Editing Daiichi Sankyo Company, Limited (section)

== Products ==
The company specialises in a diverse array of pharmaceutical goods, with drugs devoted primarily for oncological and cardiovascular treatment, with its 2 flagship products being '''ENHERTU®''' a HER2 directed antibody drug conjugate (ADC) used in the treatment of HER2 positive breast cancer, and '''LIXIANA®''' a direct factor Xa inhibitor, used to prevent blood clots and thus inhibiting risk of heart attack and stroke.<ref>https://www.daiichisankyo.com/products/</ref>

The company entered a collaboration with AstraZeneca in 2020 for a Daiichi Sankyo DXd (potent DNA topoisomerase I inhibitor) antibody drug conjugate (ADC), with $1 billion being paid upfront to Daichii Sankyo from AstraZeneca and a further $5 billion upon achievement of future regulatory and sales milestones. The company is developing a number of DXd drugs, known as the "3ADCs" in the company's R&D pipeline, however the agreement with AstraZeneca concerns '''Dato-DXd''' drugs. Both companies will jointly develop and commercialise Dato-DXds worldwide, except with Daiichi Sankyo holding exclusive rights in Japan<ref>https://www.daiichisankyo.com/media/press_release/detail/index_3126.html</ref>. This is the second global collaboration with AstraZeneca, with the first being a similar agreement for Daiichi Sanyo's ENHERTU'''®'''. 

The 3ADCs are a crucial strategic pillar of Daiichi Sankyo's 5-Year Plan, with oncology making up a significant portion of the revenue target by FY2025 (Total Revenue: 1.6 Tr HPY, Oncology > 600.0 Bn JPY), and ENHERTU'''®''' being a significant portion of oncology revenue (~90%).<ref>https://www.daiichisankyo.com/files/investors/library/materials/2021/20210405_5th_MTP_E.pdf</ref> 

Other product avenues are also explored in DS's 5-Year Plan, with another strategic pillar being "Profit Growth for Current Business and Products", with cardiovascular-targeting drugs such as LIXIANA® providing a steady stream of revenue (>220.0 Bn JPY), with increased product value being provided via offering a variety of additional dosages and administration routes. Sustainable growth in the business outside of oncology is further being aimed for, with sales for: Tarlige®, Injectafer®, Venofer®, Nilemdo®, being forecasted to increase by FY2025, as well as via additional formulation 

=== Dato-DXd ===
Trophoblast cell surface antigen 2 (TROP2) is highly expressed on a variety of epithelial tumours and correlates with a poor prognosis, Dato-DXd is being developed as a novel TROP2-directed ADC. Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors via efficent payload delivery into tumors alongside acceptable safety profiles in preclinical models, suggesting Dato-DXd could be a valuable treatment as it demonstrated a statistically significant improvement in progression-free surivival. '''However,''' recent results suggest that early on in treatment, Dato-DXd is not '''significantly''' better than the current standard of care chemotherapy. 

Daiichi Sankyo has a variety of Dato-DXd products currently in different phases of clinical trials: 

==== Phase 1: ====

* TROPION-PanTumor01 - solid tumours
* TROPION-PanTumor02 - '''NSCLC (Non-small cell lung cancer)''', '''TNBC (Triple negative breast cancer)'''
* TROPION-Lung02 - NSCLC
* TROPION-Lung04 - NSCLC
* PETRA (AZD5305 combo) - solid tumors

==== Phase 2: ====

* TROPION-PanTumor03 - solid tumors
* TROPION-Lung05 - NSCLC
* BEGONIA - TNBC
* ORCHARD - EGFR (Epidermal Growth Factor Receptor) mutated NSCLC
* NeoCOAST-2 - <u>recectable</u>* early-stage NSCLC (durvamulab combo) <u>neoadjuvant</u>**

<nowiki>*</nowiki>able to be removed via surgery

<nowiki>**</nowiki>treatment given as first step to shrink tumour

==== Phase 3: ====

* TROPION-Lung01 - NSCLC 
* TROPION-Lung07 - <u>non-squamous</u>* NSCLC
* TROPION-Lung08 - NSCLC
* TROPION-Breast01 - BC (HR+, HER2 low or negative BC)
* TROPION-Breast02 - '''TNBC (Triple negative breast cancer)'''
* TROPION-Breast03 - TNBC (mono or durvalumab combo) <u>adjuvant</u>**

<nowiki>*</nowiki>either Adenocarcinomas or large cell (undifferentiated) carcinomas

<nowiki>**</nowiki> treatment given after main treatment to reduce chance of cancer returning by destroying any remaining cancer cells

A list of Dato-DXd drugs currently in clinical trials can be found [https://www.daiichisankyo.com/files/rd/pipeline/index/pdf/pipeline2304_en.pdf here] in blue.

=== T-DXd ===
T-DXd is an ADC that uses the HER-2 targeted antibody trastuzumab to deliver a cytotoxic payload selectively to HER2-expressing cells. In the DESTINY-Breast01 phase II clinical trial, T-DXd showed clinical activity in the third-line setting for patients with HER2-positive metastatic breast cancer, these results led to accelerated approval of T-DXd in 2019 as a third-line therapy for patients with metastatic or unresectable breast cancer who have received two or more prior HER2-targeted therapies.<ref>https://www.aacr.org/about-the-aacr/newsroom/news-releases/t-dxd-yields-superior-outcomes-over-chemotherapy-based-regimens-in-patients-previously-treated-with-t-dm1/</ref> 

ENHERTU® is approved in over 30 countries for treatment of adult patients with unresectable or metastatic HER2 positive breast cancer.

A list of T-DXd drugs currently in clinical trials can be found [https://www.daiichisankyo.com/files/rd/pipeline/index/pdf/pipeline2304_en.pdf here] in orange.

=== HER3-DXd ===
Approximately 10% to 15% of patients with NSCLC in the US and Europe and 30% to 40$ of those in Asia have an EGFR-activating mutation. In these patients EGFR (Epidermal Growth Factor Receptor) -targeted tyrosine kinase inhibitors (TKI) result in high response rate and can provide extended disease control. However, relapse is typical with the development of resistance to EGFR TKI treatment, with the mechanisms associated with resistance being diverse, and a significant amount of which being unidentified.

Given that resistance mechanisms to EGFR TKIs are diverse and the efficacy of chemotherapy is limited, there is a need to develop novel treatment approaches for previously treated EGFR-mutated NSCLC that provide <u>salvage therapy</u>* across a broad spectrum of resistance-associated genomic alteration.

HER3 is expressed across a variety of malignant solid tumors and has been found in 83% of <u>primary</u>** NSCLC tumors. HER3 overexpression is associated with metastatic progression and decreased relapse-free survival in patients with NSCLC. EGFR-mutated NSCLC is associated with higher expression of HER3 compared to EGFR <u>wild-type</u>*** NSCLC.

HER3-DXd is a novel ADC, which specifically targets HER3. In a study 57 patients recieving HER3-DXd the <u>objective response rate</u>**** was found to be 39% and the median <u>progression-free survival</u>***** was 8.2 months. Responses were also observed in patients with known and unknown EGFR TKI resistance mechanisms<ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401524/</ref>

A list of HER3-DXd drugs currently in clinical trials can be found [https://www.daiichisankyo.com/files/rd/pipeline/index/pdf/pipeline2304_en.pdf here] in green.


<nowiki>*</nowiki>treatment recieved after standard treatment has failed

<nowiki>**</nowiki> used to describe the first, or primary tumor, the one from which metastatsis (development of secondary tumors) occurs

<nowiki>***</nowiki> non-mutated gene

<nowiki>****</nowiki> The total number of people whose cancer has either gone away (complete response) or shrunk (partial response)<ref name=":0">https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/clinical-trial-results/what-do-clinical-trial-results-mean-0</ref>

<nowiki>*****</nowiki> Time between treatment aimed at shrinking or controlling cancer, and signs that it has started to grow again<ref name=":0" />

=== 3ADC Conclusion ===
In conclusion, Daiichi Sankyo is developing a '''wide range''' of '''cancer-targeting drugs''', with a primary focus on breast and lung cancer, with Dato-DXds targeting advanced or metastatic NSCLC. T-DXds (ENHERTU®) targeting HER2 positive breast cancer, particularly when a patient has received prior anti-HER2 treatment. HER3-DXds targeting EFGR-positive NSCLC, and particularly in cases where the patient has become resistant to first-line treatments (such as EGFR TKIs).