ATLANTA – The investigational drug riociguat significantly improved 6-minute walk distance in patients with symptomatic pulmonary arterial hypertension in the phase III PATENT-1 trial.
Of 443 patients who participated in the randomized, double-blind trial, those who received active treatment with the novel oral soluble guanylate cyclase (sCG) stimulator experienced a 36-m improvement in 6-minute walk distance, compared with those who received placebo, after 12 weeks. This "clinically meaningful as well as highly statistically significant" improvement was evident in both treatment-naive patients and pretreated patients, who each comprised about 50% of the study population, Dr. Hossein Ghofrani reported at the annual meeting of the American College of Chest Physicians.
Treatment also resulted in "significant and robust" improvements on several secondary endpoints, including pulmonary vascular resistance, N-terminal prohormone brain natriuretic peptide, World Health Organization functional class, time to clinical worsening, and Borg dyspnea score, said Dr. Ghofrani of University Hospital Giessen and Marburg in Giessen, Germany.
For pulmonary vascular resistance, for example, a 29% reduction was noted in the treatment group, compared with the placebo group. This translated into a 226-dyne reduction, with more than a half liter increase in cardiac output and a highly statistically significant reduction of 432 ng/L in the serum biomarker, he said.
The findings suggest that riociguat – the first of the new sGC-stimulator class of drugs – represents a new treatment option for patients with PAH.
Riociguat has a dual mode of action, as it synergizes with endogenous nitric oxide and directly stimulates sGC independent of nitric oxide availability. Therefore, it may restore the NO-sGC-cGMP pathway, Dr. Ghofrani explained.
"I think it is well appreciated that, despite the major achievement over the past two decades in the field of the treatment of PAH, there is still a high mortality in this devastating progressive disease, which welcomes this representative of a new class of drug to the therapeutic armamentarium of this very special disease form," he said, noting that study of riociguat is ongoing.
Patients who participated in the multicenter, multinational PATENT-1 trial (Pulmonary Arterial Hypertension sGC-Stimulator Trial) were adults aged 18-80 years (with an average of about 50 years), including both treatment naive patients and patients pretreated with endothelin receptor antagonists or prostanoids. They were randomized to receive placebo or treatment with riociguat at a starting dose of 1 mg three times daily titrated over 8 weeks in 0.5-mg increments up to 2.5 mg three times daily.
The completion rate among participants was high, at about 93% for the treatment group and 88% for the placebo group, with 90% in the treatment group achieving the maximum dose, which reflected the tolerability of the drug, Dr. Ghofrani said.
The drug was also safe, with only 1.2% of patients experiencing an adverse event, although it is important to note that the observation period was relatively short, he added.
The 10 most frequently reported treatment-emergent adverse events occurring more often in the treatment group were headache, dyspepsia, peripheral edema, nausea, dizziness, diarrhea, nasopharyngitis, dyspnea, cough, and vomiting, he said.
When combined with phase II study data, PATENT-1 now has 5 years of follow-up, and it appears that the treatment effect is preserved for up to 12 months. Those who completed phase III had the option of continuing in an open-label phase, and results from that study are expected to be reported next year.
Additionally, riociguat was found in the phase III CHEST-1 trial to improve 6-minute walk distance in patients with inoperable chronic thromboembolic pulmonary hypertension. Thus, riociguat appears to be the first-ever drug to demonstrate robust efficacy in two distinct pulmonary hypertension groups, Dr. Ghofrani said.
The PATENT and CHEST trials are supported by Bayer, the maker of riocigualt. Dr. Ghofrani disclosed that he has received sponsored grants over the past 3 years from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, and the Germany Ministry for Education and Research. He has also received industry-sponsored grants over the last 3 years from Bayer HealthCare AG, Aires, Encysive/Pfizer, and Novartis, and has received payment for consulting and serving on speaker bureaus and/or advisory committees for Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Novartis, and GlaxoSmithKline.