14 CLINICAL STUDIES

14.1 Pulmonary Arterial Hypertension (PAH)

Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of Letairis and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg Letairis to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg Letairis to placebo. In both studies, Letairis or placebo was added to current therapy, which could have included a combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36® Health Survey were assessed.

Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease.

Patients had WHO functional class I (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian.

Submaximal Exercise Ability

Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 3 and Figure 4.

Table 3 Changes from Baseline in 6-Minute Walk Distance (meters) (ARIES-1 and ARIES-2)
	ARIES-1			ARIES-2
	Placebo (N=67)	5 mg (N=67)	10 mg (N=67)	Placebo (N=65)	2.5 mg (N=64)	5 mg (N=63)
Mean ± standard deviation
* p-values are Wilcoxon rank sum test comparisons of Letairis to placebo at Week 12 stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients
Baseline	342 ± 73	340 ± 77	342 ± 78	343 ± 86	347 ± 84	355 ± 84
Mean change from baseline	-8 ± 79	23 ± 83	44 ± 63	-10 ± 94	22 ± 83	49 ± 75
Placebo-adjusted mean change from baseline	_	31	51	_	32	59
Placebo-adjusted median change from baseline	_	27	39	_	30	45
p-value*	_	0.008	<0.001	_	0.022	<0.001

Figure 4 Mean Change in 6-Minute Walk Distance (ARIES-1 and ARIES-2)

Mean change from baseline in 6-minute walk distance in the placebo and Letairis groups.
Values are expressed as mean ± standard error of the mean.

In both studies, treatment with Letairis resulted in a significant improvement in 6-minute walk distance for each dose of Letairis and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with Letairis, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with Letairis were smaller for elderly patients (age ≥65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously.

Clinical Worsening

Time to clinical worsening of PAH was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape. Early escape was defined as meeting two or more of the following criteria: a 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; or refractory systolic hypotension. The clinical worsening events during the 12-week treatment period of the Letairis clinical trials are shown in Table 4 and Figure 5.

Table 4 Time to Clinical Worsening (ARIES-1 and ARIES-2)
	ARIES-1		ARIES-2
	Placebo (N=67)	Letairis (N=134)	Placebo (N=65)	Letairis (N=127)
Intention-to-treat population. Note: Patients may have had more than one reason for clinical worsening. Nominal p-values
Clinical worsening, no. (%)	7 (10%)	4 (3%)	13 (22%)	8 (6%)
Hazard ratio	_	0.28	_	0.30
p-value, Log-rank test	_	0.030	_	0.005

There was a significant delay in the time to clinical worsening for patients receiving Letairis compared to placebo. Results in subgroups such as the elderly were also favorable.

Figure 5 Time to Clinical Worsening (ARIES-1 and ARIES-2)

Time from randomization to clinical worsening with Kaplan-Meier estimates of the proportions of patients without events in ARIES-1 and ARIES-2.

p-values shown are the log-rank comparisons of Letairis to placebo stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients.

14.2 Combination Treatment of PAH

In a randomized, double-blind, active-controlled trial (AMBITION), 605 patients with WHO Functional Class II or III PAH were randomized 2:1:1 to once daily Letairis plus tadalafil or to Letairis or tadalafil alone. Treatment was initiated with Letairis 5 mg and tadalafil 20 mg. If tolerated, tadalafil was increased to 40 mg at 4 weeks and Letairis was increased to 10 mg at 8 weeks.

The primary endpoint was time to first occurrence of (a) death, (b) hospitalization for worsening PAH, (c) >15% decrease from baseline in 6MWD combined with WHO Functional Class III or IV symptoms sustained over 14 days (short term clinical worsening), or (d) reduction in 6MWD sustained over 14 days combined with WHO Functional Class III or IV symptoms sustained over 6 months (inadequate long term clinical response).

Patients had idiopathic PAH (55%), heritable PAH (3%), or PAH associated with connective tissue diseases, congenital heart disease, stable HIV infection, or drugs or toxins (APAH, 43%). Median time from diagnosis to first study drug administration was 25 days. Approximately 32% and 68% of patients were in WHO Functional Class II and III, respectively. The mean patient age was 55.7 years (34% were ≥65 years old). Most patients were white (90%) and female (76%); 45% were North American.

Principal results are shown in Figures 6 and 7.

Figure 6 Time to Primary Endpoint Event (AMBITION)

Figure 7 Primary Endpoint Events and First Occurrences of Each Component at Any Time (AMBITION)

The treatment effect of Letairis plus tadalafil compared with individual monotherapy on time to first primary endpoint event was consistent across subgroups. (Figure 8).

Figure 8 Primary Endpoint by Subgroups (AMBITION)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over interpreted.

Exercise Ability

Results of the 6MWD at 24 weeks for the AMBITION study are shown in Table 5 and Figure 9.

Table 5 6-Minute Walk Distance at Week 24 (meters)* (AMBITION)
	Letairis + Tadalafil (N=302)	Letairis Monotherapy (N=152)	Tadalafil Monotherapy (N=151)
* Missing values at Week 24 were imputed using Worst Rank scores for patients with an adjudicated clinical failure event of death or hospitalization, and Last Observed Carried Forward otherwise.
Baseline (median)	356	366	352
Change from baseline (median)	43	23	22
Median difference from Letairis + Tadalafil (95% CI)		24 (11, 37)	20 (8, 32)
P-Value		0.0004	0.0016

Figure 9 Median Change in 6-Minute Walk Distance (meters) in AMBITION

14.3 Long-term Treatment of PAH

In long-term follow-up of patients who were treated with Letairis (2.5 mg, 5 mg, or 10 mg once daily) in the two pivotal studies and their open-label extension (N=383), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 93%, 85%, and 79%, respectively. Of the patients who remained on Letairis for up to 3 years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with a group not given Letairis and cannot be used to determine the long-term effect of Letairis on mortality.

14.4 Adverse Effects in Idiopathic Pulmonary Fibrosis (IPF)

A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared Letairis (N=329) to placebo (N=163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate a greater risk of disease progression or death on Letairis. More patients taking Letairis died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%) [see Contraindications (4.2)].