Staccato® One Breath Technology™ Staccato®

Unleash the Speed of Staccato® One Breath Technology™ – OBT™

Rapid peak plasma levels with a simple breath

Basic Principle

Rapid vaporization = Rapid absorption = Rapid onset of action

The Staccato OBT system comprises the rapid vaporization of an excipient-free drug to form aerosol particles optimal for systemic delivery through inhalation. These aerosol particles are rapidly absorbed, resulting in peak plasma blood levels obtained in the first few minutes after administration. Immediate absorption of the drug results in rapid onset of action and therapeutic effect. The Staccato OBT system matches delivery characteristics and product attributes to patient needs for rapid and effective treatment of acute and intermittent conditions.

Key Features

Rapid drug delivery: Aerosolized particles

Consistent Particle Size Distribution Cart

The Staccato OBT system generates optimally sized aerosolized drug particles with consistent particle size distribution. Rapid vaporization of a pure drug film (rather than mechanically generating aerosols or utilizing preformed particles) enables consistent generation of particles averaging 1–5 microns in size, optimal for deep lung inhalation.

Rapid onset and pharmacology

AZ-001 Efficacy Data Chart

The aerosol produced with the Staccato OBT system is designed to be absorbed rapidly through the deep lung. Speed of therapeutic onset is comparable (almost identical) to IV administration, generally achieving peak plasma levels of drug in 2 to 5 minutes.

Onset of action is more rapid compared to other drug delivery methods such as oral tablets, fast-dissolve tablets, sublingual films, and intramuscular and subcutaneous injections.

Our commercial product ADASUVE (loxapine) inhalation powder (ADASUVE.com) and drug product candidates in our pipeline have demonstrated statistically significant onset of therapeutic effect within 10 minutes.

Ease of use: Single breath activation

Ease of use: Single breath activation

To use Staccato OBT, a patient simply places the device to their lips and inhales (there is no waiting or prep time). The Staccato device is breath actuated. Unlike many other inhalation technologies, the patient does not need to coordinate inhalation with other actions, and the patient does not need to learn a special breathing pattern. The Staccato OBT system delivers a consistent dose across a wide range of inhalation styles.

Thermal aerosol

Rapid heating of a thin film of excipient-free drug creates a drug aerosol without thermal degradation. In less than half a second, the drug is heated to a temperature sufficient to convert the solid drug film into a vapor. Because the duration of drug heating is so brief, thermal decomposition is minimal. After vaporization, the drug cools rapidly in air, condensing into pure drug aerosol particles of near ambient temperature.

Applicability

The Staccato OBT system delivers pure (unformulated) drug, which reduces development time as formulation development is not required. In addition to delivering aerosol from a single active compound, the Staccato technology can also be used for delivery of a combination of different actives in a single breath. A large number of molecules have demonstrated technical feasibility with Staccato technology.

Established Technology

  • Approved (FDA and EMA) drug delivery system
  • Demonstrated efficient clinical development
  • Proven core technology enables rapid design, development, and transfer into commercial manufacturing

The heart of the hand-held Staccato OBT system is a heated stainless steel substrate, onto which a thin film of unformulated drug is coated. When the patient draws a breath through the Staccato OBT system, the substrate surface instantaneously heats to create a condensation aerosol. The vaporized drug cools and condenses into pure drug aerosol particles. The patient inhales optimally sized particles of pure drug down into the narrower, more vascularized tissue of the deep lung, allowing fast and more complete absorption into the bloodstream for rapid systemic effect.

Ease of Use

Staccato OBT products are designed with patients in mind. Dose delivery by Staccato OBT does not require priming, hand/breath coordination, or forceful inhalation—the aerosol is simply generated and entrained in the patient's breath. A single inhalation actuates the Staccato OBT system and delivers the drug.

Developed to Meet Your Dosing Requirements

The Staccato OBT devices meet the need of different therapeutic treatments.

Disposable single dose

Disposable single dose

  • Consists of a metal substrate that is heated through an exothermic chemical reaction
  • The substrate can be coated with milligrams of drug compound
Multi-Dose

Multi-dose

  • Consists of a reusable controller and a disposable dose cartridge. The dose cartridge contains up to 25 doses coated onto individual metal substrates
  • Each metal substrate rapidly heats upon application of battery-supplied electric current and can be coated with micrograms of drug compound
Reusable single dose

Reusable single dose

  • Consists of a reusable controller and a disposable dose cartridge. The dose cartridge contains a single dose of a drug in milligram quantities
  • Each metal substrate rapidly heats upon application of battery-supplied electric current

Staccato OBT for Any Novel Compound

The Staccato OBT system can deliver both water-soluble and water-insoluble compounds without the need for excipients and additives such as detergents, stabilizers, and solvents, enabling the delivery of unformulated drug.

The Staccato OBT system is suited for delivery of drug combinations (e.g., two different actives).

The Staccato OBT devices can incorporate multiple features, including lockout to enhance safety, the convenience of patient titration, and a variety of dose administration regimens.

To find out if your compound will work in the Staccato OBT system, please contact our Business Development Group

The Innovation Story of Staccato OBT System

3 core components of the <em>Staccato</em> OBT device
  1. Heating substrate
  2. Thin film of unformulated drug coated on the substrate
  3. Breath activation—senses inhalation to automatically trigger aerosol generation
Rapid Drug Delivery

In less than half a second, the drug is heated to a temperature sufficient to convert the solid drug film into a vapor. Rapid heating ensures minimal thermal decomposition. After vaporization, the drug cools rapidly in air, condensing into pure drug aerosol particles of near ambient temperature.

Creates optimally-sized aerosol particles

The key to our proprietary technology is vaporization of drug without thermal degradation achieved by rapid heating of the drug film to generate consistent aerosol particles of 1–5 microns in size that are optimal for deep lung inhalation; it is not dependent on mechanics or preformed drug particles to create drug aerosols.

Provides smart design flexibility

The Staccato OBT system can be customized to enhance safety and security to accommodate a variety of dose administration regimens including:

  • Dosing lockout features to prevent overdose and to manage patient titration
  • Wireless (Bluetooth) communication for patient monitoring and dose tracking
  • Security features for controlled access

Staccato OBT Products

1. How can a patient with an “acute” condition use a Staccato OBT product?

Staccato OBT products are designed with patients’ use in mind. For dose delivery by the Staccato OBT system, no priming, hand/breath coordination, or forceful inhalation is required—the aerosol is simply entrained in the patient’s breath. A single inhalation actuates the Staccato OBT device and delivers the drug.

Clinical studies with a number of Staccato OBT 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.

2. How fast does Staccato OBT get drug 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 products tested to date, peak plasma levels have been achieved within 2 to 5 minutes of inhalation.

3. How fast do Staccato OBT products work?

Staccato OBT products generate a pharmacokinetic profile similar (almost identical) 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 OBT products where speed of onset has been evaluated. In the pivotal studies with ADASUVE® (loxapine) inhalation powder (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.

4. Is the effective delivery of a drug dependent on the patient's breathing pattern?

The development team at Alexza designed the Staccato OBT devices with the patient in mind. The unique feature of the Staccato OBT is achievement of a consistently delivered fine particle dose regardless of the patient's breathing pattern. All Staccato OBT devices are designed to actuate with minimal inhalation effort.

Staccato Technology

1. How do we know that a molecule will work with Staccato technology?

A screening feasibility study can be performed to determine a molecule's feasibility for thermal vaporization.

2. 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 generally do not work in our technology.

Alexza has completed feasibility testing of 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 and temperature. Based on our experience with the screened compounds, an initial assessment can be made 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.

3. How do we determine the dose strength to be delivered by Staccato technology?

The Staccato OBT products generate 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 OBT. The profiles indicated that the Staccato OBT generates PK profiles very similar (almost 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 OBT. If the compound is delivered orally, the compound’s bioavailability and metabolism will determine the Staccato OBT dose. Compounds with low bioavailability and high first-pass hepatic metabolism will most likely have a significantly reduced dose in a Staccato OBT.

4. 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 OBT products are reviewed as drug products by the FDA’s Center for Drug Evaluation and Research division. 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 OBT product.

Alexza