The recent PLATINUM clinical trial program^1-4 evaluated the efficacy and safety of the Atectura Breezhaler (indacaterol/mometasone furoate) and Enerzair Breezhaler (indacaterol/glycopyrronium bromide/mometasone furoate) in four large clinical trials of various asthma patient populations. The limbic spoke to Professor Kenneth Chapman from the University of Toronto about what the results of the PLATINUM program tell us about the place in therapy for these combination therapies.

The Atectura and Enerzair Breezhalers deliver combination therapy via a single inhaler device.^5,6 The Atectura Breezhaler delivers the long-acting beta-2 agonist (LABA) indacaterol (IND) in combination with the inhaled corticosteroid (ICS) mometasone furoate (MF),⁵ and the Enerzair Breezhaler delivers indacaterol, mometasone furoate and the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GLY). The Enerzair three-drug combination is indicated for people with asthma that is uncontrolled on an ICS plus LABA.⁶

Both the Atectura and Enerzair Breezhalers are once-daily therapies,^5,6 which Professor Chapman believes to be a key feature of these new treatments. “The availability of a once-daily maintenance therapy for asthma is so tremendously important,” said Professor Chapman. “The ability to offer patients a once-a-day preventer has enormous benefits, including in those with severe asthma,” he added.

The PLATINUM program did not assess the clinical benefits of once-daily therapy, but Professor Chapman drew on his own clinical experience with these treatments to point out the possible advantages for people with asthma. “I have been making tremendous progress with people with uncontrolled asthma arriving on a twice a day ICS/LABA inhaler combination when I simply change them to a once-a-day therapy and ask them to focus on taking the inhaler every day…More than half of my patients show a dramatic improvement in their asthma when they come back for a review. For these patients, it seems that nobody had told them what to focus on…nobody had made it easy for them to take a maintenance therapy on a regular basis.”

Professor Chapman points out that a once-daily therapy also gives patients the opportunity to make choices that may aid adherence. “One of my favourite questions for patients is, ‘Which dose do you tend to miss?’ Some of my patients report that they are great remembering their medication in the morning but tired at night and forget the night time dose,” he explained. “But nearly everyone can pick the time of day that works best for them,” he said.

The PLATINUM program studies

There are four studies in the PLATINUM program (see Table 1), each designed to assess the place in therapy of either the Atectura Breezhaler or Enerzair Breezhaler.

Table 1. PLATINUM Program^1-4

The QUARTZ study¹ compared low-dose LABA/ICS to ICS monotherapy in patients with inadequately controlled asthma.

This was a multicentre, randomised, double-blind, double-dummy study comparing once-daily low-dose IND/MF with once-daily MF monotherapy in adult and adolescent patients with inadequately controlled asthma.¹

Low-dose IND/MF significantly improved trough forced expiratory volume in one second (FEV₁; least squares mean treatment difference [LSMTD] 0.182L; P<0.001) and asthma control (Asthma Control Questionnaire [ACQ] LSMTD: -0.218; p<0.001) compared to MF. Safety was comparable. The authors concluded, “These results support the use of low-dose IND/MF 150/80 mcg once daily as a potential therapy for adult and adolescent patients with inadequately controlled asthma.”¹

Compared to MF monotherapy, low-dose IND/MF also resulted in improvements in secondary efficacy variables such as rescue medication use, rescue medication free days, night-time awakenings and daily symptom scores. The authors noted, “This study also provides evidence of the benefit of adding LABA to a lower dose ICS as per GINA guidelines⁷ and provides an important treatment option prior to advancing to combination therapies that include higher ICS dose.”¹

The PALLADIUM study² compared IND/MF medium- to high-dose to corresponding doses of MF monotherapy in patients whose asthma remained uncontrolled on medium- to high-dose ICS or low-dose ICS/LABA.

The study found that the medium- and high-dose IND/MF combinations significantly improved lung function compared to the high-dose ICS monotherapy. High-dose once-daily IND/MF combination was also found to be non-inferior (trough FEV₁ at 26 weeks) to the twice-daily combination of high-dose fluticasone propionate/salmeterol xinafoate (500 µg/50 µg) via the Diskus device.²

The IRIDIUM study³ showed that once-daily medium- or high-dose IND/GLY/MF improved trough FEV₁ versus corresponding doses of IND/MF. Overall the incidence of adverse events (AEs) was balanced across the treatment groups.

Improvements in trough FEV₁ were greater for both the medium- and high-dose once-daily three-drug combination than for high-dose twice-daily fluticasone propionate/salmeterol xinafoate (500 µg/50 µg) delivered via the Diskus device.³

Professor Chapman pointed out the significance of these results. “This is impressive, given that the fluticasone/salmeterol comparator is a strong ICS/LABA combination,” he said.

The ARGON study⁴ compared IND/GLY/MF delivered via the Breezhaler to a combination of twice-daily salmeterol/fluticasone plus once-daily tiotropium (TIO), which were delivered via separate inhalers.

The study was conducted in adult patients who were symptomatic despite treatment with medium- or high-dose ICS/LABA. Patients were randomised to receive either high-dose (150/50/160 µg) or medium-dose (150/50/80 µg) IND/GLY/MF once daily, or the free combination of high-dose SAL/FLU (50/500 µg) twice daily plus TIO (5 µg) once daily for 24 weeks.

Both medium- and high-dose IND/GLY/MF delivered once-daily via a single inhaler were non-inferior to the free combination inhalers in terms of the Asthma Quality of Life Questionnaire. The high-dose single inhaler was also found to improve lung function, asthma control and health status compared to the free combination inhalers. The medium-dose single inhaler had comparable efficacy to the free combination inhalers but at a lower steroid dose.⁴

ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; FEV1, forced expiratory volume in one second; ICS, inhaled corticosteroid; IND, indacaterol; GLY, glycopyronium; MF, mometasone furoate;

Simplifying therapy with a single inhaler

Professor Chapman believes that the results of the ARGON study should help clinicians feel comfortable to move to the Enerzair Breezhaler when considering adding a LAMA into the regimen. “Up until now, if clinicians wanted to give people with severe asthma the benefit of a LAMA prior to considering a biologic, it was a matter of adding in a separate inhaler to deliver triotropium,” he explained.

Furthermore, the benefits with a single inhaler device delivering the three-drug combination includes the potential to improve adherence, said Professor Chapman. He described results of a retrospective cohort study in people with asthma initiated on a separate tiotropium inhaler to their ICS/LABA maintenance therapy.⁸ The study found that 44–52% of patients discontinued the ICS within six months of tiotropium initiation.

“This study suggests that if you give people a separate inhaler to juggle when starting triple therapy, around half of them will end up on tiotropium monotherapy. The addition of another inhaler has the potential to confuse people, and the only sensible way forward for three-drug therapy in severe asthma is a fixed combination inhaler,” said Professor Chapman.

References

1. Kornmann O et al. Efficacy and safety of inhaled once-daily low-dose indacaterol acetate/mometasone furoate in patients with inadequately controlled asthma: Phase III randomised QUARTZ study findings. Respir Med 2020; 161:105809 https://www.sciencedirect.com/science/article/pii/S0954611119303233
2. Van Zyl-Smit RN et al. Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple dummy, controlled phase 3 study. Lancet Respir 2020; 8(10):987–999 https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30178-8/fulltext
3. Kerstjens H et al. Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study. Lancet Respir 2020; 8(10): 1000–10012 https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30190-9/fulltext
4. Gessner C et al. Fixed-dose combination of indacaterol/glycopyrronium/mometasone furoate once-daily versus salmeterol/fluticasone twice-daily plus triptropium once-daily in patients with uncontrolled asthma: A randomised, Phase IIIb, non-inferiority study (ARGON). Respir Med 2020; 170: 106021 https://www.sciencedirect.com/science/article/abs/pii/S095461112030161X
5. Atectura Breezhaler Australian Approved Product Information
6. Enerzair Breezhaler Australian Approved Product Information
7. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. www.ginasthma.org
8. Averell CM et al. Characterizing real-world use of tiotropium in asthma in the USA. J Asthma Allergy 2019;12:309-321 https://pubmed.ncbi.nlm.nih.gov/31632091/