Comprehensive Pulmonary Safety Review of Inhaled Technosphere ®  Insulin in Patients with Diabetes Mellitus

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Abstract

Background and Objective

Technosphere ^® Insulin (TI), a human insulin powder for inhalation (Afrezza ^®; MannKind Corporation, Westlake Village, CA, USA), is an ultra-rapid-acting inhaled insulin indicated to improve postprandial glycemic control in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Because TI is absorbed across the alveolar membrane, the objective of this analysis was to characterize its pulmonary safety.

Methods

Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies. Radiographic changes in the lungs were monitored in a subset of 229 patients.

Results

Among 3017 patients receiving TI, the median duration of TI exposure was 168 days; median active-comparator and TP exposure durations were 363 and 149 days for 2198 and 290 patients, respectively. Respiratory TEAEs were comparable across treatments, except for a higher incidence of mild cough with TI in active-comparator studies (28.0% vs. 5.2%). Slight reversible declines in pulmonary function from baseline were observed for TI versus TP and active-comparator treatments, including in a subpopulation of patients with retrospectively identified lung dysfunction. Lung malignancies were reported in two patients on active TI therapy with a smoking history. No clinically significant changes from baseline were observed in radiographic images.

Conclusions

Pulmonary safety assessment of the TI inhalation system did not identify any safety issues in individuals with either T1DM or T2DM.

Electronic supplementary material

The online version of this article (10.1007/s40261-020-00958-8) contains supplementary material, which is available to authorized users.

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Most cited references 16

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Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the Fremantle Diabetes Study.

P Kendall, Matthew Knuiman, Daniel M Davis … (2004)

To examine prospectively the relationship between diabetes, glycemic control, and spirometric measures. From a community-based cohort, 495 Europid (i.e., of European descent) patients with type 2 diabetes who had no history of pulmonary disease underwent baseline spirometry between 1993 and 1994. A subset of 125 patients was restudied a mean of 7.0 years later. The main outcome measures included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), vital capacity (VC), and peak expiratory flow (PEF) corrected for body temperature, air pressure, and water saturation and were expressed either in absolute terms or as percentage-predicted value for age, sex, and height. Mean percentage-predicted values of each spirometric measure were decreased >10% in the whole cohort at baseline and absolute measures continued to decline at an annual rate of 68, 71, and 84 ml/year and 17 l/min for FVC, FEV1, VC, and PEF, respectively, in the 125 prospectively studied patients. Declining lung function measures were consistently predicted by poor glycemic control in the form of a higher updated mean HbA1c, follow-up HbA1c, or follow-up fasting plasma glucose. In a Cox proportional hazards model, decreased FEV1 percentage-predicted value was an independent predictor of all-cause mortality. Reduced lung volumes and airflow limitation are likely to be chronic complications of type 2 diabetes, the severity of which relates to glycemic exposure. Airflow limitation is a predictor of death in type 2 diabetes after adjusting for other recognized risk factors.

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Inhaled antibiotics for lower airway infections.

Bradley S. Quon, Christopher Goss, Bonnie W Ramsey (2014)

Inhaled antibiotics have been used to treat chronic airway infections since the 1940s. The earliest experience with inhaled antibiotics involved aerosolizing antibiotics designed for parenteral administration. These formulations caused significant bronchial irritation due to added preservatives and nonphysiologic chemical composition. A major therapeutic advance took place in 1997, when tobramycin designed for inhalation was approved by the U.S. Food and Drug Administration (FDA) for use in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infection. Attracted by the clinical benefits observed in CF and the availability of dry powder antibiotic formulations, there has been a growing interest in the use of inhaled antibiotics in other lower respiratory tract infections, such as non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and in the post-lung transplant setting over the past decade. Antibiotics currently marketed for inhalation include nebulized and dry powder forms of tobramycin and colistin and nebulized aztreonam. Although both the U.S. Food and Drug Administration and European Medicines Agency have approved their use in CF, they have not been approved in other disease areas due to lack of supportive clinical trial evidence. Injectable formulations of gentamicin, tobramycin, amikacin, ceftazidime, and amphotericin are currently nebulized "off-label" to manage non-CF bronchiectasis, drug-resistant nontuberculous mycobacterial infections, ventilator-associated pneumonia, and post-transplant airway infections. Future inhaled antibiotic trials must focus on disease areas outside of CF with sample sizes large enough to evaluate clinically important endpoints such as exacerbations. Extrapolating from CF, the impact of eradicating organisms such as P. aeruginosa in non-CF bronchiectasis should also be evaluated.

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Is Open Access

Rate of normal lung function decline in ageing adults: a systematic review of prospective cohort studies

Elizabeth T. Thomas, Michelle Guppy, Sharon E Straus … (2019)

Objective To conduct a systematic review investigating the normal age-related changes in lung function in adults without known lung disease. Design Systematic review. Data sources MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched for eligible studies from inception to February 12, 2019, supplemented by manual searches of reference lists and clinical trial registries. Eligibility criteria We planned to include prospective cohort studies and randomised controlled trials (control arms) that measured changes in lung function over time in asymptomatic adults without known respiratory disease. Data extraction and synthesis Two authors independently determined the eligibility of studies, extracted data and assessed the risk of bias of included studies using the modified Newcastle–Ottawa Scale. Results From 4385 records screened, we identified 16 cohort studies with 31 099 participants. All included studies demonstrated decline in lung function—forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) with age. In studies with longer follow-up (>10 years), rates of FEV1 decline ranged from 17.7 to 46.4 mL/year (median 22.4 mL/year). Overall, men had faster absolute rates of decline (median 43.5 mL/year) compared with women (median 30.5 mL/year). Differences in relative FEV1 change, however, were not observed between men and women. FEV1/FVC change was reported in only one study, declining by 0.29% per year. An age-specific analysis suggested the rate of FEV1 function decline may accelerate with each decade of age. Conclusions Lung function—FEV1, FVC and PEFR—decline with age in individuals without known lung disease. The definition of chronic airway disease may need to be reconsidered to allow for normal ageing and ensure that people likely to benefit from interventions are identified rather than healthy people who may be harmed by potential overdiagnosis and overtreatment. The first step would be to apply age, sex and ethnicity-adjusted FEV1/FVC thresholds to the disease definition of chronic obstructive pulmonary disease. PROSPERO registration number CRD42018087066.

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Author and article information

Contributors

David M. Kendall:

ORCID: http://orcid.org/0000-0003-1910-2587

dkendall@mannkindcorp.com

Journal

Journal ID (nlm-ta): Clin Drug Investig

Journal ID (iso-abbrev): Clin Drug Investig

Title: Clinical Drug Investigation

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1173-2563

ISSN (Electronic): 1179-1918

Publication date (Electronic): 27 July 2020

Publication date PMC-release: 27 July 2020

Publication date (Print): 2020

Volume: 40

Issue: 10

Pages: 973-983

Affiliations

[1 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Washington University School of Medicine, ; St Louis, MO USA

[2 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA USA

[3 ]GRID grid.10698.36, ISNI 0000000122483208, University of North Carolina School of Medicine, ; Chapel Hill, NC USA

[4 ]GRID grid.419405.d, ISNI 0000 0004 0410 1247, MannKind Corporation, ; Westlake Village, CA USA

[5 ]Arcutis Biotherapeutics, Inc, Westlake Village, CA USA

Author information

David M. Kendall http://orcid.org/0000-0003-1910-2587

Article

Publisher ID: 958

DOI: 10.1007/s40261-020-00958-8

PMC ID: 7511468

PubMed ID: 32720187

SO-VID: 7fe54f37-796e-49f3-ac09-0a89302df349

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100014598, MannKind Corporation;

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Comprehensive Pulmonary Safety Review of Inhaled Technosphere ^® Insulin in Patients with Diabetes Mellitus

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Abstract

Background and Objective

Methods

Results

Conclusions

Electronic supplementary material

Related collections

In vitro alveolar region models

Most cited references 16

Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the Fremantle Diabetes Study.

Inhaled antibiotics for lower airway infections.

Rate of normal lung function decline in ageing adults: a systematic review of prospective cohort studies

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