Switching to Adempas Improves Clinical Outcomes in Intermediate-risk PAH Patients, Phase 4 Trial Shows

People with intermediate-risk pulmonary arterial hypertension (PAH) who failed to respond adequately to phosphodiesterase-5 inhibitors (PDE5i) show significant benefits when transitioned to Adempas (riociguat) treatment, a Phase 4 trial has found.

A total of 41% of patients who made that transition experienced significant clinical improvements, compared with 20% of those who remained on PDE5i therapy, meeting the REPLACE study’s (NCT02891850) primary goal.

The findings were shared at the virtual annual meeting of the European Respiratory Society in the late breaking abstract on Sept. 7, “Switching from PDE5i to riociguat in patients with PAH: The REPLACE study.” Results were presented by Marius M. Hoeper, MD, a professor at the Hannover Medical School, in Germany.

“In clinical practice, a considerable proportion of intermediate-risk patients with pulmonary arterial hypertension do not reach or maintain specific treatment goals when treated with a PDE5i-based regimen,” Sameer Bansilal, senior medical director, U.S. Medical Affairs at Bayer, said in a press release.

“It is therefore gratifying to see that forty-one percent of REPLACE study participants attained the clinical improvement endpoint when transitioning from PDE5 inhibitor therapy to Adempas,” he added.

PDE5i treatments such as taladafil (marketed as Adcirca and Alyq) and Revatio (sildenafil) are among the most common PAH therapies. But many patients fail to achieve significant clinical improvements while on these therapies.

Adempas and PDE5i therapies target different molecules belonging to the same biological pathway. This suggests that patients with inadequate responses to PDE5i therapies may benefit from a transition to Adempas treatment.

In the prior RESPITE Phase 3 trial (NCT02007629), researchers had already demonstrated that this transition improved exercise capacity, lowered a biomarker of heart failure, and improved World Health Organization (WHO) functional class in most patients.

However, all patients in this trial made the transition, meaning there was no control group that remained on PDE5i treatment for comparison.

The REPLACE Phase 4 trial, conducted by Bayer in collaboration with Merck (known as MSD outside the United States and Canada), was designed to make this comparison between groups.

As a Phase 4 trial, REPLACE evaluated this transition in a real-world population after Adempas had been approved and available to the general population.

Conducted across 22 countries, REPLACE included 226 patients with intermediate-risk PAH who showed an insufficient clinical response to stable treatment with PDE5i — taladafil or Revatio — given alone or in combination with an endothelin-receptor antagonist.

Patients were in the WHO functional class III category of PAH, meaning they feel good at rest, but show a marked limitation in physical activity and experience shortness of breath, fatigue, chest pain, and near loss of consciousness when engaging in mild activity.

Also, their six-minute walking distance (6MWD) — a measure of exercise capacity — at the time of trial initiation was from 165 to 440 meters.

Participants were randomized to continue on PDE5i treatment (115 patients) or switch to Adempas (111 patients) for a total of 24 weeks. Adempas’ dose was adjusted to an optimal level in the first eight weeks.

REPLACE’s main goal was to determine whether Adempas was better than PDE5i treatment at inducing composite clinical improvements, defined as meeting at least two of three criteria after 24 weeks, and the absence of clinical worsening or death.

Criteria included an increase by at least 10% or 30 meters in the 6MWD test; a decrease in WHO functional class; and a reduction of at least 30% in the N‐terminal pro B-type natriuretic peptide (NT-proBNP), a validated and widely accepted prognostic marker of PH.

Results showed that significantly more patients on Adempas attained such composite clinical improvement (41%), compared with 20% of those who remained on PDE5i. This meant that transitioning to Adempas increased by 2.8 times the likelihood of reaching such clinical improvement.

Also, among those who failed to achieve a clinical improvement, clinical worsening was seen in one patient on Adempas, compared with 10 patients in the PDE5i group — including three deaths.

Adverse events were similar between both groups, but serious adverse events were more common with PDE5i (17%) than with Adempas (7%).

The safety profile of Adempas was consistent with that seen in the PATENT-1 Phase 3 trial (NCT00810693), which supported the treatment’s approval for PAH.

“In addition to supporting the rationale for therapy modification, the REPLACE results add to the findings from the PATENT study, which found patients can be well-managed on Adempas-based mono or combination therapy,” said Bansilal.