Alexza Pharmaceuticals, Inc. (Nasdaq: ALXA) announced today that it completed an End-of-Review meeting with the U.S. Food and Drug Administration (FDA or Agency) for the AZ-004 New Drug Application (NDA), and has received the official FDA minutes from the meeting. In December 2010, Alexza held the End-of-Review meeting in response to a Complete Response Letter (CRL) received in October 2010. 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.
"We appreciate the FDA's review of the first NDA for our novel Staccato technology and we are working to address issues raised in the Complete Response Letter," said Thomas B. King, Alexza President and CEO. "Based on the guidance received in our End-of-Review meeting, we believe all of the issues raised in the CRL are resolvable. We plan to resubmit the AZ-004 NDA in July 2011."
As reported in October 2010, the FDA stated in the CRL 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.
In the information package submitted to the FDA in response to the CRL and in preparation for the End-of-Review meeting, Alexza presented evidence that the placebo device is safe, including a blinded expert review of the flow-volume loops data from the healthy subject study as further evidence that there appears to be no consistent pattern suggestive of airway obstruction in these subjects. Alexza also provided an analysis showing that there is no meaningful temporal relationship between placebo administration and decreases in FEV1. Alexza believes this evidence and analysis confirms that the changes seen were likely background events in the population studied, where the repeated and extensive pulmonary function testing may have contributed to some of the observations. Additionally, Alexza showed that the aerosol characterization does not indicate a basis for concern. The Agency asked that Alexza reiterate these arguments in its resubmission.
In the information package, Alexza also showed that the pulmonary safety program in subjects with asthma and COPD had identified patients who may be susceptible to bronchospasm, the nature of this event, how it can be managed, and that Alexza believed the risk in these patients could be mitigated through labeling and a Risk Evaluation and Mitigation Strategy (REMS) program. At the End-of-Review meeting, the Agency stated that it would be reasonable to propose a REMS program for the use of Staccato loxapine, and requested that as part of the Company's resubmission, Alexza provide a detailed REMS proposal including labeling, a medication guide, a communication plan, and post-approval studies to manage the potential risks. In the resubmission Alexza must also show how to identify patients at risk of developing pulmonary side-effects, as well as a way to decide who should and should not be treated with Staccato loxapine when they present for treatment.
The FDA stated in the meeting minutes that it would likely present the AZ-004 application to an Advisory Committee. Alexza believes that the AZ-004 NDA is a Class 2 resubmission and the review period will be 6 months.
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 pre-approval manufacturing inspection, which was completed in August 2010. Alexza believes it understands these issues and that the issues can be adequately addressed in the AZ-004 NDA resubmission.
Since AZ-004 incorporates a novel delivery system, the CRL included input from FDA's Center for Devices and Radiological Health (CDRH). In the CRL, CDRH requested a human factors study and related analysis to validate that the product can be used effectively in the proposed clinical setting. Prior to the End-of-Review meeting, Alexza provided a human factors study draft protocol for review by CDRH, on which the FDA provided input and comments. Alexza expects to finalize the protocol with the FDA and complete this study in the coming months. Alexza is not required to conduct any additional efficacy or safety clinical trials.
CDRH also requested further bench testing of the product under an additional "worst-case" manufacturing scenario. Alexza has completed this additional "worst-case" bench testing of the product, submitted data to the FDA and believes that this issue has been adequately addressed.
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