AstraZeneca’s triple combination therapy PT010 (budesonide/glycopyrrolate/formoterol fumarate) improved lung function and reduced the rate of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in a Phase 3 trial, compared with dual combination therapies.
Results of the trial were published in the study, “Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicenter, phase 3 randomized controlled trial,” in the journal The Lancet Respiratory Medicine, and recently presented at the European Respiratory Society International Congress 2018 in Paris.
The Phase 3 KRONOS trial (NCT02497001) tested the effectiveness and safety of PT010 compared with the dual combination therapies Bevespi Aerosphere (glycopyrrolate/formoterol fumarate), Symbicort (PT009, budesonide/formoterol fumarate), and Symbicort Turbuhaler (budesonide/formoterol fumarate) in COPD patients.
PT010 is a single inhaler, fixed-dose triple combination therapy containing budesonide, an inhaled corticosteroid with potent anti-inflammatory properties; glycopyrrolate, a long-acting muscarinic agonist (LAMA) that triggers lung muscle contraction and mucus release in the airways; and formoterol fumarate, a long-acting beta2-agonist (LABA) that allows the airways to open (bronchodilator).
This investigational therapy combines the action of both approved Bevespi and Symbicort. Like Bevespi, PT010 is also being developed using AstraZeneca’s Aerosphere Delivery Technology, a drug delivery method based on a special aerosol formulation (inhalation aerosol).
While Symbicort is delivered through a metered-dose inhaler as an inhalation aerosol, which is combined with a gas to force the medicine into the patients’ airways, the Symbicort Turbuhaler is a dry powder inhaler that relies on the patient’s inhalation for the medicine to reach the lungs. Plus, while Symbicort holds 320 micrograms of budesonide and 9.6 mcg of formoterol, the Turbuhaler version tested has 400 mcg of budesonide and 12 mcg of formoterol.
PT010 was administered at doses of 320 mcg of budesonide, 18 mcg of glycopyrrolate, and 9.6 mcg of formoterol; and Bevespi at doses of 18 mcg of glycopyrrolate and 9.6 mcg of formoterol.
Primary objectives of the trial focused on lung function, measured by FEV1 — the amount of air a person can forcefully exhale in one second — between medicine intake and four hours after the treatment, and changes from initial FEV1 in the morning, before taking the medicine. Both measurements were performed over 24 weeks of treatment.
Secondary goals included improvements in lung function and the rate of moderate to severe COPD exacerbations, and frequency of treatment-related adverse events.
Between August 2015 and January 2018, 3,047 COPD patients were screened from 215 sites, and 1,902 were enrolled in the study. About 74% of these patients had not reported an exacerbation in the previous year.
Of these participants, 64o were randomized to receive PT010, 627 to Bevespi, 316 to Symbicort, and 319 to Symbicort Turbuhaler. Participants were given two inhalations twice a day of their assigned therapy.
Over 24 weeks, patients taking PT010 showed significantly improved FEV1 values, compared with those taking Symbicort or Symbicort Turbuhaler. PT010 also increased patients’ initial FEV1 values in the morning versus Bevespi.
After 24 weeks of treatment, PT010 significantly improved FEV1 values over Symbicort.
Notably, PT010 led to a significant 52% reduction in the rate of moderate to severe COPD exacerbations compared with Bevespi. The same trend was seen compared with Symbicort and Symbicort Turbuhaler, although to a lesser extent and not statistically significant (18% and 17%, respectively).
The most common adverse events reported were nasopharyngitis, an inflammation of the pharynx and nasal cavities, and upper respiratory tract infection across all treatments analyzed. Pneumonia incidence was low (less than 2%) and similar across treatments.
These results highlight the potential of the triple combination therapy in improving the lung function of COPD patients.
“We are encouraged by the results of the KRONOS trial which demonstrate PT010’s efficacy in improving lung function and its potential value as a triple combination therapy for patients with COPD,” Colin Reisner, MD, head of Respiratory Global Medicines at AstraZeneca, said in a press release.
“Importantly, PT010 also halved the rate of moderate or severe exacerbations compared to glycopyrrolate/formoterol fumarate [Bevespi Aerosphere] and we look forward to the ETHOS exacerbation trial results in 2019 to further characterize PT010,” he said.
The Phase 3 ETHOS trial (NCT02465567) is specifically evaluating the impact of PT010 on COPD exacerbations.
“Preventing exacerbations is a priority in the management of COPD because they are known to have an impact on lung function and mortality, and patients are at risk even if they haven’t had an exacerbation in the previous 12 months. The KRONOS trial demonstrated that PT010 reduces the risk of an exacerbation,” said lead author Gary Ferguson, MD, a professor at the Pulmonary Research Institute of Southeast Michigan.
AstraZeneca anticipates making the first regulatory submissions for PT010 by the end of 2018.