Following approval of Alexza's (NASDAQ:ALXA) ADASUVE (loxapine for inhalation) for the treatment of adult agitated patients with schizophrenia or bipolar disorder, it may be time to address two of the issues that have arisen, concerning ADASUVE and the STACCATO device that is used for drug delivery, and their implications for Alexza. The STACCATO device is designed to vaporize a drug for inhalation without thermal degradation.
There is no evidence that the STACCATO device itself presents a risk of pulmonary toxicity
While this concern appears to have somewhat dissipated, there were reports that there were risks of pulmonary toxicity related to the device itself. These initial concerns might have been related to the unfortunate use of the word placebo, suggesting the vaporizing of an inert substance. However, ALXA clarified with the FDA that the "The placebo device is the same device as the active device without any drug. There are no binders or excipients in the placebo device. The physical analysis of the output (or airstream) from the device demonstrates that it does not contain substances from the device at any level of significance that would raise a concern for pulmonary toxicity." The only known effect from use of the STACCATO device itself is a clinically insignificant elevation in the temperature of the airstream. That adverse events (such as sedation) were recorded with use of the device alone, attests to the power of the placebo effect and the necessity of having a control arm in clinical trials, rather than an intrinsic issue with the safety of the device.
Risk of pulmonary toxicity with ADASUVE
In a recent article discussing whether ALXA was overvalued, a statement was made that
The FDA and PDAC [Psychopharmacologic Drugs Advisory Committee] were pretty focused on the pulmonary safety of ADASUVE, specifically the drop in FEV1 on the second dose in a 24 hour period. […] As a result, the FDA and PDAC felt as though dosing Adasuve twice in a 24-hour period was not acceptably safe.
While this statement is correct, it does not adequately summarize a complex discussion surrounding the safety assessment of ADASUVE and its delivery device, and the following additional points need to be made:
Pulmonary function tests (PFTs) are unfortunately effort dependent. Loxapine is a sedative drug and sedation from drug effects, as opposed to pulmonary toxicity, as well as testing fatigue can effect PFT results. The conservative assumption is to assume that such changes in PFT are related to ADASUVE, but an alternative explanation is that such findings may be, at least in part, an artifact of the testing method, particularly in such a patient population.
There was agreement between the Alexza and FDA that patients with a history of reactive airway disease, such as asthma or COPD, should not be treated with ADASUVE. FDA expressed concern that such patients, perhaps as a result of a greater prevalence of smokers in this particular patient population, were more common in the agitated patient population than the population at large. As a consequence, the issue arose as to whether such patients could be identified prospectively because patients in an agitated state may not be able to provide an adequate medical history. This subset of patients with reactive airway disease was the major concern with respect to safety.
Concern was also voiced about the difficulty of detecting early signs of respiratory compromise in patients in an agitated state and differentiating such respiratory compromise from drug induced sedation.
The FDA in approving ADASUVE came to the conclusion that the benefits of ADASUVE, e.g., likely more rapid onset of action and non-invasive method of administration, outweighed the risks in a controlled environment, such as an Emergency Room. Without prejudging the outcome of safety post-marketing studies with ADASUVE, it is possible to argue that some of these concerns may not be applicable or may differ for follow-on drugs that use the STACCATO device because (1) insofar as inhaled loxapine has an irritant effect when inhaled in the lungs, such an effect might differ with a different drug administered with the same device, indeed such an effect might be greater or lesser, (2) that evaluation of the safety of ADASUVE, as opposed to the safety of a drug delivered by STACCATO device, was complicated by the sedative nature of loxapine and the characteristics of the patient population and (3) insofar as it may be necessary to restrict use of the STACCATO device to patients without reactive airway disease, even with the delivery of a different drug, it is likely that such patients could more reliably provide the necessary medical history and follow-up and hence that such a restrictive REMS may not be necessary on that basis alone.
The STACCATO device as a platform for drug delivery
ALXA reports that the STACCATO device has been able to vaporize approximately 200 drugs. A report has been published by Alezxa describing the aerosolization by their device of drugs for the treatment of breakthrough pain (fentanyl), migraine headache (rizatriptan), nerve gas poisoning (atropine), erectile dysfunction (sildenafil), insomnia (zolpidem), and seizures (phenytoin and midazolam). One potential limitation of the STACCATO device is that the drug proposed for delivery be sufficiently thermally stable. However, now that the device has been approved, it is quite possible that pharmaceutical companies seeking a method of delivery that may offer a less invasive or more rapid onset of action for a currently approved drug, may seek to enter into collaborative agreements. This may be particularly attractive for companies with drugs nearing the end of their patent life.
In summary, while uncertainty remains about the ultimate role of the STACCATO device in the marketplace, it is interesting to note that the market capitalization of the company remains significantly below that of peer companies with an approved drug and platform technologies facing similar promise and challenges.