FDA Rejects Athenex’s Breast Cancer Treatment, Recommends Another Clinical Trial

On March 1st, New York-based Athenex Oncology, a global pharmaceutical company, announced receiving a complete response letter (CRL) from the FDA for its Encequidar. The agency expressed concern about the safety and efficacy of oral Paclitaxel plus Encequidar for the treatment of metastatic breast cancer. Athenex was recommended to conduct another clinical trial to address the concerns. After the news, Athenex’s stock fell more than 54%. It was the largest decline from any company listed on major US exchanges.

Phase 3 Clinical Trial

Encequidar is a selective inhibitor of the P-glycoprotein (P-gp), a transport protein located in the gastrointestinal tract. By blocking this P-gp, Athenex aimed at increasing the absorption of chemotherapies such as Paclitaxel. The goal was to deliver Paclitaxel orally instead of the currently approved intravenous way of delivery.

The safety and efficacy of oral Paclitaxel and Encequidar were determined in a randomized Phase 3 clinical trial that enrolled 402 patients with metastatic breast cancer. In December 2020, Athenex presented results suggesting that treatment with oral Paclitaxel and Encequidar improved progression-free survival and overall survival compared to intravenous Paclitaxel. Based on this data, the FDA granted priority review for the treatment.

FDA’s Complete Response Letter

The FDA rejection was based on the two main concerns. The first was safety since there was an increase in neutropenia-related sequelae, which means some patients in the oral Paclitaxel showed a significant decrease in neutrophil levels, a type of white blood cell when compared to IV Paclitaxel.

The second was that the blinded independent central review (BICR) reconciliation and re-read process might have led to bias and influenced the interpretation of the primary endpoint, making the results uncertain.

The FDA recommended Athenex to conduct a new clinical trial. New strategies to mitigate toxicity, dose optimization and exclusion of patients deemed to be high risk are necessary to support the approval of an NDA.

“Our clinical and regulatory teams are disappointed by the complete response letter,” said Dr. Rudolf Kwan, Chief Medical Officer of Athenex. “We plan to work with the Agency to resolve the issues raised in the CRL and to obtain approval for oral Paclitaxel plus Encequidar in metastatic breast cancer.”

Dr. Johnson Lau, Chief Executive Officer of Athenex, added, “We remain committed to the breast cancer community and will explore the best path forward to obtain regulatory approval. In the interim, we will identify and undertake the appropriate internal organizational adjustments accordingly.”

The safety issues are a major concern for the company as the combination of oral Paclitaxel and Encequidar are currently in clinical trials for angiosarcoma. Additionally, oral Paclitaxel and Encequidar, combined with different antibody therapies, are currently in Phase 2 clinical trials for neoadjuvant breast cancer and Phase 1 gastric cancer and solid tumors.

Athenex plans to meet with the FDA to discuss the next steps, but it will be crucial to determine if the safety risks can be mitigated.

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Daniel Ojeda