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The rejected drug, patritumab deruxtecan, was part of a $4 billion upfront ADC deal between Merck and Daiichi Sankyo. In the second setback for the HER3 field in days, the FDA has rejected Daiichi Sankyo’s Merck & Co.-partnered antibody-drug conjugate (ADC) patritumab deruxtecan. The drug, also known as HER3-DXd, was slated for an FDA decision Wednesday in EGFR-mutated non-small cell lung cancer following at least two systemic therapies until Daiichi and Merck delivered the bad news in the evening. Under a priority review, the drug was previously on track to be the first HER3 drug to reach the market and the first ADC launch for Merck. The FDA’s complete response letter is related to problems found during an inspection of a contractor’s manufacturing facility, rather than any issues with the efficacy or safety data, the two firms said. The identity of the contractor, as well as the nature of the production shortfalls, was not revealed.  “We will work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible in order to bring the first HER3 directed medicine to patients with previously-treated EGFR-mutated non-small cell lung cancer,” Daiichi’s R&D head, Ken Takeshita, M.D., said in a statement. In a statement to Fierce Pharma, a Merck spokesperson said the New Jersey pharma is “working with Daiichi Sankyo and the third-party manufacturer to quickly resolve the issues identified by the FDA and will share more information about anticipated timing as available.” The FDA rejection for HER3-DXd comes only a few days after BioNTech said the FDA had put a partial clinical hold on a phase 1 trial of its rival HER3-targeted ADC, BNT326, following reports of three patients’ deaths. Shortly before the FDA’s move, BioNTech had decided to focus further development on dose levels below 4.0 mg/kg to balance the drug’s efficacy-safety profile. BioNTech got BNT326 from MediLink Therapeutics, which is running the phase 1 study. HER3-DXd is one of three ADC assets that Merck paid Daiichi $4 billion upfront last fall to co-develop and co-commercialize, and it’s the closest to market under the partnership. The other two programs target B7-H3 and CDH6, respectively. In the pivotal HERTHENA-Lung01 trial, patritumab deruxtecan led to a tumor shrinkage rate of 29.8%, with the median duration of response lasting 6.4 months in a group of EGFR-mutated NSCLC patients who had progressed following a tyrosine kinase inhibitor and chemotherapy. Among the 225 trial participants, one drug-related death was recorded as a result of interstitial lung disease, a known side effect of Daiichi’s DXd technology. Besides the phase 2 HERTHENA-Lung01 study, Daiichi is also running the phase 3 HERTHENA-Lung02 trial, which is pitting patritumab deruxtecan against platinum-based chemo as a second-line therapy following failure of an EGFR TKI. The pair is also evaluating the drug in breast cancer. Under the Merck deal, Daiichi is responsible for manufacturing. While still tapping outside manufacturers, the Japanese pharma has been investing in internal ADC production capabilities for years, beginning with a 15 billion yen investment in 2017 to build new and refurbish manufacturing lines at three of the company’s plants in Japan. This February, Daiichi unveiled a 1 billion euro ($1.1 billion) investment to expand its Pfaffenhofen site in Germany. Besides additional capacities to produce drugs for cardiovascular disease, ADCs are a key part of the upgrade.

Pictured: Sign outside BioNTech's building in Germany/iStock, U. J. Alexander The FDA has slapped a partial clinical hold on BioNTech and MediLink’s Phase I study of an antibody-drug conjugate candidate for types of non-small cell lung cancer or breast cancer, following multiple patient deaths. The German biotech announced the hold Monday in an SEC filing. The antibody-drug conjugate (ADC) is being tested as a later-line treatment option for patients with heavily pre-treated advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) or HR+/HER2-negative breast cancer. The hold prevents enrollment of new U.S. patients in the trial, according to BioNTech. BioNTech’s partner MediLink, who is sponsoring the open-label trial, said the FDA cited concerns that higher doses of BNT326 may expose patients to “unreasonable and significant risk of illness or injuries.” MediLink has paused enrollment to review clinical and safety data, including observed grade 5 adverse events resulting in death. The trial abstract, shared late last month at the 2024 American Society of Clinical Oncology annual meeting, included a safety pro “adequate safety and tolerability.” By design, ADCs are intended to target cancer cells more precisely than chemotherapy to avoid damage to healthy cells. In the 52 participants in the dose escalation trial, BioNTech reported one grade 3 dose limiting toxicity event at the highest dosing group—febrile neutropenia. Additional treatment-related adverse events included anemia, nausea, fatigue and decreased white blood cell, neutrophil, lymphocyte and platelet counts. Among the 46 evaluable patients, the companies reported one complete response, 16 partial responses and 26 patients with stable disease. The ADC candidate is being developed by the partners in a research collaboration announced in October 2023 that is worth potentially over $1 billion. BioNTech has been teaming recently with other companies to expand its cancer pipeline as sales of its COVID-19 vaccine continue to wane. Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.