Expert Opinion on Investigational Drugs

ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20

Bedoradrine for treating asthma and chronic obstructive pulmonary disease Sabina Antoniu MD PhD To cite this article: Sabina Antoniu MD PhD (2014) Bedoradrine for treating asthma and chronic obstructive pulmonary disease, Expert Opinion on Investigational Drugs, 23:8, 1149-1156 To link to this article: http://dx.doi.org/10.1517/13543784.2014.928284

Published online: 18 Jun 2014.

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Date: 10 September 2015, At: 07:56

Drug Evaluation

Bedoradrine for treating asthma and chronic obstructive pulmonary disease 1.

Introduction

2.

Introduction to the compound and overview of its potential market

3.

Pharmacokinetics and

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metabolism 4.

Conclusion

5.

Expert opinion

Sabina Antoniu University of Medicine and Pharmacy, Grigore T Popa Iasi, Department of Interdisciplinarity Palliative Care Nursing, Iasi, Romania

Introduction: In severe asthma attacks or in severe chronic obstructive pulmonary disease (COPD) exacerbations, inhaled short-acting bronchodilators, such as salbutamol (albuterol), terbutaline or ipratropium, often have a limited effectiveness due to significantly impaired ventilation. For these reasons, the use of a systemic bronchodilator medication might be more appropriate as therapeutic options. However, such formulations, especially salbutamol, are usually, and unfortunately, associated with a high risk of cardiovascular events. For this reason, they are only seldom used, especially in the case of paediatric populations. Areas covered: This drug evaluation paper reviews the potential therapeutic agent bedoradrine, an ultraselective b2 agonist, which is currently under development for treating exacerbated asthma and COPD. The article includes a review of both in vitro and in vivo studies as well as a review of the pharmacokinetics, efficacy, safety and tolerability. Expert opinion: The intravenous use of bedoradrine has demonstrated promising preliminary efficacy in existing clinical trials for exacerbated asthma. However, the efficacy of bedoradrine is still uncertain in exacerbated COPD. Further clinical studies should assess the efficacy and safety of bedoradrine as an add-on therapy to usual standardised approach and exacerbation-related variables should be used as outcome measures. Keywords: asthma, bedoradrine, bronchodilators, COPD, exacerbations, MN-221, safety Expert Opin. Investig. Drugs (2014) 23(8):1149-1156

1.

Introduction

Asthma is a disease with increased prevalence and morbidity worldwide. In the United States, for example, in 2010, an estimated number of 18.7 millions of adults were known with asthma; in 2009, this disease was associated with a number of 3388 deaths and 479,300 hospitalisations and there were 1.9 millions of emergency department visits [1]. Asthma, an inflammatory disease of the airways, is most commonly related to allergen exposure, and is characterised by bronchospasm attacks, which occur as a result of exposure to various triggers such as allergens, cold anxiety or exercise. If such attacks occur, their therapy is represented by inhaled short-acting b2 agonists such as salbutamol, terbutaline or fenoterol or by short-acting anticholinergic drugs delivered via inhalers, and which are usually able to relieve it. If asthma attack is more severe, then higher doses of inhaled bronchodilators are needed and their administration via nebulisers is needed and patient monitoring in the emergency department or even hospital referral is needed. However, sometimes this latter approach can be ineffective and intensive care therapy is needed. Such extreme cases might be prevented to occur if a systemic bronchodilator with very good cardiovascular safety, and yielding a rapid and sustained bronchodilation would exist. 10.1517/13543784.2014.928284 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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Box 1. Drug summary. Drug name Phase Indication Mechanism of action Chemical structure

Bedoradrine II Exacerbated asthma or COPD Bronchodilator, ultraselective b2 agonist OH O

S

O

N O

H3C

OH

O

N H OH

OH

OH

CH3

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OH

CH3

N O

H 3C

N H

O

Pivotal trial(s)

OH

Currently, systemic formulations of salbutamol(albuterol) are only used in paediatric population and on sporadic basis in adult population due to the fact that the latter is more prone to severe cardiovascular side effects especially at the older ages. Bedoradrine (KUR-1246, MN221) (Box 1) is a b2 agonist, which was initially developed as a tocolytic agent and subsequently was also entered in a clinical development program as a bronchodilator. This review summarises the preclinical and clinical data available and discusses the therapeutic potential of the compound for asthma attacks and for exacerbated chronic obstructive pulmonary disease (COPD). 2. Introduction to the compound and overview of its potential market

Bedoradrine is an ultraselective b2 agonist for systemic use, which is currently in Phase II of clinical development as a rescue bronchodilator for exacerbated asthma or COPD. Currently, there is no systemic bronchodilator specifically authorised in both EU and the USA for such therapeutic indications in adults in whom repeated nebulisations of salbutamol associated or not with ipratropium are usually used for example in exacerbated asthma. Chemistry In terms of chemical structure bedoradrine is a (2)-bis (2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) phenyl]ethyl} amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}N,N-dimethyl-acetamide)monosulfate [2]. 2.1

Pharmacodynamics The pharmacodynamics of bedoradrine were initially studied for the purpose of a potential development of this drug as a tocolytic agent mostly in preclinical experiments, and 2.2

1150

OH

MN-221-CL-004, MN-221-CL-005

subsequently its bronchodilator effects were tested in clinical studies. In vitro experiments Pharmacodynamics of KUR-1246 were initially studied when the compound was developed as an uterine myorelaxant agent. In vitro, it was tested for its ability to induce relaxation on spontaneous and on drug (oxytocin, PGF2a and KCL)induced myometrial contractions of pregnant rabbits and rats. The potency of KUR-1246 was compared to that of isoproterenol, ritodrine and terbutaline. The variable used to quantify this effect was chosen to be pD2, which is the negative logarithm of the EC50 (the 50% effective concentration of the b-agonist). In the experiment involving the myometrial strips isolated from the pregnant rat, the part subexperiment involving the spontaneous myometrial contractions in rats demonstrated that isoproterenol had the most potent myorelaxing effect, with a pD2 of 9.44 mM, followed by the KUR-1246 9.04 mM, terbutaline 7.66 and ritodrine 7.22. In druginduced experiments the same ranking was maintained. In particular, the pD2 for KUR-1246 oxytocin-induced contractions was 8.53, for PGF2a-induced 7.30 and for KCl 8.51 mM. All b2 agonists were the least potent on PGF2ainduced myometrial contractions. KUR-1246 was found to be 25 -- 50 times more potent than ritodrine and 10 -- 33 times more potent than terbutaline. The amplitude of the myorelaxing effect was found to be concentration dependent [2]. In the experiment involving strips from the pregnant rabbit myometrium, a similar concentration-dependent efficacy was found for KUR-1246, and the same potency ranking was also demonstrated, this time the pD2 of the compound being closer to that of isoproterenol on both spontaneous and drug-induced myometrial contractions (eg 8.71 versus 8.99 in the former and 8.60 versus 8.53 for oxytocin-induced contractions) [2]. 2.3

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Bedoradrine

The specificity of the KUR-1246 for the b2 receptors was demonstrated by measuring the concentration--response curve for the myorelaxing effects induced by this compound on myometrial strips from pregnant rats in the presence of b1, b2 and b3 antagonists, respectively. These effects were only reduced by the b2 antagonist, suggesting a high receptor specificity of KUR-1246. This binding specificity was further demonstrated in vitro on atrial myocardium and on proximal colon from pregnant rabbit: KUR-1246 was able to increase the myocardial contraction with the lowest percentage over the basal rate among the agonists tested (81.4% with isoproterenol, 81.8% with terbutaline, 54.6% with ritodrine and 15.8% with KUR-1246). KUR-1246 exhibited the lowest intrinsic activity relative to isoproterenol among the b agonists tested: 0.20 for KUR-1246, 0.69 for ritodrine and 0.96 for terbutaline. When tested on portions of fragments of colon of the pregnant rat, KUR-1246 was less potent than isoproterenol or than ritodrine and more potent than terbutaline in inducing the spontaneous contractions of the colon. Human receptor binding affinity experiments demonstrated that KUR-1246 was able to dislocate the radioligands from b1 or b2 receptors with a dissociation constant Kd 0.4 and 0.16 nM, respectively, whereas that for b3 was 1.05 nM. The binding affinity of KUR-1246 was reported to be 39.2 times higher than that for b1 and 198.2 times higher than that for the b3 [2]. Other in vitro studies were performed in order to evaluate the b receptor specificity in ovary cells of the Chinese hamster expressing human b1, b2 or b3 receptors [3]. This specificity was evaluated with the amount of cyclic adenosine monophosphate released by these cells as a result of their exposure to bedoradrine, ritodrine or isoprenaline and EC50 (50% effective dose) for bedoradrine was reported to be 2400 nmol/l for b1, 2.9 for b2 and 363 for b3. These results indicated a 832-fold higher selectivity for b2 than for b1 and a 126-fold selectivity of b2 over b3. [3]. In vivo studies The tocolytic effects and the safety of an intravenous infusion of KUR-1246 given at a rate varying from 0.1 to 10 mg/kg/min, spontaneous oscillation of the intrauterine pressure, heart rate and blood pressure were monitored in the pregnant rat. The compound reduced the pressure oscillations in a dosedependent manner without increasing significantly the blood pressure or the heart rate. A similar effect was obtained with higher doses of KUR-1246 (3 -- 10 mg/kg/min). When the ritodrine, terbutaline or KUR-1246 was assessed for their effect of decreasing the spontaneous uterine activity, a reported ED30 (defined by the authors as 30% effective dose) was calculated to be 51.29 mg/kg/min for ritodrine, 0.76 mg/kg/min for terbutaline and 0.13 mg/kg/min for KUR-1246, making the latter to be 6 times more potent than terbutaline and 400 times more potent than ritodrine. In terms of the size of the positive inotropic effect, this was 2.4

dose-dependent and detected with all compounds but was the smallest with KUR-1246: for example, it was reported that the highest KUR-1246 dose (10/mg/kg/min) resulted in an increase of the heart rate of only 20 beats/min, whereas the maximal increases in the heart rate with ritodrine or terbutaline were 50 -- 55 beats/min compared to the basal level. All three b2 agonists reduced the mean blood pressure in a comparable manner. Another in vivo study was performed in order to evaluate the effects of KUR-1246 in comparison with those of ritodrine in pregnant or puerperal rats or guinea pigs. In pregnant rats the effects of continuous infusions of ritodrine (1, 10, 100 µg/kg/min) or KUR-1246 (0.003, 0.3, 3 µg/kg/min) on the uterine contractions, heart rate or blood pressure were measured at the gestational day 21. Both compounds were able to reduce in a dose-dependent manner the spontaneous uterine motility (measured with intrauterine pressure variations) with the ED50 (50% of the effective dose) being 1.1 µg/kg/min for KUR-1246, 42.9 µg/kg/min for ritodrine, the potency of the former being about 40 times greater than that of the other. KUR-1246 did not decrease the blood pressure or increase the heart rate in a significant manner as compared to baseline levels, whereas this effect was significant with the highest dose of ritodrine [4]. Placental transfer of both compounds was measured in both pregnant rats and guinea pigs with their concentrations in maternal and fetal plasma and amniotic fluid. After 2 h from an infusion of 30 µg/kg/min of KUR-1246, in rats, mean maternal plasma concentration was 902 ng/ml and the fetal plasma concentration was 47.6 ng/ml, whereas in guinea pigs these were 1815 and 28.7 ng/ml, respectively. When fetal/maternal plasma ratio was calculated, this was 5.3% for rats and 1.6% in guinea pigs. For ritodrine, these ratios were, respectively, 8.3 and 5.4%, which was superior to that of the former compound. In puerperal rats, the KUR-1246 concentration in milk was 21.3 ng/ml 6 h after injection and it lowered rapidly, so that after 48 h from injection it was below the limit of detection. Bedoradrine was able to delay the spontaneous delivery in pregnant rats: in control rats receiving normal saline, the birth started on day 21 of the pregnancy at 0:30, and by 18:00 about 76% animals have had finished it. In rats receiving bedoradrine, this was delayed so that by the same hour only 65% of the rats receiving 1 ng/kg/min, 52% of the rats receiving 10 ng/kg/min, 27.3% of the rats receiving 30 ng/kg/min and 17.3% of the rats receiving 100 ng/kg/min finished the delivery. In rats, the effect of bedoradrine on delaying the natural delivery was reported to be 5.5 h with the 30 ng/kg/min, and this corresponds to a duration of 3.2 days for the human beings. Clinical studies In a study evaluating the pharmacodynamics of bedoradrine in patients with mild to moderate asthma, it was demonstrated 2.5

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that the effects on QTc were influenced by the plasma levels of the drug, whereas a different compartment was reported to influence FEV1 dynamics. In patients with exacerbated COPD the maximal effect compartment was defined as an increase in the FEV1%pred of 19%, which was calculated overall for all doses, whereas that for 1200 µg it was found to be 55% [5,6].

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3.

Pharmacokinetics and metabolism

Pharmacokinetics of intravenous bedoradrine was evaluated in the two Phase II studies discussed below (MN-221-CL-004 and MN-221-CL-005) and was found to be linear and dose dependent. In the first study, MN-221-CL-004, which was a randomised, double-blind, placebo-controlled, dose-escalating one, infusions of 0.35, 1, 3.5, 10, 16 and 30 µg/min were given in a consecutive manner (2 weeks apart) over a prespecified duration of 15 min and the next dose was given if the safety review allowed it. The total sample enrolled included 23 patients. In the MN-21-CL-004 study an infused dose of 10 µg/min had a Cmax of 4654 pg/l, whereas a six times higher dose had a Cmax of 26980 pg/l. Similarly, a 240 µg had an AUC of 8.4 ng h/ml whereas that of the 450 µg was 19.7 ng h/ml. The elimination half-life was ~ 11 h, was constant across both genders and independent of the dose used. MN-221-CL-005 evaluated two different infusion schedules: period 1 (P1) consisted of an initial dose of 16 µg followed by 8 µg for 105 min (for a total of 1080 µg over 2 h) and period 2 (P2) comprised an initial dose of 30 µg for 15 min followed by 15 µg infused over 45 min (1125 µg infused over 1 h). In the MN-221-CL-005 study enrolling 17 patients, both infusion schedules resulted in a comparable total dose (1080 µg for period 1 over 2 h and 1225 for the period 2 given over 1 h) but that in period 2 it was associated with a significantly higher (71.8%) Cmax (geometric mean) than that of period 1 (9 µg/ml for the period 1 and 16 µg/ml). The AUCs were dose proportional and thus comparable for both schedules, 36.6 ng h/ml for period 1 and 35.7 ng h/ml for period 2. The elimination half-life value was comparable to that reported in the previous study and a three-compartment pharmacokinetics model, which was different from that of the other b agonists, was described [6-8]. Clinical efficacy An overview of the clinical trials performed in asthma and COPD is presented in Table 1. 3.1

Phase I clinical studies Bedoradrine (MN-221, KUR-1246) was subsequently developed in Europe for asthma as an ultraselective b2 agonist for rescue (asthma attacks or exacerbations use). Two Phase Ib studies were performed in COPD patients. The first Phase Ib study (MN-221-CL-011) was a placebocontrolled dose-escalating study, which evaluated the safety, tolerability pharmacokinetics and preliminary bronchodilator 3.1.1

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efficacy in patients with stable moderate to severe COPD. Intravenous bedoradrine was given in three groups, Group 1 received 300 µg of bedoradrine over 1 h, Group 2 600 µg over 1 h and Group 3 1200 µg over 1 h. Matching groups received matched placebo [9]. The other Phase Ib study (MN-221-CL-011) evaluated the safety, tolerability and preliminary efficacy of repeated doses of intravenous bedoradrine administered in patients with exacerbated COPD. The doses were scheduled as follows: 1200 µg infused once daily over 1 h during Day 1, 1200 µg infused twice daily each over 1 h during Day 2, the same schedule for Day 3 and the same schedule as Day 1 for Day 4 [10]. Phase II clinical studies Two Phase II studies, MN-221-CL-004 and MN-221-CL-005, were performed in patients with mild to moderate asthma and moderate to severe asthma, respectively [7,8,11]. MN-221-CL-004 study evaluated the pharmacokinetics, efficacy safety and tolerability of bedoradrine given via intravenous infusion in patients with mild to moderate stable asthma. This was a randomised double-blind, placebocontrolled sequential dose-escalation study in which patients were enrolled to one of the four dose-escalation schedules, the results being reported with doses ranging from 150 to 900 µg. Efficacy endpoints were represented by the increases from pre-infusion levels in FEV1%pred (and in peak expiratory flow rate) and by the persistence of this effect. Safety was also monitored. The mean change from baseline (preinfusion level) over placebo in FEV1%predicted was also measured and found to be significant with 150 µg (8%) (p < 0.0001), 240 µg (7.2%) (p < 0.001), 450 µg (11.6%) (p < 0.0001) and 900 µg (8.1%) (p < 0.0001). These differences were reported to be dose-related in terms of duration and to peak about 1 h and 15 min from infusion end for doses higher than 10 µg/min (p < 0.0001). These effects were evident 1 hour after infusion in the intention-to-treat population (n = 17) and were reported to persist at 6 -- 8 h in the per-protocol population. The most effective doses were considered to be 450 and 900 µg, respectively [11]. This study was also used to establish the dose to be further evaluated in a Phase II study in patients with exacerbated asthma [7,11,12]. In the MN-CL-221-005 the FEV1 differences from baseline at 1 h were 0.38 l for P1 and 0.68 for P2 infusion regimens. The subsequent two studies (MN-CL-221-006 and 007) changed the investigational population from stable asthma to acute asthma requiring emergency department management or hospitalisation. Another randomised, placebo-controlled Phase II study (MN-221-CL-006) evaluated the efficacy and safety of intravenous bedoradrine added to the conventional therapy in patients with asthma exacerbations [13]. The primary efficacy endpoint was represented by the change from baseline in the FEV1 %predicted at 2 h after initiation of bedoradrine 240 µg over 15 min (G1) or 3.1.2

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Bedoradrine

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Table 1. Overview of the clinical development of bedoradrine for asthma and COPD. Study code (NCT)

Phase

Design

Disease

NCT 1013142 [9]

Ib Ib

Placebo-controlled dose-escalation study Placebo controlled

Moderate to severe stable COPD Exacerbated COPD

NCT 01551316 [10] NCT 00679263 [8]

II

Placebo controlled

-

II

Placebo controlled

NCT00683449 [7,17]

II

NCT00838591 [7,13]

II

Placebo-controlled dose-escalation study Placebo controlled

Moderate to severe stable asthma Mild to moderate stable asthma Exacerbated asthma Exacerbated asthma

Efficacy Preliminary efficacy endpoints: lung function (FEV1, PEFR) Preliminary efficacy endpoints: lung function (FEV1, PEFR) Change from baseline in FEV1%pred Change from baseline in FEV1%pred Change hospital Change hospital

from baseline in FEV1%pred, FEV1 (l), admissions rate from baseline in FEV1%pred, FEV1 (l), admissions rate, dyspnea

COPD: Chronic obstructive pulmonary disease; PEFR: Peak expiratory flow rate.

450 µg over 15 min (G2) or 1080 µg over 105 min (G3) or 1995 µg over 15 min or over 25 min (G4). Baseline FEV1% pred was measured after two consecutive nebulisations of salbutamol (2.5 mg + 0.5 mg ipratropium administered over 20 min). Secondary endpoints were represented by the FEV1 (l) and change from baseline in FEV1 (l) and by the hospital admissions rate. Safety was also included as a secondary endpoint. The patients with asthma exacerbation and no signs of cardiac rhytm disturbances presenting at the ED with confirmed status asthmaticus, requiring supplemental oxygen as well as nebulised bronchodilators as described above, being given at least 60 mg prednisone or equivalent for intravenous formulations and having a FEV1%pred ‡ 55% within 10 min of completion of the nebulised therapy were eligible. In a total of 29 patients, 13 were included in placebo group and 16 in the treatment arms (n = 5 in G1, n = 6 in G2, n = 3 in G3, n = 2 in G4). The overall mean age was 37.83. The mean change in the primary efficacy endpoint (FEV1%predicted) was 3.88% in placebo group, 16.57% in G1, 4.27% in G2, 3.03 in G3 and -0.82 in G4. Changes from baseline in FEV1 (l) were as follows: 0.10 l with placebo, 0.60 l in G1, 0.12 in G2, 0.10 in G3 and -0.02 in G4. Subsequently, the MN-221-CL-007 a Phase II b study evaluating the efficacy and safety of 1200 µg was performed in a larger sample (n = 175 patients) with acute asthma not responding to the initial acute phase therapy with steroids and inhaled bronchodilators and presenting at the emergency department [14]. A total dose of 1200 µg (40 µg/min over 15 min, followed by 13.3 µg/min over 45 min) added to the usual standard of care was evaluated against this latter approach and placebo. The primary endpoint was represented by the baseline (preinfusion) improvement of the FEV1% pred over placebo and other endpoints were represented by FEV1 (l) improvements, dyspnea scores, the hospital admission rate and safety. The primary endpoint was not met, that is, there was no significant improvement in the FEV1% pred over placebo. However, bedoradrine was able to significantly improve the

FEV1 (l) versus placebo over a period of up to 2 h from baseline (AUC0-1 improvement over placebo 225%, p = 0.043, AUC0-2 improvement over placebo 172%, p = 0.05). It also improved in a sustained manner the symptom severity (AUC0-3 improvement in dyspnea score over baseline 34%, p = 0.055) and reduced, although nonsignificantly, the hospitalisation admission rate (38% compared to 46% with placebo) [14]. This last study was planned to represent the end of Phase II program and the transition to Phase III program for asthma. A Phase II study was performed in 16 patients with moderate to severe COPD in order to evaluate the efficacy and safety of three dose levels 300, 600 or 1200 µg over placebo given intravenously half of the total dose being administered over 15 min and the remaining half over 45 min. Bedoradrine was found to increase the FEV1 (l) as compared to baseline by 21.5% (p = 0.0025) for the 1200 µg dose and 16.2% (p = 0.02) for the 600 µg dose, the 300 µg resulting in a nonsignificant increase of 9.2% compared to placebo, which decreased this variable by 4% [15]. Phase III studies Phase III studies are currently in the planning phase. 3.1.3

Safety and tolerability Preclinical safety was evaluated in dogs, which received nebulised albuterol followed by infused bedoradrine and afterwards received albuterol combined with bedoradrine. Albuterol in combination with various doses of bedorardine had an augmenting effect on the heart rate, which was comparable to that observed after treatment with individual components. The bronchodilator combination was also reported to have no significant influence on Qtc and on monophasic action potential [16]. In the MN-221-CL-004 study, no severe adverse events were reported, and no discontinuations due to the study drug were detected. Most patients (20 out of the 23, 87%) experienced at least one mild or moderate treatment-emergent 3.2

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adverse event. The most frequent adverse events were represented: tremor (56.5%), headache (47.8%), feeling jittery (26.1%) and palpitations (26.1%). However, most of these adverse events were not considered as being related to the study drug especially for bedoradrine doses of no more than 16 µg and for placebo. Such events and in particular tremor were more frequent in patients receiving higher bedoradrine doses. The incidence of the adverse events was higher with 10 -- 60 µg/min (76.5 -- 86.7%) doses than with placebo (63.6%). Similarly, in the MN-221-CL-005 study, there were no severe adverse events and no deaths. A total of 13 patients (76.5%) in both arms reported at least one treatmentemergent adverse event, and most of these were labelled as mild to moderate. One treatment-emergent adverse event represented by sinus tachycardia was considered to be drug related and also severe. Among these patients, four were in the placebo arm (66.7%), nine (81.8%) during P1 and five patients (55.6%) during P2. During P1 one patient experiencing tremor and flushing was discontinued from the study and these events were considered to be related to the drug. Among the treatment-emergent adverse events, tremor hypokalemia and headache were the most commonly reported (41.2% and 29.4%, respectively). These were also the most common drug-related adverse events, which were found in no patient in placebo arm compared to two patients in the treatment arms. None of the clinical laboratory tests used to monitor safety in both MN-221-CL-004 and 005 were abnormal except for the potassium level. In MN-221-CL-004, mild hypokalemia was detected in three patients receiving MN-221. In five patients (two in placebo arm and three in MN-221 arm), potassium serum levels below 3 mEq/l were found. Mild or moderate transient hyperglycemia was also detected in three patients (two during placebo and one during 10 µg/min dosing). In MN-221-CL-005, serum potassium level reductions as compared to baseline were observed at 1 h and were (mean values) -0.98 mEq/l in MN-221 P2, -0.87 MN-221 in P1 and -0.17 in placebo. The same patient experienced hypokalemia twice, which was considered to be related to the study drug and which required corrective treatment. Blood glucose levels increased from baseline at most of the time points in each treatment group, the peak increase (maximum difference from baseline) being detected at 2 h for each treatment group and being 4.05 in P2, 3.61 in P1 and 0.95 in placebo. These values were constantly higher at any time points in the treatment groups compared to placebo group. The pre-infusion heart rates were comparable across the arms in both studies. In MN-221-CL-004, this ranged from 67.5 to 75.6 beats/min. MN-221 doses of at least 3.5 µg were associated with increases in heart rate, which were detected at the end of the infusion period and were considered to be dose-related. In placebo group the mean heart rate was 66.4 beats/min, whereas in the 60 µg/min dose group it increased to 98.5 beats/min. This effect was found to persist 1154

at both 30 min and 1 h post-infusion but it gradually decreased in amplitude. In the other study the mean increases in the heart rate from pre-infusion level occurred in both P1 and P2 groups from 15 min to 12 h post-infusion, the peak increase being found at 1 h post-infusion (mean increase 14.8 beats/min in P1 and 18.1 beats/min in P2). In placebo group a decrease of the heart rate with a mean of 14.4 was concomitantly detected. In MN-221-CL-006 there were no reports on the hospital admission rates. Among the severe adverse events, the most commonly reported were asthma exacerbations and pneumonia, which were reported by 30.77 to be 7.69% in placebo group 0% in G1, 2, 3 or 4, respectively [13,17]. In MN-221-CL-007 no significant clinical safety issues were reported [14]. Regulatory affairs KUR-1246 was initially developed by Kissei Corp in Japan and then licensed in the USA to MediciNova as MN-221, the compound receiving finally the name bedorardine. Initially, it was developed as a tocolytic agent to prevent the spontaneous abortion and subsequently it was repurposed to be a bronchodilator to be used for asthma attacks and for COPD exacerbations. 3.3

4.

Conclusion

In conclusion, bedoradrine is a new b2 agonist with longer duration of action, which is claimed to have an ultraselective profile in favour of the b2-receptor and which currently seems to be developed as a potential exacerbation medication for asthma and COPD. What is novel apart from its structure is the route of administration, which is intravenous and which would be appropriate for patients in whom conventional nebulisation cannot be considered. However, the early clinical data discussed above cannot allow to define appropriately the role of such a therapy in exacerbation based on the fact that the optimal dose is not yet known, the rhythm of dosing not defined and the duration of such a therapy not calculated. 5.

Expert opinion

In severe acute asthma attacks requiring usually hospitalisation, the persistent bronchospasm is difficult to be relieved with single doses of usual short-acting bronchodilators such as (b2 agonist) salbutamol or (anticholinergic) ipratropium bromide given via inhalation route (nebulisation). Consequently, repeated doses are needed and this approach has the potential to increase the medication-related side-effects and especially those regarding the cardiovascular type. On the other hand, in status asthmaticus, for example, the ventilation might be severely impaired and therefore the chance of such medications to be inhaled properly are reduced even when nebulisation is used. Therefore, in this setting, systemic administration of bronchodilators should be contemplated in

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patients in whom nebulisation is not possible, not tolerated as a device or ineffective. Oral formulations can be good alternatives but the latency of the bronchodilation is longer than with inhaled formulation, and heavier the systemic exposure, the risk of severe cardiovascular impairment is higher. Parenteral formulations have the advantage of a rapid bronchodilating effect but on the expense of even a higher likelihood of cardiovascular side effects. However, by reducing the dose per minute and prolonging the infusion time for example, an acceptable bronchodilation can be safely obtained. Furthermore, if this effect is persistent, then fewer dosing is necessary and this can also improve indirectly the safety of such a therapy. Bedorardine for intravenous use is claimed to be an ultraselective b2 agonist and the data presented in this review also support its rapid onset of action and its longer duration of action. These attributes and the early clinical data support its further evaluation as a potential medication for asthma attacks and for severe COPD exacerbations. Initially, bedoradrine was evaluated in patients with stable asthma and COPD as an intravenous formulation. However, in such patients, the use of this medication on daily and regular basis is not supported even by the most exceptional efficacy and safety data on the one hand because of the route of administration, which always require a healthcare professional and a venous access and on the other hand because based on the studies done so far it is not clear how many times this medication should be given. Furthermore, it is not known if bedoradrine is superior to the existing (long-acting) b agonists used as regular therapy in asthma and COPD. In Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

CDC. Asthma’s impact on the nation. Data from the CDC national asthma control program 2012

2.

Kobayashi M, Takeda K, Murata S, et al. Pharmacological Characterization of KUR-1246, a Selective Uterine Relaxant. J Pharmacol Exp Ther 2001;297(2):666-71

3.

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asthma in particular, the b-agonist monotherapy given as maintenance therapy is even contraindicated by the existing guidelines, whereas in COPD the ultra-long-acting b agonist, indacaterol, is given as inhaled therapy and as a stand-alone treatment. In exacerbated asthma and COPD its potential use seems to be more plausible but so far only a limited body of data seems to be available especially in exacerbated COPD. Further clinical studies should assess the efficacy and safety of bedoradrine as an add-on therapy to usual standardised approach and exacerbation-related variables should be used as outcome measures. This compound was formulated for intravenous infusions but other injectable routes such as subcutaneous one might also be appropriate to be considered in order to improve the safety profile. To conclude, intravenous bedoradrine might be a new rescue medication for status asthmaticus or severe COPD exacerbations but further clinical data especially for the latter condition are needed in order to support its marketing authorisation.

Declaration of interest S Antoniu has no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Sabina Antoniu MD PhD Lecturer, University of Medicine and Pharmacy Grigore, T Popa Iasi, Department of Interdisciplinarity Palliative Care Nursing, 16 Universita˘t¸ ii Str, Iasi, 700115, Romania E-mail: [email protected]. ro

Bedoradrine for treating asthma and chronic obstructive pulmonary disease.

In severe asthma attacks or in severe chronic obstructive pulmonary disease (COPD) exacerbations, inhaled short-acting bronchodilators, such as salbut...
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