How can a patient with an ‘acute' condition use a Staccato® product?
Staccato® products are designed with patients' use in mind. For a dose delivery by Staccato, no priming, hand/breath coordination or forceful inhalation is required – the aerosol is simply entrained in the patient's breath. A single inhalation actuates Staccato and delivers the drug.
Clinical studies with a number of Staccato-based product candidates have demonstrated patient compliance and confirmed that the intuitive nature of inhaling in a single breath to receive the dose is suitable for patients with acute conditions.
How fast does the drug get into the lung and systemic circulation?
The drug is vaporized off the substrate within 500 milliseconds and drawn into the patient’s lungs within 1 second for absorption into systemic circulation. Alexza has demonstrated that for the 5 products tested to date, peak plasma levels have been achieved within 3 to 5 minutes of inhalation.
How fast do Staccato® products work?
Staccato products generate a pharmacokinetic profile similar to IV delivery while delivering medicine in a non-invasive way. They fulfill a significant unmet medical need by providing new treatment options to patients and physicians.
The Alexza clinical team has conducted a number of clinical studies, with Staccato products, where speed of onset has been evaluated. In the pivotal studies with Adasuve® Staccato loxapine, statistically significant onset of effect was observed as early as 10 minutes after dosing. At this first time point measured, patients with underlying schizophrenia and bipolar disorder taking Staccato loxapine showed significant improvement in their agitation symptoms versus placebo.
Is the effective delivery of a drug dependent on the patient's breathing pattern?
The development team at Alexza designed the Staccato devices with the patient in mind. The unique feature of the Staccato system is achievement of a high emitted-dose regardless of the patient's breathing pattern. All Staccato platforms are designed to actuate at the minimum inhalation and airflow rate of approximately 15 liters per minute.
How do we know that our molecule will work in the Staccato® system?
With knowledge of the chemical structure, we can perform a virtual screen and determine a molecule's likely feasibility for thermal vaporization. However, when the chemical structure is proprietary, we can perform an experimental feasibility study that requires minimal amount of drug and takes approximately 2 months to complete.
Is there a general rule regarding molecular structure that determines whether a drug will vaporize or not?
There is no general rule. A variety of functional groups may be acceptable depending on their particular molecular arrangement as well as other physical and chemical properties of the drug. Moreover, molecular weight is usually key, in that macromolecules, peptides and proteins do not work in our technology.
We have completed feasibility testing over 400 compounds, approximately half of which have demonstrated positive initial vaporization feasibility, resulting in high purity aerosols when vaporized at an appropriate film thickness. Based on our experience with the compounds we've screened, we can make an initial assessment as to whether a particular drug will generate an aerosol with an acceptable purity profile. Compounds from many different therapeutic areas have shown initial vaporization feasibility.
How do we determine the dose strength to be delivered by the Staccato system?
The Staccato system generates a PK profile generally observed by IV delivery (i.e. same Tmax and Cmax). Two Phase 1 clinical studies with our migraine and breakthrough pain programs have directly compared delivery of the same dose by IV and Staccato system. The profiles indicated that the Staccato system generates PK profiles very similar to IV, with the same bioavailability and peak plasma levels. Thus, if there is an existing IV formulation for the compound of choice then that is the most appropriate dose for the Staccato system. If the compound is delivered orally, the compound's bioavailability and metabolism will determine the Staccato dose. Compounds with low bioavailability and high first-pass hepatic metabolism will most likely have a significantly reduced dose in a Staccato system.
What are the Regulatory paths to IND and NDA?
After the initial feasibility study, the path to IND will often depend on conducting IND-enabling inhalation toxicology studies and optimizing the delivery platform for a specific compound. In addition, particle size optimization is often performed in order to assure deep lung delivery. The Staccato products are reviewed by the FDA's Center for Drug Evaluation and Research division, as drug products. If the drug compound has already been approved in a formulation such as oral or IV, a 505(b)(2) regulatory strategy may be considered for a Staccato system-based product.