AZ starts next-gen ADC dev with confidence from Enhertu

Phase III trial on datopotamab started in Korea and abroad… targets triple-negative breast cancer

Signs agreement for 2 ADCs with Daiichi Sankyo worth 15 trillion won

Also plans to reveal its next-gen ADC that applied their own linker technology

AstraZeneca is leading the next-generation ADC development environment.

 

The company, which has successfully commercialized ‘Enhertu’ in partnership with Daiichi Sankyo, is targeting areas slow in development such as triple-negative breast cancer.

 

On the 31st, AstraZeneca received approval for its Phase III trial of a new ADC drug last month.

 

The new ADC drug subject to the trial is ‘datopotamab deruxtecan (DS-1062, hereafter datopotamab),’ a TROP2 targeting ADC that is being co-developed by AstraZeneca and Daiichi Sankyo.

 

The Phase III trial for datopotamab will be conducted on patients with unresectable locally advanced or metastatic triple-negative breast cancer.

 

The trial will evaluate the drug’s efficacy as a first-line treatment in patients who are not eligible for treatment using PD-(L)1 immunotherapies in comparison to chemotherapy.

 

MoA of datopotamab(Source: Daiichi Sankyo)

ADC is a next-generation drug that is produced by coupling a potent cytotoxic agent to a monoclonal antibody that binds to a specific antigen on the surface of a tumor cell.

 

It minimizes the side effects while increasing the treatment effect by selectively working on cancer cells.

 

Although ‘Kadcyla’ marked the start of the commercialization of ADC drugs, the drugs were unable to make significant performance in the earlier stages due to technical limitations.

 

Since then, the development of next-generation ADCs, such as linkers that control the drug-antibody ratio (DAR) or enhance blood stability, is being developed in earnest.

 

AstraZeneca already has experience commercializing an HER-2 targeted ADC, ‘Enhertu’ after signing a joint development agreement with Daiichi Sankyo.

 

Enhertu had demonstrated superior efficacy over the early-generation ADC drug ‘Kadcyla’ as a second-line treatment in HER2-positive breast cancer.

 

According to results from the DESTINY-Breast03 that was presented last year, Enhertu reduced the risk of disease progression and deaths by 72% compared to Kadcyla in the head-to-head trial.

 

Also, the objective response rate (ORR) was significantly higher, 80% in the Enhertu group as compared to 34% in the Kadcyla group.

 

The new ADC therapy that will be presented by AstraZeneca will target the field of triple-negative breast cancer that has poor prognosis.

 

In the Phase I trial, datopotamab showed positive results with an ORR of 43% and DCR of 95%.

 

If significant results continue on in the follow-up trials, AstraZeneca’s new ADC will likely compete with Gilead’s ADC therapy.

 

Like datopotamab, Gilead’s ADC drug ‘Trodelvy’ also targets TROP2.

 

Trodelvy was approved by the US FDA as a treatment for triple-negative breast cancer last April.

 

AstraZeneca paid Daiichi Sankyo $1 billion (₩1.22 trillion) in upfront payment for the development rights of datopotamab.

 

AstraZeneca will pay additional conditional amounts up to $6 billion according to the company’s achievement of development and commercialization milestones.

 

In the past, AstraZeneca had signed a $6.9 billion (₩8.41 trillion) agreement with Daiichi Sankyo for the development rights of Enhertu.

 

The company is also investigating using datopotamab in combination with its immunotherapy ‘Imfinzi’ in addition to another trial that assesses the effect of datopotamab in NSCLC.

 

In addition to the ADC technology the company had bought from other companies, AstraZeneca is also developing a next-generation ADC using its linker technology, 'AZD8205.’ 'AZD8205 is a new drug candidate that targets overexpression of B7-H4 found in various solid cancers.

 

The company plans to first disclose study results for AZD8205 at the ‘AACR 2022’ that will be held from the 8th.