Alexza Pharmaceuticals has commenced a Phase III clinical study for its lead candidate AZ-004, which combines its proprietary Staccato technology with the atypical antipsychotic loxapine. The company outlined the first of two planned Phase III trials evaluating the drug Feb. 25.

The initial trial will evaluate the drug for the treatment of acute agitation in 300 patients with schizophrenia. A second Phase III study, projected to begin in the third quarter, is similar in design to the first trial but will enroll patients with bipolar disorder.

Alexza expects to make data from the trials, which will be conducted sequentially, available in the latter part of 2009, Senior VP-R&D James Cassella said in an interview with "The Pink Sheet" DAILY. Both studies will support an NDA filing, targeted for the first half of 2010, he added.

Benefit is noninvasive, fast-acting delivery

Alexza's Staccato technology is a hand-held, chemically-heated, single-dose inhaler that can offer deep lung drug delivery, similar to intravenous pharmacokinetics, according to the company. AZ-004 could serve as an alternative to invasive intramuscular injections often used in emergency rooms or psychiatric hospitals to treat acute agitation. It also is an alternative to rapid-dissolve or standard tablets that have a slower onset of action, the firm said.

"The real advantage is that it is a non-invasive, fast-acting treatment," Cassella said.

Loxapine is available as a generic and used to treat agitation in patients with psychiatric disorders via injection, according to Alexza. In addition, Pfizer's Geodon (ziprasidone) is approved for the treatment of agitation associated with schizophrenia and Lilly's Zyprexa (olanzapine) has approval for agitation from schizophrenia and bipolar disorder.

However, Geodon and Zyprexa are indicated for agitation via intramuscular injection.

Even when experiencing an agitated episode, patients with schizophrenia and bipolar disorder can make informed decisions on their treatment and prefer noninvasive therapies, according to Alexza. In Phase II testing, the company enrolled patients more quickly than anticipated due to patients' willingness to use the product, Cassella noted.

In the Phase II study, treatment with a 10 mg dose of AZD-004 significantly reduced agitation from baseline to the two-hour post-dose time point compared to placebo - the primary endpoint of the trial. It also showed a rapid onset of effect with a statistically significant improvement in the Positive and Negative Symptom Scale (PANSS) Excited Component score at 20 minutes post-dose compared with placebo.

The Phase III program similarly measures the change from baseline in the PANSS Excited Component score at two hours after the first dose. Investigators will assess patients' agitation at pre-specified time points over the first four hours following treatment. The randomized, double-blind, placebo-controlled study will test AZ-004 at 5 mg and 10 mg doses.

Acute agitation is estimated to impact 90 percent of patients with schizophrenia and bipolar disorder, about 70 percent of whom experience agitation episodes one to six times per year, Alexza said.

"This is a transitional year in our history as we move into the early commercial planning for the manufacturing, regulatory submissions and potential sales and marketing of AZ-004," Alexza said. The firm is developing the drug through a partnership with biopharma investment firm Symphony Capital.

Mountain View, Calif.-based Alexza is developing several other drugs based on Staccato, with a total of six in clinical stages. The company is studying a lower dose of Staccato loxapine (AZ-104) for treatment of migraine headaches in Phase II.

Also in development for migraine is AZ-001 (Staccato proclorperazine), which has completed Phase II testing. AZ-002 (Staccato alprazolam) is in Phase II to treat panic attacks and AZ-007 (Staccato zaleplon) is in Phase I for treatment of insomnia.

In December, the company entered into a North American licensing agreement with Endo for AZ-003 (Staccato fentanyl) for the treatment of breakthrough pain (¹ Also see "Endo Gains Alexza’s Inhalation Therapy To Deliver Fentanyl For Pain Treatment" - Pink Sheet, 28 December, 2007.).

-Jessica Merrill (j.merrill@elsevier.com)

Alexza Moves&nbsp;Lead Candidate AZ-004 Into Phase III For Agitation In Schizophrenia

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Alexza Moves Lead Candidate AZ-004 Into Phase III For Agitation In Schizophrenia