FDA Issues CRL Citing Safety, Data Issues for Athenex’s Oral Encequidar

Photo courtesy of Athenex

Photo courtesy of Athenex.

Cancer therapy company Athenex suffered a regulatory setback with the receipt of a complete response letter from the U.S. Food and Drug Administration (FDA), denying an approval for its oral P-glycoprotein pump inhibitor encequidar in combination with paclitaxel for metastatic breast cancer pending an additional clinical study that yields improved toxicity data.

The company said the FDA flagged an increase in neutropenia-related sequelae compared with patients receiving paclitaxel intravenously.

Neutropenic sepsis is a common adverse reaction to chemotherapy and can be life-threatening in patients.

Buffalo-based Athenex’s lead therapy, Klisyri, launched in the U.S. last month following an approval in December for topical treatment of actinic keratosis on the face and scalp. But the company has clearly focused on encequidar, which is being tested in at least eight ongoing clinical trials for a range of solid tumors.

P-glycoprotein is known to impact the bioavailability of some medicines, including chemotherapies, and encequidar is designed to inhibit P-glycoprotein specifically in the gastrointestinal tract, improving drug absorption and allowing chemotherapies to be delivered orally.

The clinical trials combine encequidar with paclitaxel, irinotecan, docetaxel, topotecan, eribulin, and in some cases in combination with anticancer antibodies like Cyramza, Keytruda, or ramucirumab.

In a poster presentation at the 2020 San Antonio Breast Cancer Symposium, data from Athena’s oral paclitaxel and encequidar Phase III trial showed improved efficacy and tolerability compared with IV paclitaxel, including improved progression-free survival (PFS) and on overall survival (OS), which supported superiority for its primary endpoint, increasing the overall response rate.

The median PFS for oral paclitaxel was 8.4 months compared to 7.4 months for IV paclitaxel, and median OS data was 23.2 months compared to 16.3 months, respectively.

But according to Athena, the FDA questioned the trial’s blinded independent central review, which it said may have had unmeasured bias due to its reconciliation and re-read process. Neither the FDA nor Athena have released the full letter.

The company is planning to work with the FDA to address the issues and try to move forward with an approval in metastatic breast cancer, said Rudolf Kwan, Chief Medical Officer of Athenex.

“We remain committed to the breast cancer community,” said CEO Johnson Lau, adding that “we will identify and undertake the appropriate internal organizational adjustments accordingly” to find the best path forward.

P-glycoprotein inhibitors are approved to treat a host of diseases, and P-glycoprotein plays a known role in tumors developing chemoresistance during cancer progression by aiding in drug efflux. But while several generations of P-glycoprotein have been tested in the clinic for treating cancer, none have yet been approved. Athenex’s stock was down by 52% at midday.

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