FDA Panel Recommends Approval of Inhaled Antipsychotic

Yael Waknine

December 13, 2011

December 13, 2011 — A US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) has recommended approval of inhaled loxapine (Adasuve, Alexza Pharmaceuticals), as the first inhaled antipsychotic for agitation associated with schizophrenia and bipolar disorder (BD).

The handheld, single-dose inhaler enables rapid drug delivery with greater comfort and convenience for patients who typically must be physically restrained and treated by injection.

"We view the recommendations by the PDAC today as another step forward in the development of [inhaled loxapine] ... We appreciate the Advisory Committee's recognition of agitation as a serious and underappreciated symptom of schizophrenia and bipolar disorder," said Thomas B. King, President and Chief Executive Officer of Alexza, in a company news release.

"If approved, we believe [inhaled loxapine] represents a valuable treatment option for patients and physicians alike. We look forward to continuing to work toward our goal of bringing [inhaled loxapine] to market in 2012," Mr. King added.

In October, 2010, the FDA declined approval of the rapid-acting drug because of concerns regarding pulmonary toxicity, particularly in patients with asthma or chronic obstructive pulmonary disorder.

If approved, inhaled loxapine will be administered once every 24 hours, in accordance with a proposed Risk Evaluation and Mitigation Strategy (REMS) that includes screening patients for respiratory risks and monitoring them for 1 hour after treatment.

However, it may be difficult for health-care providers to identify respiratory distress in psychiatric patients who are "uncooperative and severely disorganized," Francis Becker, MD, a medical officer in the FDA’s division of psychiatry products, told the advisory panel.

Inhaled loxapine is a thermally generated aerosol formulation that represents a new formulation of the antipsychotic that has been orally available in the United States since 1975.

Its approval would engender competition with injectable forms of olanzapine (Zyprexa, Eli Lilly & Co), aripiprazole (Abilify, Bristol-Myers Squibb, Co), and ziprasidone HCl (Geodon, Pfizer, Inc), which are part of a newer class of medicines known as atypical antipsychotics.

The product is also being considered for approval by the European Medicines Agency (EMA).

Beneficial Effects

A company-funded study published in January in the British Journal of Psychiatry demonstrated the potential benefits of inhaled loxapine in that effects were noticeable within 10 minutes and more effective than placebo for cutting agitation levels within 2 hours.

However, pulmonary safety data from 3 double-blind, placebo-controlled studies (n = 1,653) revealed respiratory concerns.

The studies evaluated the use of two 10-mg doses of inhaled loxapine given 8 to 10 hours apart in 30 healthy patients with normal pulmonary function, 52 with mild to persistent asthma, and 53 with chronic obstructive pulmonary disease (COPD).

Although adverse events were generally mild to moderate in severity (dysgeusia, 13%; sedation, 10.5%), the rate of "notable" respiratory signs and symptoms were significantly higher among patients with asthma who received inhaled loxapine rather than placebo (69% vs 12%).

"Notable signs" were defined as a ≥20% decrease from baseline in forced expiratory volume in the first second (FEV1), an airway adverse event, or use of rescue bronchodilator medication.

Overall, about 54% of patients who had asthma and were treated with inhaled loxapine experienced adverse airway events (vs placebo, 11.5%), including bronchospasm (27%), chest discomfort (23%), wheezing (15%), and dyspnea (11.5%).

Similarly, 58% of COPD patients given inhaled loxapine experienced respiratory symptoms, compared with 22% of COPD patients who were given placebo, corresponding with an increased rate of airway adverse events (19% vs 11%), which included dyspnea (11.5%), cough (11.5%), and wheezing (8%). None of these events occurred in more than 1 COPD patient given placebo.

FDA Concerns

Study candidates were recruited "very quickly" because they "wanted to use this product," said James Cassella, Alexza’s senior vice president for research and development, in a presentation to the panel. He noted that the product is "noninvasive, noncoercive, and helps maintain the patient-physician therapeutic alliance."

However, FDA reviewers noted that the study patients were carefully screened and may have been better suited for treatment with inhaled loxapine than "real-world" patients.

Another concern regarded the lack of studies directly comparing the drug with others currently approved to treat agitation in patients with schizophrenia and bipolar disorder, they said.

Also, whereas use of the REMS would help to screen out patients with lung disorders, it is likely that some patients will require respiratory support.

"The scenario that all of us are worried about at FDA is that a patient whose asthma is not detected for whatever reason gets treated in an emergency setting, calms down, and is sort of put off to the side and not carefully observed," Thomas Laughren, director of the FDA’s Division of Psychiatry Products, said at the meeting. "And they’re slowly getting into trouble because no one’s monitoring them."

Risk Mitigation Plan

Alexza resubmitted its application in August, 2011, with a proposed REMS that includes screening patients to identify those at risk for lung problems and monitoring patients for 1 hour after treatment with inhaled loxapine.

Those proposals did not resolve FDA concerns because it may be difficult for health-care providers to monitor psychiatric patients for early signs of bronchial spasms, the report said.

"Psychotic and agitated patients who develop respiratory symptoms may not be able to notify health-care personnel in a timely manner, and respiratory distress may be confused with acute agitation to the casual observer," agency staff said, adding that the drug’s sedating effect may also mask respiratory signs and symptoms while causing further respiratory suppression.

Also, respiratory problems may be more prevalent with general use of the drug than were encountered in clinical studies.

"In a controlled study setting, obtaining an accurate history and physical, providing instructions on use of the device, and monitoring for the development of respiratory signs and symptoms may be easier than in a real-world setting such as an acute presentation to an emergency room," the FDA reviewers noted.

The FDA asked its Psychopharmacologic Drugs Advisory Committee to discuss the drug’s efficacy and safety and determine whether its benefits outweigh the associated risks.

Voting Results

The Committee voted on the following questions:

Has inhaled loxapine been shown to be effective as a treatment for agitation in patients with schizophrenia or bipolar mania? Yes/No/Abstain: 17/1/0.

Does the committee conclude that inhaled loxapine has been shown to be acceptably safe for use as a treatment for agitation in patients with schizophrenia or bipolar mania:

  • When used in conjunction with the REMS proposed by the sponsor? Yes/No/Abstain: 1/17/0

  • When used in conjunction with the REMS proposed by the FDA? Yes/No/Abstain: 5/12/1

Does the committee conclude that inhaled loxapine would be acceptably safe for use as a single-dose in 24 hours as a treatment for agitation in patients with schizophrenia or bipolar mania when used in conjunction with the REMS proposed by FDA? Yes/No/Abstain: 11/5/2.

Does the committee conclude that inhaled loxapine should be approved for use as a single dose in 24 hours when used with the FDA recommended REMS, for the treatment for agitation in patients with schizophrenia or bipolar mania? Yes/No/Abstain: 9/8/1.

Related Materials

Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. BJ Psych. Published online January 24, 2011. Full article

Draft Questions to the Committee

FDA Psychopharmacologic Drugs Advisory Committee Recommends Approval of Alexza's ADASUVE(TM)

FDA Briefing Information for the December 12, 2011, Meeting of the Psychopharmacologic Drugs Advisory Committee

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