This concern is already described in detail in Jason's report. Here's the copy/paste
Alexza has spent the past few months analyzing the data from the pulmonary safety programs and from the phase 3 trial. The company hired outside consultants to help analyze if there is a safety concern with Staccato or AZ-004. Some of the key points that management made in their discussion with the FDA
- All respiratory symptoms that developed after treatment in the phase 1 study were either self-limiting (resolved spontaneously) or readily managed with an inhaled bronchodilator.
- No intravenous intervention was necessary due to respiratory side-effects in either the phase 1 pulmonary safety study or the pivotal phase 3 program.
- There were no serious adverse events (SAEs) in the phase 1 or the phase 3 pivotal program. Respiratory events in the phase 3 program (~750 patients) were less than 1%.
- During the clinical trials, use of standard bronchodilators was prohibited while on drug
Alexza believes it has 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 meaningful or 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. Management 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. Management plans to include this information in the new filing for approval.
The information that Alexza has complied over the past several months on the pulmonary safety will also help develop a Risk Evaluation and Mitigation Strategy (REMS) program designed to identify potential subjects that could exhibit pulmonary safety issues on AZ-004 (e.g. patients with asthma and COPD). The FDA noted at the meeting in December 2010 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.
We note in April 2011, Alexza met again with the FDA for a Type-C meeting to discuss the proposed REMS and the key elements within the REMS for screening at risk patients prior to taking AZ-004. At this meeting, the FDA emphasized that there are two key components for a risk mitigation proposal: 1) Adequacy of monitoring, via patient observation, for a period of time relative to the likely occurrence of a respiratory adverse reaction, and 2) Availability of rescue medication (e.g., inhaled albuterol) should an adverse reaction occur.
Alexza plans to address this updated guidance from the FDA in its draft REMS proposal contained within the AZ-004 NDA resubmission. The FDA indicated that a complete review of the proposed REMS in conjunction with the full clinical review of the resubmitted NDA will be necessary to determine whether the REMS will be acceptable. The FDA stated it would present the AZ-004 application to an Advisory Committee. The objective of this Advisory Committee meeting would be to discuss the proposed approach for managing the risks of AZ-004 in relationship to its patient benefits. We believe this is good news. It allows Alexza management to discuss the pulmonary safety of Staccato in an open, back-and-forth, dialogue with the FDA. It also allows shareholders to listen in and make an investment decision prior to the actual PDUFA date.
AI
