Lung Delivery of Indacaterol and Mometasone Furoate Following Inhalation of QMF149 via the Twisthaler® Device in Healthy Volunteers

QMF149 is a once-daily fixed-dose combination of the long-acting β2-agonist indacaterol and the inhaled corticosteroid mometasone furoate (MF) under development for the treatment of asthma and chronic obstructive pulmonary disease. This study evaluated the contribution of pulmonary and gastrointestinal (GI) absorption to the systemic exposure of indacaterol and MF following inhalation of QMF149 via the Twisthaler® device. This was an open-label, single-dose, four-period crossover study in 20 healthy subjects. Pharmacokinetics of indacaterol and MF were evaluated after inhalation of QMF149 (indacaterol maleate/MF) 500/400 μg via the Twisthaler® device with and without post-dose mouth rinsing, and in the presence of activated charcoal. Indacaterol alone was evaluated after inhalation of indacaterol maleate 300 μg via the Breezhaler® device. The relative bioavailability of indacaterol and MF for inhalation with vs. without activated charcoal, based on AUClast, was 0.25 (90% confidence interval [CI]: 0.18, 0.35) and 0.70 (90% CI: 0.52, 0.93), respectively. Thus, 25% of systemic exposure of indacaterol and 70% of systemic exposure of MF after inhalation via the Twisthaler® device were due to lung absorption and 75% and 30%, respectively, were due to GI absorption. Total systemic exposure of indacaterol was higher (~1.5 fold) when administered without mouth rinsing, whereas no relevant effect of mouth rinsing was seen for MF. Dose normalized AUClast for indacaterol inhaled via the Breezhaler® device was 2.3-fold higher than that for QMF149 via the Twisthaler® device. All treatments had a good safety profile and were well tolerated. Comparison with data from a similar charcoal block study of indacaterol inhaled via the Breezhaler® device showed that the Breezhaler® device was more efficient than the Twisthaler® device for lung delivery of indacaterol

Efficacy and safety of QGE031, a novel anti-IgE antibody, in atopic subjects

Background: Omalizumab has a mid-range affinity for IgE, and the clinical effects of deeper IgE suppression are largely unknown. Objective: To explore the safety, pharmacokinetics and pharmacodynamics of QGE031, a novel high-affinity anti-IgE antibody. Methods: Preclinical assessments and two randomized, placebo-controlled, double-blind clinical trials were conducted in atopic subjects. The first trial administered QGE031 (0.1-10 mg/kg) or placebo intravenously, while the second trial administered QGE031 (0.2- 4 mg/kg) or placebo subcutaneously. Both trials included an open-label omalizumab arm. Results: Sixty of seventy-three (82%) and 96/110 (87%) subjects completed the intravenous and subcutaneous studies, respectively. Exposure to QGE031 and its half-life were dependent on the dose of QGE031 and serum IgE level. QGE031 had a biexponential pharmacokinetic profile after intravenous administration and a terminal half-life of approximately 20 days (subcutaneous study; range, 13-26 days). QGE031 demonstrated dose- and time-dependent suppression of free IgE, basophil FcεRI and basophil surface IgE superior in extent (free IgE and surface IgE) and duration to omalizumab. At Day 85, six weeks after the last dose, skin-prick wheal responses to allergen were suppressed by >95% and 41% in subjects treated subcutaneously with QGE031 (2 mg/kg) or omalizumab, respectively (P < .001). Urticaria was observed in QGE031- and placebo-treated subjects and was accompanied by systemic symptoms in one subject treated with 10 mg/kg intravenous QGE031. There were no serious adverse events. Conclusion and clinical relevance: These are the first clinical data obtained with QGE031, a novel anti-IgE monoclonal antibody; they demonstrate that increased suppression of free IgE compared with omalizumab translated to superior reduction of pharmacodynamic endpoints in atopic subjects, including those with high levels of IgE. QGE031 may therefore benefit patients unable to receive, or not optimally treated with, omalizumab

Patient perspectives on current and potential therapies and clinical trial approaches for cocaine use disorder

BackgroundCocaine use disorder (CUD) is characterized by the continued use of cocaine despite serious impacts on life. This study focused on understanding the perspective of individuals with current CUD, individuals in CUD remission, and their supporters regarding current therapies, future therapies, and views on clinical trials for CUD.MethodsThe online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. Following completion of a screening questionnaire to determine eligibility, individuals in CUD remission and their supporters logged in to the OBB and responded to questions posed by the moderator. Individuals with current CUD participated in a one-time virtual focus group.ResultsAll individuals with current CUD and 94% of those in CUD remission reported a diagnosis consistent with CUD or substance use disorder during screening. Individuals with current CUD and their supporters were recruited from the United States (US). Individuals in CUD remission were recruited from five countries, including the US. Individuals with current CUD reported hesitation about seeking treatment due to stigma, a lack of privacy, and being labeled as a drug seeker; barriers to therapy included time, cost, and a lack of privacy. Participants wanted a safe therapy to stop cravings and withdrawal symptoms. Seven clinical trial outcomes, including long-term abstinence and craving control, were suggested based on collected insights.ConclusionThis study can help inform the design of clinical trials and emphasize the need for effective, safe, and accessible therapies. Recruiting participants will require significant trust building

DataSheet_1_Patient perspectives on current and potential therapies and clinical trial approaches for cocaine use disorder.docx

BackgroundCocaine use disorder (CUD) is characterized by the continued use of cocaine despite serious impacts on life. This study focused on understanding the perspective of individuals with current CUD, individuals in CUD remission, and their supporters regarding current therapies, future therapies, and views on clinical trials for CUD.MethodsThe online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. Following completion of a screening questionnaire to determine eligibility, individuals in CUD remission and their supporters logged in to the OBB and responded to questions posed by the moderator. Individuals with current CUD participated in a one-time virtual focus group.ResultsAll individuals with current CUD and 94% of those in CUD remission reported a diagnosis consistent with CUD or substance use disorder during screening. Individuals with current CUD and their supporters were recruited from the United States (US). Individuals in CUD remission were recruited from five countries, including the US. Individuals with current CUD reported hesitation about seeking treatment due to stigma, a lack of privacy, and being labeled as a drug seeker; barriers to therapy included time, cost, and a lack of privacy. Participants wanted a safe therapy to stop cravings and withdrawal symptoms. Seven clinical trial outcomes, including long-term abstinence and craving control, were suggested based on collected insights.ConclusionThis study can help inform the design of clinical trials and emphasize the need for effective, safe, and accessible therapies. Recruiting participants will require significant trust building.</p

Presentation_1_Understanding the patient and supporter journey in cocaine use disorder.pdf

BackgroundThere is a paucity of literature describing experiences and journey of individuals with cocaine use disorder (CUD) and supporters who care for them. The aim of this study was to understand and document the journey of individuals with current CUD, those in CUD remission, and supporters.MethodsThe online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. After completing a 15-minute screening questionnaire determining eligibility, individuals in CUD remission and supporters participated in an OBB for 60 minutes, split across 8 days over 2 weeks. Individuals with current CUD participated in a one-time virtual focus group discussion for 90 minutes.ResultsIndividuals in CUD remission (n=35) were from Brazil, France, Spain, the UK, and the US; those with current CUD (n=5) and supporters (n=6) were from the US. Key insights were that individuals with current CUD were seeking a ‘euphoric high’ that cocaine provides. Those in CUD remission described a ‘euphoric high’ when they first tried cocaine, but over time it became harder to re-create this feeling. Individuals in CUD remission expressed a ‘rollercoaster’ of emotions from when they first started using cocaine to when they stopped. Supporters were sad, isolated, and worried about a potential cocaine overdose for their loved ones with CUD.ConclusionThe study provides valuable insights into the experiences and journey of individuals with CUD and their supporters. Data generated from this study gives insights into this under-served and growing population.</p

Presentation_2_Understanding the patient and supporter journey in cocaine use disorder.pdf

BackgroundThere is a paucity of literature describing experiences and journey of individuals with cocaine use disorder (CUD) and supporters who care for them. The aim of this study was to understand and document the journey of individuals with current CUD, those in CUD remission, and supporters.MethodsThe online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. After completing a 15-minute screening questionnaire determining eligibility, individuals in CUD remission and supporters participated in an OBB for 60 minutes, split across 8 days over 2 weeks. Individuals with current CUD participated in a one-time virtual focus group discussion for 90 minutes.ResultsIndividuals in CUD remission (n=35) were from Brazil, France, Spain, the UK, and the US; those with current CUD (n=5) and supporters (n=6) were from the US. Key insights were that individuals with current CUD were seeking a ‘euphoric high’ that cocaine provides. Those in CUD remission described a ‘euphoric high’ when they first tried cocaine, but over time it became harder to re-create this feeling. Individuals in CUD remission expressed a ‘rollercoaster’ of emotions from when they first started using cocaine to when they stopped. Supporters were sad, isolated, and worried about a potential cocaine overdose for their loved ones with CUD.ConclusionThe study provides valuable insights into the experiences and journey of individuals with CUD and their supporters. Data generated from this study gives insights into this under-served and growing population.</p

DataSheet_2_Patient perspectives on current and potential therapies and clinical trial approaches for cocaine use disorder.docx

BackgroundCocaine use disorder (CUD) is characterized by the continued use of cocaine despite serious impacts on life. This study focused on understanding the perspective of individuals with current CUD, individuals in CUD remission, and their supporters regarding current therapies, future therapies, and views on clinical trials for CUD.MethodsThe online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. Following completion of a screening questionnaire to determine eligibility, individuals in CUD remission and their supporters logged in to the OBB and responded to questions posed by the moderator. Individuals with current CUD participated in a one-time virtual focus group.ResultsAll individuals with current CUD and 94% of those in CUD remission reported a diagnosis consistent with CUD or substance use disorder during screening. Individuals with current CUD and their supporters were recruited from the United States (US). Individuals in CUD remission were recruited from five countries, including the US. Individuals with current CUD reported hesitation about seeking treatment due to stigma, a lack of privacy, and being labeled as a drug seeker; barriers to therapy included time, cost, and a lack of privacy. Participants wanted a safe therapy to stop cravings and withdrawal symptoms. Seven clinical trial outcomes, including long-term abstinence and craving control, were suggested based on collected insights.ConclusionThis study can help inform the design of clinical trials and emphasize the need for effective, safe, and accessible therapies. Recruiting participants will require significant trust building.</p

TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease

The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro, administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonical NF-?B signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF-?B signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify the TWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression