Difficulty expanding indications for antibody-drug conjugate

Will combo therapies open the door to indication expansion of ADCs in Korea?

Company gives up expanding Trodelvy’s indication to urothelial cancer

Korea’s LigaChem Biosciences’ technology export gains attention…underpinned by Padcev’s success

Drug candidates that received much expectation as next-generation antibody-drug conjugates (ADCs) based on the success of Enhertu are on a struggling path to reimbursement in Korea.

 

  Although the companies aimed to expand the scope of coverage of their drugs based on their effectiveness in specific cancer types, the expectations damped somewhat due to the disappointing clinical research results.

 

Nevertheless, the domestic and international pharmaceutical and bio industries are attempting to develop new drugs by starting clinical research on the combined use of ADCs and immuno-oncology drugs.

 

The TROP-2 class of drugs has been receiving the most attention as the next generation of ADCs in the global pharmaceutical and biotechnology industries and clinical sites.

 

The leading products in the market include TRODELVY® (sacituzumab govitecan-hziy, Gilead), and datopotamab deruxtecan (AstraZeneca, Daiichi Sankyo).

 

However, these candidates have recently struggled to expand their indications.

 

According to industry sources on the 25th, Gilead recently formalized the ‘abandonment’ of its application to expand Trodelvy’s indication to urothelial cancer in consultation with the US Food and Drug Administration (FDA).

 

Troldelvy binds to the Trop-2 protein, which is highly expressed in a variety of cancers including breast cancer, and releases the drug inside the tumor cells, destroying not only the tumor cells but also the tumor microenvironment, with minimal impact on healthy cells.

 

Currently, it has demonstrated efficacy in advanced triple-negative breast cancer (TNBC) and HR+/HER- breast cancer.

 

However, the company abandoned its other promising indication - urothelial carcinoma.

 

The company failed to demonstrate overall survival (OS) in the TROPiCS-04 study, a Phase III confirmatory trial that was part of the conditional approval.

 

The Keytruda (pembrolizumab, MSD) and Padcev (enfortumab vedotin, Astellas) combination therapy, which has been introduced in Korea as a first-line treatment option for urothelial carcinoma, stood out in the trial, demonstrating its relative effect.

 

Another TROP-2 class ADC, datopotamab deruxtecan, Dato-DXd, is also facing difficulties.

 

The final OS analysis HR+/HER2 low- or negative-expressing breast cancer did not show a statistically significant improvement over chemotherapy.

 

At the same time, it failed to achieve statistical significance in OS compared to docetaxel in advanced/metastatic NSCLC.

 

Following the failure of Trodelvy in demonstrating survival benefits in metastatic stage IV NSCLC, datopotamab deruxtecan is also struggling to gain traction in the lung cancer space.

 

However, AstraZeneca and Daiichi Sankyo have applied to the FDA for the approval of datopotamab deruxtecan for advanced/metastatic non-squamous NSCLC, as they believe it could be a new treatment option.

 

As such, the FDA is expected to make a decision on whether to approve datopotamab deruxtecan for NSCLC by December 20th.

 

Dr.

 

Min-Hee Hong, professor of Medical Oncology at Severance Hospital, said, “If you think about the role of ADCs in NSCLC, nothing has been approved so far.

 

“However, if you look at Trop-2-targeted ADC studies, there is some talk that some subgroup analysis results were good.

 

But whether the company can get FDA approval with the data remains in question, as it didn't meet its primary endpoint.” “I think it shows what we call “cherry picking” in the medical community, where they're really cherry-picking the data that they want to show, so I think it's fair to say that there's no approved drug and no role for the drug at this point.

 

But we'll have to wait and see because the FDA’s decision hasn't been announced yet.” While global pharmaceutical companies' next-generation ADC candidates are struggling to expand their scope, the domestic pharmaceutical and biotech industry's presence in ADC development has been growing.

 

The Korean pharmaceutical and biotechnology industries are attempting various clinical trials with the combination of ADCs and immuno-oncology drugs, which are being actively conducted around the world and are leading to actual technology export results.

 

Gilead, AstraZeneca, and Daiichi Sankyo are already attempting clinical studies with immuno-oncology drugs such as Keytruda or Imfinzi (durvalumab) in combination with Trodelvy and datopotamab deruxtecan.

 

One representative domestic company is LigaChem Biosciences.

 

LigaChem Biosciences is a company specializing in ADC development that has signed a total of 10 technology transfer agreements.

 

Starting with the technology transfer to China's Fosun Pharma in 2015, the company successfully exported its LCB84 technology to Janssen in December last year.

 

LCB84 is an ADC candidate that can target various solid cancers, including triple-negative breast cancer and non-small cell lung cancer.

 

LigaChem Biosciences also recently announced that it has signed 2 technology transfer agreements with Japan's Ono Pharmaceutical Industries, including LCB97, which targets the L1CAM protein.

 

The total value of the two agreements is worth over USD 700 million (KRW 943.5 billion), with the specific upfront payment amount undisclosed as per the parties' agreement.

 

LCB97 targets L1CAM, a protein expressed in several solid tumors, including lung, pancreatic, and colorectal cancers.

 

In February of last year, LigaChem Biosciences entered into a research and development agreement with Elthera AG in Switzerland for the L1CAM antibody, securing worldwide rights, including for ADC use.

 

In addition, various domestic biotech companies such as NeoImmuneTech and TXINNO Bioscience are attempting clinical research with the concept of ADC and immuno-oncology combination therapy.

 

A domestic pharmaceutical and biotech industry official said, “The success of the Padcev+Keytruda combination attracted much attention to the combination of ADCs and immuno-oncology drugs.

 

And the combination’s reimbursement is gaining great interest in Korea.

 

Although it has no commercialized items yet, LigaChem Biosciences gained attention for signing licensing agreements with global big pharma companies such as Ono Pharmaceutical, Janssen, and Amgen.

 

This is because ADCs are being regarded as the next cash cow in the global market.”