NO Big Deal: Two Types of Pulmonary Hypertension Respond to Novel Agent

July 25, 2013

BOSTON, Massachusetts — A drug that boosts performance of nitric oxide (NO) pathways, but novel for its mechanism of action, seemed to improve both pulmonary artery (PA) hemodynamics and exercise capacity in patients with pulmonary hypertension in two parallel randomized trials published today [1,2].

The multicenter, phase 3 studies tracked the same set of functional, hemodynamic, and biomarker end points in two separate populations: 443 patients with symptomatic pulmonary-artery hypertension (PAH) of various etiologies [1] and 261 patients mostly with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but also <25% with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy [2].

After several months of treatment, patients in both trials taking riociguat (Bayer Healthcare), an oral soluble guanylate cyclase (sGC) stimulator, showed significant improvements in, among other end points, six-minute walk distance, pulmonary vascular resistance, natriuretic peptide levels, and World Health Organization (WHO) functional class.

 
It is definitely exceeding the efficacy of nitrates or PDE-5 inhibitors by orders of magnitude.
 

"This is the first time that one drug has shown positive results in two distinct pulmonary-hypertension populations," according to Dr Hossein-Ardeschir Ghofrani (University of Giessen and Marburg Lung Center, Germany), lead author of both reports, which appear in tandem in the July 25, 2013 New England Journal of Medicine. Also "unique" with riociguat, he told heartwire , is that there was "a uniform responsiveness on parameters of pulmonary hemodynamics, serum biomarkers, changes in functional class, dyspnea scores, and perhaps even quality of life."

The PAH trial entered patients who were naïve to drug therapy, as well as those who were stable on endothelin-receptor antagonists, such as bosentan (Tracleer, Actelion), or nonintravenous prostanoids, such as iloprost (Ventavis, Bayer). The latter group saw additive benefit from riociguat. The CTEP trial excluded patients on endothelin-receptor antagonists or nonintravenous prostanoids. Both trials excluded patients on phosphodiesterase type-5 (PDE-5) inhibitors, such as sildenafil (Revatio, Pfizer) or tadalafil (Adcirca, United Therapeutics).

Riociguat isn't approved for any indication on either side of the Atlantic, but was submitted to both the Food and Drug Administration (FDA) and European Medicines Agency for use in PAH and inoperable CTEP based on the two studies. The regulating agencies had proposed their parallel design, Ghofrani said, "so the protocols would complement each other and be supportive of each other, provided the outcome was positive, and therefore could be used as confirmatory trials." On April 8, 2013, Bayer HealthCare announced that the FDA plans to give the drug's application a priority review.

 
There was a uniform responsiveness on parameters of pulmonary hemodynamics, serum biomarkers, changes in functional class, dyspnea scores, and perhaps even quality of life.
 

In theory, according to Ghofrani, riociguat might work synergistically with PDE-5 inhibitors, nitrates, or inhaled NO, because they all work on the same signaling pathway that relaxes pulmonary vascular tone. "However, [their] coadministration is discouraged, because riociguat, itself, is the most potent stimulator of this pathway and is basically replacing the requirement for endogenous nitric oxide," he said. "And it is definitely exceeding the efficacy of nitrates or PDE-5 inhibitors by orders of magnitude."

Despite what he calls only a "modest improvement" in six-minute walk distance with riociguat in the two trials, Dr Stephen L Archer (Queen's University, Kingston, ON) writes in an accompanying editorial [3] that "riociguat appears to be safe and is a promising addition to the pharmacopeia" for WHO classification group 1 pulmonary hypertension (PAH) "and potentially the first effective oral therapy for inoperable group 4 pulmonary hypertension" (CTEP).

Riociguat in PAH

In the PAH trial, called Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 (PATENT-1), 443 patients with symptomatic PAH were randomized to placebo or riociguat in doses up to either 2.5 mg or 1.5 mg three-times daily (patients getting the lower maximum dose were included "for exploratory purposes," but not in the main analysis).

Mean Changes in Primary* and Selected Secondary End Points at Week 12 in Patients With PAH (PATENT-1)

End points Placebo, n=126 Riociguat up to 2.5 mg tid, n=254
6-min walk distance* (m) -6 +30
Pulmonary vascular resistance (dyn s/cm5) -9 -223
NT-proBNP (pg/mL) +232 -198
Pulmonary artery pressure (mm Hg) -0.5 -4
Cardiac output (L/min) -0.01 +1

All differences vs placebo p<0.0001

NT-proBNP=n-terminal pro-brain natriuretic factor

Half of patients were receiving no other PAH therapy, 44% were on endothelin receptor antagonists ("primarily bosentan"), and 6% were taking prostanoid therapy ("primarily inhaled iloprost"). In a prespecified analysis, riociguat's effect on six-minute walk distance was significant regardless of other drug therapies.

"This is the first time that an oral pulmonary hypertension treatment drug, in a quite well-characterized PAH population, showed efficacy both in patients who were otherwise treatment naïve as well as in pretreated patients," according to Ghofrani. And the effect was similar in both groups. Some earlier trials in more mixed populations with pulmonary hypertension, he said, failed to show such incremental benefit in patients already on drug therapy.

Any adverse event was seen in 86% of placebo recipients and 89% of those who received riociguat at a maximum of 2.5 mg three times daily. Of the major adverse effects, the report says, syncope was common, seen in 4% and 1% of patients, respectively.

According to Archer's editorial, "the major limitation of PATENT-1 is the modest effect-size achieved. 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. It appears that riociguat may be another pulmonary hypertension drug of modest efficacy."

Riociguat in CTEPH

In called Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 (CHEST-1), 261 patients with inoperable CTEP or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy were randomized to placebo or riociguat. The latter was started at 1 mg three times daily and guided by systemic arterial pressures "and signs or symptoms of hypotension" until week 8, at which time the final tolerated dosage (range, 0.5–2.5 mg three times daily) was given for another eight weeks.

Mean Changes in Primary* and Selected Secondary End Points at Week 16 in Patients With CTEPH (CHEST-1)

End points Placebo, n=88 Riociguat, n=173
6-min walk distance* (m) -6 +39
Pulmonary vascular resistance

(dyn s/cm5)

+23 -226
NT-proBNP (pg/mL) +76 -291
Pulmonary artery pressure

(mm Hg)

+0.8 -4
Cardiac output (L/min) -0.03 +0.8

All differences vs placebo p<0.0001

NT-proBNP=n-terminal pro-brain natriuretic factor

The caveat with CHEST-1, according to Archer, is that "the benefits with pulmonary endarterectomy . . . surpass the benefits with riociguat. . . . Since most centers do not perform pulmonary endarterectomy, there may be a temptation to take the easy route and prescribe riociguat. Patients who are suitable candidates for surgery should continue to undergo surgery and not be relegated to an inferior treatment."

Ghofrani emphasized to heartwire that CHEST-1 included only patients for whom surgery, or further surgery, was not an option. Some patients with CTEP are candidates for potentially curative surgery and riociguat is not an alternative for them, he said. The three main target populations, reflected in the CHEST-1 population, he noted, are: the estimated 30% to 60% of CTEP patients who are inoperable, for whom there is no specifically indicated drug therapy, "so this is really an area of high unmet medical need"; those with residual pulmonary hypertension after surgery; and those with initially successful surgery in whom pulmonary hypertension recurs over the long term.

In the PATENT-2 and CHEST-2 long-term-extension studies of patients successfully completing the initial randomized trials, described briefly in the two reports, six-minute walk distances were seen to improve further over an additional 12 weeks of treatment with riociguat, the latter part on an open-label basis.

Other Caveats?

In the editorial, Archer raises cautions about Bayer involvement in the two trials, which went beyond financial sponsorship to include collaboration on trial design and provision of statisticians for data analysis, as well as funding separate commercial editorial assistance--all of which are clearly mentioned in the reports. "In light of the financial stakes [of any riociguat approval], both real and apparent investigator autonomy remain key to ensuring the delivery of new drugs for pulmonary hypertension for patients."

The editorial also takes CHEST-1 and PATENT-1 to task for failing, it says, "once again" in pulmonary-hypertension drug trials, to show the drug's effects on the right ventricle (RV). RV failure is the usual cause of death in both patient populations, the editorialist notes. "On the basis of the hemodynamic data in CHEST-1, it appears that the drop in pulmonary vascular resistance was driven as much by an increase of 1 L/min in cardiac output as by the decrease of 4 mm Hg in mean pulmonary-artery pressure."

Ghofrani counters that the two trials are the first of their kinds in which all patients underwent baseline and follow-up right-heart catheterization to measure RV cardiac output, which "is still the gold standard" for measuring RV function. Together, he said, the improvements in functional, hemodynamic, and biomarker end points indicate that the drug enhances RV unloading.

Both trials were funded by Bayer HealthCare, which collaborated in the design of the trials. Manuscripts were prepared with editorial assistance, funded by Bayer, from Adelphi Communications. Ghofrani discloses serving as a board member for Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, and Takeda Pharmaceuticals; receiving consulting fees from Actelion, Bayer, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, and Takeda; receiving lecture fees from Actelion, Bayer, GlaxoSmithKline, Eli Lilly, Novartis, and Pfizer; and receiving grant support through his institution from Actelion, Bayer, Novartis, and Pfizer. Disclosures for all authors of CHEST-1 are included in the report, and for authors of both studies at http://www.nejm.org/ . Archer reports that he has no potential conflicts of interest.

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