TRIXEO AEROSPHERE (formoterol/ glycopyrronium/ budesonide)

Key points

Favourable opinion for reimbursement as maintenance treatment in adult patients with severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting beta2-agonist or combination of a long-acting beta2-agonist and a long-acting muscarinic antagonist.

Unfavourable opinion for reimbursement as maintenance treatment in moderate COPD.

What therapeutic improvement?

No clinical added value in the management of severe COPD.

Role in the care pathway?

The Committee reiterates:

• the importance of supporting patients in the overall management of their COPD, including smoking cessation, physical activity and therapeutic education,
• that compliance with treatment, the inhaler technique, comorbidities and the evolution of respiratory function should be systematically assessed before any adjustment of treatment;
• that in the event of insufficient efficacy or adverse effects, a decrease of treatment, in particular discontinuation of inhaled corticosteroids, should be considered.

The therapeutic strategy, recommended by the SPLF since 2016, is as follows:

In all patients, as soon as COPD has been diagnosed by a pulmonary function test (FEV₁/CV <0.70), physical activity is recommended, as well as smoking cessation aid;

When symptoms (dyspnoea) are episodic and not very intense, pharmacological treatment is limited to short-acting inhaled bronchodilators on demand;

In the case of daily dyspnoea and/or exacerbations, the first-line treatment is long-acting beta2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) bronchodilator monotherapy.

If symptoms persist, despite well managed treatment, dual therapy may be proposed after having:

• eliminated any other cause of treatment lack of efficacy (differential or associated diagnosis, poor compliance, incorrect inhaler technique),
• verified the implementation of help to quit smoking,
• performed a respiratory function assessment.

This dual therapy is based on a combination of two long-acting bronchodilators (LABA + LAMA) for patients whose primary symptom is dyspnoea, or exacerbations associated with dyspnoea (mMRC ≥2). For patients with exacerbations, but with no associated significant dyspnoea, the combination of an inhaled corticosteroid (ICS) with a LABA may be considered.

Triple therapy (LABA + LAMA + ICS) is indicated if exacerbations persist despite dual therapy. In addition, recent international guidelines mention that a modulation of efficacy according to blood eosinophil count should be considered.

In all cases, a clinical and functional assessment is offered 1 to 3 months after changing the treatment, then every 3 to 12 months, depending on the severity of the COPD.

Role of the medicinal product in the care pathway

TRIXEO AEROSPHERE is a triple fixed-dose combination containing a LABA, a LAMA and a high-dose ICS, respectively formoterol, glycopyrronium and budesonide.

Considering the available data, in particular having demonstrated a modest efficacy on the reduction of exacerbations compared to LABA/ICS or LABA/LAMA dual therapy, and the characteristics of this medicinal product containing a high-dose ICS preventing any adjustment, TRIXEO AEROSPHERE represents a therapeutic alternative for patients with severe COPD, who are not adequately treated by a combination of an ICS and a LABA or a combination of a LABA and a LAMA, and who continue to have persistent exacerbations.

In addition, in view of the accumulation of exploratory data on the efficacy of triple fixed-dose combinations evaluated by eosinophil count, including for this combination, and in accordance with the recent GOLD 2021 and ERS 2020 guidelines, the prescription of TRIXEO AEROSPHERE should be preferred for patients with an eosinophil count ≥ 150 cells/µL, considering that the addition of ICS treatment would have little or no effect for patients with an eosinophil count < 150 cells/µL.

Finally, it should be noted that only the TRIXEO AEROSPHERE triple fixed-dose combination containing a high-dose ICS has been granted an MA, despite the development of a triple fixed-dose combination containing a moderate-dose ICS. In view of the data provided, which does not demonstrate any difference of efficacy between the moderate and high doses, the Committee regrets that this triple fixed-dose combination including a moderate-dose ICS is not available in order to enable the adjustment of treatment by looking for the minimum effective dose of inhaled corticosteroid.

Reassessment of treatment will make it possible to consider discontinuation of TRIXEO AEROSPHERE in the event of inadequate efficacy or adverse effects.

In view of the data, the available alternatives and the characteristics of this medicinal product, TRIXEO AEROSPHERE has no role in the management of moderate COPD.

 Special recommendations

The provisions of article L. 162-17 of the French Social Security Code concerning the retail formulary list of reimbursed medicinal products and the provisions of article L. 5123-2 of the French Public Health code concerning the hospital formulary list of medicinal products approved for use indicate that the Committee may, in view of the requirements of quality and safety of care relative to the medicinal product that it is assessing, issue recommendations that may, in particular, concern the qualification or expertise of prescribers.

In application of these provisions, the proper use of a medicinal product for patients at an advanced stage of the disease, whose management is difficult, may require a special supervision of the prescription of the medicinal product.

For the advanced stage of the disease, the Committee reiterates that patients eligible for treatment with TRIXEO AEROSPHERE have:

• severe COPD, with persistent exacerbations,
• despite dual therapy with ICS+LABA or LABA+LAMA, for which the prescription has been optimised based on the recommended indications and dosage,
• and taking into account the complementary non-pharmacological approach (smoking cessation, physical activity, differential diagnosis).

Furthermore, recent guidelines favour the addition of an ICS in the context of a triple combination, such as TRIXEO AEROSPHERE, for patients with an eosinophil count ≥ 150 cells/µL.

At this advanced stage, the repeated occurrence of exacerbations can be life-threatening. Reducing the number of exacerbations is therefore a major objective in both the short and long term.

The Committee’s recommendations concerning the proper use of this medicinal product are made in a context of known misuse of triple free combinations, and of dual fixed-dose inhaled combinations containing corticosteroids, at stages in which monotherapy or dual therapy with long-acting bronchodilators would be more appropriate. Firstly, there is no need to prescribe a triple combination when monotherapy is adequate and relevant and, secondly, the guidelines recommend the combination of a LABA/LAMA or an ICS/LABA combination depending on the dyspnoeic or exacerbating profile of patients requiring dual therapy.

The Committee highlights the fact that the prescription of TRIXEO AEROSPHERE at this stage of the disease involves a clinical and functional respiratory assessment in order to target the recommended patient population (definite diagnosis) in view of the study data available. In addition, this prescription should take into account the fact that this medicinal product provides a high dose of ICS from the outset and does not allow dose adjustment.

Consequently, the Transparency Committee recommends that initial prescription of TRIXEO AEROSPHERE should be reserved for pulmonology specialists only.