Alexza Pharmaceuticals, Inc. announced that it has received a Complete Response Letter (CRL) from the US Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for AZ-004 (Staccato loxapine), submitted as Adusuve Staccato (loxapine) inhalation aerosol, 5 mg and 10 mg. A CRL is issued by FDA's Center for Drug Evaluation and Research indicating that the NDA review cycle is complete and the application is not ready for approval in its present form. AZ-004 is being developed for the rapid treatment of agitation in schizophrenia or bipolar disorder patients.

In the CRL, the FDA stated that their primary clinical safety concern was related to data from the three phase 1 pulmonary safety studies with AZ-004. This concern was primarily based on observed, dose-related post-dose decreases in forced expiratory volume in one second, or FEV1, a standard measure of lung function, in healthy subjects and in subjects with COPD and asthma. The agency also noted that decreases in FEV1 were recorded in subjects who were administered device-only, placebo versions of AZ-004. Alexza intends to meet with the FDA in the near future to discuss steps to address this FDA concern. As Alexza has previously reported, there were no serious or severe respiratory adverse events in these trials or reported in the two phase 3 clinical trials of AZ-004. All respiratory symptoms that developed after treatment in the phase 1 subjects with COPD and asthma were either self-limiting or readily managed with an inhaled bronchodilator.

The CRL also raised issues relating to the suitability of the stability studies undertaken by Alexza and certain other items relating to the agency's recently completed pre-approval manufacturing inspection. Because AZ-004 incorporates a novel delivery system, the CRL also included input from FDA's Center for Devices and Radiological Health (CDRH). CDRH requested a human factors study and related analysis to validate that the product can be used effectively in the proposed clinical setting. CDRH also requested further bench testing of the product under an additional "worst-case" manufacturing scenario.

"We are reviewing the Complete Response Letter and plan to meet with the FDA as soon as possible to discuss the Agency's pulmonary safety concern. Alexza shares the agency's deep interest in patient safety, and believes the pulmonary data is supportive of the safety of AZ-004. We look forward to discussing the appropriate way to address this issue," said Thomas B. King, Alexza President and CEO. "We are also undertaking steps to address the other items raised in the CRL. We appreciate the FDA's review of the first NDA for our novel Staccato technology, and we expect to work closely with FDA to resolve the issues raised in the Complete Response Letter. Alexza continues to believe in the safety and efficacy of AZ-004 based on the comprehensive clinical development program we have conducted."

Alexza Pharmaceuticals is a pharmaceutical company focused on the research, development and commercialization of novel, proprietary products for the acute treatment of central nervous system conditions.