- 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 which requires minimal amount of drug and takes approximately 2-3 weeks 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. We have pre-screened over 400 compounds approximately half of which have demonstrated 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.
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- Does the molecular weight of the drug matter?
No. In our experience, molecular weight is not a determining factor. We have formed high purity aerosols of molecules with a molecular weight of >600 daltons. Some lower molecular weight compounds vaporize well and some do not. The same is true for the compounds with a higher molecular weight.
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- What is the purity of the thermal condensation aerosols?
We consider a compound suitable for the Staccato system if the purity of the aerosol generated is in the range of 90% or greater. We also consider what degradants may be formed and present in the aerosol. If, as is fairly common, the degradant is a known metabolite, the threshold for the aerosol purity may be lower.
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- 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 compared delivery of the same dose by IV and Staccato system. The profiles indicated that the Staccato system generates PK profiles identical 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.
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- How fast does the drug get into the lung and systemic circulation?
The drug is vaporized off the substrate within 500 milliseconds (about half a second) and drawn deep into the patient’s lungs within 1 second. Peak plasma levels for all 6 products in clinical development have been achieved within 3 to 5 minutes of inhalation.
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- Is the effective delivery of a drug dependent on the patient’s breathing pattern?
The engineering team at Alexza has designed the Staccato devices with the patient in mind. One important characteristic is the minimum inhalation rate for actuating the product to deliver the drug. All Staccato platforms are designed to actuate at an airflow rate of approximately 15 liters per minute. This value was chosen to be high enough to prevent accidental actuations (for example, from dropping the device) but simple to achieve by a patient. The unique feature of the Staccato system is achievement of a high emitted dose regardless of the patient's breathing pattern.
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- 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. A drug in the Staccato system will be reviewed by the FDA (Center for Drug Evaluation and Research) as a drug product. If the drug compound has already been approved in a formulation such as oral or IV, a 505(b)(2) new drug application strategy may be considered for a Staccato system-based product.
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- Why is Staccato different from Exubera?
The Staccato system is designed for the treatment of acute and intermittent conditions, and the product is only used periodically when the condition occurs (e.g. 4 to 5 times per month), unlike Exubera, which was designed as a treatment taken multiples times per day for a chronic condition. Additionally, with the Staccato system, only pure, small molecule drug is delivered to the patient, whereas with Exubera, the drug formulation comprises hormone API as well as excipients. However, despite the very different intended use of Staccato products versus Exubera, we are conducting a series of lung safety studies for the product registrations.
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