Regulatory Decision Summary for Trimbow

This New Drug Submission (NDS) was filed by Chiesi Farmaceutici S.p.A. to obtain market authorization for Trimbow, pursuant to section C.08.004 of the Food and Drugs Regulations.

Trimbow is a pressurized inhalation solution for oral inhalation, containing 100 microgram (mcg) beclomethasone dipropionate/10 mcg glycopyrronium bromide/6 mcg formoterol fumarate dihydrate per metered actuation, for the long-term maintenance treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema, to reduce COPD exacerbations in patients with a history of such events.

Upon review of the submitted data package, Health Canada authorized Trimbow for the following indication, clarifying Trimbow is to be used solely in adult COPD patients who are not adequately treated with dual combination therapies:

In adult patients who are not adequately treated with a combination of an inhaled corticosteroid (ICS) and a long-acting beta2-adrenergic agonist (LABA), or a combination of a LABA and a long-acting muscarinic antagonist (LAMA), for the long-term, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema, to reduce exacerbations of COPD in patients with a history of exacerbations.

The safety and efficacy of Trimbow were primarily supported by the Phase 3 clinical development program in chronic obstructive pulmonary disease (COPD) which was conducted with beclomethasone dipropionate (BDP), glycopyrronium bromide (GB), formoterol fumarate dihydrate (FF) (100 micrograms [mcg] of BDP, 10 mcg of GB, and 6 mcg of FF per metered actuation) and included two pivotal 52-week, active-controlled studies.

Trimbow (BDP/GB/FF) demonstrated a statistically significant improvement in lung function (as defined by change from baseline in pre-dose forced expiratory volume in 1 second [FEV₁] at Week 26 and change from baseline in 2-hour post dose FEV₁; co-primary endpoints) compared with BDP/FF. Trimbow showed a numerical improvement compared with BDP/FF at Week 26 for dyspnea severity measured by the transitional dyspnea index (TDI) focal score (co-primary endpoint) but did not reach statistical significance. The lung function and TDI outcomes at Week 52 were consistent with the results observed at Week 26.

Trimbow also demonstrated a statistically significant reduction in the annual rate of moderate/severe exacerbations (i.e., requiring treatment with antibiotics or corticosteroids or hospitalization) compared with indacaterol (IND)/GB (primary endpoint). Time to first moderate/severe COPD exacerbation, as well as the analyses of moderate and severe COPD exacerbations (considered separately) showed a trend toward a delay in time to the first event and a reduction of the rate of exacerbation but did not reach statistical significance. Although not statistically significant, Trimbow improved the average pre-dose FEV₁ over the 52-week treatment period compared to a long-acting muscarinic antagonist (LAMA)/ long-acting beta2-adrenergic agonist (LABA) combination by 22 millilitres (mL) (p = 0.018).

The overall safety profile of Trimbow was generally consistent with the known pharmacologic class effects of inhaled corticosteroids (ICSs), LAMAs and/or LABAs. In the Phase 3 clinical trials conducted in patients with severe to very severe COPD, a total of 1451 patients were treated with Trimbow (BDP/GB/FF total daily dose 400/50/24 mcg) with a mean duration of exposure of 341 days and 342 days in the two pivotal studies, respectively. The most common treatment-related adverse events reported were oral candidiasis (1.2%), muscle spasms (0.6%), dry mouth (0.5%), and dysphonia (0.3%). Safety issues are identified in the Product Monograph.

There were uncertainties with Trimbow from a clinical perspective related to its ability to reduce the rate of exacerbations due to lack of overwhelming statistically significant improvements across secondary endpoints measuring exacerbation outcomes, however Trimbow reached statistical significance in the key primary endpoints thus supporting the authorized indication.

The non-clinical studies reviewed suggest that the risk of the triple combination is consistent with known risks of the mono-components.

A Notice of Non-Compliance (NON) was issued by Health Canada previously due to the following major deficiencies identified from a Quality perspective:

• The comparative in vitro data provided was not considered to be sufficient to bridge the pivotal clinical batches and commercial batches.

• It was not clear whether the container closure system (CCS) used in the leachables study is representative of the proposed commercial CCS.

• The nitrosamine risk assessment provided was not considered to be robust.

• Data was missing to demonstrate stability-indicating nature of the high-performance liquid chromatography (HPLC) method for assay and related substances of the drug product.

• The supplier of the canisters used in stability studies for the drug product was not specified.

In response to the NON, the sponsor addressed the major deficiencies as follows:

• The sponsor provided additional data and in vitro product comparisons to demonstrate that the differences in formulation and device did not result in significantly different in vitro performance characteristics. The drug product performance (Aerodynamic Particle Size Distribution) was statistically comparable between the pivotal clinical batches and commercial batches.

• The sponsor provided clarifications for the extractables/leachables study results. These were reviewed to be satisfactory to support the use of the proposed container closure system.

• The updated nitrosamine risk assessment provided was reviewed to conclude negligible risk in formation of the nitrosamine impurities in the manufacturing process and on storage.

• Sufficient validation data were provided to support the intended use of the HPLC method for assay and related substances of the drug product.

Sufficient stability data were provided to support the proposed shelf life (including in-use period) of the drug product.

The chemistry and manufacturing information submitted for Trimbow has demonstrated that the drug substance and drug product can be consistently manufactured to meet the authorized specifications.

A Risk Management Plan was reviewed by Health Canada and considered acceptable.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile of Trimbow (100 mcg beclomethasone dipropionate/10 mcg glycopyrronium bromide/6 mcg formoterol fumarate dehydrates) is favourable for the authorized indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance was issued.

For further details about Trimbow, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.