Novel Pulmonary Hypertension Drug From Bayer Shows Modest Promise In Phase 3 Trials


Source: Forbes

A new drug appears to have promising– but not game-changing– effects in people with two forms of pulmonary hypertension. Riociguat, a soluble guanylate cyclase stimulator under development by Bayer, is thought to have vasodilating, antiproliferative and antifibrotic effects.

Ball-and-stick model of the riociguat molecule...

Results of two phase 3 placebo-controlled trials were published today in the New England Journal of Medicine. CHEST-1 studied the clinical impact of riociguat in 262 patients with chronic thromboembolic pulmonary hypertension; PATENT-1 studied the the drug in 443 patients with pulmonary arterial hypertension.

Both forms of pulmonary hypertension are characterized by blockage of the pulmonary vasculature. Patients with pulmonary hypertension are at high risk for right ventricular failure and death. Even though there are now several approved therapies for pulmonary arterial hypertension, the yearly mortality rate remains high at about 15%. No drugs are now approved for chronic thromboembolic pulmonary hypertension, though a surgical procedure, pulmonary endarterectomy, can cure the disease when it is successful. However, pulmonary endarterectomy is a difficult procedure that should only be performed at a very few centers with experience performing the procedure.

In CHEST-1, the primary endpoint of the study, the distance walked in 6 minutes after 16 weeks of treatment, increased by 39 m in the riociguat group, compared with a 6 m decrease in the placebo group (mean difference 46 m, CI 25-67, p<0.001). The investigators also reported that pulmonary vascular resistance decreased in the riociguat group and increased in the placebo group. NT-proBNP levels and WHO functional class also improved in the riociguat group. RV failure occurred in 3% of patients in each group; syncope occurred in 2% of the riociguat group and 3% of the placebo group.

In PATENT-1, the primary endpoint of the study, the distance walked in 6 minutes at 12 weeks, increased by 30 m in the riociguat group, compared with a 6 m decrease in the placebo group (mean difference 36 m, CI 20-52, p<0.001). Riociguat was equally effective in patients taking no other therapy and in those taking other drugs. Riociguat was also associated with improvements in pulmonary vascular resistance, NT-proBNP levels, WHO functional class , time to clinical worsening, and Borg dyspnea score. Syncope occurred in 4% of the placebo group versus 1% of the riociguat group.

Exploratory analyses of long-term extension studies– CHEST-2 and PATENT-2– suggested that the increase in walking time associated with riociguat may continue to grow after the initial 12 and 16 weeks of the original trials.

In an an accompanying editorial,  Stephen Archer gave a cautious endorsement of riociguat, but noted that the increase in walking distance was modest in both trials. In PATENT-1 the improvement found with riociguat just reached the mark for the smallest beneficial change justifying a change in treatment. The improvement in CHEST-1 was somewhat greater, Archer said, but the expected benefits associated with pulmonary endarterectomy are considerably larger, resulting in a 100 m increase in walking distance instead of the 46 m increase associated with riociguat. He recommended that suitable surgical candidates “should continue to undergo surgery and not be relegated to an inferior treatment.”

Archer concluded:

…the glass may be seen to be half empty because of the modest improvement in 6-minute walk distance with riociguat. However, I view the glass as half full, because riociguat appears to be safe and is a promising addition to the pharmacopeia for Group 1 pulmonary hypertension and potentially the first effective oral therapy for inoperable Group 4 pulmonary hypertension.

Archer discussed another important reason to remain cautious until riociguat undergoes FDA review:

The study was supported by Bayer HealthCare, and although the manuscript was drafted by the first author, editorial assistance was provided by a company supported by the sponsor (Adelphi Communications). In addition, although the authors had access to the complete database, the statistician was employed by Bayer HealthCare.

John Ryan, an expert on pulmonary hypertension, posted the following commentary (reprinted with permission) on CardioExchange


In the New England Journal of Medicine this week Ghofrani et al present two multicenter clinical trials on the role of a new oral pulmonary vasodilator in pulmonary hypertension. Riociguat is a soluble guanylate cyclase stimulator which promotes vasodilation in the pulmonary circulation. Riociguat represents a new class of medicines available for pulmonary hypertension and therefore will change the landscape of therapeutic options available in this disease process. However, there are a couple of aspects worth noting about these studies.

In the PATENT-1 trial, the authors study the effects of riociguat in Group 1 PH, pulmonary arterial hypertension (PAH). Current treatment options available for this group are prostacyclins, endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i) and calcium channel blockers (the latter used only in those deemed reversible on right heart catheterization). Epoprostenol (prostacyclin) has been shown to improve survival in PAH but is administered via continuous intravenous infusion, and is thus limited in terms of ease of use as well as its cost. ERA and PDE5i have been shown to improve 6-minute walk distance, which is the same primary outcome used in PATENT-1 study. Most of these agents typically improve 6-minute walk distance by about 30 to 50 meters. In the PATENT-1 study, only 21% of treated patients had a functional improvement at 12 weeks. Therefore it appears riociguat is going to be another PAH drug of modest efficacy. Because of the near equivalent outcomes, decision making regarding which agents to use as first line or in combination therapy is subject to remarkable physician variability, depending on cost, familiarity, experience, access and pharmaceutical company influence. To address this variability in care, primary outcomes that include end-points such as mortality and hospitalization are becoming more standard in PAH trials, with decreasing emphasis being placed on 6-minute walk distance. Also, the trials in PAH remain small because it is still a rare disease with a prevalence of 6.6 cases/million adults. In addition, this study does not reflect the largest population of pulmonary hypertension in clinical practice, namely Group 2 PH (PH secondary to left heart disease), for which are still no dedicated therapies.

The CHEST-1 trial of riociguat in chronic thromboembolic pulmonary hypertension (CTEPH, Group 4 PH) is a unique study as it marks the first large, multicenter RCT of medical therapy to demonstrate marked clinical benefit in CTEPH. The primary outcome again is 6-minute walk distance, which improved by 46 meters in the treatment group compared with placebo. However, this surrogate clinical outcome is markedly inferior to the outcomes observed from pulmonary endarterectomy for treatment of this rare disease (accounting for about 2% of all cases of pulmonary hypertension). Therefore, it is important that patients identified as having CTEPH should still be presented with pulmonary endarterectomy as the first-line therapeutic option. In fact, to enter into CHEST-1, patients had to be deemed inoperable or had residual PH after undergoing pulmonary endarterectomy. The rare incidence of CTEPH coupled with the infrequent determination of inoperability should ultimately make riociguat a rarely prescribed agent for this group with PH.

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