Ranibizumab (in hundred million USD)

Data source: Roche, Novartis

Notably, leveraging its first-mover advantage, ranibizumab has experienced robust sales growth in China. Following its NMPA approval in 2011, its first indication, wAMD, was added to the national medical insurance catalog in 2017. By 2019, indications including DME, RVO, and CNV were also listed under Category B of the National Medical Insurance Catalog. In 2019, ranibizumab generated RMB 1.16 billion in domestic sales. However, mirroring the global competitive landscape, the drug faces mounting pressure from biosimilars in the Chinese market. Qilu Pharmaceutical’s biosimilar candidate QL1205 entered Phase III clinical trials in July 2019 and is poised for approval by late 2021, positioning it as the first biosimilar to challenge the originator brand, Lucentis.

Certainly, reimbursement for ranibizumab under the medical insurance fund is subject to certain conditions, such as the requirement for angiography or optical coherence tomography (OCT). The maximum cumulative coverage is limited to 9 vials per eye, with a cap of 5 vials in the first year. The vial counts for aflibercept, ranibizumab, and conbercept are calculated collectively. Additionally, the newly approved indication for diabetic retinopathy is not yet covered by medical insurance, but is expected to be included in the National Medical Insurance Class B Catalog by the end of the year at the earliest.

Conbercept's Challenging Global Expansion

What is the path forward for international expansion?

Conbercept is a recombinant fusion protein developed by Kanghong Pharmaceutical, genetically engineered by fusing a VEGF receptor with the Fc fragment of human immunoglobulin. It is manufactured using a Chinese Hamster Ovary (CHO) cell expression system. Conbercept effectively binds to VEGF in the vasculature and tissues, thereby blocking VEGF-mediated signal transduction that promotes neovascular sprouting and growth. Approved for market launch in March 2014, it has currently received regulatory approval for wet age-related macular degeneration (wAMD), pathologic myopia choroidal neovascularization (pmCNV), and diabetic macular edema (DME). In 2017, following a 17% price reduction, it was included in the national medical insurance list for the wAMD indication. In 2019, after a further 25% price cut through renewed medical insurance negotiations, coverage was extended to all three indications.

Since its market launch, Conbercept has rapidly emerged as the primary driver of Kanghong Pharmaceutical’s performance growth. Market data indicates that in 2019, Conbercept generated RMB 1.155 billion in sales, capturing a 46% market share, slightly trailing Ranibizumab’s 48%, with the two products being closely matched. To further expand its market reach, Kanghong pursued an overseas strategy for Conbercept. However, this international expansion has yielded mixed results. On one hand, in June 2020, Conbercept obtained a drug registration certificate in Mongolia for the wet age-related macular degeneration (wAMD) indication, marking its successful entry into the overseas market. On the other hand, in April 2021, Kanghong Pharmaceutical suspended the global multicenter clinical trial for Conbercept ophthalmic injection after data revealed that over half of the subjects exhibited a change from baseline equal to or less than zero following injection. This development ultimately caused Kanghong Pharmaceutical’s stock price to be halved.

Conbercept’s path to internationalization has been anything but smooth. Can it continue to break through against its two competitors, aflibercept and ranibizumab, in the future? And how should it navigate the next steps of its global expansion? Only time will tell!

Three Major Advantages of Aflibercept

Surpassing Ranibizumab

Aflibercept shares a similar structure with conbercept and is a fully human fusion protein. Jointly developed by Regeneron and Bayer, with Bayer responsible for markets outside the United States, it received FDA approval for marketing in 2011. Compared with ranibizumab, aflibercept boasts three significant advantages: first, as a fully human fusion protein, it can simultaneously block VEGF-A, VEGF-B, and PlGF, offering a broader target spectrum; second, it effectively binds to VEGF dimers with higher affinity; and third, it exhibits a longer duration of action and more sustained therapeutic efficacy, allowing the dosing interval to be extended to 3–4 months. Consequently, following its market launch, aflibercept rapidly eroded ranibizumab's market share, with its own market share continuously rising. In 2015, global sales of aflibercept surpassed those of ranibizumab for the first time, and the gap between the two gradually widened thereafter. By 2020, global sales of aflibercept reached $7.91 billion, while ranibizumab's sales stood at only $3.377 billion.

Figure: Global Sales of Aflibercept (in 100 million USD)

Data Source: Bayer, Regeneron

In 2018, aflibercept received NMPA approval for commercialization and was subsequently approved for indications including DME and nAMD. In 2019, it was included in China’s national medical insurance reimbursement list, with its price reduced to 4,100 RMB per vial. Due to its later market entry, aflibercept’s market share in China remains relatively low, significantly trailing that of ranibizumab and conbercept. Although the current competitive landscape among the three is characterized by a "two-leader, one-strong-competitor" dynamic, global development trends indicate that a tripartite market equilibrium will inevitably become the prevailing pattern in the future.

Future Trends

Anti-VEGF Price War Poised to Erupt

In the ophthalmic drug market, alongside the three-way rivalry among the top giants, niche segments continue to see intense competitive undercurrents. In the future, as biosimilars, innovative anti-VEGF therapeutics, and novel bispecific antibodies enter the market, competition in the anti-VEGF sector is poised to intensify, making a price war inevitable.

Biosimilars: Qilu Pharmaceutical has strategically positioned itself in the development of ranibizumab and aflibercept biosimilars. In addition to the aforementioned QL1205, QL1207 is an aflibercept biosimilar currently in Phase III clinical trials for the wet age-related macular degeneration (wAMD) indication. Furthermore, Shanghai United Sier is developing a ranibizumab biosimilar, while Shandong Boan Biopharmaceutical and Huabo Biotech are pursuing aflibercept biosimilars. Naturally, given that the ranibizumab patent expires at the end of 2021 and the aflibercept patents expire between 2024 and 2025, the commercialization of these biosimilars will still require time. However, the remaining market exclusivity for originator drugs is indeed steadily shrinking.

Innovative Drugs: Companies such as Bio-Thera and 3SBio have strategically prioritized the development of innovative anti-VEGF drugs. Among them, Bio-Thera's BAT5906 leads in clinical progress, with both wAMD and DME indications currently in Phase II clinical trials. From a pharmacodynamic perspective, BAT5906 is a full-length IgG1 antibody drug with a stable structure; from a safety standpoint, although it possesses an Fc domain, it exhibits no ADCC or CDC activity, demonstrating a favorable safety profile for intravitreal injection.

Innovative Bispecific Antibody: Innovent Biologics has strategically advanced its R&D in bispecific antibody therapeutics. IBI302 is a dual-target specific recombinant fully human fusion protein directed against VEGF and the complement system, currently in Phase I clinical trials. The N-terminus of IBI302 binds to the VEGF family, blocking VEGF-mediated signaling pathways and inhibiting the survival and proliferation of vascular endothelial cells, thereby suppressing angiogenesis and reducing vascular permeability. The C-terminus specifically binds to C3b and C4b, inhibiting the activation of the classical and alternative complement pathways and mitigating complement-mediated inflammatory responses, thereby achieving the treatment and control of AMD.

Managing Editor: Sanqi

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