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By December 21, 2012, the FDA will determine whether to approve Alexza Pharmaceuticals's (NASDAQ:ALXA) Adasuve, an investigational product for acute treatment of agitation associated with schizophrenia and bipolar disorder. In this article, we review scientific and medical aspects of Adasuve. Despite a narrowly positive advisory committee vote for Adasuve last year, we conclude that significant safety concerns remain. These concerns may cause the FDA to deny approval for Adasuve, which would result in a substantial decline in Alexza's stock price.

Background

Alexza is a pharmaceutical company developing novel products for acute treatment of central nervous system conditions. All of Alexza's product candidates are based on the Staccato system, a proprietary technology for vaporizing drugs into a breathable form. Delivery of drugs in this manner allows for rapid uptake through deep lung inhalation. The company's lead candidate, Adasuve, is a device for the delivery of the FDA-approved drug loxapine. Adasuve has been developed for acute treatment of acute agitation in adult schizophrenia and bipolar patients.

Acute agitation is a state of motor restlessness and mental tension with accompanying behaviors such as pacing, fidgeting, and wringing of the hands. Within a short period of time, the condition can progress to highly disruptive and aggressive behavior. Currently available treatments include oral and intramuscular administration of antipsychotic drugs. However, each of these methods of delivery is problematic. Despite being effective, oral administration involves slow systemic absorption. Symptom relief takes 30 to 60 minutes, during which time patient behavior sometimes escalates to a level requiring physical restraint or seclusion. In contrast, intravenous administration affords rapid onset of action, but is often impractical given these patients' agitation.

Adasuve differentiates itself by allowing for rapid onset of action as well as ease of administration. Oral inhalation through the device initiates controlled, rapid heating of a thin film of loxapine. The system generates a highly pure drug vapor that patients breathe into their lungs. After being absorbed by the lung, loxapine quickly enters the bloodstream, providing fast therapeutic onset comparable to intravenous administration, but with greater ease, patient comfort and convenience. Nevertheless, as discussed below, insufficient proof of relative efficacy and serious safety risks accompany these benefits.

Adasuve's clinical trials lack meaningful controls

Two independent, randomized double-blind phase III trials were conducted evaluating Adasuve against a placebo. One involved 344 adult schizophrenia patients and the other involved 314 adult bipolar patients. In each study, a single inhalation of loxapine was administered to patients staying at an in-patient treatment facility. Inhaled loxapine produced a statistically significant improvement in primary and key secondary endpoints. Consequently, in its 2011 advisory committee meeting, Adasuve received a solid endorsement in terms of efficacy, with a 17/1/0 (yes/no/abstain) vote. This result is not surprising given that the active ingredient in Adasuve is loxapine, an already FDA-approved medication. Notably, however, in both studies, no intravenous or intramuscular comparator was used. In other words, Adasuve was never evaluated alongside traditional treatments for acute agitation. Therefore, without additional data, it is impossible to determine whether Adasuve is superior or inferior to existing treatment options. Given that these alternative therapies are quite safe, the lack of head-to-head comparison limits assessment of whether Adasuve's efficacy outweighs its safety risks.

Alexza failed to address salient long-term safety concerns

Although inhalable drugs have been quite effective in treating respiratory diseases such as asthma, inhaler therapy designed for non-pulmonary diseases has, thus far, performed poorly. For example, Pfizer (NYSE:PFE) and Nektar Therapeutics's (NASDAQ:NKTR) inhalable insulin drug Exubera was approved in 2006 and was expected to revolutionize diabetes care. However, it was pulled from the market the following year. Soon after Exubera was introduced to the market, concerns surfaced about potential negative effects of the drug on the lungs. One study found a reduction in lung function caused by the drug. Additional concern emerged during a post-marketing study where patients treated with Exubera developed lung cancer. Recently, MannKind Corporation (NASDAQ:MNKD) has had difficulty getting its inhalable insulin therapy Afrezza approved. Therefore, it is notable that clinical studies for Adasuve were conducted on a short-term basis without an extended follow-up study. It is uncertain what long-term effects Adasuve may have on patients. Agitation medication is not taken on a regular, daily basis, which marginally reduces this concern. However, existing treatment options for agitation do not carry this long-term unknown, so the FDA is likely to be especially cautious with its upcoming decision regarding Adasuve.

Adasuve's advisory committee provided unclear guidance

At the end of 2011, the advisory committee voted 9/8/1 (yes/no/abstain) to recommend that ADASUVE be approved for use with the FDA-proposed Risk Evaluation and Mitigation Strategy (REMS). In terms of safety, Adasuve did not receive a strong endorsement. Twelve out of eighteen panel members voted that Alexza had not shown Adasuve to be acceptably safe when used according to the FDA-proposed REMS. Notably, the FDA is not bound by an advisory committee's overall recommendation, and the FDA is less tolerant of safety risks for new drugs when existing therapies are known to be safe. Thus, the unfavorable vote on Adasuve's safety may be a critical determinant in whether Adasuve gains approval. Alternative therapies for acute agitation are well-established and safe. There is no pressing need to approve Adasuve or any other similarly targeted drug without demonstrated comparative superior efficacy.

Summary

From scientific and clinical perspectives, Adasuve offers advantages in fast onset of action and ease of administration. These benefits are clear. However, Adasuve also bears significant safety risks. We believe the risks outweigh the benefits and, consequently, Adasuve may not receive FDA approval.

Source: Alexza's Adasuve May Not Be Ready For FDA Approval

Additional disclosure: Beacon VP Investments is a team of analysts. This article was written by Qinghui Yu, one of our team members.