Inhaled treprostinil tied to favourable outcomes in PH-ILD

In post hoc analyses of the phase III INCREASE trial presented at ATS 2021, patients on inhaled treprostinil (iTre) for pulmonary hypertension due to parenchymal lung disease (PH-ILD) were less inclined to have multiple clinical worsening events and more likely to experience clinical improvement vs those on placebo.

INCREASE saw 326 participants (mean age 66 years, 53 percent male) who were randomized 1:1 to receive iTre or placebo. The study met its primary endpoint of change in 6MWD* (31 metres; p<0.001) and showed fewer clinical worsening events with iTre vs placebo (hazard ratio [HR], 0.61, p_log-rank=0.04). [N Engl J Med 2021;384:325-334]

Multiple disease progression

One analysis explored the effect of continued iTre treatment on multiple clinical worsening or disease progression events (defined as ≥15-percent decline in 6MWD, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, or death). [ATS 2021, abstract A1027]

“We looked specifically at what happened after the first clinical worsening events, so [we evaluated] patients who … had at least ≥2 clinical worsening events,” said Dr Steven Nathan from Inova Fairfax Hospital, Falls Church, Virginia, US.

At week 16, the percentage of clinical worsening events was lower with iTre vs placebo (48 percent [150 events in 79 patients] vs 58 percent [226 events in 95 patients]).

The fraction of patients who had multiple progression events was also significantly lower with iTre vs placebo (21 percent vs 39 percent; p<0.001), the most frequent being 6MWD decline (n=48 vs 97), exacerbation of lung disease (n=34 vs 56), and cardiopulmonary hospitalization (n=17 vs 28).

Despite similar total death rates between the iTre and the placebo arms (n=10 vs 12), the rate of death after a disease progression event was lower with iTre vs placebo (n=5 vs 12; p=0.08).

iTre was associated with delayed time to first disease progression event (HR, 0.75; p=0.061) and delayed time to second event (HR, 0.59; p=0.014).

Despite the short trial duration and almost a quarter of participants withdrawing from the study, the findings support the continuation of iTre despite evidence of clinical worsening, noted Nathan.

“I think this is very helpful for clinicians in the field, [as] some patients and physicians may consider changing or discontinuing therapies when there are signs of progression of PH-ILD,” said Nathan. “For patients on iTre, if they do have clinical worsening, they should continue. It does not mean that the drug is not working … [T]hey can have continued benefit with regard to subsequent clinical worsening events including mortality.”

Clinical improvement

Another analysis looked into the proportion of patients achieving clinical improvement (ie, a composite of absence of clinical worsening, ≥10-percent improvement in 6MWD or in forced vital capacity from baseline, and ≥30-percent drop in NT-proBNP** from baseline) at week 16. [ATS 2021, abstract A1911]

Week 16 saw more iTre vs placebo recipients demonstrating the composite endpoint (16.0 percent vs 5.5 percent; p≤0.0037), as well as each of its components such as absence of clinical worsening (77 percent vs 67 percent), 6MWD improvement (33 percent vs 20 percent), NT-proBNP reduction (32 percent vs 13 percent), and absence of lung disease exacerbation (74 percent vs 61 percent).

Factoring the absence of exacerbation of underlying disease into the clinical improvement definition, more iTre vs placebo recipients had clinical improvement (13 percent vs 5 percent; p≤0.018).

“The results suggest that, in addition to the improved exercise tolerance previously reported, iTre improves overall clinical status in patients with PH-ILD,” said Dr Aaron Waxman from the Brigham and Woman’s Hospital, Boston, Massachusetts, US, in his poster presentation.

“We continue to look forward to the results of the ongoing long-term extension study, [which] will provide information on whether [these] improvements … are sustained over time,” Waxman concluded.