title: Evaluation of bedoradrine sulfate (MN-221), a novel, highly selective beta2-adrenergic receptor agonist for the treatment of asthma via intravenous infusion.
abstract: BACKGROUND
  The number of hospitalizations or deaths due to asthma, most of which result from acute exacerbations of asthma, has remained the same for the past 20 years. MN-221 (bedoradrine sulfate) is a novel, highly selective beta2- (β2-) adrenergic agonist administered via intravenous (IV) infusion in development for the treatment for acute exacerbation of asthma.
  
  
  OBJECTIVE
  Trial MN-221-CL-004 assessed the safety profile and preliminary efficacy of MN-221 in escalating doses in patients with stable mild-to-moderate asthma. Study MN-221-CL-005 assessed the safety profile and preliminary efficacy of MN-221 in patients with stable moderate-to-severe asthma when given as a fixed dose over 1- or 2- hr infusion.
  
  
  METHODS
  Two randomized, placebo-controlled clinical trials (n = 40) were performed to evaluate the pharmacokinetic (PK) and clinical effects of a novel, highly selective β2-agonist, MN-221, via IV infusion. Safety evaluations included vital signs, adverse events (AEs), clinical laboratory parameters, and electrocardiogram results. Efficacy evaluation included measurement of forced expiratory volume in 1 second (FEV) a₁nd PK parameters were additionally monitored. The study was reviewed and approved by the Institutional Review Board at each site.
  
  
  RESULTS
  Adverse effects were mild or moderate and there were no serious AEs or deaths during the studies. The most frequently reported AEs were tremor, hypokalemia, and headache. There were no consistent dose-dependent effects of MN-221 on any safety parameters, with the exception of heart rate, which was not considered to be clinically significant and did not require any treatment. Moderate hypokalemia occurred once in one subject in the MN-221-CL-004 study and twice in one subject in the MN-221-CL-005 study and were transient and returned to normal range following single oral potassium chloride treatments. PK assessments indicated a linear response in MN-221 plasma concentrations for the doses evaluated. Dose escalation results showed that mean changes in FEV₁ from pre-infusion were significantly greater than placebo and an overall dose response was statistically significant (p < .0001). Post-infusion FEV1 improvements appeared to plateau at the 30 μg/min dose level despite a higher peak plasma concentration at 60 μg/min. Dose-rate escalation results demonstrated greater mean increases in change in FEV₁ compared to the placebo group with the largest increase associated with the higher MN-221 dose rate and peak plasma concentration.
  
  
  CONCLUSIONS
  The safety profile of MN-221 and evidence of dose- and plasma-concentration-related bronchodilation supports further clinical development and suggests the potential for clinical benefit without increased clinical risk, particularly for patients where inhaled or nebulized therapy is not adequate or possible. Trial registry name and registration number:Name: MN-221-CL-005Number: NCT00679263.
authors.affiliation: MediciNova, Inc., San Diego, CA 92122, USA. matsuda@medicinova.com
authors.forename: Kazuko
authors.initials: K
authors.lastname: Matsuda
authors.forename: Malath
authors.initials: M
authors.lastname: Makhay
authors.forename: Kirk
authors.initials: K
authors.lastname: Johnson
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Iwaki
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009281:Naphthalenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000081:Acetamides; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D009281:Naphthalenes; C425888:bedoradrine