Sales of ADC Drugs From 2020 To 2023

1. Huateng Pharma https://us.huatengsci.com Sales of ADC Drugs From 2020 To 2023 Antibody-drug conjugates (ADCs) are a new type of tumor therapy that can selectively deliver potent chemotherapy cytotoxins directly into tumor cells to exert their effects. After four generations of technical iterations, the current ADCs have the characteristics of low toxicity and can kill tumor cells in a targeted manner, while minimizing the bystander effect and ensuring the removal of tumor-adjacent cells. Up to now, 15 ADC drugs have been approved for marketing in the world, and more than 400 ADC drugs are in different stages of research and development. Among the 15 approved ADC drugs, 13 are marketed in the United States, 1 in China and 1 in Japan. Overall, the current global sales of ADC drugs on the market are showing a rapid growth trend, with growth rates of 50.66%, 31.35%, and 46.7% from 2020 to 2022, reaching a peak of $7.718 billion in 2022. The first half of 2023 continued the growth rate of the previous three years, with gratifying results, and sales totaled $4.976 billion. Among them, Enhertu and Polivy grew the most, followed by Adcetris, Trodelvy, Tivdak, and Padcev, and Kadcyla, Besponsa, and Zynlonta slowed down. Blenrep’s sales dropped sharply due to the failure of validated clinical trials (Figure 1). According to the current trend, the total global ADC drug sales are expected to exceed $10 billion in 2023, which will become another important milestone in the ADC field. Figure 1. Global ADC Drug Sales Below we will present the sales of each ADC drug in recent years.

2. Huateng Pharma https://us.huatengsci.com At present, three HER2 ADC drugs have been approved worldwide, including trastuzumab emtansine (Kadcyla), trastuzumab deruxtecan (Enhertu) and Disitamab Vedotin (Aidixi, RC48). Enhertu and Kadcyla focused on breast cancer, while Aldixi has switched to other indications and has been approved for gastric cancer and urothelial cancer. 1. Trastuzumab emtansine (Kadcyla) Kadcyla is the first approved HER2-targeting ADC drug jointly developed by Roche and ImmunoGen. It was approved by the FDA for HER2-positive metastatic breast cancer on February 22, 2013. Kadcyla, a second-generation ADC, is obtained by coupling the microtubule inhibitor DM1 to the humanized IgG1 targeting HER2 through a non-cleavable thioether linker (MCC linker). The linker of Kadcyla is non-cleavable and has no bystander effects. Compared with the first-generation ADC, the humanized monoclonal antibody is used, which is a more effective cytotoxic drug, which reduces the immunogenicity and improves the activity of toxic drugs. As the first HER2 ADC product to market, sales have been steadily coming to market since its launch, with global sales of Kadcyla reaching $2.18 billion in 2021, reaching $2.288 billion in 2022, and sales of $1.195 billion in the first half of 2023, down from last year. This is mainly due to competition between biosimilars and Enhertu (Figure 2). Figure 2. Sales of Kadcyla (Source: References[3]) 2. Trastuzumab deruxtecan (Enhertu, T-DXd, DS-8201)

3. Huateng Pharma https://us.huatengsci.com Trastuzumab (Enhertu, T-DXd, DS-8201) is an ADC drug jointly developed by AstraZeneca and Daiichi Sankyo that received accelerated FDA approval in December 2019 for third-line treatment in adult patients with unresectable or metastatic HER2-positive breast cancer who have already received two or more anti-HER2 therapies. Enhertu is a third-generation ADC drug consisting of an anti-HER2 IgG1 monoclonal antibody through a cleavable tetrapeptide linker and a cytotoxic topoisomerase I inhibitor Dxd (10 times more potent than irinotecan). Compared with Kadcyla, Enhertu has a much higher drug antibody ratio (DAR), Enhertu's DAR is as high as 8 (Kadcyla's DAR is about 3.5). The linker of Enhertu is cleavable and has a certain bystander effect. The emergence of Enhertu is a huge threat to Kadcyla. It not only overcomes the indications of gastric cancer that Kadcyla did not overcome. On January 18, 2021, Enhertu was approved by the FDA for the treatment of locally advanced or metastatic HER2-positive gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma in adults who have received trastuzumab treatment, becoming the first HER2-ADC drug approved by the FDA for the treatment of gastric cancer. Up to now, Enhertu has been approved for at least 5 tumor indications in the world: HER2 positive breast cancer, gastric cancer, gastroesophageal junction cancer, HER2 low expression breast cancer and non-small cell lung cancer. The most prominent sales growth in the first half of this year is also Enhertu, with sales as high as 1.169 billion US dollars. According to the growth rate of Enhertu in the past two years, it increased by 3450% year-on-year in 2021 and 153.52% year-on-year in 2022. It is reasonable to speculate that it will exceed Kadcyla to rank first at the end of this year beyond Kadcyla with almost no suspense. 3. Brentuximab vedotin (Adcetris) Adcetris is a CD30-targeting ADC product originally developed by Seagen (formerly Seattle Genetics) and later jointly developed with Takeda. It was approved by the FDA in 2011 for the treatment of Hodgkins lymphoma (HL) and system anaplastic large cell lymphoma (sALCL). Adcetris was approved by the European Union as a first-line treatment for CD30-expressing sALCL in 2021, becoming the world's first ADC for first-line treatment. Adcetris was approved in China on May 14, 2020 for the treatment of relapsing/refractory CD30-positive HL or sALCL, becoming the second ADC drug approved in China. Adcetris is obtained by coupling the monoclonal antibody brentuximab targeting CD30 with the cytotoxic drug tubulin inhibitor

4. Huateng Pharma https://us.huatengsci.com MMAE by dipeptide linker. The sales of Adcetris have increased steadily since its listing, reaching $1.473 billion in 2022, and $821 million in the first half of this year, showing a significant growth rate. 4. Polatuzumab vedotin (Polivy) Polivy (polatuzumab vedotin) is the first approved ADC developed by Roche that targets the B-cell antigen receptor complex associated protein beta chain (CD79b), a part of the B-cell receptor (BCR). Approved for marketing in the United States and China in June 2019 and January 2023, respectively. In April this year, the FDA approved Polivy combined with R-CHP regimen (rituximab + cyclophosphamide + doxorubicin + prednisone) for the first-line treatment of diffuse patients with malignant large B-cell lymphoma (DLBCL), making it the first new therapy approved by the FDA for the first-line treatment of DLBCL in nearly 20 years. Polivy is composed of Polatuzumab, a recombinant humanized IgG1 monoclonal antibody targeting CD79, connected to the cytotoxin MMAE (monomethyl auristatin E) through a cleavable linker mc-vc-PABC. Its DAR is 3-4 and its molecular weight is about 150kDa. Polivy's sales have steadily increased since its launch in 2019, reaching $181 million in 2020, $326 million in 2021, and $591 million in 2022, thanks to the FDA approval of Polivy in combination with R-CHP first-line therapy for DLBCL patients. Sales in the first half of 2023 amounted to CHF 353 million (approximately USD 405 million), an increase of 114% year-on-year (Figure 3). Figure 3. Sales of Polivy (Source:References[3])

5. Huateng Pharma https://us.huatengsci.com 5. Sacituzumab govitecan (Trodelvy) Trodelvy (sacituzumab govitecan) was originally developed by Immunomedics as a new ADC drug targeting Trop-2. In September 2020, Gilead acquired Immunomedics for $21 billion and incorporated Trodelvy under its umbrella. Trodelvy is obtained by coupling the humanized monoclonal antibody hRS7IgG1κ (also known as sacituzumab) to the active metabolite SN-38 of irinotecan via the hydrolyzable linker CL2A. Trodelvy was launched in the U.S. and China on April 22, 2020 and June 10, 2022, respectively, for the treatment of adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies. Since its launch, the FDA has also approved Trodelvy for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) and HR+/HER2- patients who have received endocrine therapy and received ≥2 lines of systemic therapy (for metastatic disease). The new indication for patients with unresectable locally advanced or metastatic breast cancer further expands the patient population of Trodelvy. On July 27 this year, Trodelvy was approved in the EU for the treatment of HR+/HER2-negative metastatic breast cancer. As the only Trop2 ADC currently on the market, Trodelvy has been approved for three indications in urothelial carcinoma, HR-positive breast cancer and triple-negative breast cancer. Trodelvy's first full annual performance since its launch was $380 million, mainly due to the continued increase in the proportion of TNBC and UC patients, and the approval of multiple regulatory agencies, further driving sales growth, and sales in 2022 reached $680 million , an increase of 78.9% year-on-year. In the first half of 2023, sales were $482 million, and the growth rate did not meet analysts' expectations, mainly because of the general efficacy of Trodelvy and fierce external competition, such as Enhertu, a strong competitor in the field of breast cancer. 6. Enfortumab vedotin (Padcev) Padcev (enfortumab vedotin) is the first ADC drug targeting Nectin-4, a cell surface protein highly expressed in bladder cancer, jointly developed by Seattle Genetics/Astellas. It was approved by FDA in December 2019 for the treatment of Adult patients with locally advanced or metastatic UC. Padcev was fully approved by the FDA on July 11, 2021, and the FDA also expanded its indication for locally advanced or metastatic patients who have previously received PD-1/PD-L1 inhibitor therapy and are not eligible for cisplatin therapy patients with urothelial carcinoma.

6. Huateng Pharma https://us.huatengsci.com Padcev is obtained by linking the microtubule disruptor MMAE and the Nectin-4-targeting human IgG1 monoclonal antibody enfortumab using Seattle Genetics' proprietary linking technology. It is structurally similar to Polivy except for the antibody part. Padcev only took 2 months from the submission of the listing application (BLA) to the approval, and quickly opened up the market after listing. The global sales in 2022 have reached $757 million, and the sales in the first half of 2023 reached $466 million. The growth rate is obvious. 7. Inotuzumab ozogamicin (Besponsa) Besponsa (inotuzmab ozogamicin) is an ADC drug targeting CD22 jointly developed by Pfizer/Wyeth, which was approved by the FDA in 2017 for CD22-positive B-cell acute lymphoblastic leukemia (B-ALL). Besponsa uses a recombinant humanized monoclonal IgG4 antibody (G544) with a DAR of approximately 6 that is selective for CD22 expressed on B cells in all mature B-ALL patients and >90% of precursor B-ALL patients. Sales have been flat since it went public in August 2017. Sales in 2021 was $192 million, sales in 2022 was $219 million, and in the first half of 2023, Besponsa only achieved sales of $117 million. 8. Mirvetuximab soravtansine (Elahere) Elahere (Mirvetuximab soravtansinegynx) is the first ADC drug targeting FRα developed by ImmunoGen. In November 2022, the FDA received accelerated approval for the treatment of patients who have received 1 to 3 systemic therapies and are FRα-positive and platinum-resistant adult patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Elahere couples the anti-FRα humanized monoclonal antibody M9346A to DM4 through a cleavable sulfo-SPDB linker. The cleavable linker can maintain stability in the blood stream. Elahere has grown rapidly since its launch, with sales of $107 million in the first half of the year, and is expected to exceed $500 million in the first year, mainly due to its excellent curative effect. On May 3 this year, Elahere's Phase 3 verification clinical MIRASOL obtained positive key data. The results of the study showed that compared with the chemotherapy group, the Elahere treatment group extended OS from 12.75 months to 16.46 months, and ORR increased from 15.9% to 42.3%. The PFS was extended from 3.98 months to 5.62 months, and the risk of death was reduced by 33%. As a result, the world’s first new drug that prolongs the OS of patients with platinum-resistant ovarian cancer may appear. ImmunoGen plans to submit a supplementary biological product license application in the United States in the second half of this year.

7. Huateng Pharma https://us.huatengsci.com 9. Loncastuximab tesirine (Zynlonta) Zynlonta (loncastuximab tesirine-lpyl) is a CD19-targeting ADC product developed by ADC Therapeutics. Zynlonta was approved by the FDA in April 2021 for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) who have received 2 or more systemic therapies, including diffuse large B-cell lymphoma (DLBCL), DLBCL originating from low-grade lymphoma, and high-grade cell lymphoma. Zynlonta is a humanized IgG1k mAb conjugated via a protease-cleavable valine linker to SG3199, a cytotoxic pyrrole benzodiazepine (PBD) dimer alkylating agent. The commercialization of Zynlonta has been difficult to improve since its launch in 2021. Sales in the first half of this year were $40 million U.S., not optimistic. And serious safety problems were found in the first-line therapy. After seven patient deaths and five serious safety incidents in a Phase 2 clinical trial called LOTIS-9, the company announced the suspension of the Zynlonta clinical study, which is a further setback for both Zynlonta and ADC Therapeutics. The road to future commercialization is even harder. 10. Disitamab vedotin (Aidixi, RC48) Aidixi (RC48), the first approved domestic ADC drug developed by RemeGen, was approved by the National Medical Products Administration (NMPA) on June 9, 2021 for the treatment of HER2-overexpressing locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) in patients who have received at least 2 types of systemic chemotherapy. Its antibodies, linkers and cytotoxins are different from Kadcyla and Enhertu. The antibody part of RC48 uses a new HER2 antibody independently developed by RC48, Disitamab (Disitamab), which has different HER2 epitopes from trastuzumab and has higher affinity. The cytotoxic drug of RC48 uses the tubulin inhibitor MMAE, which has higher membrane permeability than Kadcyla's DM1, and can penetrate adjacent cells to produce paracide effects after toxin release. The linker of RC48 adopts the cleavable Mc-Val-Cit-PABC linker, which has a certain bystander effect. RC48 was originally intended to compete with Roche’s Kadcyla, hoping to be a me-better drug, but it backfired. According to clinical data, RC48 has stronger blood toxicity, and 33.3% of the adverse reactions were leukopenia and neutropenia symptoms, respectively. Therefore, RC48 has avoided the approved indications of Kadcyla, and switched to gastric cancer and urothelial

8. Huateng Pharma https://us.huatengsci.com cancer. There are not so many patients. Its sales revenue in 2021 is $12 million, and its revenue in 2022 is about $72 million. Sales in the first half of this year have not been disclosed. 11. Tisotumab vedotin (Tivdak) Tivdak (tisotumab Vedotin-TFTV) is an ADC drug targeting tissue factor (TF) jointly developed by Seagen and Genmab, which was approved by the FDA in September 2021 for the treatment of recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. Tivdak is composed of human anti-TF IgG1 antibody coupled to MMAE through a protease-cleavable mc-vc-PABC linker, and its DAR is about 4. In addition, in vitro studies have shown that the ADC also mediates ADCP and ADCC effector functions, thereby providing multimodal anti tumor activity. Since Tivdak went public, its sales have risen steadily. In 2022, the sales was $62 million, and in the first half of 2023, the sales reached $41 million, showing a significant growth rate. 12. Belantamab mafodotin (Blenrep) Blenrep (Belantamab mafodotin) is an ADC product targeting BCMA developed by GSK. BCMA, also known as TNFRSF17 or CD269, is a member of the TNF receptor superfamily 17 and is highly expressed on the surface of advanced B lymphocytes and malignant plasma cells. The expression level on hematopoietic stem cells is low, and there is no expression in non-hematopoietic cells. It is a popular target for MM new drug development. Blenrep received accelerated approval from the U.S. FDA in August 2020 for the treatment of relapsed or refractory multiple myeloma (MM) who have received at least 4 prior therapies, including anti-CD38 antibodies, proteasome inhibitors, and immunomodulators. It is the world's first approved BCMA-targeted therapy for adult patients. Blenrep is a humanized, fucosylated BCMA antibody (J6MO) conjugated with a high-efficiency tubulin inhibitor maleimidocaproyl monomethyl auristatin (mcMMAF) through a non-cleavable linker maleimide diacyl. However, a Phase 3 DREAMM-3 (DRiving Excellence in Approaches to Multiple Myeloma-3) validation study of Blenrep showed that the median overall survival of the Blenrep group and the control group were 21.2 and 21.1 months, respectively. did not show a stronger effect. The product was withdrawn from the U.S. market late last year at the request of the FDA. Affected by this, Blenrep's sales in the first half of this year shrank sharply, and sales fell to $25 million.

9. Huateng Pharma https://us.huatengsci.com 13. Gemtuzumab ozogamicin (Mylotarg) There are several ADCs that did not disclose sales, presumably because of unsatisfactory sales, including Mylotarg, Lumoxiti and Akalux, which target CD33, CD22 and EGFR respectively. Mylotarg, the first approved ADC product, received accelerated approval for relapsed CD33-positive acute myeloid leukemia (AML) in 2000, but was voluntarily withdrawn from the market in 2010 after post-approval studies failed to demonstrate survival benefits and had a higher lethal toxicity rate than chemotherapy alone. However, the FDA re-approved Mylotarg in 2017 with an alternative dosing regimen of 3 mg/m2 in 3 doses (previously 1 dose of 9mg/m2) and introduced a different patient population. 14. Moxetumomab pasudotox (Lumoxiti) Lumoxiti, a CD22-targeting ADC developed by Astrazeneca, was approved by the FDA on September 13, 2018, for the treatment of adult patients with recurrent or refractory hair cell leukemia who have received at least two previous systemic therapies. However, clinical use of Lumoxiti has been very low since its launch, and Astrazeneca has filed a withdrawal application for Lumoxiti in the European Union and the United States. 15. Cetuximab sarotalocan (Akalux) Another ADC drug targeting EGFR, Akalux, developed by Rakuten Medical, did not disclose its sales. It was approved by the Ministry of Health, Labor and Welfare of Japan on September 25, 2020. It is used as a photoimmunotherapy drug to treat malignant tumors of the head and neck. This is the world's first approved photoimmunotherapy drug. Conclusion There is no doubt about the popularity of ADC drugs. In the first half of this year, the sales scale has reached nearly 5 billion US dollars, and it is expected to exceed 10 billion US dollars in the whole year. Competition in the global ADC drug market remains fierce. Compared with 2022, the ADC market structure in the first half of 2023 has been refreshed. In terms of sales ranking, Roche’s Kadcyla still dominates, Enhertu rises to second place, and Adcetris, which has been ranked second for a long time, drops to third place. In the first half of 2023, a total of two new ADC drugs reached $1 billion in sales, namely Kadcyla and Enhertu. Among them, Kadcyla has a total sales of

10. Huateng Pharma https://us.huatengsci.com $1.195 billion, followed by Enhertu with a total sales of $1.169 billion, only $26 million away from the first place. Among the single drugs, Enhertu has the most prominent growth rate. The sales volume in the first half of this year has approached last year's total sales of $1.26 billion, mainly due to its curative effect and continuous approval of indications. According to Enhertu's growth rate in the past two years (year-on-year growth of 3450% in 2021 and year-on-year growth of 153.52% in 2022), it is reasonable to speculate that it is almost no suspense to surpass Kadcyla at the end of this year and rank first. Polivy, Adcetris, Trodelvy, Tivdak, and Padcev also have significant growth rates, while Kadcyla, Bespnsa, and Zynlonta have slowed down, and Zynlonta has fatal safety problems when it hits the first-line therapy. The subsequent commercialization road is doomed to be bumpy. Confirmatory clinical failure led to withdrawal from the market in the United States and a sharp drop in sales. In general, ADC drugs for the treatment of solid tumors perform better than ADC drugs for the treatment of hematological tumors. In the future, ADCs need to further optimize their efficacy and safety, and discover more, better and safer drugs. Huateng Pharma is a leading PEG supplier supplies high-quality PEG derivatives, PEG raw materials and PEG linkers to empower our customers’ ADC and PDC discovery and development projects. References: [1].Charles Dumontet, Janice M. Reichert, Peter D. Senter, John M. Lambert & Alain Beck, Antibody–drug conjugates come of age in oncology, Nature Reviews Drug Discovery | Volume 22 | August 2023 | 641–661 [2].https://www.adcreview.com/ado-trastuzumab-emtansine-kadcyla-drug-desc ription/ [3].https://assets.cwp.roche.com/f/176343/x/418a8c95c6/irp230727.pdf [4].Juliana T. W. Tong, Paul W. R. Harris, Margaret A. Brimble and Iman Kavianinia, An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy, Molecules 2021, 26, 5847. [5].Fan Shi, Yanli Liu, Xuexiao Zhou, Pei Shen, Ran Xue & Min Zhang, Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy, DRUG DELIVERY 2022, VOL. 29, NO. 1, 1335–1344 [6].https://www.creative-diagnostics.com/news-anti-mmae-monomethyl-auristatin-e-antib odies-and-mmae-conjugates-for-pk-pd-studies-on-mmae-adc-113.htm [7].Mythili Shastry, Saya Jacob, Hope S. Rugo, Erika Hamilton, Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer, The Breast 66 (2022) 169–177.

11. Huateng Pharma https://us.huatengsci.com Related articles: [1].ADC Based Combination Therapies: Next Generation ADCs [2].ADCs Targeting the HER Family [3].FRα: Another Hot Target In The ADC Field [4].Approved Antibody–Drug Conjugates (ADCs) and In Clinical Trials