With the launch of fam-trastuzumab-deruxtecan-nxki (Enhertu®), Daiichi Sankyo’s first antibody-drug conjugates, coupled with a strong pipeline of innovative ADC, the company has established a strong foundation of a new unified oncology business unit aligning the markets in the United States and Europe. An increase in investment, as well as a strategic collaboration with AstraZeneca, is expected to further bolster the company’s global oncology footprint.

Trastuzumab deruxtecan, which was approved in Japan in September 2020, received additional approval by the U.S. Food and Drug Administration (FDA) for its second indication of gastric cancer in January 2021. The drug was initially approved for the treatment of patients with unresectable or metastatic HER2-positive breast cancer in the United States, Japan, and Europe respectively. It is being further evaluated in nine registrational trials for additional HER2 cancer indications, including breast, gastric and lung cancers.

Pipeline
Datopotamab deruxtecan (DS-1062, Dato-DXd) and patritumab deruxtecan (U3-1402, HER3-DXd) are two antibody-drug conjugates in the company’s growing pipeline. Bith investigational drugs are Phase II clinical trials. In addition, Daiichi Sankyo is developing five other deruxtecan-based ADCs*, as well as additional second-generation ADCs, new concept ADCs, bispecific antibodies, and gene and cell therapies.

Datopotamab deruxtecan is Daiichi Sankyo’s proprietary trophoblast cell-surface antigen 2 (TROP2)-directed ADC and potential new medicine for the treatment of multiple tumor types that commonly express the cell-surface glycoprotein TROP2, which is overexpressed in the majority of non-small cell lung cancers and breast cancers.[1][2][3][4]

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Patritumab deruxtecan is a novel, investigational, HER3-directed ADC that consists of the patritumab antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. The drug’s target, HER3, is expressed in more than 80% of EGFR-mutant non–small cell lung cancer (NSCLC). Overexpression of HER3 is generally associated with poor outcomes.

Accelerated approval
The FDA accelerated approval of trastuzumab deruxtecan was, based on the DESTINY-Breast01 trial (NCT03248492), a multicenter, single-arm trial enrolling 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies.

“Daiichi Sankyo got a strategic breakthrough with trastuzumab-deruxtecan becoming the fastest FDA approved biologic in oncology through the accelerated approval program within two months of submission based on its registrational Phase II study data. Although its current oncology foundation is based on three highly potential ADCs, including trastuzumab, it is trying to build up new growth drivers by conducting additional lifecycle management studies and diversifying its pipeline to gain a ‘competitive advantage in oncology’,” noted Sasmitha Sahu, Pharma Analyst at GlobalData.

Daiichi Sankyo established its new oncology business unit in April 2021. Subsequently, the company announced in its 5-Year Business Plan (FY2021‒FY2025) that it expects to achieve a target of ¥ 1.6 trillion (US $ 14bn), including ¥ 600 bn (US $ 5.5bn) by FY2025.**

The company expects that it can successfully achieve this goal by increasing its oncology product share over non-oncology products to 95% in the United States and 45% in European markets. The strategic targets outlined in the 2016-2020 5-Year Business Plan were achieved with the international market entry of its first ADC therapy trastuzumab-deruxtecan in 2020.

“Daiichi Sankyo Cancer Enterprise unit was involved in its ADC oncology pipeline advancement through strategic planning and prioritization. The new business unit establishment will now deal with the commercial aspects of the oncology businesses following product launches, mainly in the US and European markets where it expects to gain significant market share,” Sahu added.

Investment
Furthermore, which ranks second in Japan in terms of R&D investment and is the fifth-largest company in Japan in terms of revenue with annual revenue of US $ 9bn in FY2020the company will invest over ¥ 1.5 trillion (US $ 13.8bn) in its three ADCs through 2025. It has also invested ¥ 15bn (US $ 135m) in manufacturing facilities for ADCs.

Strategic partnership
Daiichi-Sankyo has entered into a new co-development and collaboration agreement with AstraZeneca for datopotamab deruxtecan and a clinical trial collaboration for patritumab deruxtecan and osimertinib (Tagrisso®) combination in metastatic non-small cell lung cancer.

“Building on the successful outcomes for trastuzumab collaboration with AstraZeneca, Daiichi-Sankyo is trying to expand its global outreach by entering into a further series of collaborations with AstraZeneca, which is one of the top global oncology players. Barring offsets caused by litigation, augmented R&D and manufacturing investments, and strategic alliances will collectively drive Daiichi Sankyo’s oncology revenues,” Sahu said.

Commenting on the strategic collaboration, Pascal Soriot, Chief Executive Officer, noted: “We see significant potential in […] antibody-drug conjugates in lung as well as in breast and other cancers that commonly express TROP2. We are delighted [to] build on the successful launch of Trastuzumab deruxtecan to further expand our pipeline and leadership in Oncology. We now have six potential blockbusters in Oncology with more to come in our early and late pipelines.”

“[Our] strategic collaboration with AstraZeneca, a company with extensive experience and significant expertise in the global oncology business, will enable us to deliver Datopotamab deruxtecan to more patients around the world as quickly as possible. As we have done with Trastuzumab deruxtecan, we will jointly design and implement strategies to maximize the value of Datopotamab deruxtecan,” said Sunao Manabe, Representative Director, President, and Chief Executive Officer of Daiichi Sankyo.

Litigation
Daiichi Sankyo is facing litigation with Seagen over its ADC technology. In 2020 Seagen filed a court complaint against Daiichi Sankyo over its cancer-focused drug delivery technology. In the latest case, filed in the U.S. District Court of the Eastern District of Texas, Seagen claims that trastuzumab deruxtecan, Daiichi Sankyo’s first antibody-drug conjugates, violates Seagen’s patents related to the company’s own ADC-technology.

The case, filed on October 19, 2020, is separate from the ongoing arbitration brought by Seagen against Daiichi Sankyo over the ownership of the ADC technology. Seagen claims that the technology used in trastuzumab deruxtecan was supplied to Daiichi Sankyo as part of a seven-year collaboration.

In turn, on November 13, 2020, Daiichi Sankyo filed an intellectual property patent lawsuit against Seagen. This case was filed in U.S. District Courts, Delaware District. [5][6]

Note
* Deruxtecan, the payload used in Daiichi Sankyo’s ADCs, is an exatecan derivative (DX-8951 derivative, DXd), that has the characteristics of low membrane permeability and shows considerably less myelotoxicity than that shown by exatecan mesylate, which is an extensively modified derivative of camptothecin, but has an additional alicyclic ring fused to rings A and B that bears a solubilizing primary amine (an equivalent to a 7-CH2NH2 substituent on camptothecin). Deruxtecan is about 2.5-fold more potent than SN38,  the active metabolite of irinotecan). [7]

** At the time of publication, ¥ 1 = US $ 0.0092

Clinical trials
A Study of DS-8201a in Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine (T-DM1) – NCT03248492

Highlights of prescribing information
Fam-trastuzumab-deruxtecan-nxki (Enhertu®; Daiichi Sankyo)[Prescribing Information]
Osimertinib (Tagrisso®; AstraZeneca)[Prescribing Information]

Reference
[1] Inamura K, et al. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. Oncotarget. 2017; 8 (17): 28725-28735. [Article]
[2] Zhao W, et al. Trop2 is a potential biomarker for the promotion of EMT in human breast cancer. Oncol Rep. 2018; 40 (2): 759-766.[Article] .
[3] Zaman S, et al. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019; 12: 1781-1790.[Article]
[4] Zeng P, et al. Impact of TROP2 expression on prognosis in solid tumors: A Systematic Review and Meta-analysis. Sci Rep. 2016; 6: e33658.[Article]
[5] Seagen Inc. v. Daiichi Sankyo Co., Ltd. Justia Dockets. Online Last accessed on May 19, 2021.
[6] Daiichi Sankyo Co., Ltd. v. Seagen Inc. UniCourt. Online. Last accessed on May 19, 2021
[7] Denny WA. Anti Cancer: DNA Topoisomerase Inhibitors; Reference Module in Chemistry, Molecular Sciences and Chemical Engineering, 2013, Pages 111 -128. https://doi.org/10.1016/B0-08-045044-X/00206-6 [Article]

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