The Patients' Experience of Severe Asthma Add-On Pharmacotherapies: A Qualitative Descriptive Study.

PURPOSE: Add-on therapies for severe asthma are continually emerging with proven efficacy in randomised controlled trials. To date, however, there are no qualitative studies exploring patients' experiences with these treatments. We aimed to understand the experience of patients who were treated with an add-on therapy for their severe asthma. PATIENTS AND METHODS: A qualitative descriptive study was conducted, participants were recruited from the respiratory clinics and databases of a tertiary referral hospital. Participants with treatment-refractory severe asthma (n=20) prescribed an add-on therapy for >4 months (75% mepolizumab; 25% omalizumab, and 25% macrolide) were recruited. Qualitative semi-structured interviews were conducted, with interviews thematically analysed. RESULTS: Participants' mean (SD) age was 59.5 (15.3) years, and 50% were male. Participants reported 4.5 (2.3) exacerbations in the past year. Asthma Control Questionnaire score was 2.0 (1.4). The monoclonal add-on therapies had been prescribed for a median (IQR) of 12.5 (7.0, 24.0) months. Experience was captured in four emergent themes: "Life is just easier" provided an overall message that the add-on therapy made the participants' life easier in terms of increasing participation, levelling out symptoms, providing more energy and reducing healthcare use. "Prednisone: A necessary evil" was discussed, particularly in terms of dose and dependence and damaging side effects. The theme "worry and hope for the future" referenced treatment non-response or cessation of effect which was discussed by some participants. Finally, "holistic care" was centred on the sentiment that the participant's asthma management and overall health were not related to one aspect or medication alone. CONCLUSION: Patients with severe asthma experience vast improvements in quality-of-life and life participation with add-on therapies, but there remains a significant burden related to oral corticosteroids and incomplete treatment responses. Addressing this residual burden is an important area for future research.

Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody.

Systemic cytokine release and on-target/off-tumor toxicity to normal tissues are the main adverse effects limiting the clinical utility of T cell-redirecting therapies. This study was designed to determine how binding affinity for CD3 and tumor target HER2 impact the efficacy and nonclinical safety of anti-HER2/CD3 T cell-dependent antibodies (TDBs). Affinity was found to be a major determinant for the overall tolerability. Higher affinity for CD3 associated with rapidly elevated peripheral cytokine concentrations, weight loss in mice, and poor tolerability in cynomolgus monkeys. A TDB with lower CD3 affinity was better tolerated in cynomolgus monkeys compared with a higher CD3-affinity TDB. In contrast to tolerability, T cell binding affinity had only limited impact on in vitro and in vivo antitumor activity. High affinity for HER2 was critical for the tumor-killing activity of anti-HER2/CD3 TDBs, but higher HER2 affinity also associated with a more severe toxicity profile, including cytokine release and damage to HER2-expressing tissues. The tolerability of the anti-HER2/CD3 was improved by implementing a dose-fractionation strategy. Fine-tuning the affinities for both the tumor target and CD3 is likely a valuable strategy for achieving maximal therapeutic index of CD3 bispecific antibodies.

Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report.

"Treatable traits" have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.