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Ethanol content of inhalers – What is the significance?

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New Medicines

Bevespi AerosphereChronic obstructive pulmonary disease (COPD)

Information

Bevespi Aerosphere
New formulation
AstraZeneca
Pearl Therapeutics

Development and Regulatory status

Launched
Licensed but not launched
Launched
January 2021
Jan 21Launched in UK. Price 120 doses = £32.50 [25].
Dec 18Approved in the EU [23].
Oct 18Recommended for EU approval by CHMP - the full indication is "as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD)" [22].
Jul 17Filed in EU via centralised procedure [18].
Dec 16EU filing now expected 2017 [17].
Jun 16EU filing planned 2H 16 [16].
Apr 16Approved in the US under the brand name of Bevespi Aerosphere [15].
Sep 15Filed accepted in the US; EU filing planned for H2 2016 [14].
Mar 15Pearl Therapeutics is a subsidiary of AstraZeneca [12].
Dec 14AstraZeneca anticipate filing in the US Q3 15 & in the EU 1H 16 [11].
Apr 14Current plan to file in EU in 2016 and US in 2015 [10].
Dec 13EU filing now planned for 2015, followed by US filing in 2016 [9].
Jun 13EU filing planned for 2016 [7].
May 13US filing expected mid 2015, followed later by filings in the EU and Canada [4].
Nov 12PII studies have been completed. Two PIII studies are planned to start mid 2013 with results available end-2014 [3].

Category

Long acting beta agonist plus muscarinic receptor antagonist
It is estimated that 3 million people in the UK are affected by COPD. Approximately 900,000 of these are diagnosed, whilst another 2 million are estimated to be affected but undiagnosed (www.nice.org.uk/CG101).
Chronic obstructive pulmonary disease (COPD)
Inhalation

Trial or other data

Dec 18Primary outcome met in PINNACLE 1, 2 and 3 [24].
Aug 18AstraZeneca report mixed results from PIIIb AERISTO trial. Although non-inferiority to umeclidinium/vilanterol (Anoro Ellipta) on peak FEV1 was demonstrated, it failed to demonstrate superiority on peak FEV1 or non-inferiority on trough FEV1 [21]. 24/08/2018 09:11:11
Sep 17Positive results from another PIII trial, PINNACLE 4 (NCT02343458) announced in which glycopyrronium+formoterol demonstrated a statistically significant improvement in lung function as measured by trough FEV1 vs. its monotherapy components and placebo, all administered twice daily via pMDI to patients with moderate to very severe COPD. The results of this trial, as well as data from previous trials, will be taken to regulators in China and Japan in 2018 [19].
Jun 17First patient commences dosing in the PIII AERISTO trial (NCT03162055) in 1,000 patients with moderate-to-very severe COPD. Bevespi will be compared with umeclidinium + voilanterol. Data are expected H2 18 [20].
Mar 15Positive results of the PIII double-blind trial announced which included more than 3,700 patients with COPD at over 275 study sites. During the year-long trial some patients were provided with a placebo, while others were administered PT003 twice per day [13].
Oct 13NCT01970878 This is a multi-center, randomized, double-blind chronic dosing, active-controlled, 28-week safety extension study of two PIII 24-week safety and efficacy studies (PT003006 and PT003007). This study is designed to assess the long-term safety and tolerability of GFF, GP and FF in 850 subjects with moderate to very severe COPD over 52 weeks. Open-label Spiriva is included as an active control. The study starts Dec 13 and is due to complete Jan 15 [8].
Jun 13AstraZeneca is buying Pearl Therapeutics and with it, the twice-daily fixed dose combination of formoterol fumarate and glycopyrrolate. The biotech believes that a twice-daily dosing at critical times of the day will prove superior to the once-daily approach taken by other companies [6].
May 13NCT01854645 (PINNACLE 1) is a randomized, double blind, chronic dosing, multicentre study of GP+FF vs GP, and FF in 1527 subjects with moderate to very severe COPD, vs placebo and Spiriva® Handihaler® (tiotropium Bromide 18µg open-label) as an active control. The primary outcome is change from baseline in morning pre-dose trough FEV1 at 24 weeks. The study starts Jun 13 and is due to complete Nov 14 [5].
May 13(PINNACLE 2) is a randomized, double blind, chronic dosing, multicentre study of GP+FF vs GP, and FF in 1200 subjects with moderate to very severe COPD, vs placebo. The primary outcome is change from baseline in morning pre-dose trough FEV1 at 24 weeks. The study starts Jul 13 and is due to complete Dec 14 [5].
May 13PINNACLE, a global PIII programme of glycopyrrolate and formoterol fumarate (PT003) delivered via a pressurized hydrofluoroalkane (HFA MDI) using a novel co-suspension formulation platform has started. The PINNACLE programme will enrol >2,700 subjects with moderate-to-severe COPD in two studies in the US, Canada, Europe, Australia and New Zealand. Studies will compare a single dose of PT003 vs its components and placebo. In one study, open label tiotropium will serve as active control. A 28-week extension study to assess long-term safety is planned. The primary efficacy endpoint is improvement in lung function assessed by FEV1; additional co-primary endpoints will also be assessed to support regulatory requirements in certain regions. Enrolment is expected to be complete by mid 2014 [4].
Oct 12NCT01587079 a randomized, double-blind, dose-ranging PIIb trial of PT003 in patients with moderate-to-severe COPD has completed. The study assessed five twice daily doses of PT003, in which formoterol fumarate (FF) was co-formulated with five descending doses of glycopyrrolate (GP). Multiple doses of PT003 were shown to provide superior bronchodilation vs open-label tiotropium and monotherapy components, GP MDI (PT001) and FF MDI (PT005). Based on the two PIIb studies a dose of PT003 for testing in PIII has been selected. The study also demonstrated the benefit of combining GP and FF in the fixed-dose combination, PT003, providing evidence for the US requirement known as the ‘combination rule.’ PIII studies are planned for 2013 [3].
Sep 11Further results from the PIIb study (NCT01085045) presented at ERS Congress concenring the comparison between PT003 and tiotropium (Spiriva HandiHaler). The two doses of PT003 (72mcg GP/9.6mcg FF and 36mcg GP/9.6mcg FF) and Spiriva provided statistically significant improvements in inspiratory capacity (IC) vs placebo on day one (p<0.0001 all comparisons) and on day seven (p<0.0004 all comparisons). Both doses of PT003 provided a benefit on day one relative to Spiriva, with the higher dose showing statistical difference vs Spiriva (p<0.05). Further improvement was observed with chronic dosing, with both doses of PT003 providing a statistically significant benefit on day 7 pre-dose and two hours post-dose relative to Spiriva (p<0.05) [2].
May 11PIIb trial results (n=118). Pts randomised to four of eight treatments in a cross-over study: glycopyrrolate/formoterol fumarate (GP/FF) (36/9mcg or 73/9.6mcg bd), GP 36mcg bd, FF (7.2 or 9.6mcg bd), Spiriva (tiotropium), Foradil (formoterol) or placebo. The main outcome was improvement in lung function after one week of dosing, as assessed by FEV1 AUC (0-12) relative to baseline at the start of treatment. Treatment with PT 003 resulted in a statistically significant improvement in mean FEV1 AUC (0-12) of 47% (93 mL) over Foradil and 49% (95 mL) over Spiriva after one week of dosing. PT 003 treatment also showed a statistically significant improvement in peak FEV1 on day one vs. all comparators and placebo: improvements in peak FEV1 levels on day 1 were 42% (64mL) over Foradil and 75% (92mL) over Spiriva, and of 37% (89mL) and 75% (141mL) on day 7. Morning trough FEV1 levels in the PT 003 arm were improved by 48% (or 68 mL) over Foradil and 52% (or 73 mL) over Spiriva. Data presented at American Thoracic Society, Denver, US, May 2011. [1]
May 11As part of a previously conducted dose-ranging study, Pearl determined that a BID administration 9.6 mcg formoterol (FF) MDI provided equivalent bronchodilation to Foradil. In another study, multiple doses of glycopyrrolate (GP) were tested against the currently marketed LAMA, Spiriva, and the results supported the progression of 36 mcg and 72 mcg BID. [1]

Evidence based evaluations