FDA Panel Recommends Riociguat (Adempas) for 2 Pulmonary Hypertension Indications

Troy Brown

August 07, 2013

An advisory committee to the US Food and Drug Administration (FDA) voted unanimously yesterday to recommend riociguat (Adempas, Bayer Healthcare) for the indication of chronic thromboembolic pulmonary hypertension (CTEPH; World Health Organization [WHO] group 4) to improve exercise capacity and improve WHO functional class.

The committee also voted unanimously to recommend riociguat for the indication of pulmonary arterial hypertension (PAH; WHO group 1) to improve exercise capacity, improve WHO functional class, and delay clinical worsening.

"I thought the data were convincing and showed efficacy and acceptable safety," voting member Vasilios Papademetriou, MD, a staff cardiologist at Veterans Affairs Medical Center in Washington, DC, said.

Both diseases are rare. The current treatment of choice for those with symptomatic, operable CTEPH is surgical pulmonary endarterectomy, which is often curative. There are no approved pharmacotherapies for those with inoperable disease or with residual pulmonary hypertension after pulmonary endarterectomy.

PAH is a progressive, fatal disease with no surgical cure. Vasodilator agents including phosphodiesterase 5 inhibitors, endothelin receptor antagonists, and prostanoids provide symptomatic relief and improve long-term outcomes in some patients.

Riociguat is a vasodilator that restores the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate (NO-sGC-cGMP) pathway by directly stimulating sGC independent of NO and sensitizing sGC to low levels of NO.

The panel reviewed the results of 2 randomized, double-blind, placebo-controlled, multicenter, multinational phase 3 studies of riociguat, which were published in the July 25 issue of the New England Journal of Medicine.

The primary endpoint in both trials was change in the 6-minute walk distance (6MWD) test from baseline until the end of the study (12 weeks in Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 [PATENT-1] and 16 weeks in Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 [CHEST-1]). Secondary endpoints included pulmonary vascular resistance changes, N-terminal prohormone brain-type natriuretic peptide, WHO functional class, time to clinical worsening, Borg scores, EuroQoL 5-dimensional Classification Component scores, and Living with Pulmonary Hypertension scores.


A total of 443 patients were randomly assigned 4:2:1 to receive riociguat 3 times daily (TID) with individual dose titration (IDT; from 1.0 to 2.5 mg TID, 254 patients), placebo TID (126 patients), or riociguat TID with capped titration (CT; from 1.0 to 1.5 mg TID, 63 patients) in an 8-week titration phase.

There was a statistically significant, clinically relevant improvement in 6MWD at week 12 in the riociguat group compared with the placebo group, with a least squares mean treatment difference for change from baseline of 35.78 (95% confidence interval, 20.06 - 51.51; P < .0001). The CT (1.0 - 1.5 mg) was analyzed only in an exploratory manner, and those results were not included.


A total of 261 patients (173 riociguat IDT, 88 placebo) were randomly assigned to receive either placebo or riociguat (1, 1.5, 2, or 2.5 mg) TID, and the dose was titrated over the course of 8 weeks (increased every 2 weeks, as tolerated).

At 16 weeks, there was a clinically relevant improvement in 6MWD in patients in the riociguat group compared with those in the placebo group. The least squares mean treatment difference for this change was 45.69 (95% confidence interval, 24.74 - 66.63; P < .0001).

WHO Functional Class Improved

For time to clinical worsening, the treatment difference was statistically significant in those with PAH (stratified log-rank test P = .0046 in PATENT-1) and not for those with CTEPH (P = .1724 in CHEST-1). The proportion of patients with clinical worsening was lower in the riociguat IDT group compared with the placebo group (2.3% vs 5.7% in CHEST-1 and 1.2% vs 6.3% in PATENT-1), as was death as a component of clinical worsening (1.2% vs 3.4% in CHEST-1 and 0.8% vs 2.4% in PATENT-1).

For improved WHO functional class, the treatment difference in percentage of patients with improvement of a least 1 functional class was 18 points in CHEST-1 and 7 points in PATENT-1.

For improvement of Borg CR 10 score (difference of mean values), which describes the perceived exertion at the end of the 6MWD test, the mean change to last visit was −0.83 for the riociguat IDT group and 0.17 for the placebo group in CHEST-1 and −0.44 and 0.09, respectively, in PATENT-1.

Positive Safety Profile

Adverse event data were pooled from both studies. Adverse events included headache (132 [26.9%] riociguat and 37 [17.3%] placebo), dizziness (94 [19.2%] riociguat and 26 [12.1%] placebo), dyspepsia (87 [17.8%] riociguat and 17 [7.9%] placebo), and hypotension (43 [8.8%] riociguat and 6 [2.8%] placebo).

"The benefit-risk...was really positive," voting member Philip Sager, MD, a consulting professor of medicine at Stanford University School of Medicine and chair of the Scientific Programs Committee, Cardiac Safety Research Consortium, San Francisco, California, said of his vote in favor of recommending approval of riociguat for PAH.

The committee thought that the full range of doses should be available. "I think all these doses should be available to patients," Dr. Papademetriou said.

In considering the interaction of riociguat with nitrates, the committee said the concomitant use of riociguat with nitrates should be contraindicated.

"Assuming inoperability, this is probably the only medical therapy that has been shown to have a benefit," Linda F. Fried, MD, MPH, chief of peritoneal dialysis at Veterans Affairs Pittsburgh Healthcare System and a professor of medicine, epidemiology, and clinical and translational science at the University of Pittsburgh in Pennsylvania, said of her vote in favor of recommending riociguat for patients with CTEPH. She echoed the opinion of several others that riociguat should not be limited to patients with inoperable CTEPH and that all patients with CTEPH should have the option of using the drug.

The committee members have disclosed no relevant financial relationships.

FDA Cardiovascular and Renal Drugs Advisory Committee Meeting. Silver Spring, Maryland. August 6, 2013. Background materials


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