Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids.

BACKGROUND: Asthma is a disease with marked heterogeneity in its clinical course and response to treatment. IL-13 is central to type 2 inflammation, which contributes to many key features of asthma. Lebrikizumab is an anti-IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy, especially in periostin-high patients. OBJECTIVE: This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of lebrikizumab in asthmatic patients not receiving inhaled corticosteroids. METHODS: Patients were randomized to receive 125, 250, or 500 mg of lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period. The primary efficacy end point was the relative change in prebronchodilator FEV1 from baseline to week 12. RESULTS: A total of 212 patients were randomized. The mean relative change in FEV1 was numerically higher in all lebrikizumab dose groups versus the placebo group, although the difference was neither statistically nor clinically significant. There were no meaningful differences in changes in FEV1 between the dose groups and the placebo group by the periostin subgroup. Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo (P < .001), and results were similar by the periostin subgroup, with no apparent differences between doses of lebrikizumab. Lebrikizumab was generally well tolerated. CONCLUSION: Blocking IL-13, a single cytokine, in this population of asthmatic patients is insufficient to improve lung function. There is evidence that IL-13 blockade may improve disease control, as measured by prevention of protocol-defined treatment failure in these patients.

Lebrikizumab treatment in adults with asthma.

BACKGROUND: Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity. METHODS: We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin-13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level. RESULTS: At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 µg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045). CONCLUSIONS: Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .).

Long-term safety study of levalbuterol administered via metered-dose inhaler in patients with asthma.

BACKGROUND: Previous studies have raised concerns regarding the safety of regular use of beta2-agonists for treating asthma. Few studies have explored the safety of at least 1 year of use of racemic albuterol, and none have examined long-term dosing of levalbuterol. OBJECTIVE: To examine the long-term safety of levalbuterol hydrofluoroalkane (HFA) vs racemic albuterol HFA administered via metered-dose inhaler (MDI) in patients with stable asthma. METHODS: Patients with mild to moderate asthma (mean forced expiratory volume in 1 second [FEVI], 68.3% of predicted) 12 years or older participated in a multicenter, parallel-group, open-label study. Patients were randomized to levalbuterol HFA MDI (90 microg; 2 actuations of 45 microg; n = 496) or racemic albuterol HFA MDI (180 microg; 2 actuations of 90 microg; n = 250) for 52 weeks of 4 times daily dosing. The primary end point was the incidence of postrandomization adverse events. Asthma exacerbations and pulmonary parameters were also assessed. RESULTS: The overall incidence of adverse events was similar for levalbuterol (72.0%) and racemic albuterol (76.8%). Rates of beta-mediated adverse events, serious adverse events, and discontinuations because of adverse events were low (<15%) and were comparable between groups. Rates of asthma adverse events for levalbuterol and racemic albuterol were 18.3% and 19.6%, respectively. Mean percentage of predicted FEV1 improved after dosing and was stable for both groups. CONCLUSION: In this trial, up to 52 weeks of regular use of levalbuterol HFA MDI or racemic albuterol HFA MDI was well tolerated, and no deterioration of lung function was detected during the study period.

Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173). RESEARCH DESIGN AND METHODS: Multicenter, randomized, double-blind 28-day study of QID levalbuterol 90 microg, racemic albuterol 180 mug, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV(1) from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV(1) percent change from pre-dose curve and peak % predicted FEV(1). Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms. RESULTS: Levalbuterol significantly improved the least square mean peak percent change in FEV(1) compared with placebo (levalbuterol 25.6% +/- 1.3% [p < 0.001]; racemic albuterol 21.8% +/- 1.8% [p = ns]; placebo 16.8% +/- 1.9%). Results for levalbuterol were similar for the other spirometry endpoints (p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV(1) < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use (p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QT(c-F) that were similar to placebo. CONCLUSIONS: In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4-11 years with a safety profile that was similar to placebo.

A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults.

UNLABELLED: This multicenter, randomized, double-blind trial compared nebulized levalbuterol (Lev) and racemic albuterol (Rac) in the treatment of acute asthma. METHODS: Adults with acute asthma exacerbations (FEV(1) 20%-55% predicted) received prednisone and either Lev (1.25 mg, n = 315) or Rac (2.5 mg, n = 312). Nebulized treatments were administered every 20 minutes in the first hour, then every 40 minutes for 3 additional doses, then as necessary for up to 24 hours. The primary end point was time to meet discharge criteria. Secondary end points included changes in lung function and hospitalization rates. A subset of 160 patients had plasma (S)-albuterol concentrations determined at study entry. RESULTS: Time to meet discharge criteria did not differ between the 2 treatments. FEV(1) improvement was greater following Lev compared with Rac, both after dose 1 and cumulatively over the entire treatment period (dose 1 in intent to treat [ITT] group: Lev 0.50 +/- 0.43 L, Rac 0.43 +/- 0.37 L; P = .02), particularly among the 60% of patients not on recent steroid therapy (dose 1: Lev 0.58 +/- 0.47 L, Rac 0.44 +/- 0.37 L; P < .01), and patients whose entry (S)-albuterol concentrations were in the highest quartile of those measured. A small and similar proportion of Lev-treated (7.0%) and Rac-treated (9.3%) patients required hospitalization (P = .28). Among patients not on steroids, fewer Lev- than Rac-treated patients required admission (3.8% vs 9.3%, P = .03), as was also the case for patients with high plasma (S)-albuterol concentrations. Asthma relapses (5% in 30 days) were lower than in previous reports and did not differ between groups. CONCLUSIONS: This study suggests that early, regular nebulized beta(2)-agonist and systemic corticosteroid therapy may reduce hospitalization and relapse rates in patients with acute severe asthma. Lev was well tolerated and compared favorably with Rac in improving airway function, particularly in those who were not on inhaled or oral corticosteroids and in those who had high plasma (S)-albuterol concentrations at presentation.

Evaluation of the efficacy and safety of levalbuterol in subjects with COPD.

The efficacy and safety of nebulized levalbuterol in adults with chronic obstructive pulmonary disease (COPD) was evaluated in this multicenter, randomized, double-blind, parallel design study. Randomized subjects (n = 209) received levalbuterol (LEV) 0.63 mg or 1.25 mg, racemic albuterol (RAC) 2.5 mg, or placebo (PBO) TID for 6 weeks. Serial spirometry was completed in-clinic after study drug alone (weeks 0, 2, and 6) or in combination with ipratropium bromide 0.5 mg (week 4). The primary endpoint was the averaged FEV1 AUC(0-8 hrs) over weeks 0, 2 and 6 compared with placebo. Other endpoints included rescue medication use, safety parameters, COPD exacerbations, and global evaluations. All active treatments demonstrated improvements in the percent change in FEV1 AUC(0-8 hrs) over the double-blind period and at each visit vs PBO (p < 0.05). Rescue medication use vs. baseline (doses/day) changed over time: PBO +0.38 +/- 3.3; LEV 0.63 mg +0.07 +/- 3.3; LEV 1.25 mg -0.84 +/- 3.8 (p = 0.02 vs. RAC); RAC +0.97 +/- 2.5. The overall rate of adverse events was PBO 56.4%, LEV 0.63 mg 56.6%, LEV 1.25 mg 67.3%, and RAC 65.4%. Protocol-defined COPD exacerbations occurred in all groups (PBO 12.7%, LEV 0.63 mg 11.3%; LEV 1.25 mg 18.4%; RAC 21.2%). Withdrawals due to COPD exacerbations were significantly higher in the RAC group compared with PBO (PBO 0%; LEV 0.63 mg 1.9%; LEV 1.25 mg 4.1%; RAC 9.6% p = 0.01 vs. PBO). In this study, levalbuterol treatment in subjects with COPD was generally well tolerated, produced significant bronchodilation compared with PBO, and improved clinical control of COPD as evidenced by reductions in rescue medication use compared with PBO and/or RAC.

Evaluation of the safety and efficacy of levalbuterol in 2-5-year-old patients with asthma.

The purpose of this study was to evaluate the safety and efficacy of single-isomer (R)-albuterol (levalbuterol, LEV) in children aged 2-5 years. Children aged 2-5 years (n = 211) participated in this multicenter, randomized, double-blind study of 21 days of t.i.d. LEV (0.31 mg or 0.63 mg without regard to weight), racemic albuterol (RAC, 1.25 mg for children <33 pounds (lb); 2.5 mg for children >/=33 lb), or placebo (PBO). Endpoints included adverse-event (AE) reporting, safety parameters, peak expiratory flow (PEF), the Pediatric Asthma Questionnaire(c) (PAQ), and the Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ). Baseline disease severity was generally mild in all groups, as defined by PAQ scores that ranged from 6.3-7.3 on a scale of 0-27 and 1.5 days/week of uncontrolled asthma. After treatment, the PAQ decreased in all groups (P = NS). In the subset of subjects able to perform PEF (51.7%), all active treatments improved in-clinic PEF after the first dose (mean +/- SD: PBO, 1.4 +/- 20.8; LEV 0.31 mg, 12.4 +/- 12; LEV 0.63 mg, 16.7 +/- 15.4; RAC, 18.0 +/- 16.5 l/min; P < 0.01). PACQLQ measurements improved more than the minimally important difference only in the LEV-treated groups, and were significant in children <33 lb (P < 0.05). Asthma exacerbations occurred primarily in children >/=33 lb, and one serious asthma exacerbation occurred in the 2.5-mg RAC group. RAC and LEV 0.63 mg, but not LEV 0.31 mg or placebo, led to significant increases in ventricular heart rate. In this study of levalbuterol in children aged 2-5 years with asthma, LEV was generally well-tolerated, and in children able to perform PEF, led to significant bronchodilation compared with placebo.

CD40 contributes to lethality in acute sepsis: in vivo role for CD40 in innate immunity.

Sepsis induces an early inflammatory cascade initiated by the innate immune response. This often results in the development of multisystem organ failure. We examined the role of CD40, a costimulatory molecule that is integral in adaptive immunity, by using a murine model of polymicrobial sepsis. CD40 knockout (KO) mice had delayed death and improved survival after cecal ligation and puncture (CLP). In addition, they had less remote organ injury as manifested by reduced pulmonary capillary leakage. The improvements in survival and remote organ dysfunction in CD40 KO mice were associated with reduced interleukin-6 (IL-6) and IL-10 levels in serum and bronchoalveolar lavage fluid compared to the levels in wild-type (WT) controls. Furthermore, in contrast to WT mice, CD40 KO mice had no induction of the Th1 cytokines IL-12 and gamma interferon in serum or lungs after CLP. The alterations in cytokine production in CD40 KO mice were associated with similar changes in transcription factor activity. After CLP, CD40 KO mice had attenuated activation of nuclear factor kappaB and signal transducer and activator of transcription 3 in both the lung and the liver. Finally, WT mice had increased expression of CD40 on their alveolar macrophages. These data highlight the importance of CD40 activation in the innate immune response during polymicrobial sepsis and the subsequent development of remote organ dysfunction.