Ranibizumab is approved for new indications, tens of billions of anti-VEGF biosimilars are gearing up
August 23, 2021
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 after retinal vein occlusion (RVO), diabetic macular edema (DME) and choroidal neovascular disease (CNV). Ranibizumab is a VEGF receptor inhibitor. VEGF inhibitors can inhibit vascular endothelial cell proliferation, vascular penetration and cardiovascular production by binding to and blocking VEGF receptors. Ranibizumab, Conbercept and Aflibercept are three classic VEGF inhibitors used to treat fundus diseases, and the three-legged competition is stable. Data show that China's anti-VEGF monoclonal antibody biosimilar drug market is expected to reach 9.9 billion yuan in 2030. Looking to the future, biosimilar drugs, innovative drugs and innovative double antibodies are about to enter the battlefield one after another. What kind of competitive landscape will the three drugs usher in, and how will the track change?
Ranibizumab patent is about to expire, generic drugs are gearing up
The brand name of ranibizumab is Nuo Shide, which was jointly developed by Roche and Novartis. Roche has the commercialization rights of ranibizumab in the United States, while Novartis has the exclusive rights to countries and regions outside the United States. As a new type of vascular endothelial growth factor inhibitor, ranibizumab can inhibit angiogenesis and reduce vascular permeability through antagonism, so as to promote the rapid absorption of intraretinal fluid and improve the visual quality of patients. Ranibizumab is about to usher in the cliff of patents, and generic drugs are eager to try. In 2006, ranibizumab was approved by the FDA for marketing, and has been approved for wet wAMD, RVO, DME, mCNV and other indications in the world. In 2020, ranibizumab achieved sales of US$3.377 billion, a year-on-year decline of 13.67%. Specifically, the US market fell 16%, and markets outside the US fell 7%. According to Roche's financial report, the main reason for the decline of ranibizumab in 2020 is the impact of COVID-19, and some patients delay or cancel treatment. But what is more worrying is the approaching patent period of ranibizumab. The patent of ranibizumab will expire in the second half of 2021. Biogen and Samsung jointly developed SB11 (a biosimilar of ranibizumab). The BLA was submitted to the FDA at the end of 2020, and it is expected to formally "war" against Nostal in 2022. It is worth mentioning that the structures of ranibizumab and bevacizumab are very similar, and both are developed by Genentech, but the price gap between the two is significant. In 2005, bevacizumab was launched at a price of only US$460, while the price of ranibizumab, which was one year late, was as high as US$1,600, which was nearly four times the price of bevacizumab. Therefore, considering the price disparity between the two, some ophthalmologists and patients abroad use bevacizumab to treat ophthalmic diseases including AMD, and even a paper published by the National Institutes of Health in the New England Journal of Medicine. It is pointed out that ranibizumab and bevacizumab have the same efficacy in maintaining vision in AMD patients. Of course, Roche has never started a clinical trial of bevacizumab ophthalmic indications. It was originally from the same root. Since ranibizumab has a better profitability, why bother with bevacizumab?
Figure: Global sales of ranibizumab (US$100 million)
Data source: Roche, Novartis
It is worth mentioning that with the first-mover advantage, the sales of Leibizumab in the country have been surging. In 2011, ranibizumab was approved for marketing by NMPA, and the first indication wAMD was included in medical insurance in 2017. In 2019, DME, RVO, CNV and other indications were included in the national medical insurance category B catalog. In 2019, ranibizumab achieved sales of 1.16 billion yuan in China. However, similar to the global competitive landscape, ranibizumab also faces the impact of biosimilar drugs in China. Qilu Pharmaceutical’s QL1205 entered Phase III clinical trials in July 2019. It is expected to be approved for listing at the end of 2021, and the first imitation will challenge Nuoxet. Of course, the payment of ranibizumab into the medical insurance fund needs to meet some conditions. If angiography or OCT is required, a maximum of 9 payments per eye, and a maximum of 5 payments in the first year, aflibercept, ranibizumab, and Compaq Consolidated calculation of Xipu counts. In addition, the approved diabetic retinopathy has not yet been included in the medical insurance, and it is expected to be included in the national medical insurance category B list as soon as the end of the year.
Compaq is going to sea difficultly. How is the internationalization progress going?
Compaqcept is a fusion protein of VEGF receptor and human immunoglobulin Fc gene recombination developed by Kanghong Pharmaceutical. It is a recombinant fusion protein produced by the Chinese Hamster Ovary (CHO) cell expression system. Conbercept can effectively bind to VEGF in blood vessels and tissues, and block VEGF-mediated signal transmission that promotes the sprouting and growth of new blood vessels. In March 2014, Conbercept was approved for listing, and has been approved for wAMD, pmCNV and DME. In 2017, Conbercept reduced its price by 17% and included it in medical insurance, and the indication was wAMD. In 2019, it was downgraded by 25% again, and the medical insurance negotiation was renewed to include all three indications. Since its listing, Compaq has become the main driving force for the growth of Kanghong Pharmaceutical's performance. From a market perspective, data shows that in 2019, Conbercept achieved sales of 1.155 billion yuan, with a market share of 46%, which is slightly lower than the 48% of ranibizumab, and the two are equally indistinguishable. In order to further expand the market, Compaq chose to go overseas. However, the road to the sea can be described as mixed. On the one hand, in June 2020, Conbercept's wAMD indication was awarded the Mongolian drug registration certificate, marking the successful export of Conbercept; on the other hand, in April 2021, Kanghong Pharmaceutical Stopping the global multi-center clinical trial of Conbercept ophthalmic injection, more than half of the subjects had a change from baseline to zero or even less than zero after the injection. This event eventually led to the direct cut of Kanghong Pharmaceutical's stock price. The uneven road of Conbercept's internationalization, can it continue to break through the two competing products of aflibercept and ranibizumab in the future, and what is the next step in the internationalization process? Wait and see!
Three advantages of Aflibercept catching up with ranibizumab
Aflibercept is similar in structure to Conbercept and is a completely human fusion protein. Aflibercept was jointly developed by Regeneron and Bayer, and Bayer was responsible for markets outside the United States. In 2011, it was approved by the FDA for marketing. Compared with ranibizumab, aflibercept has three significant advantages. First, aflibercept is a fully human fusion protein that can block VEGF-A, VEGF-B and PGF at the same time, and has a better target. Wide; Second, it can effectively bind to VEGF dimer, with higher affinity; Third, it has a longer action time and a longer-lasting effect. The injection interval can be extended to 3 to 4 months. Therefore, after aflibercept was listed, it quickly eroded the ranibizumab market, and its market share continued to increase. In 2015, aflibercept's global sales surpassed ranibizumab for the first time, and the gap between the two gradually widened. In 2020, aflibercept's global sales reached 7.91 billion US dollars and ranibizumab was only 3.377 billion US dollars.
Figure: Aflibercept's global sales (US$100 million)
Data source: Bayer, Regeneron
In 2018, aflibercept was approved by the NMPA for marketing, and has been approved for indications such as DME and nAMD. In 2019, aflibercept was included in medical insurance, and the price dropped to 4,100 yuan per stick. Due to the late launch time, aflibercept has a low domestic market share, which is far lower than ranibizumab and conbercept. Although the three currently present a competitive pattern of "two supers and one strong", judging from the global development path, the three pillars will become the general trend in the future.
Future Trends Anti-VEGF price war is on the verge
In the ophthalmic medicine market, apart from the Big Three, the subdivision track is still surging. In the future, as biosimilar drugs, innovative anti-VEGF drugs and innovative double antibodies join the battlefield, competition in the anti-VEGF market may become fierce, and price wars are inevitable. Biosimilar drugs: Qilu Pharmaceutical has in-depth deployment of ranibizumab biosimilars and aflibercept biosimilars. In addition to QL1205 mentioned above, QL1207 is a biosimilar of aflibercept, and the current indications for wAMD are in clinical phase III. In addition, Shanghai and Searle have deployed ranibizumab biosimilars, and Shandong Boan and Huabo Biologicals have deployed aflibercept biosimilars. Of course, considering that the patent of ranibizumab will expire at the end of 2021 and the patent of aflibercept will expire in 2024-2025, the marketization of biosimilar drugs will take time, but the time left for the original research drug is indeed longer. The less come. Innovative drugs: Biotech, Sansheng Guojian and other companies have focused on the deployment of innovative anti-VEGF drugs. Among them, Biotec's BAT5906 has the leading clinical progress, and both wAMD and DME indications are in clinical phase II. From the analysis of pharmacodynamics, BAT5906 is a complete IgG1 antibody drug with stable antibody structure. From the perspective of safety, although BAT5906 has an Fc domain, it does not have ADCC and CDC effects. It is safer for intravitreal injection. Innovative double antibodies: Innovent Biologics is deeply engaged in the research and development of double antibodies. IBI302 is an anti-VEGF and anti-complement dual target specific recombinant fully human fusion protein, currently in clinical phase I. The N-terminal of IBI302 can bind to the VEGF family, block VEGF-mediated signaling pathways, inhibit the survival and proliferation of vascular endothelial cells, thereby inhibit angiogenesis and reduce vascular permeability; the C-terminal can specifically bind C3b and C4b to inhibit The activation of the classical and alternative pathways of complement reduces the inflammatory response mediated by complement, so as to achieve the purpose of treating and controlling AMD.
