Comprehensive Report on Albuterol Sulfate/Fluticasone Propionate (TEV-'248, Teva Branded Pharmaceutical Industries)

1. Introduction

The management of asthma, a chronic inflammatory disease of the airways, continues to evolve with the development of new therapeutic strategies and drug delivery systems. One such investigational product is a fixed-dose combination of albuterol sulfate and fluticasone propionate, identified by the development codes TEV-'248 and TEV-56248, from Teva Branded Pharmaceutical Industries. This combination aims to provide both rapid symptom relief and address underlying inflammation, aligning with current global asthma management guidelines. TEV-'248 is delivered via a multi-dose dry powder inhaler (MDPI), potentially incorporating Teva's Digihaler technology, and is intended for use as a rescue medication in asthma.[1] This report provides a comprehensive overview of albuterol sulfate/fluticasone propionate (TEV-'248), detailing its individual components, the rationale for the combination, its pharmacokinetic profile, the ongoing clinical development program, anticipated safety and tolerability, regulatory standing, and its position within Teva's existing respiratory product portfolio.

2. Components: Albuterol Sulfate and Fluticasone Propionate

2.1. Albuterol Sulfate

Albuterol sulfate is a well-established short-acting beta$_2$-adrenergic agonist (SABA).2

Therapeutic Class and Mechanism of Action: Albuterol belongs to the family of medicines known as adrenergic bronchodilators.2 It acts selectively on beta$_2$-adrenergic receptors in the lungs, leading to relaxation of bronchial smooth muscle, and thereby causing bronchodilation.3 This action helps to relieve cough, wheezing, and dyspnea by increasing airflow through the bronchial tubes.2

Approved Indications: Albuterol is indicated for the treatment or prevention of bronchospasm in patients with reversible obstructive airway disease, such as asthma, bronchitis, and emphysema.2 It is also used to prevent exercise-induced bronchospasm (EIB).2

Dosage Forms and Strengths: Albuterol sulfate is available in various formulations, including inhalation aerosols, inhalation powders, inhalation solutions for nebulization, oral tablets, and syrup.2 Teva Pharmaceuticals markets ProAir® Digihaler™, an inhalation powder that delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouthpiece per actuation.5 For bronchospasm, the typical dosage for adults and children 4 years and older using an inhaler is two puffs every 4 to 6 hours as needed.2 For EIB, two puffs are taken 15 to 30 minutes before exercise.2

2.2. Fluticasone Propionate

Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity.7

Therapeutic Class and Mechanism of Action: Fluticasone propionate belongs to the corticosteroid (cortisone-like) class of medicines.7 As an inhaled corticosteroid (ICS), it works by decreasing swelling and irritation in the airways.9 It exhibits a high affinity for glucocorticoid receptors and has a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils) and mediators (e.g., histamine, cytokines) involved in inflammation.8

Approved Indications: Inhaled fluticasone propionate is used for the long-term maintenance treatment of asthma to help prevent symptoms and reduce the frequency and severity of asthma attacks.7 It is not indicated for the relief of acute bronchospasm or an asthma attack that has already started; a SABA is required for such events.7

Dosage Forms and Strengths: Fluticasone propionate is available as an inhalation aerosol, inhalation powder, and nasal spray.7 Teva's ArmonAir® Digihaler™ is an inhalation powder available in strengths of 55 mcg, 113 mcg, and 232 mcg per actuation, administered as one inhalation twice daily for the maintenance treatment of asthma in patients 12 years and older.11 The recommended starting dosage is based on asthma severity and current therapy.12

3. TEV-'248: The Investigational Combination Product

3.1. Product Description and Rationale

TEV-'248 is an investigational fixed-dose combination product containing albuterol sulfate (a SABA) and fluticasone propionate (an ICS).[1] It is delivered as an inhalation powder via Teva's breath-activated, multi-dose dry powder inhaler (MDPI), which is used with other approved medicines in Teva's respiratory product portfolio, such as the Digihaler™ line.[1] Some clinical trial information refers to this combination as Fp/ABS eMDPI, suggesting the incorporation of an electronic module, characteristic of the Digihaler system.[14]

The rationale for developing an ICS/SABA combination for rescue use is strongly supported by evolving asthma management guidelines, particularly those from the Global Initiative for Asthma (GINA). GINA guidelines now recommend against the use of SABA alone for asthma symptom relief in most patients, due to evidence that SABA-only treatment does not address underlying airway inflammation and may be associated with an increased risk of severe exacerbations and mortality with frequent use.[1] Instead, guidelines advocate for the inclusion of an ICS component with reliever therapy to address both immediate symptoms (via SABA) and long-term inflammation (via ICS).[1] This approach is considered safer and more effective, leading to improved asthma management and a significant reduction in the risk of severe exacerbations.[1] TEV-'248, as a dual-action asthma rescue inhaler, aims to meet this need by providing both rapid bronchodilation from albuterol and anti-inflammatory effects from fluticasone with each actuation.[1]

3.2. Development Codes and Alternative Names

The albuterol sulfate/fluticasone propionate combination product from Teva is referred to by several identifiers in various sources:

• TEV-'248 [1]
• TEV-56248 [13]
• ICS-SABA (referring to the drug classes) [1]
• Fluticasone propionate/albuterol sulfate (or salbutamol sulfate) [13]
• Fp/ABS eMDPI (Fluticasone propionate/Albuterol Sulfate electronic Multi-Dose Powder Inhaler) [13]

3.3. Originator and Collaborations

TEV-'248 is being developed by Teva Pharmaceutical Industries Ltd. (also referred to as Teva Branded Pharmaceutical Industries).[1] To accelerate the clinical research program for TEV-'248, Teva has entered into a clinical collaboration agreement with Launch Therapeutics, Inc., and a strategic development funding agreement with Abingworth.[1] Under this agreement, Abingworth will provide Teva with up to $150 million to offset R&D costs, and Launch Therapeutics will manage the execution of clinical trials.[1] Teva will retain full rights to the ICS/SABA program, including manufacturing, regulatory interactions, and potential commercialization.[1]

This collaborative approach, involving external funding and specialized clinical trial management, suggests a strong commitment from Teva to advance TEV-'248 efficiently. Such partnerships are increasingly common in the pharmaceutical industry to share risk, leverage expertise, and expedite the development of high-priority assets, particularly those aligned with significant shifts in treatment paradigms, such as the move towards ICS-containing relievers in asthma. The substantial financial commitment from Abingworth underscores the perceived market potential and scientific merit of TEV-'248.

4. Pharmacokinetics

4.1. Albuterol Sulfate

Absorption: When inhaled, albuterol acts directly on bronchial smooth muscle. Systemic absorption is limited, with trace amounts appearing in the blood approximately 2 to 3 hours post-inhalation.6 Peak plasma concentrations (Cmax​) are generally low at recommended inhaled doses. For example, a high dose of 1080 mcg of albuterol base via an HFA inhaler resulted in a Cmax​ of approximately 3 ng/mL, with a time to peak concentration (Tmax​) of 0.42 hours.6 Oral albuterol tablets are rapidly absorbed, with Cmax​ achieved within 2 hours.20

Distribution: Intravenous studies in rats indicate that albuterol crosses the blood-brain barrier, reaching brain concentrations of about 5% of plasma levels.20 The volume of distribution (Vd​) in humans is reported as 156 ± 38 L.6 Specific protein binding data for inhaled albuterol were not detailed in the provided materials.

Metabolism: Albuterol is metabolized in the liver to albuterol 4'-O-sulfate, an inactive metabolite.6 Minimal metabolism occurs in the lung itself. Direct administration to the respiratory tract bypasses significant first-pass metabolism.6

Excretion: Following oral administration, approximately 76% of the dose is excreted in the urine over 3 days, with 60% of this being the metabolite.20 After inhalation, about 70% of a dose is eliminated in urine within 24 hours, and 80-100% of albuterol and its metabolites are excreted within 72 hours. Up to 10% may be excreted in feces.6 The elimination half-life (t1/2​) for inhaled albuterol ranges from 3.8 to approximately 5 hours.6 Orally administered albuterol has a half-life of about 5-6 hours.6

4.2. Fluticasone Propionate

Absorption: Fluticasone propionate acts locally in the lungs. Oral systemic bioavailability is negligible (<1%) due to incomplete absorption and extensive first-pass metabolism in the gut and liver.8 However, the portion of an inhaled dose that reaches the lungs is systemically absorbed.8 Inhaled bioavailability has been reported as 9.0% in one study 21 and varied from 6.3-18.4% in another.22 Systemic exposure (AUC) increases proportionally with inhaled doses.8 Cmax​ typically occurs in about 1 hour after inhalation.8

Distribution: Following intravenous administration, fluticasone propionate has a rapid initial disposition phase, consistent with its high lipid solubility and tissue binding. The average Vd​ is 4.2 L/kg.8 It is highly protein-bound in human plasma, averaging 99%.8

Metabolism: Fluticasone propionate is primarily cleared by hepatic metabolism via the cytochrome P450 3A4 (CYP3A4) enzyme system.8 It is hydrolyzed at the S-fluoromethyl carbothioate group to form an inactive 17$\beta$-carboxylic acid derivative, which is the only circulating metabolite detected in humans.8

Excretion: Fluticasone propionate is mainly eliminated in the feces, with less than 5% of an oral or inhaled dose excreted in the urine as metabolites.8 Following intravenous dosing, it shows polyexponential kinetics with a terminal elimination half-life of approximately 7.8 hours.8 Another study reported a half-life of 14.0 hours after IV administration and 10.8 hours after inhalation.21 Total clearance is high (average, 1,093 mL/min).8

4.3. Pharmacokinetic Considerations for the Combination (TEV-'248)

The pharmacokinetic profile of TEV-'248 will be determined by the individual properties of albuterol sulfate and fluticasone propionate. Given their different primary routes of metabolism (albuterol primarily hepatic, not extensively via CYP enzymes for its main inactivation pathway to the sulfate conjugate; fluticasone propionate extensively via CYP3A4), significant pharmacokinetic interactions between the two active components within the combination product are generally not anticipated. However, the potential for fluticasone propionate to be affected by potent CYP3A4 inhibitors remains a consideration for the combination product, as this could increase systemic exposure to the corticosteroid component.

Teva has conducted a Phase 1 clinical trial (NCT06290102) specifically to determine the pharmacokinetic profile of fluticasone propionate and albuterol sulfate when delivered in combination from TEV-'248 in children with asthma aged 4 to 11 years.[15] This study also aimed to compare the PK profiles of fluticasone propionate from two different dose strengths of TEV-'248 to that of a fluticasone propionate MDPI alone, and to compare the PK of albuterol sulfate between the two TEV-'248 strengths.[15] Understanding the pharmacokinetics in this pediatric population is crucial, as children can have different drug absorption, distribution, metabolism, and excretion characteristics compared to adults, and asthma is a prevalent condition in this age group. The results of this study, once available, will provide critical data on the systemic exposure and behavior of both components when administered together via the eMDPI in children.

5. Clinical Development Program for TEV-'248

The clinical development program for TEV-'248 (albuterol sulfate/fluticasone propionate) spans from Phase 1 to Phase 3 trials, aiming to establish its pharmacokinetic profile, safety, and efficacy as a rescue treatment for asthma in both adult and pediatric populations.

5.1. Overview of Clinical Trials

Several clinical trials are underway or have been completed for TEV-'248. These studies are designed to evaluate different aspects of the combination product, including its effect on severe asthma exacerbations, airway relaxation, and its safety and pharmacokinetic profile in various age groups. The table below summarizes key publicly available information on these trials. It is important to note that specific dosage strengths (in mcg) for the "Low Dose" and "High Dose" arms of TEV-'248 are not consistently provided in the available documentation.

Table 1: Overview of Key Clinical Trials for TEV-'248 (Albuterol Sulfate/Fluticasone Propionate)

Trial ID (NCT #, Other ID)	Phase	Brief Title/Primary Objective	Patient Population (Age, Condition)	Intervention Arms (TEV-'248 Doses, Comparator(s))	Key Primary Endpoint(s)	Status (as of latest info)	Estimated/Actual Primary Completion Date
NCT06290102 (TV56248-RES-10204)	Phase 1	Pharmacokinetic Profile and Safety of Fluticasone Propionate and Albuterol Sulfate in Combination When Compared to Fluticasone Propionate Multidose Dry Powder Inhaler (Fp MDPI)	Children 4-11 years, Asthma	TEV-56248 (2 different dose strengths), Fp MDPI	PK parameters of fluticasone propionate and albuterol sulfate (AUC0−t​, Cmax​)	Completed 13	October 2024 (Actual) 13
NCT06052267 (FpA-AS-30094, EudraCT 2023-505435-12-00)	Phase 3	A Study to Test if a Fixed-Dose Combination of Fluticasone Propionate/Albuterol Sulfate is Effective in Preventing Asthma Exacerbations / Assess efficacy of high and low dose Fp/ABS eMDPI vs ABS eMDPI in decreasing severe clinical asthma exacerbations (CAEs)	≥ 4 years, Asthma	TEV-56248 (Low Dose), TEV-56248 (High Dose), Albuterol sulfate eMDPI	Annualized severe CAE rate 25; Time to first severe asthma attack 14	Recruiting 24	July 2026 (Estimated) 25
NCT06664619 (FpA-AS-30093)	Phase 3	Planned: To demonstrate the airway relaxation effect of albuterol in the combination product.1 (Further details not available in provided snippets, title based on Teva press release description)	Adolescents, Adults, Elderly with Asthma (Adjunctive treatment) 13	Details not specified, likely TEV-'248 vs. components/placebo	Details not specified, likely related to bronchodilation (FEV1​)	Planned (Nov 2024) 13	Details not specified

Sources: 1

Note: Specific mcg dosages for "Low Dose" and "High Dose" TEV-'248 arms are not consistently detailed in the provided materials.

5.2. Phase 1 Studies (e.g., NCT06290102)

The Phase 1 study, NCT06290102, focused on the pharmacokinetic profile and safety of TEV-56248 in children aged 4 to 11 years with persistent asthma.[15] The primary objectives were to determine the PK parameters (AUC, Cmax​) of fluticasone propionate (Fp) and albuterol sulfate (ABS) delivered in combination from a single dose of TEV-56248 (Fp/ABS eMDPI), and to compare these profiles for two different dose strengths of TEV-56248 against an Fp MDPI and between the TEV-56248 strengths for ABS.[15] A secondary objective was to evaluate the safety of single doses of TEV-56248 and Fp MDPI.[15] This trial has been reported as completed [13], with an actual primary completion date of October 2024.[13] Results from this study are pending public disclosure.

5.3. Phase 3 Studies (e.g., NCT06052267 / FpA-AS-30094, NCT06664619 / FpA-AS-30093)

Two key Phase 3 studies are central to the late-stage development of TEV-'248:

• NCT06052267 (FpA-AS-30094): This is a randomized, double-blind, multicenter, active-controlled, parallel-group study evaluating the efficacy and safety of TEV-56248 on severe asthma exacerbations in patients with asthma aged 4 years and older.[24] The primary objective is to assess the efficacy of high-dose and low-dose fluticasone propionate/albuterol sulfate (Fp/ABS) eMDPI compared to albuterol sulfate (ABS) eMDPI alone in decreasing severe clinical asthma exacerbations (CAEs).[25] The primary outcome measure is the annualized severe CAE rate.[25] Another primary outcome listed for this trial (EudraCT 2023-505435-12-00) is the time to first severe asthma attack.[14] Secondary objectives include evaluating effects on systemic corticosteroid (SCS) exposure and overall safety and tolerability.[25] The study is actively recruiting, with an estimated enrollment of 2196 participants and an estimated primary completion date of July 2026.[24] Participants will use the assigned inhaler (TEV-56248 Low Dose, TEV-56248 High Dose, or Albuterol sulfate eMDPI) with a dosing frequency of 2 inhalations as needed to control asthma symptoms.[25]
• NCT06664619 (FpA-AS-30093): This Phase 3 trial is planned to start in November 2024 and aims to demonstrate the airway relaxation effect of albuterol in the TEV-'248 combination product.[1] It is intended for adolescents, adults, and elderly patients with asthma as an adjunctive treatment.[13] Further details on the specific design, endpoints, and intervention arms are not yet fully available in the provided documentation.

5.4. Dosage Strengths Investigated

The specific microgram (mcg) strengths of fluticasone propionate and albuterol sulfate within the "Low Dose" and "High Dose" TEV-'248 formulations used in the Phase 3 trial NCT06052267 are not explicitly stated in the provided public clinical trial registry information or press releases.[24] Similarly, for the Phase 1 trial NCT06290102, while "2 different dose strengths" of TEV-56248 were studied, the precise mcg values are not detailed.[15] Clinical trial information for FpA-AS-30094 (NCT06052267) refers to intervention arms as "Experimental: TEV-56248 Low Dose" and "Experimental: TEV-56248 High Dose".[25] The disclosure of these specific strengths will be critical for interpreting the clinical trial results and understanding the therapeutic window of the product.

6. Safety and Tolerability

6.1. Anticipated Safety Profile based on Individual Components

The safety profile of TEV-'248 is anticipated to reflect the known adverse effects of its individual components, albuterol sulfate and fluticasone propionate.

Albuterol Sulfate: Common adverse effects associated with inhaled albuterol include tremor, nervousness, headache, dizziness, tachycardia, and palpitations.2 More serious potential effects include paradoxical bronchospasm (worsening of wheezing immediately after inhalation), cardiovascular effects (e.g., increased heart rate, higher blood pressure, arrhythmias, QT prolongation), hypokalemia (low potassium levels), and allergic reactions (e.g., rash, angioedema).2 Excessive use can be dangerous and has been associated with fatalities in people with asthma.11

Fluticasone Propionate: Common side effects of inhaled fluticasone propionate include oral candidiasis (thrush), hoarseness (dysphonia), cough, sore throat, and upper respiratory tract infections.10 With long-term use or high doses, there is a potential for systemic corticosteroid effects, although the risk is lower with inhaled administration compared to oral corticosteroids. These can include adrenal suppression, reduced bone mineral density, glaucoma, cataracts, and effects on growth in children.7 Increased wheezing (bronchospasm) can also occur immediately after using fluticasone inhalers.9

6.2. Safety Data from Clinical Trials

As of the latest available information, detailed safety results from the TEV-'248 clinical trials have not been publicly disclosed. The Phase 1 study (NCT06290102) had safety evaluation as a secondary objective, focusing on single-dose safety in children.[15] The ongoing Phase 3 trial NCT06052267 includes the collection of adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs as outcome measures, which will provide comprehensive safety data upon completion.[25]

A significant consideration for the safety of TEV-'248, when used as an as-needed rescue inhaler, will be the cumulative exposure to inhaled corticosteroids. Patients with poorly controlled asthma might use their rescue inhaler frequently, potentially leading to higher daily doses of fluticasone propionate than if they were on a fixed-dose maintenance ICS regimen. While GINA guidelines promote the inclusion of ICS with every reliever dose to improve outcomes by addressing inflammation [1], the long-term implications of such as-needed ICS dosing patterns on systemic side effects (e.g., adrenal function, bone density, ocular health) will be a key area of interest from the Phase 3 data and any subsequent long-term extension or real-world studies. The NCT06052267 trial does include "Total Annualized SCS Exposure Over the Treatment Period" as an outcome [25], but this primarily refers to systemic corticosteroids used for treating exacerbations, not the cumulative inhaled steroid from the investigational product itself.

6.3. Contraindications, Warnings, and Precautions for the Combination

Specific contraindications for TEV-'248 will be formally established upon regulatory review. However, based on its components and information from similar ICS/SABA products like Airsupra® (albuterol/budesonide), potential contraindications would likely include:

• Hypersensitivity to albuterol sulfate, fluticasone propionate, or any of the excipients in the formulation.[5]
• If lactose is used as an excipient (as it is in Teva's ProAir Digihaler and ArmonAir Digihaler [5]), severe hypersensitivity to milk proteins could be a contraindication.[5]

Warnings and precautions would likely encompass those relevant to both ICS and SABA classes, including but not limited to [5]:

• Deterioration of asthma and acute asthma episodes.
• Paradoxical bronchospasm.
• Cardiovascular effects.
• Not exceeding recommended dosage (risk of SABA overuse).
• Immediate hypersensitivity reactions.
• Risks associated with sympathomimetic amines in patients with coexisting conditions (e.g., convulsive disorders, hyperthyroidism, diabetes).
• Hypokalemia.
• Immunosuppression and increased risk of infections (including caution with active or quiescent tuberculosis, and exposure to chickenpox or measles in susceptible individuals).
• Oropharyngeal candidiasis (advise rinsing mouth after use).
• Hypercorticism and adrenal suppression with high doses or prolonged use.
• Reduction in bone mineral density.
• Glaucoma and cataracts.
• Effects on growth in pediatric patients (monitoring growth will be important).

6.4. Potential Drug Interactions

Clinically significant drug interactions for TEV-'248 would primarily involve those known for albuterol and fluticasone propionate:

• Albuterol-related interactions:
• Beta-blockers: May block the bronchodilating effect of albuterol and induce severe bronchospasm. Generally contraindicated in asthma patients.[29]
• Non-potassium-sparing diuretics (e.g., loop or thiazide diuretics): May potentiate hypokalemia or ECG changes.[29]
• Digoxin: Albuterol may decrease serum digoxin levels.[29]
• Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants: May potentiate the action of albuterol on the cardiovascular system; use with extreme caution.[29]
• Fluticasone propionate-related interactions:
• Strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, clarithromycin): Can significantly increase systemic exposure to fluticasone propionate by inhibiting its metabolism, potentially leading to systemic corticosteroid effects like Cushing's syndrome and adrenal suppression. Concomitant use should be approached with caution.[10]

7. Regulatory Status and Market Outlook

7.1. Current Regulatory Status

Albuterol sulfate/fluticasone propionate (TEV-'248) is currently an investigational drug product. It has not yet received marketing authorization from the U.S. Food and Drug Administration (FDA) or other regulatory agencies. The product is in Phase 3 of clinical development.[1]

7.2. Potential Indications and Patient Population

TEV-'248 is being developed as a "Dual-Action Asthma Rescue Inhaler".[1] The targeted indication is the treatment of asthma, potentially for both adult and pediatric patients.[1] Clinical trials are evaluating its use in patients aged 4 years and older, including adolescents and adults.[13] If approved, it would offer an alternative to SABA-only rescue inhalers, providing both rapid symptom relief and anti-inflammatory action.

7.3. Competitive Landscape

The market for asthma therapies is extensive and includes SABA-only rescue inhalers, various ICS maintenance therapies, ICS/LABA (long-acting beta-agonist) combination maintenance therapies, and more recently, ICS/SABA combination rescue inhalers. A key competitor in the ICS/SABA rescue space is Airsupra® (albuterol/budesonide), developed by AstraZeneca and approved by the FDA.[30] TEV-'248 would compete with Airsupra® and also aim to replace SABA-only relievers as per evolving treatment guidelines. Its differentiation may lie in the specific ICS component (fluticasone propionate vs. budesonide), the delivery device (Teva's MDPI, potentially with Digihaler technology), and the breadth of its approved patient population, including pediatrics, if successfully demonstrated in trials.

7.4. Future Perspectives and Unanswered Questions

The potential approval of TEV-'248 could significantly impact asthma management by providing another option for guideline-concordant rescue therapy. Its success will depend on the full results of the Phase 3 clinical trials, particularly demonstrating a favorable efficacy and safety profile, including the long-term implications of as-needed ICS/SABA use. Key unanswered questions from the currently available information include the specific microgram strengths of fluticasone propionate and albuterol sulfate in the "Low Dose" and "High Dose" formulations being tested, which are crucial for assessing the risk-benefit profile.

Teva's significant investment in TEV-'248, evidenced by its progression to Phase 3 trials and strategic collaborations with Launch Therapeutics and Abingworth for development funding and execution [1], signals a strong belief in the product's potential. These partnerships are designed to accelerate the clinical program and manage the substantial costs associated with late-stage development. This approach reflects a strategic decision to prioritize an asset that aligns with the paradigm shift in asthma care towards ICS-containing reliever therapy, aiming to capture a share of this evolving market. The success of TEV-'248 could be a notable growth driver for Teva, leveraging its experience in respiratory medicines and digital health.

8. Comparison with Teva's Existing Digihaler Portfolio

TEV-'248, if it incorporates the Digihaler technology as suggested by the "eMDPI" designation in some trial information [14], would expand Teva's portfolio of digitally connected inhalers. This portfolio currently includes products for different aspects of asthma and COPD management.

Table 2: Teva's Inhaled Respiratory Products (Digihaler Line and Investigational TEV-'248)

Product Name	Active Ingredient(s)	Therapeutic Class	Primary Indication(s)	Delivery System Type
ProAir® Digihaler™	Albuterol Sulfate	SABA	Treatment or prevention of bronchospasm in patients $\geq$4 years with reversible obstructive airway disease; prevention of exercise-induced bronchospasm in patients $\geq$4 years 5	Breath-actuated MDPI with electronic sensor and app connectivity 5
ArmonAir® Digihaler™	Fluticasone Propionate	ICS	Maintenance treatment of asthma in patients $\geq$12 years 11	Breath-actuated MDPI with electronic sensor and app connectivity 11
AirDuo® Digihaler™	Fluticasone Propionate / Salmeterol	ICS/LABA	Treatment of asthma in patients $\geq$12 years (for patients uncontrolled on ICS or whose disease severity warrants ICS/LABA) 33	Breath-actuated MDPI with electronic sensor and app connectivity 33
TEV-'248	Albuterol Sulfate / Fluticasone Propionate	ICS/SABA (Investigational)	Investigational for as-needed rescue treatment of asthma in adults and children 1	Breath-actuated MDPI, potentially with electronic sensor and app connectivity (eMDPI) 1

Sources: [1]

The existing Digihaler products cover SABA rescue (ProAir Digihaler), ICS maintenance (ArmonAir Digihaler), and ICS/LABA maintenance (AirDuo Digihaler). TEV-'248, as an ICS/SABA combination for rescue use, would fill a distinct therapeutic niche within this portfolio, aligning with the latest asthma management recommendations.

The development of TEV-'248 represents a strategic expansion of Teva's Digihaler platform. By offering a comprehensive suite of digitally-connected inhalers for various asthma management needs (SABA rescue, ICS maintenance, ICS/LABA maintenance, and potentially ICS/SABA rescue), Teva aims to provide an integrated ecosystem. This could simplify asthma management for patients who might need to use different types of inhalers, by providing a consistent device platform. For healthcare providers, a unified Digihaler system could streamline patient training and allow for consolidated data review via the Digihaler dashboard [35], potentially leading to more informed treatment decisions. Such an integrated approach could offer Teva a competitive advantage by enhancing patient engagement and adherence.

9. Device: Digihaler Technology

The Digihaler™ system is a key feature of Teva's modern respiratory product line and is likely to be incorporated into TEV-'248, as suggested by references to it as an "eMDPI" (electronic Multi-Dose Powder Inhaler).[14]

9.1. Features of the Digihaler System

Teva's Digihaler devices are breath-actuated multi-dose dry powder inhalers that contain built-in sensors.[11] These sensors are designed to detect, record, and store data on inhaler events, including usage (e.g., number of actuations, time of use) and, for some products like ProAir Digihaler and ArmonAir Digihaler, data on peak inspiratory flow rate (L/min).[5] The inhalers are equipped with Bluetooth® wireless technology to transmit this data to a companion mobile application.[11] The device itself does not require connection to the app for medication delivery.[11] Each Digihaler also includes a dose counter.[5]

9.2. Companion Mobile Application and Dashboard

The Digihaler system includes a companion mobile app that allows patients to view their inhaler usage data over time.[11] Patients can choose to share this data with their healthcare providers.[33] Healthcare providers, with patient consent, can access this inhaler event data through a secure online platform called the Digihaler Dashboard.[35] This dashboard enables HCPs to view data from single or multiple patients, assess usage patterns and inspiratory flow rates, and access daily, weekly, or monthly reports.[35] The app may also offer features like medication reminders.[33]

9.3. Benefits and Limitations of Digital Inhaler Technology

Digital inhaler technology, such as Teva's Digihaler system, offers several potential benefits. These include the possibility of improved medication adherence through tracking and reminders, more informed treatment discussions between patients and HCPs based on objective usage data, and increased patient engagement in their own asthma management.[33]

However, there are also limitations and considerations. Data privacy and security are paramount concerns when dealing with health information. Patient and HCP adoption and consistent use of the digital features are necessary for the system to be effective. The cost-effectiveness of such technology also needs to be considered. Furthermore, while the technology provides data on inhaler use, translating this into proven improvements in hard clinical outcomes, such as reduced exacerbation rates or hospitalizations solely due to the digital features, is an ongoing area of evaluation. For instance, the prescribing information for ArmonAir Digihaler explicitly states that "There is no evidence the use of the App leads to improved clinical outcomes, including safety and effectiveness".[37] This underscores that while the data capture is innovative, its direct impact on improving clinical outcomes beyond adherence monitoring requires further robust evidence. The ultimate value proposition of digital inhalers will depend on demonstrating tangible clinical and economic benefits to patients, healthcare systems, and payers.

10. Conclusion

TEV-'248, Teva Pharmaceutical Industries' investigational fixed-dose combination of albuterol sulfate and fluticasone propionate, represents a significant development in asthma therapeutics. Designed as a dual-action rescue inhaler delivered via a multi-dose dry powder inhaler (likely incorporating Digihaler technology), it aims to provide both rapid symptom relief and address underlying airway inflammation, aligning with current GINA recommendations that advocate for ICS-containing reliever therapy.

The individual components, albuterol sulfate (a SABA) and fluticasone propionate (an ICS), have well-established efficacy and safety profiles. The ongoing Phase 3 clinical trials are crucial for determining the efficacy of TEV-'248 in reducing severe asthma exacerbations and its overall safety profile in diverse patient populations, including children and adults. The pharmacokinetic profile, particularly in children, is also under investigation.

The strategic collaborations and funding secured by Teva highlight the company's commitment to this program and the perceived potential of TEV-'248 in the evolving asthma market. If successful, TEV-'248 would not only offer a new therapeutic option but also expand Teva's Digihaler portfolio, potentially creating a more integrated digital ecosystem for asthma management.

However, final conclusions on the clinical utility, safety, and specific role of TEV-'248 in asthma management must await the complete results from the Phase 3 clinical trials and subsequent regulatory review. Key data, including the precise dosage strengths of the "Low Dose" and "High Dose" formulations and long-term safety data for as-needed ICS/SABA use, will be critical for a comprehensive assessment.

11. References

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