The FDA has imposed a partial clinical hold on the Phase I trial of an antibody-drug conjugate (ADC) cancer therapy candidate being co-developed by BioNTech and MedLink Therapeutics, three days after BioNTech disclosed the deaths of three patients in the study.

The partial hold affects the enrollment of new U.S. patients in the Phase I trial (NCT05653752), a MedLink-sponsored study designed to assess BNT326/YL202 as a later-line treatment in heavily pre-treated patients with advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) or HR+/HER2-negative breast cancer. The multicenter, open-label, first-in-human study was conducted in the United States and China, where MedLink is headquartered in Suzhou.

The FDA acted after BioNTech disclosed June 14 that two patients in the 18-patient fifth dosing cohort (4.0 mg/kg) and one patient dosed in the three-patient seventh dosing cohort (5.5 mg/kg) died during the trial of treatment-related adverse events (TRAEs).

The disclosure came in a presentation by BioNTech posted June 14 on the company’s website. Neither that presentation nor the regulatory filing offered details on the deaths.

However, John Newman, PhD, a senior biotechnology analyst with Canaccord Genuity, wrote in a research note that the two deaths reported for the fifth dosing cohort resulted from sepsis, while the death at the seventh and highest cohort came from COVID-19 and interstitial lung disease.

“The FDA has shared with MediLink concerns that BNT326/YL202 may, at higher doses, expose human subjects to unreasonable and significant risk of illness or injuries,” BioNTech disclosed in a regulatory filing. “In order to address the FDA requests, certain steps need to be taken, including reviewing clinical and safety data, sharing available pharmacological data with the Agency and providing additional information in the investigators brochure regarding the safety findings including grade 5 adverse events observed in studies YL202-INT-101-01 and YL202-CN-201-01.”

YL202-INT-101-01 is the Phase I study, in which the first patient was dosed in May, MedLink announced that month. YL202-CN-201-01 is a multicenter, open-label Phase II trial (NCT06107686) evaluating BNT236/YL202 in China. The Phase II trial is intended to evaluate the efficacy, safety, and PK characteristics of YL202 in an estimated up to 200 participants with locally advanced or metastatic solid tumors, including NSCLC, breast cancer, and head and neck squamous cell carcinoma (HNSCC).

Smaller dose focus

“Further clinical development will focus on dose levels below 4.0 mg/kg, where the safety profile was manageable and promising clinical activity was observed,” BioNTech said in its presentation.

That should mitigate the FDA’s safety concerns, Newman observed. He noted that BNT326/YL202 showed overall response rates of 42% at the 2 mg/kg dosage and 60% at 3 mg/kg dosage, “which we view as very competitive.”

The fact that patients already enrolled in the Phase I BNT326/YL202 study will continue to receive the drug suggested that the FDA’s concerns were manageable,” Newman added.

The BioNTech presentation was a revised version of a June 4 presentation made during the recent 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, and no longer available on the company’s website.

BNT326/YL202 consists of an anti-HER3 IgG1 monoclonal antibody linked to eight molecules of YL0010014, a novel topoisomerase I inhibitor, via a tripeptide linker.

BioNTech is partnering with MedLink to develop BNT326/YL202 through an up to $1.07 billion-plus collaboration launched in 2023.

MedLink granted BioNTech exclusive rights to develop, manufacture, and commercialize one of MediLink’s ADC candidates worldwide except China, its Hong Kong Special Administrative Region, and Macau Special Administrative Region. In return, BioNTech agreed to pay MedLink $70 million upfront plus potentially more than $1 billion tied to achieving development, regulatory, and commercial milestones.

BioNTech shares fell on the news by 4%, to $88.44 at today’s close of trading, from Friday’s closing price of $92.08.

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