Regulatory Decision Summary for INSPIOLTO RESPIMAT

The nonclinical program for Tio+Olo 5/5 mcg was carried out according to international regulatory requirements regarding nonclinical safety evaluation of drug combinations [United States Food and Drug Administration (FDA) 2006 and European Medicines Agency (EMA) 2008]. A comprehensive non-clinical package was previously submitted and reviewed for Spiriva Respimat [tiotropium 5 mcg once a day (qd), NDS control number 171012] and Striverdi Respimat (olodaterol 5 mcg qd, NDS control number 155649), respectively. There are no new safety concerns identified from preclinical studies for the combination product.

Results from a dedicated PK interaction study and a Phase III study showed that there was no notable pharmacokinetic interaction between tiotropium and olodaterol when inhaled as fixed dose combination formulation.

The efficacy and safety of Inspiolto Respimat (Tio+Olo 5/5 mcg) were evaluated in two replicated, 52-week, randomized, double-blind, parallel-group trials in COPD patients (Studies 1237.5 and 1237.6). The primary objective of these studies was to evaluate the efficacy and safety of 52 weeks of once-daily treatment with orally inhaled Inspiolto Respimat (Tio+Olo 5/5 mcg) compared with the individual components (tiotropium 5 mcg and olodaterol 5 mcg) in patients with COPD. The primary efficacy endpoints were response [change from pre-treatment baseline forced expiratory volume in one second area under the curve (FEV₁ AUC_0-3h, up to 3 hours post-dose)] and trough FEV₁ (23-24 hours post dose) after 24 weeks. A total of 5,162 subjects were randomized and treated in the 52-week pivotal studies. Significant improvements in FEV₁ AUC_0-3h response and trough FEV₁ response after 24 weeks were observed for Inspiolto Respimat (Tio+Olo 5/5 mcg) compared to its single components, tiotropium 5 mcg and olodaterol 5 mcg. The increased bronchodilator effects of Inspiolto Respimat compared to the single components tiotropium 5 mcg and olodaterol 5 mcg were maintained throughout the 52-week treatment period. Results from secondary and other efficacy endpoints including St. Georges Respiratory Questionnaire (SGRQ) and Mahler Transition Dyspnea Index (TDI) generally support the results of the primary endpoints.

One uncertainty regarding the efficacy of Inspiolto Respimat (Tio+Olo 5/5 mcg) is that the minimal clinically important difference (MCID) between the combination product and the single components for lung function (FEV₁ AUC_0-3h and trough FEV₁) has not been clearly defined nor has the MCID for the improvement of SGRQ or TDI; however, improvement in lung function and SGRQ and TDI were observed in patients treated with Tio+Olo 5/5 mcg when compared with the single components.

The most frequently reported adverse events (AEs) were in the system organ class (SOC) of infections and infestations disorders. The percentage of patients experiencing AEs was generally comparable between treatment with Inspiolto Respimat (Tio+Olo 5/5 mcg) and tiotropium 5 mcg and olodaterol 5 mcg. The most common AEs were nasopharyngitis, upper respiratory tract infection, bronchitis, urinary tract infection, sinusitis, oropharyngeal candidiasis, dizziness, hypertension, cough, oropharyngeal pain, dysphonia, diarrhea, constipation, dry mouth, edema peripheral, fatigue, back pain, and arthralgia. A total of 96 deaths were reported in two pivotal trials; there was no imbalance between treatment groups. Approximately 16.4% of patients in these studies reported serious adverse events (SAEs). The highest frequency of SAEs was reported in the SOC of respiratory, thoracic and mediastinal disorders. There were no apparent imbalances regarding number of deaths and SAEs between Inspiolto Respimat and its single components (tiotropium 5 mcg and olodaterol 5 mcg). In the pivotal studies, cardiovascular AEs by standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) were generally balanced across treatment groups. The most frequent cardiovascular AEs were cardiac arrhythmias and ischaemic heart disease. The incidence across the major cardiac adverse event (MCAE) endpoints was also balanced across treatment groups.

Uncertainties regarding the safety of Inspiolto Respimat (Tio+Olo 5/5 mcg) include:

1. long-term safety beyond one year of use, in particular, adverse cardiovascular events;
2. use in patients who have a recent history of myocardial infarction, unstable or life-threatening cardiac arrhythmia, paroxysmal tachycardia, and decompensated heart failure; and
3. use in patients with hepatic impairment or severe renal impairment, or pregnant or breast-feeding women.

The evidence submitted in this NDS supports the safety and efficacy of Inspiolto Respimat (Tio+Olo 5/5 mcg) for the recommended indication and dosage administration. The risk-benefit profile of Inspiolto Respimat (Tio+Olo 5/5 mcg) is considered favorable.