DailyMed – TYVASO DPI TYVASO DPI – Inergency

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DailyMed – TYVASO DPI TYVASO DPI – Inergency


14.1 Pulmonary Arterial Hypertension (WHO Group 1) (TRIUMPH I)

TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled, multicenter study of patients with PAH (NCT00147199). The study population included 235 clinically stable subjects with PAH (WHO Group 1), nearly all with NYHA Class III (98%) symptoms who were receiving either bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase-5 inhibitor) for at least 3 months prior to study initiation. Concomitant therapy also can have included anticoagulants, other vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digitalis, but not a prostacyclin. These patients were administered either placebo or Tyvaso Inhalation Solution in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. Patients were predominately female (82%), had the origin of PAH as idiopathic/heritable (56%), secondary to connective tissue diseases (33%) or secondary to HIV or previous use of anorexigens (12%); bosentan was the concomitant oral medication in 70% of those enrolled, sildenafil in 30%.

The primary efficacy endpoint of the trial was the change in 6MWD relative to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10 and 60 minutes after dosing), and 3 to 5 hours after bosentan or 0.5 to 2 hours after sildenafil. Patients receiving Tyvaso Inhalation Solution had a placebo-corrected median change from baseline in peak 6MWD of 20 meters at Week 12 (p<0.001). The distribution of these 6MWD changes from baseline at Week 12 were plotted across the range of observed values (Figure 1). 6MWD measured at trough exposure (defined as measurement of 6MWD at least 4 hours after dosing) improved by 14 meters. There were no placebo-controlled 6MWD assessments made after 12 weeks.

Figure 1: Distributions of 6MWD Changes from Baseline at Week 12 During Peak Plasma Concentration of Tyvaso Inhalation Solution

DailyMed – TYVASO DPI TYVASO DPI – Inergency

The placebo-corrected median treatment effect on 6MWD was estimated (using the Hodges-Lehmann estimator) within various subpopulations defined by age quartile, gender, geographic region of the study site, disease etiology, baseline 6MWD quartile, and type of background therapy (Figure 2).

Figure 2: Placebo-Corrected Median Treatment Effect (Hodges-Lehmann Estimate with 95% CI) on 6MWD Change from Baseline at Week 12 During Peak Plasma Concentration of Tyvaso Inhalation Solution for Various Subgroups

Figure 2

14.2 Long-term Treatment of PAH

In long-term follow-up of patients who were treated with Tyvaso Inhalation Solution in the pivotal study and the open-label extension (N=206) (NCT00147199), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 97%, 91%, and 82%, respectively. These uncontrolled observations do not allow comparison with a control group not given Tyvaso Inhalation Solution and cannot be used to determine the long-term effect of Tyvaso Inhalation Solution on mortality.

14.3 Pulmonary Hypertension Associated with ILD (WHO Group 3)

INCREASE was a 16-week, randomized, double-blind, placebo-controlled, multicenter study that enrolled 326 patients with PH-ILD (NCT02630316). Enrolled study patients predominately had etiologies of idiopathic interstitial pneumonia (45%) inclusive of idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema (25%), and WHO Group 3 connective tissue disease (22%). The mean baseline 6MWD was 260 meters.

Patients in the INCREASE study were randomized (1:1) to either placebo or Tyvaso Inhalation Solution in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) per session and a maximum dose of 12 breaths (72 mcg) per session over the course of the 16-week study. Approximately 75% of patients randomized to Tyvaso Inhalation Solution titrated up to a dose of 9 breaths, 4 times daily or greater, with 48% of patients randomized to Tyvaso Inhalation Solution reaching a dose of 12 breaths, 4 times daily during the study.

The primary efficacy endpoint was the change in 6MWD measured at peak exposure (between 10 and 60 minutes after dosing) from baseline to Week 16. Patients receiving Tyvaso Inhalation Solution had a placebo-corrected median change from baseline in peak 6MWD of 21 meters at Week 16 (p=0.004) using Hodges-Lehmann estimate (Figure 3).

Figure 3: Hodges-Lehmann Estimate of Treatment Effect by Visit for 6MWD at Peak Exposure of Tyvaso Inhalation Solution (PH-ILD)

Figure 3

The treatment effect on 6MWD at Week 16 was consistent for various subgroups, including etiology of PH-ILD, disease severity, age, sex, baseline hemodynamics, and dose (Figure 4).

Figure 4: Forest Plot on Subgroup Analyses of Peak 6MWD (Meter) at Week 16 (PH-ILD)

Figure 4

Time to clinical worsening in the INCREASE study was defined as the time of randomization until 1 of the following criteria were met: hospitalization due to a cardiopulmonary indication, decrease in 6MWD >15% from baseline directly related to PH-ILD at 2 consecutive visits and at least 24 hours apart, death (all causes), or lung transplantation. Treatment with Tyvaso Inhalation Solution in patients with PH-ILD resulted in numerically fewer hospitalizations. The numbers of reported deaths were the same for both treatment groups (Table 3). Overall, treatment with Tyvaso Inhalation Solution demonstrated a statistically significant increase in the time to first clinical worsening event (log-rank test p=0.041; Figure 5), and a 39% overall reduction in the risk of a clinical worsening event (HR=0.61 [95% CI; 0.40, 0.92]; Figure 5).

Figure 5: Kaplan-Meier Plot of Time to Clinical Worsening Events (PH-ILD)

Figure 5


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