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Novel drug improved walk distance in pulmonary hypertension patients

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Scrutinize industry support

Riociguat "is poised for examination by the Food and Drug Administration as a therapy for pulmonary hypertension and, if approved, has the potential to generate substantial revenue" for the sponsor of these two clinical trials, said Dr. Stephen L. Archer.

Both CHEST-1 and PATENT-1 were sponsored by Bayer HealthCare, which also provided the statistician and editorial assistance for both trials. "In light of the financial stakes, both real and apparent investigator autonomy remain key to ensuring the delivery of new drugs for pulmonary hypertension for patients," he noted.

Although riociguat yielded only "modest" gains in exercise capacity, it looks promising and may prove to be the first effective oral therapy for inoperable Group 4 pulmonary hypertension, Dr. Archer added.

However, he noted limitations in both studies. The CHEST-1 trial was limited by its "failure to examine the effects of the study drug on the right ventricle. The 6-minute walk distance is as reflective of right ventricular or skeletal-muscle function as it is of reduction in pulmonary vascular resistance, the authors’ presumed mechanism of benefit."

PATENT-1 was limited by its modest effect size, he added. "This is particularly important, since 50% of the patients were receiving no other treatment for pulmonary arterial hypertension, and the rate of response to treatment among such patients is usually higher than the rate among patients who are receiving concomitant treatment for pulmonary arterial hypertension," Dr. Archer said.

Dr. Archer is in the department of medicine at Queen’s University, Kingston, Ont. He reported no financial conflicts of interest. These remarks were taken from his editorial accompanying Dr. Ghofrani’s reports (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMe1306684]).


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Riociguat, an agent from a new class of compounds known as soluble guanylate cyclase stimulators, was found effective and safe for treating two different types of pulmonary hypertension in separate industry-sponsored phase III clinical trials reported online July 25 in the New England Journal of Medicine.

Compared with placebo, daily oral riociguat significantly improved exercise capacity as measured by 6-minute walk distance, and also improved pulmonary vascular resistance and World Health Organization (WHO) functional class. The results are from one international study involving 261 patients who had chronic inoperable thromboembolic pulmonary hypertension and another study involving 443 patients who had pulmonary arterial hypertension.

The magnitude of the improvement was greater than that reported for existing medications such as endothelin-receptor antagonists and prostanoids, both groups of researchers said.

The pathogenesis of pulmonary hypertension involves impairment of both nitric oxide synthesis and signaling through the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide and also increases the enzyme’s sensitivity to nitric oxide. The drug also raises levels of cyclic guanosine monophosphate, which induces vasorelaxation and has additional antiproliferative and antifibrotic effects.

The CHEST-1 trial

In the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator) trial, funded by Bayer HealthCare, the drug was assessed in adults with chronic thromboembolic pulmonary hypertension who were either ineligible for the standard surgical treatment (pulmonary endarterectomy) or whose condition persisted or recurred after they underwent the surgery. It is estimated that 63% of patients with this disorder are ineligible for endarterectomy, which is the only potentially curative treatment available, and that thromboembolic pulmonary hypertension persists or recurs in 35% of patients who do have the procedure. So an alternative approach is clearly needed, said Dr. Hossein-Ardeschir Ghofrani of University Hospital Giessen and Marburg, Germany, and his associates.

The CHEST-1 study subjects, who were treated and followed at 89 medical centers in 26 countries, were randomly assigned to receive either riociguat (173 patients) or matching placebo (88 patients) for 16 weeks.

The primary endpoint was change in 6-minute walk distance. In the intention-to-treat analysis, this increased by a mean of 39 m in patients taking riociguat, compared with a decrease of 6 m in those taking placebo. The benefit was similar in a per-protocol analysis, the investigators reported (N. Engl. J. Med. 2013 July 25 [doi: 10.1056/NEJMoa1209657]).

Riociguat improved 6-minute walk distance by 54 m in the patients who were ineligible for surgery and by 26 m in those who had persistent or recurrent disease after surgery. The drug’s beneficial effect on exercise capacity was consistent across several subgroups of patients.

In addition, the active drug significantly reduced pulmonary vascular resistance; improved other hemodynamic factors, including mean pulmonary artery pressure and cardiac output; improved WHO functional class, which is known to correlate with survival; and decreased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).

In exploratory analyses, riociguat also improved scores on the Borg dyspnea index when compared with placebo, and nominally improved scores on one measure of quality of life but not on a disease-specific QOL tool.

Drug-related serious adverse effects included three cases of syncope and one case each of gastritis, acute renal failure, and hypotension with riociguat, and one case each of syncope and trauma with placebo. Three percent of the riociguat group and 2% of the placebo group dropped out of the study owing to adverse events, and another 2% of each group dropped out because of serious adverse events that were not considered to be related to the study drug.

There were two deaths in the riociguat group and three in the placebo group.

A total of 237 of these study subjects elected to enroll in an extended study of the long-term safety and efficacy of riociguat (the CHEST-2 clinical trial). An exploratory analysis of data from the first 12 weeks of that study showed further increases of 51-63 m in the 6-minute walk distance, Dr. Ghofrani and his associates said.

The PATENT-1 trial

The other phase III clinical trial reported in the New England Journal of Medicine was the PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator) study. This trial also was funded by Bayer HealthCare and headed by Dr. Ghofrani.

In it, 443 patients who had symptomatic pulmonary arterial hypertension were treated and followed up at 124 medical centers in 30 countries. These subjects had idiopathic or familial disease, or pulmonary arterial hypertension associated with connective-tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, anorexigen use, or amphetamine use.

A total of 44% of patients were already receiving an endothelin-receptor antagonist (usually bosentan), and 6% were taking prostanoids (usually inhaled iloprost) for the disorder, and the other half of the study population was not receiving any other treatments. Concomitant therapy with oral anticoagulants, diuretics, and supplemental oxygen was permitted during the study.

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