Riociguat improves chronic thromboembolic pulmonary hypertension (CTEPH)

Riociguat Improves Chronic Thromboembolic Pulmonary Hypertension (CTEPH): CHEST-1

Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of pulmonary embolism, in which the pulmonary blood vessels become occluded by the body's ongoing reaction to residual blood clots. The result is slowly worsening shortness of breath, pulmonary hypertension, and eventually right heart failure. People with chronic thromboembolic pulmonary hypertension often go undiagnosed for months or years until the condition is advanced. Without treatment, CTEPH is often fatal.

Surgery to clean out the blocked pulmonary arteries (pulmonary endarterectomy) is the best treatment and can often cure chronic thromboembolic pulmonary hypertension. However, not all patients can undergo the potentially lifesaving surgery: some have occlusions that are inaccessible (in the periphery of the lung); some are too ill; and the surgery is only done well at a few locations worldwide, limiting access.

For these surgery-ineligible patients with chronic thromboembolic pulmonary hypertension, and for those who have persistent pulmonary hypertension after pulmonary endarterectomy, medical treatment is the only option. However, no FDA-approved treatments exist for CTEPH; physicians instead use off-label vasodilators approved for other forms of PH.

This month, Bayer announced favorable Phase III results for its new agent riociguat (BAY 63-2521) for chronic thromboembolic pulmonary hypertension. Riociguat (stay tuned for the sexy trade name) is in a new class of pulmonary hypertension drugs called soluble guanylate cyclase stimulators. Their results of the CHEST-1 trial, from authors Hossein-Ardeschir Ghofrani et al, are in the July 25, 2013 New England Journal of Medicine.

What They Did

Investigators randomized 261 people with documented chronic thromboembolic pulmonary hypertension who were all treatment-naive to receive riociguat or placebo three times daily for 16 weeks. CTEPH is a clinical diagnosis; subjects could be included as long as they had pulmonary hypertension by right heart catheterization, a clinical diagnosis of chronic thromboembolic pulmonary hypertension, and 2 concordant imaging tests (ventilation-perfusion scans, magnetic resonance imaging, pulmonary angiography, and/or CT-angiography).

Most subjects had mild to moderately severe symptoms (WHO functional class II - III) and most (72%) had inoperable CTEPH as opposed to post-operative residual CTEPH.

The primary end point was 6 minute walk distance after 4 months of treatment.

What They Found

Riociguat improved 6-minute walk distance by an average of 39 meters, compared to a 6 meter loss in the placebo group. Riociguat also favorably affected other parameters of pulmonary hypertension treatment: reduction of pulmonary vascular resistance (-226 vs. +23 dyn/sec/cm -5); reduced pulmonary artery pressure, improved cardiac output, and lower NT-pro-BNP and WHO functional class.

After about 3 months of treatment, those receiving riociguat and still in follow-up (~94%) had 6 minute walk distances about 63 meters longer than the placebo group's.

Adverse events were unusual in general and did not differ between groups; only 5 patients discontinued riociguat (3%) compared to 2 in placebo (2%). Eighteen patients withdrew from the study before week 16.

What It Means

For people with inoperable or persistent post-endarterectomy CTEPH, t.i.d. riociguat improved hemodynamic measurements as well as exercise tolerance and subjective dyspnea. Not too shabby, especially compared to bosentan, the only other vasodilator tested for CTEPH in a randomized trial: bosentan did not improve 6-minute walk distance and was less effective at reducing pulmonary vascular resistance.

Surgery (pulmonary endarterectomy) is still the definitive and superior treatment for chronic thromboembolic pulmonary hypertension. Patients with CTEPH should be referred to expert surgical centers whenever feasible, at the time of diagnosis.

The CHEST-1 trial is only one maneuver in Bayer's assault on the lucrative pulmonary hypertension market. Bayer has multiple clinical trials of riociguat underway, with the aim of gaining multiple indications for pulmonary hypertension treatment, and competing directly with Tracleer, Letairis, and the rest of that expensive gang. The PATENT-1 trial published in the same issue of the New England Journal showed modest benefits of riociguat on patients with pulmonary arterial hypertension. Riociguat has been projected to bring in $700 million in annual revenues for Bayer within a few years.

Hossein-Ardeschir Ghofrani et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension (CHEST-1). N Engl J Med 2013; 369:319-329