A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical Trials.

Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo-controlled clinical studies: a phase Ia single ascending-dose study (7-700 mg subcutaneously (s.c.)) in healthy subjects and a phase Ib multiple ascending-dose study (70-420 mg s.c. every 2 weeks (q2w)) in patients with rheumatoid arthritis. Rozibafusp alfa exhibited nonlinear PK and dose-related and reversible dual-target engagement. Maximal reduction of naïve B cells from baseline (> 40%), reflective of BAFF inhibition, was achieved with rozibafusp alfa exposure (area under the concentration-time curve from time 0 to time infinity (AUCinf ) and AUC within a dosing interval from day 0 to day 14 (AUCtau )) above 51 and 57 days•µg/mL for the single-dose (≥ 70 mg) and multiple-dose studies (≥ 70 mg q2w), respectively. ICOSL receptor occupancy on circulating B cells, a surrogate PD end point for ICOSL inhibition, was directly related to drug concentration. PK/PD analysis showed > 90% RO at rozibafusp alfa ≥ 22.2 µg/mL (≥ 420-mg single dose or ≥ 210 mg q2w multiple dose), with saturation occurring at higher drug concentrations. These results informed the design and dose selection of a phase IIb study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus.

Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials.

Rationale: Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT03347279) trials. Objectives: To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR. Methods: PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs. This pooled analysis included patients with severe, uncontrolled asthma (PATHWAY, 18-75 years old; NAVIGATOR, 12-80 years old) who received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The annualized asthma exacerbation rate over 52 weeks and secondary outcomes were calculated in the overall population and in subgroups defined by inflammatory biomarker levels or clinical characteristics. Measurements and Main Results: Overall, 1,334 patients were included (tezepelumab, n = 665; placebo, n = 669). Tezepelumab reduced the annualized asthma exacerbation rate versus placebo by 60% (rate ratio, 0.40 [95% confidence interval, 0.34-0.48]) in the overall population, and clinically meaningful reductions in exacerbations were observed in tezepelumab-treated patients with type 2-high and type 2-low disease by multiple definitions. Tezepelumab reduced exacerbation-related hospitalization or emergency department visits and improved secondary outcomes compared with placebo overall and across subgroups. The incidence of adverse events was similar between treatment groups. Conclusions: Tezepelumab resulted in clinically meaningful reductions in exacerbations and improvements in other outcomes in patients with severe, uncontrolled asthma, across clinically relevant subgroups. Clinical trials registered with www.clinicaltrials.gov (NCT02054130 [PATHWAY], NCT03347279 [NAVIGATOR]).

Tezepelumab and Mucus Plugs in Patients with Moderate-to-Severe Asthma.

Tezepelumab and Mucus Plugs in Patients with AsthmaMucus plugs in airways of asthma patients are associated with airway obstruction and the activity of inflammatory cytokines. This article reports prespecified and post hoc analyses of the effect of tezepelumab treatment on mucus plugs identified by computed tomography imaging in patients with moderate-to-severe asthma. At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers and negatively with lung function measures. Patients treated with tezepelumab had resolution of more mucus plugs than patients taking placebo.

Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study.

OBJECTIVE: To assess the safety and biological activity of rozibafusp alfa, a first-in-class bispecific antibody-peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). METHODS: This phase 1b, double-blind, placebo-controlled, multiple ascending dose study included 34 patients (18-75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints-C-reactive protein [DAS28-CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow-up. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28-CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease). RESULTS: TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t1/2  = 4.6-9.5 days) and dose-related, reversible PD (>90% ICOSL receptor occupancy in 210- and 420-mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti-rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210- and 420-mg cohorts. CONCLUSION: Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease.

Targeting TSLP in Asthma.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the initiation and persistence of inflammatory pathways in asthma. Released in response to a range of epithelial insults (eg, allergens, viruses, bacteria, pollutants, and smoke), TSLP initiates multiple downstream innate and adaptive immune responses involved in asthma inflammation. Inhibition of TSLP is postulated to represent a novel approach to treating the diverse phenotypes and endotypes of asthma. Tezepelumab, the TSLP inhibitor farthest along in clinical development, is a human monoclonal antibody (IgG2λ) that binds specifically to TSLP, preventing interactions with its heterodimeric receptor. Results of recently published phase 2 and 3 studies, reviewed in this article, provide evidence of the safety and efficacy of tezepelumab that builds on initial findings. Tezepelumab is safe, well tolerated, and provides clinically meaningful improvements in asthma control, including reduced incidence of exacerbations and hospitalizations in patients with severe asthma. Clinical benefits were associated with reductions in levels of a broad spectrum of cytokines (eg, interleukin [IL]-5, IL-13) and baseline biomarkers (eg, blood eosinophils, immunoglobulin [Ig]E, fractional exhaled nitric oxide [FeNO]) and were observed across a range of severe asthma phenotypes (ie, eosinophilic and non-eosinophilic). These data strengthen the notion that anti-TSLP elicits broad inhibitory effects on pathways that are key to asthma inflammation rather than on narrower inhibition of individual downstream factors. This review presents the rationale for targeting TSLP to treat asthma, as well as the clinical effects of TSLP blockade on asthma outcomes, biomarkers of disease activity, airway inflammation, lung physiology, and patient symptoms.

Baseline type 2 biomarker levels and response to tezepelumab in severe asthma.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER. METHODS: Adults with severe, uncontrolled asthma (n = 550) were randomized to tezepelumab (70 mg or 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. Blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum total immunoglobulin (Ig)E, interleukin (IL)-5, IL-13, periostin, thymus and activation-regulated chemokine (TARC), and TSLP were measured at baseline and over 52 weeks. AAERs were analyzed by baseline threshold (high/low) biomarker levels. RESULTS: Positive correlations were observed between T2 inflammatory biomarkers (blood eosinophil count, FeNO, IL-5, IL-13 and periostin) at baseline. At Week 52, treatment with tezepelumab 210 mg reduced all biomarker levels measured from baseline versus placebo. Exacerbations were reduced by 55-83% in the pooled tezepelumab cohort versus placebo, irrespective of baseline blood eosinophil count, FeNO, or serum total IgE, IL-5, IL-13, periostin, TARC, or TSLP, when these biomarkers were assessed individually. CONCLUSION: At baseline, positive correlations between specific T2 inflammatory biomarkers were observed. Tezepelumab reduced multiple T2 inflammatory biomarkers, which indicates decreased airway inflammation, and reduced exacerbations irrespective of baseline T2 biomarker profiles in patients with severe asthma.

Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target.

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma and Perennial Allergy.

BACKGROUND: Tezepelumab is an anti-thymic stromal lymphopoietin mAb. In the PATHWAY phase IIb study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. OBJECTIVE: This post hoc analysis assessed the efficacy of tezepelumab in PATHWAY participants with perennial allergy. METHODS: Adults (N = 550) with severe, uncontrolled asthma were randomized to receive tezepelumab (70 mg or 210 mg every 4 weeks or 280 mg every 2 weeks) or placebo, for 52 weeks. The AAER over 52 weeks was analyzed in patients grouped by sensitivity to perennial aeroallergens and by eligibility for omalizumab treatment according to the US or European Union prescribing information. Change from baseline to week 52 in prebronchodilator FEV1 and type 2 biomarkers was assessed in the perennial allergy subgroups. RESULTS: Across doses, tezepelumab reduced the AAER versus placebo by 66% to 78% in patients with perennial allergy (n = 254) and 67% to 71% in patients without perennial allergy (n = 261). Tezepelumab improved prebronchodilator FEV1 and reduced blood eosinophil counts and fractional exhaled nitric oxide levels over 52 weeks, irrespective of perennial allergy status. Tezepelumab reduced the AAER versus placebo by 61% to 82% in omalizumab-eligible patients (US, n = 159; European Union, n = 101) and 63% to 70% in omalizumab-ineligible patients (US, n = 372; European Union, n = 440), respectively. CONCLUSIONS: Treatment with tezepelumab reduced exacerbations, improved lung function, and reduced type 2 biomarkers versus placebo in patients with severe, uncontrolled asthma with or without perennial allergy, further supporting its efficacy in a broad population of patients with severe, uncontrolled asthma.

Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine. In phase 2b and 3 studies, tezepelumab significantly reduced exacerbations versus placebo in patients with severe uncontrolled asthma, irrespective of baseline levels of type 2 inflammatory biomarkers. We investigated the mechanism of action of tezepelumab by assessing its effects on airway inflammatory cells, airway remodelling, and airway hyperresponsiveness. METHODS: CASCADE was an exploratory, double-blind, randomised, placebo-controlled, parallel-group, phase 2 study done in 27 medical centres in Canada, Denmark, Germany, the UK, and the USA. Adults aged 18-75 years with uncontrolled, moderate-to-severe asthma were randomly assigned (1:1) to receive tezepelumab 210 mg or placebo administered subcutaneously every 4 weeks for a planned 28 weeks, extended to up to 52 weeks if COVID-19-related disruption delayed participants' end-of-treatment assessments. Randomisation was balanced and stratified by blood eosinophil count. The primary endpoint was the change from baseline to the end of treatment in the number of airway submucosal inflammatory cells in bronchoscopic biopsy samples. Eosinophils, neutrophils, CD3+ T cells, CD4+ T cells, tryptase+ mast cells, and chymase+ mast cells were evaluated separately. This endpoint was also assessed in subgroups according to baseline type 2 inflammatory biomarker levels, including blood eosinophil count. Airway remodelling was assessed via the secondary endpoints of change from baseline in reticular basement membrane thickness and epithelial integrity (proportions of denuded, damaged, and intact epithelium). Exploratory outcomes included airway hyperresponsiveness to mannitol. All participants who completed at least 20 weeks of study treatment, had an end-of-treatment visit up to 8 weeks after the last dose of study drug, and had evaluable baseline and end-of-treatment bronchoscopies were included in the primary efficacy analysis. All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, NCT03688074. FINDINGS: Between Nov 2, 2018, and Nov 16, 2020, 250 patients were enrolled, 116 of whom were randomly assigned (59 to tezepelumab, 57 to placebo). 48 in the tezepelumab group and 51 in the placebo group completed the study and were assessed for the primary endpoint. Treatment with tezepelumab resulted in a nominally significantly greater reduction from baseline to the end of treatment in airway submucosal eosinophils versus placebo (ratio of geometric least-squares means 0·15 [95% CI 0·05-0·41]; nominal p<0·0010), with the difference seen across all baseline biomarker subgroups. There were no significant differences between treatment groups in the other cell types evaluated (ratio of geometric least-squares means: neutrophils 1·36 [95% CI 0·94-1·97]; CD3+ T cells 1·12 [0·86-1·46]; CD4+ T cells 1·18 [0·90-1·55]; tryptase+ mast cells 0·83 [0·61-1·15]; chymase+ mast cells 1·19 [0·67-2·10]; all p>0·10). In assessment of secondary endpoints, there were no significant differences between treatment groups in reticular basement membrane thickness and epithelial integrity. In an exploratory analysis, the reduction in airway hyperresponsiveness to mannitol was significantly greater with tezepelumab versus placebo (least-squares mean change from baseline in interpolated or extrapolated provoking dose of mannitol required to induce ≥15% reduction in FEV1 from baseline: tezepelumab 197·4 mg [95% CI 107·9 to 286·9]; placebo 58·6 mg [-30·1 to 147·33]; difference 138·8 [14·2 to 263·3], nominal p=0·030). Adverse events were reported in 53 (90%) patients in the tezepelumab group and 51 (90%) patients in the placebo group, and there were no safety findings of concern. INTERPRETATION: The improvements in asthma clinical outcomes observed in previous studies with tezepelumab are probably driven, at least in part, by reductions in eosinophilic airway inflammation, as shown here by reduced airway eosinophil counts regardless of baseline blood eosinophil count. Tezepelumab also reduced airway hyperresponsiveness to mannitol, indicating that TSLP blockade might have additional benefits in asthma beyond reducing type 2 airway inflammation. FUNDING: AstraZeneca and Amgen.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma with and without Nasal Polyposis: A Post Hoc Analysis of the Phase 2b PATHWAY Study.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine implicated in asthma pathogenesis, from binding to its heterodimeric receptor. In the phase 2b PATHWAY study, tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control, in adults with severe, uncontrolled asthma. This post hoc analysis assessed the efficacy of tezepelumab in adults with severe, uncontrolled asthma with and without nasal polyposis (NP). METHODS: In this post hoc analysis of the PATHWAY study (NCT02054130), participants (N=550) were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The AAER over 52 weeks and the change from baseline to week 52 in blood eosinophil count, fractional exhaled nitric oxide (FeNO) levels and serum levels of interleukin (IL)-5 and IL-13 with tezepelumab 210 mg (the phase 3 dose) and placebo were analyzed in patients grouped by self-reported presence (NP+) or absence (NP-) of NP at screening. RESULTS: At baseline, NP+ patients had higher blood eosinophil counts, higher FeNO levels and higher serum IL-5 and IL-13 levels than NP- patients. Tezepelumab 210 mg reduced the AAER versus placebo to a similar extent in both NP+ and NP- patients (NP+, 75% [95% confidence interval (CI): 15, 93], n=23; NP-, 73% [95% CI: 47, 86], n=112). Patients treated with tezepelumab 210 mg demonstrated greater reductions in blood eosinophil count and levels of FeNO, IL-5 and IL-13 than placebo-treated patients, irrespective of NP status. DISCUSSION: Tezepelumab reduced exacerbations and reduced type 2 inflammatory biomarkers in patients with and those without NP, supporting its efficacy in a broad population of patients with severe asthma.

Tezepelumab Reduces Exacerbations Across All Seasons in Patients with Severe, Uncontrolled Asthma: A Post Hoc Analysis of the PATHWAY Phase 2b Study.

INTRODUCTION: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in airway inflammation in asthma, from binding to its heterodimeric receptor. In the PATHWAY phase 2b study, tezepelumab significantly reduced exacerbation rates compared with placebo in adults with severe, uncontrolled asthma, irrespective of baseline disease characteristics. OBJECTIVE: To evaluate the effect of tezepelumab on asthma exacerbations on a seasonal basis. METHODS: This was a post hoc analysis of the PATHWAY study (NCT02054130). Adults (N=550) with severe, uncontrolled asthma were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The annualized asthma exacerbation rate (AAER), total number of days with an exacerbation, proportion of patients with at least one exacerbation or 0, 1 or ≥2 exacerbations, and proportion of patients experiencing an exacerbation per day were evaluated by season and over the year, by treatment in the overall study population and in subgroups according to baseline blood eosinophil count (≥300 cells/µL or <300 cells/µL) or atopic asthma status (fluoro-enzyme immunoassay [FEIA]+ or FEIA-). RESULTS: Seasonal variations in exacerbation rates were found, with peaks observed in fall and winter, and greater variations in patients with high blood eosinophil counts (≥300 cells/µL). Tezepelumab treatment consistently reduced exacerbation rates across all seasons compared with placebo. Furthermore, there was a trend, which was not significant, toward a reduction in the total number of days with exacerbations and in the proportion of patients with exacerbations during each season in patients treated with tezepelumab compared with those who received placebo, irrespective of blood eosinophil count or atopic asthma status. CONCLUSION: Tezepelumab reduced exacerbations across all seasons, irrespective of evaluated baseline disease characteristics. These data support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma.

Pharmacokinetic and Pharmacodynamic Modeling of Tezepelumab to Guide Phase 3 Dose Selection for Patients With Severe Asthma.

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine involved in asthma pathogenesis. In the phase 2b PATHWAY study (ClinicalTrials.gov identifier: NCT02054130), tezepelumab significantly reduced exacerbations in adults with severe, uncontrolled asthma. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling to guide tezepelumab dose selection for phase 3 trials in patients with severe asthma. PK data from 7 clinical studies were used to develop a population PK model. Population PK-PD models were developed to characterize the relationship between tezepelumab PK and asthma exacerbation rate (AER) and fractional exhaled nitric oxide (FeNO) levels (using phase 2b PD data only). Tezepelumab PK were well described by a 2-compartment model with first-order absorption; PK parameter estimates were consistent with those of other immunoglobulin G2 antibodies. PK-PD models predicted that subcutaneous dosing at 210 mg every 4 weeks was associated with ≈90% of the maximum drug effect of tezepelumab on AER and FeNO; further dose increases were not expected to result in additional, clinically meaningful treatment benefit. No clinically significant covariates of treatment effects on AER and FeNO were identified. Population PK simulations, exposure-response relationships and safety profiles of tezepelumab at doses up to 280 mg every 2 weeks suggested that no dose adjustment based on body weight or for adolescents was required. These results support the selection of 210 mg every 4 weeks subcutaneously as the dose for phase 3 studies of tezepelumab in adults and adolescents with severe asthma.

Tezepelumab improves patient-reported outcomes in patients with severe, uncontrolled asthma in PATHWAY.

BACKGROUND: Patients with severe, uncontrolled asthma experience frequent exacerbations and hospitalization, leading to poor health-related quality of life. In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced exacerbations by up to 71% and improved lung function, asthma control, and health-related quality of life vs placebo. OBJECTIVE: This analysis further assessed the impact of tezepelumab on patient-reported outcomes (PROs) in PATHWAY. METHODS: Adults with severe, uncontrolled asthma were randomized to subcutaneous tezepelumab (70 mg every 4 weeks, 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. PROs were assessed using the asthma control questionnaire-6 (ACQ-6) and the asthma quality of life questionnaire (standardized) for patients aged 12 years or older (AQLQ[S]+12). The proportions of responders (defined by improvements of ≥0.5 in ACQ-6 or AQLQ(S)+12 scores) and patients whose asthma was well-controlled, partially-controlled, or uncontrolled in the tezepelumab and placebo groups were identified. The Asthma Daily Diary questionnaire was used to assess changes in overall symptom severity. RESULTS: Overall, 550 patients were randomized. Up to 82% and 77% of tezepelumab-treated patients were ACQ-6 and AQLQ(S)+12 responders, respectively, compared with 70% and 64% of placebo-treated patients, respectively. The proportions of patients with well-controlled or partially-controlled asthma were higher in the tezepelumab-treated group than in the placebo group. In addition, tezepelumab improved the overall symptom severity. CONCLUSION: Tezepelumab treatment improved PROs vs placebo, as indicated by the higher proportion of ACQ-6 and AQLQ(S)+12 responders and improvements in symptom severity in the tezepelumab dose groups. These data further support the benefits of tezepelumab in patients with severe, uncontrolled asthma.

CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma.

BACKGROUND: Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study. METHODS: CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18-75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants' type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit. DISCUSSION: CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation. TRIAL REGISTRATION: NCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.

Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study.

BACKGROUND: Interleukin 15 (IL-15) is implicated in the pathophysiology of coeliac disease. AMG 714 is the first anti-IL-15 monoclonal antibody to be investigated for the treatment of coeliac disease. We aimed to investigate the effects of AMG 714 in patients with coeliac disease who underwent gluten challenge. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial was done at three clinical sites in Finland. Inclusion criteria included age 18-80 years, a confirmed diagnosis of coeliac disease, and adherence to a gluten-free diet for at least 12 months before screening. Patients were randomly assigned (1:1:1) to 150 mg AMG 714, 300 mg AMG 714, or placebo using permuted blocks and stratified by study site and sex. Patients and study staff were masked to treatment assignment. Treatments were administered by two subcutaneous injections every 2 weeks for 10 weeks (total six doses). Patients without severe villous atrophy at baseline received a gluten challenge (2-4 g daily) during weeks 2-12. Small bowel biopsy samples were obtained for histological assessments at baseline and week 12. The primary efficacy endpoint was the percentage change from baseline to week 12 in villous height-to-crypt depth (VHCD) ratio. Secondary endpoints were CD3-positive intraepithelial lymphocyte density; clinical symptoms measured by gastrointestinal symptom rating scale (GSRS), coeliac disease GSRS, and Bristol stool form scale (BSFS); and changes in anti-tTG and anti-DGP antibodies from baseline. The primary analysis was done in the per-protocol 1 population of patients who received at least one dose of study drug and who underwent the gluten challenge. Safety analyses were done in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, NCT02637141 and EudraCT, 2015-003647-19. FINDINGS: Between April 13, 2016, and Nov 22, 2016, 64 patients were enrolled and randomly assigned to either the 150 mg AMG 714 group (n=22), the 300 mg AMG 714 group (n=22), or the placebo group (n=20). Two patients did not start treatment and two did not provide post-treatment biopsy samples. 49 patients underwent the gluten challenge (per-protocol 1 population) and 11 patients did not because of baseline villous atrophy. AMG 714 did not prevent mucosal injury due to gluten challenge. The least square mean difference in the relative change from baseline in VHCD ratio was -2·49% (95% CI -16·82 to 11·83; p=0·73) between 150 mg AMG 714 and placebo and 6·39% (-7·07 to 19·85; p=0·34) between 300 mg AMG 714 and placebo. Neither comparison was statistically significant. The density of CD3-positive intraepithelial lymphocytes increased in all groups, with smaller increases in the 300 mg group (-41·24% [95% CI -79·28 to -3·20] vs placebo, nominal p=0·03) but not the 150 mg group (-14·32% [-54·39 to 25·74], nominal p=0·47). Clinical symptoms were ameliorated with AMG 714 treatment between baseline and week 12, particularly diarrhoea as measured by the BSFS (nominal p=0·01 for 150 mg vs placebo, and nominal p=0·0002 for 300 mg vs placebo). Serum antibody titres for anti-tTG and anti-DGP antibodies increased in all three treatment groups, with no significant difference between AMG 714 and placebo. Treatment-emergent adverse events occurred in 21 (95%) patients in the 150 mg AMG 714 group, 0 (95%) in the 300 mg AMG 714 group, and 19 (100%) in the placebo group. The most common treatment-emergent adverse events were gastrointestinal disorders (17 [77%] participants in the 150 mg AMG 714 group, 16 [76%] in the 300 mg AMG 714 group, and 13 [68%] in the placebo group). Injection site reactions were the most common individual adverse event, reported in eight (36%) patients in the 150 mg AMG 714 group, 11 (52%) in the 300 mg group, and five (26%) in the placebo group. No serious adverse events occurred. INTERPRETATION: The primary endpoint, change in VHCD ratio from baseline after 12 weeks of treatment in patients with coeliac disease undergoing gluten challenge, was not significantly different between placebo and AMG 714 at either 150 mg or 300 mg. Effects on intraepithelial lymphocyte density and symptoms suggest that further research of AMG 714 may be warranted in patients with non-responsive coeliac disease. FUNDING: Celimmune and Amgen.

Safety and efficacy of AMG 714 in patients with type 2 refractory coeliac disease: a phase 2a, randomised, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2. METHODS: This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36). FINDINGS: From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4·85% (90% CI -30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38·22% (90% CI -95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI -1·60-1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI -38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was -12·73% (95% CI -77·57-52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was -0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group). INTERPRETATION: In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2. FUNDING: Celimmune and Amgen.

Pharmacokinetics, Safety, and Tolerability of Tezepelumab (AMG 157) in Healthy and Atopic Dermatitis Adult Subjects.

Tezepelumab (AMG 157) is a monoclonal antibody that targets thymic stromal lymphopoietin and has shown benefits in treating asthma. We assessed the safety, tolerability, and pharmacokinetics of single-ascending and multiple-ascending doses in two randomized, double-blind, placebo-controlled phase I studies. Healthy and atopic dermatitis subjects were enrolled in the single-dose study, and healthy subjects in the multiple-dose study. Tezepelumab showed linear pharmacokinetics in both healthy and atopic dermatitis subjects. The half-life after a subcutaneous or intravenous administration ranged from 19.9 to 25.7 days. After multiple doses, the mean area under the curve accumulation ratio was 1.82, 1.64, and 1.59 for the 35 mg, 105 mg, and 210 mg monthly subcutaneous doses, respectively. The mean maximum serum concentration (Cmax ) accumulation ratio was 1.59, 2.84, and 6.74 for the 210 mg dose given every 28, 14, and 7 days, respectively. Tezepelumab was well tolerated in both studies with no evidence of immunogenicity.