LONDON – Astrazeneca plc is broadening its antibody-drug conjugate (ADC) relationship with Daiichi Sankyo Co. Ltd. in a potential $6 billion development and commercialization deal.

The two companies are to work together on DS-1062, Daiichi’s trophoblast antigen2 (TROP2) ADC, which is in phase I development in multiple tumors that express the cell surface glycoprotein. These include breast cancer and non-small-cell lung cancer (NSCLC), areas of strategic focus for Astrazeneca.

The agreement builds on the March 2019 $6.9 billion pact between the two for Enhertu (trastuzumab deruxtecan), the HER2-targeted ADC now on course for blockbuster status, following FDA approval in December 2019 and U.S. launch at the start of the year.

Cambridge, U.K.-based Astrazeneca is paying $350 million up front, with a further $325 million at one year and $325 million two years into the deal.

Another $1 billion will be paid in milestones tied to regulatory approvals, with $4 billion to follow in sales-related milestones.

The pair will jointly develop and commercialize DS-1062 worldwide, excluding Japan where Daiichi has exclusive rights. All costs will be shared equally, apart from in Japan. Similarly, profits will be divided 50-50 except in Japan, where Daiichi will pay Astrazeneca mid-single-digit royalties.

Daiichi is responsible for manufacture and supply of DS-1062.

The new collaboration adds to Astrazeneca’s significant investment in ADCs as a class, a strategy initiated in 2013 to add value to its Medimmune antibody arm. At that point, it stuck a first toe in the water in a preclinical collaboration with ADC Therapeutics SA to jointly develop two ADCs, while also acquiring the Swiss company’s ADC linker specialist, Spirogen.

Pascal Soriot, Astrazeneca CEO, said the new agreement adds another potential blockbuster to the portfolio and will build on the successful launch of Enhertu. “We see significant potential in [DS-1062] in lung as well as in breast and other cancers that commonly express TROP2,” said Soriot.

Daiichi CEO Sunao Manabe said DS-1062 has the potential to be the best in class TROP2 ADC in multiple tumor types. The deal will allow the Tokyo-based company to get the drug to market worldwide as quickly as possible, he said. “As we have with Enhertu, we will jointly design and implement strategies to maximize the value of DS-1062.”

Daiichi is not in the lead in TROP2, with Immunomedics Inc.’s Trodelvy (sacituzumab govitecan) ADC receiving FDA approval in triple-negative breast cancer in April. However, analyst Andrew Berens at SVB Leerink Research agreed with Manabe’s assessment, saying DS-1062’s more potent payload and more stable linker “could enable best in class potential.”

DS-1062 comprises a humanized anti-TROP2 monoclonal antibody to which a topoisomerase 1 inhibitor is attached by a tetrapeptide linker. Preclinical studies showed the product selectively binds to the TROP2 receptor on tumor cells.

At the start of July, the first patient was treated with DS-1062 in the triple-negative breast cancer arm of the phase I trial, in hopes of adding to the limited treatment options for this aggressive tumor, where high TROP2 expression has been reported in up to 80% of cases.

Moving DS-1062 into triple-negative breast cancer followed promising preliminary results in NSCLC, where high TROP2 expression also has been identified in a majority of cases, and is associated with cancer cell growth and proliferation and poor outcomes. The data were presented at the virtual 2020 meeting of the American Society of Clinical Oncology in May.

Following on from phase I, one aspect of DS-1062 clinical development already in place is a combination study with Merck & Co. Inc.’s Keytruda (pembrolizumab). Under the terms of the agreement between the two companies announced in May, Daiichi will conduct a 60-patient phase Ib study in advanced NSCLC.

In addition, Daiichi is collaborating with the French cancer center Gustave Roussy in assessing multiple combination strategies for DS-1062. That will be as part of a 100-patient adaptive phase II trial to evaluate efficacy, safety and markers of response and resistance. Continuous clinical and biomarker assessments will be used to identify factors associated with individual patient responses, to fine-tune future development of DS-1062.

Building an Enhertu franchise

U.S. and Japanese approvals of Enhertu, Daiichi’s lead ADC (with the file accepted and under review by the EMA) in breast cancer, means that two elements of DS-1062 – the payload and the linker – already are validated.

Enhertu also has demonstrated the potential of a single ADC to treat multiple tumors. The initial approval in HER2-positive breast cancer has been followed by positive phase II data in advanced HER2-expressing gastric, NSCLC and colorectal cancers.

In NSCLC, 62% of patients had a tumor response, with median progression-free survival of 14 months. The product has FDA breakthrough designation as the first HER2-directed therapy in that indication.

Enhertu also has breakthrough designation and the Japanese equivalent, Sakigake, in gastric cancer, and in May, Daiichi submitted a supplemental application in that indication in Japan, underlining the opportunity of building a franchise around the product.

If approved, Enhertu will be the first ADC on the market for HER2-positive gastric cancers. Japan has the third highest incidence of gastric cancer worldwide, of which approximately 20% of cases are HER2-positive.

The partnership of Daiichi and Astrazeneca is on a mission to end the binary HER2-positive/HER2-negative definitions, arguing for levels of expression to be seen as a spectrum. Tumors classified as HER2-negative can still express the growth factor, and the precision with which Enhertu can target the receptor and deliver its payload opens up the possibility of treating tumors that currently would not be classified HER2-positive.

Daiichi Sankyo is in a dispute with ADC pioneer Seattle Genetics Inc., of Bothell, Wash., over Enhertu, with Seattle claiming the product is based on intellectual property developed in a collaboration between the two companies, which ran from 2008 to 2015.

Seattle was seeking arbitration, but in November 2019 Daiichi filed a court action, saying it believes “any such claim to be without merit.” The development agreement between the two focused on ADCs which are distinct from those currently in its portfolio, Daiichi said.

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