Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics incl. triple combinations with corticosteroids.

ATC code: R03AL12

Mechanism of action
Enerzair Breezhaler is a combination of indacaterol, a long-acting beta2-adrenergic agonist (LABA), glycopyrronium, a long-acting muscarinic receptor antagonist (LAMA) and mometasone furoate, an inhaled synthetic corticosteroid (ICS). Following oral inhalation, indacaterol and glycopyrronium act locally on airways to produce bronchodilation by separate mechanisms and mometasone furoate reduces pulmonary inflammation.

Indacaterol

Indacaterol is a long-acting beta2-adrenergic agonist for once-daily administration. The pharmacological effects of beta2-adrenoceptor agonists, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol is a weak partial agonist at beta1 receptors with a potency more than 24-fold greater at beta2- receptors compared to beta1-receptors and is a full agonist at beta3-receptors with a potency 20-fold greater at beta2-receptors compared to beta3-receptors.



ENE API JUL22 V2.1                                                          Australian PI Dec2021 When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a nearly full agonist at the human beta2-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.

Although beta2-adrenergic receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the human heart, there are also beta2- adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors.
The precise function of beta2-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.

Glycopyrronium

Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anti-cholinergic).
Glycopyrronium works by blocking the broncho constrictor action of acetylcholine on airway smooth muscle cells thereby dilating the airways. Of the five known muscarinic receptor subtypes (M1-5), only subtypes M1-3 have a defined physiological function in the human lung. Glycopyrronium is a high affinity muscarinic receptor antagonist of these three receptor subtypes. It demonstrated 4- to 5-fold selectivity for the human M3 and M1 receptors over the human M2 receptor in competition binding studies. It has a rapid onset of action, as evidenced by observed receptor association/dissociation kinetic parameters and by the onset of action after inhalation in clinical studies. The long duration of action can be partly attributed to sustained drug concentrations in the lungs as reflected by the prolonged terminal elimination half-life of glycopyrronium after inhalation via the inhaler in contrast to the half-life after intravenous administration (see section 5.2 PHARMACOKINETIC PROPERTIES - Excretion).

Mometasone furoate

Mometasone furoate is a synthetic corticosteroid with high affinity for glucocorticoid receptors and local anti-inflammatory properties. Studies in asthmatic patients have demonstrated that inhaled mometasone furoate provides a favorable ratio of pulmonary to systemic activity. It is likely that much of the mechanism for the effects of mometasone furoate lies in its ability to inhibit the release of mediators of the inflammatory cascade. In vitro, mometasone furoate inhibits the release of leukotrienes (LT) from leukocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of LT production and an extremely potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+ T-cells.

Pharmacodynamics
The primary pharmacodynamics of Enerzair Breezhaler in obstructive airway disease reflects the complementary mechanisms of action of the individual components.

The pharmacodynamic response profile of Enerzair Breezhaler is characterized by rapid onset of action within 5 minutes after dosing (see section 5.1 CLINICAL TRIALS) and sustained effect over the whole 24-hour dosing interval.

No tachyphylaxis to the lung function benefits of Enerzair Breezhaler were observed over time.

ENE API JUL22 V2.1                                                          Australian PI Dec2021 Effects on the QTc interval

The effect of Enerzair Breezhaler on the QTc interval has not been evaluated in a thorough QT (TQT) study. For mometasone furoate, no QTc prolonging properties are known.

Clinical trials
The safety and efficacy of Enerzair Breezhaler in adult patients with asthma was evaluated in a phase III randomized, double-blind study IRIDIUM. The study was a multi-center, 52-week study evaluating Enerzair Breezhaler 114/46/68 micrograms once daily (N=620) and 114/46/136 micrograms once- daily (N=619) via Breezhaler compared to indacaterol/mometasone furoate 215/127.5 micrograms once daily (N=617) and 125/260 once daily (N=618), respectively. A third active control arm included subjects treated with salmeterol xinafoate /fluticasone propionate (SAL/FP) 50/500 micrograms twice daily (N=618). The study was not powered for statistical comparisons between active comparator treatments.

All subjects were required to be symptomatic and were on asthma maintenance therapy using a medium or high dose ICS and LABA combination therapy for at least 3 months prior to study entry.
The mean age was 52.2 years. At screening, 99.9% of patients reported a history of exacerbation in the past year. At study entry, the most common asthma medications reported were LABA and medium dose of ICS (62.6%) and LABA and high dose of ICS (36.7%). (see section 4.2 POSOLOGY AND METHOD OF ADMINISTRATION - Posology).

The primary objective of the study was to demonstrate superiority of either Enerzair Breezhaler 114/46/68 micrograms once daily over indacaterol/mometasone furoate 150/160 micrograms once daily or Enerzair Breezhaler 114/46/136 micrograms once daily to indacaterol/mometasone furoate 125/260 micrograms once daily in terms of trough FEV1 at week 26.

Systemic exposures of mometasone furoate (MF) 80 (medium dose) and 160 (high dose) micrograms in Enerzair Breezhaler once daily are comparable to MF 160 (medium dose) and 320 (high dose) micrograms in Atectura Breezhaler (indacaterol/mometasone furoate) delivered via unit dose dry powder inhaler, respectively (see Section 5.2 Pharmacokinetic Properties – Absorption).

Lung function

Enerzair Breezhaler 114/46/136 micrograms once daily demonstrated statistically significant improvements in trough FEV1 at week 26 when compared to indacaterol/mometasone furoate at corresponding dose. The results of other lung function efficacy endpoints such as mean morning PEF and mean evening PEF are generally consistent with and support of the results of the primary endpoint. Findings at week 52 were consistent with week 26. (See Table 2).

ACQ-7

In study IRIDIUM, the mean change from baseline in ACQ-7 score at week 26 (key secondary endpoint) was around -1 for all treatment groups. The ACQ-7 responder rates (defined as a change in score of ≥0.5) were about 70% for all treatment groups at week 26. At week 52 the ACQ-7 responder rates were comparable between Enerzair Breezhaler and indacaterol/MF for both doses (See Table 2).


ENE API JUL22 V2.1                                                       Australian PI Dec2021 Exacerbations

Exacerbations were one of the "other secondary endpoints" (not part of confirmatory testing strategy). Enerzair Breezhaler 114/46/136 micrograms once daily demonstrated numerical reduction compared to indacaterol/mometasone furoate 125/260 micrograms once daily. (See Table 2).

Table 2           Results of primary and secondary endpoints in IRIDIUM study at weeks 26 and 52 
Enerzair Breezhaler vs IND/MF1
High dose
Time                                    (114/46/136 od)
Endpoint        Point/Duration                                versus high dose
(125/260 od)
Lung Function
Trough FEV1*
Treatment           Week 26 (Primary                             65 mL difference          endpoint)                                    <0.001 P value                                                         (31, 99) (95% CI)

Week 52                                       86 mL
<0.001
(51, 120)
Symptoms

ACQ responders (percentage of patients achieving minimal clinical important difference (MCID) from baseline with ACQ ≥0.5)
Percentage                                                 71% vs 74% 
Week 26
Odds ratio                                                    0.92
(95% CI)                                                  (0.70, 1.20) Percentage                                                79% vs 78%

Odds ratio     Week 52                                          1.10
(95% CI)                                                    (0.83, 1.47) Annualised rate of asthma exacerbations

Moderate or severe exacerbations

RR***        Week 52                                       0.85
(95% CI)                                                  (0.68, 1.04) Severe exacerbations

RR***        Week 52                                       0.78
(95% CI)                                                  (0.61,1.00) 1
IND/MF: Indacaterol/mometasone furoate;
Mometasone furoate 136 mcg in Enerzair Breezhaler (high dose) is comparable to mometasone furoate 260 mcg in indacaterol/mometasone furoate.
* Trough FEV1: the mean of the two FEV1, values measured at 23 hour 15 min and 23 hour 45 min after the evening dose.
** Mean value for the treatment duration.
ENE API JUL22 V2.1                                                      Australian PI Dec2021 ***RR <1.00 favours indacaterol/glycopyrronium/mometasone furoate
Primary endpoint (trough FEV1 at week 26) and key secondary endpoint (ACQ-7 score at week 26) were part of confirmatory testing strategy and thus controlled for multiplicity. All other endpoints were not part of confirmatory testing strategy.
RR = rate ratio, od = once daily, bid = twice daily

Pharmacokinetic Properties