Christian Meier

Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial

BACKGROUNDnChronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received riociguat for at least 2 years.nnnMETHODSnEligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429.nnnFINDINGSn237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89-96) and clinical worsening-free survival was 82% (77-87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued riociguat therapy because of adverse events.nnnINTERPRETATIONnRiociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers.nnnFUNDINGnBayer Pharma AG.

Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2

Background The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD). Methods Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5u2005mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received riociguat (maximum 2.5u2005mg three times daily); the primary endpoint was safety and tolerability. Results In patients with PAH-CTD, riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2u2005years. Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population. Conclusions Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2u2005years in patients with PAH-CTD. Trial registration numbers PATENT-1 (NCT00810693), PATENT-2 (NCT00863681).

Updating clinical endpoint definitions

The 6-Minute Walk Distance (6-MWD) has been the most utilized endpoint for judging the efficacy of pulmonary arterial hypertension (PAH) therapy in clinical trials conducted over the past two decades. Despite its simplicity, widespread use in recent trials and overall prognostic value, the 6-MWD has often been criticized over the past several years and pleas from several PAH experts have emerged from the literature to find alternative endpoints that would be more reliable in reflecting the pulmonary vascular resistance as well as cardiac status in PAH and their response to therapy. A meeting of PAH experts and representatives from regulatory agencies and pharmaceutical companies was convened in early 2012 to discuss the validity of current as well as emerging valuable endpoints. The current work represents the proceedings of the conference.

Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study

BackgroundFollowing positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH.MethodsWe performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1xa0mg three times daily (tid) to a maximum of 2.5xa0mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (nxa0=u200984) underwent a washout period of at least 3xa0days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints.ResultsIn total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47xa0weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, meanu2009±u2009standard deviation 6MWD had increased by 33u2009±u200942xa0m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups.ConclusionsRiociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed.Trial registrationClinicalTrials.org NCT01784562. Registered February 4, 2013.

REVEAL risk scores applied to riociguat-treated patients in PATENT-2: Impact of changes in risk score on survival

BACKGROUNDnThe Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk score (RRS) calculator was developed using data derived from the REVEAL registry, and predicts survival in patients with pulmonary arterial hypertension (PAH) based on multiple patient characteristics. Herein we applied the RRS to a pivotal PAH trial database, the 12-week PATENT-1 and open-label PATENT-2 extension studies of riociguat. We examined the effect of riociguat vs placebo on RRS in PATENT-1, and investigated the prognostic implications of change in RRS during PATENT-1 on long-term outcomes in PATENT-2.nnnMETHODSnRRS was calculated post hoc for baseline and Week 12 of PATENT-1, and Week 12 of PATENT-2. Patients were grouped into risk strata by RRS. Kaplan-Meier estimates were made for survival and clinical worsening-free survival in PATENT-2 to evaluate the relationship between RRS in PATENT-1 and long-term outcomes in PATENT-2.nnnRESULTSnA total of 396 patients completed PATENT-1 and participated in PATENT-2. In PATENT-1, riociguat significantly improved RRS (p = 0.031) and risk stratum (p = 0.018) between baseline and Week 12 compared with placebo. RRS at baseline, and at PATENT-1 Week 12, and change in RRS during PATENT-1 were significantly associated with survival (hazard ratios for a 1-point reduction in RRS: 0.675, 0.705 and 0.804, respectively) and clinical worsening-free survival (hazard ratios of 0.736, 0.716 and 0.753, respectively) over 2 years in PATENT-2.nnnCONCLUSIONSnRRS at baseline and Week 12, and change in RRS, were significant predictors of both survival and clinical worsening-free survival. These data support the long-term predictive value of the RRS in a controlled study population.

FRI0445 Efficacy and Safety of Riociguat in Patients with Pulmonary Arterial Hypertension (PAH) Associated with Connective Tissue Disease (CTD): Results from Patent-1 and Patent-2

Background PAH associated with CTD (PAH-CTD) has a worse prognosis than idiopathic/familial PAH (IPAH). Objectives Here we report a prospective subgroup analysis of patients (pts) with PAH-CTD from the PATENT studies of the soluble guanylate cyclase stimulator, riociguat. Methods PATENT-1 was a 12-wk, randomized Phase III trial in which pts with PAH received either riociguat individually dose-adjusted up to 2.5 mg tid (2.5 mg–maximum group), riociguat up to 1.5 mg tid (1.5 mg–maximum group; exploratory), or placebo (pbo). The primary endpoint was change from baseline in 6-minute walking distance (6MWD). Long-term safety and survival were assessed during the PATENT-2 open-label extension. Results In PATENT-1, 111 pts had PAH-CTD (systemic sclerosis [SSc; n=66, including diffuse SSc and limited SSc] non-SSc CTD [n=39], and unspecified CTD [n=6], derived from the medical history using MedDRA preferred terms). Of the overall group of PAH-CTD pts, 71, 15, and 25 were randomized to riociguat 2.5 mg–maximum, riociguat 1.5 mg–maximum, and pbo, respectively. At baseline, mean ± SD 6MWD was 348±70 m in the riociguat 2.5 mg–maximum group and 361±88 m in the pbo group versus 363±69 m in the overall PAH population. At Wk 12, there was an improvement in 6MWD in the 2.5 mg–maximum riociguat group (+18 m) and a deterioration in the pbo group (–8 m) (Figure 1a; PAH-CTD population; intention-to-treat [ITT], imputed values). Consistent with other studies, the least-squares mean treatment difference between riociguat and pbo (+28 m) was lower than that observed in the overall study population (+36 m). No pts in the riociguat 2.5 mg–maximum group required additional PAH therapy during PATENT-1, compared with 2 pts in the pbo group. At the March 2014 cut-off for PATENT-2, 70 pts with PAH-CTD had been receiving treatment for ≥2 yrs. Figure 1b shows change in 6MWD during PATENT-2 in pts with PAH-CTD. At 2 yrs, mean ± SD 6MWD had increased from PATENT-1 baseline by 25±82 m in pts with PAH-CTD versus 47±85 m in the overall population (ITT; observed values). Survival rates at 1 yr in pts with PAH-CTD, IPAH, and the overall population were 97% (95% CI: 90–99%), 98% (95% CI: 95–99%), and 97% (95% CI: 95–98%), respectively. Survival rates at 2 yrs were 93% in all cohorts (95% CI: 85–97%, 89–96%, and 90–95%, respectively). Riociguat had a similar safety profile in pts with PAH-CTD as observed in the overall population. Conclusions In pts with PAH-CTD, riociguat was associated with long-term improvements in exercise capacity. The 1- and 2-yr survival rates in riociguat-treated pts with PAH-CTD were high and similar to pts with IPAH. Disclosure of Interest C. Denton Consultant for: Bayer, Speakers bureau: Novertis, Pfizer, J. Coghlan: None declared, H.-A. Ghofrani Consultant for: Novertis, Pfizer, Speakers bureau: Novertis, Pfizer, F. Grimminger: None declared, J. He: None declared, G. Riemekasten Consultant for: Bayer, Speakers bureau: Bayer, C. Vizza Grant/research support from: Bayer, Actelion, GSK, Novartis, Gilead, Consultant for: Bayer, Actelion, GSK, Utel, A. Boeckenhoff Employee of: Bayer Pharma AG, C. Meier Employee of: Bayer Pharma AG, S. Nikkho Employee of: Bayer Pharma AG, J. Pena Employee of: Bayer Pharma AG, M. Humbert Consultant for: Novartis, Pfizer, GSK, Actelion, Bayer, Speakers bureau: Novartis, Pfizer, GSK, Actelion, Bayer

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison

Objective PATENT-1 and CHEST-1 were pivotal, international phase III trials assessing riociguat for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Here we compare Chinese patients from these studies with the overall populations, and report the clinical effect and safety of riociguat in Chinese patients with PAH and CTEPH. Methods PATENT-1 was a 12-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5u2005mg three times daily or 1.5u2005mg three times daily (exploratory) in patients with PAH. CHEST-1 was a 16-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5u2005mg three times daily) in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. The primary endpoint in each study was change from baseline to study end in 6u2005min walking distance (6MWD). Secondary endpoints included pulmonary vascular resistance (PVR), N-terminal prohormone of brain natriuretic peptide, WHO functional class (FC), and time to clinical worsening. Results Chinese patients in PATENT-1 (n=77) and CHEST-1 (n=32) were younger and had better baseline 6MWD and WHO FC versus the overall population. Riociguat increased 6MWD versus placebo in Chinese patients in PATENT-1 and CHEST-1, with a greater increase observed in CHEST-1 (least-squares mean differences +46u2005m and +102u2005m in PATENT-1 and CHEST-1, respectively). Riociguat also improved several secondary endpoints in both studies, and was well tolerated. Conclusions Chinese patients displayed differences in baseline characteristics versus the overall populations in PATENT-1 and CHEST-1. Riociguat improved 6MWD, PVR, WHO FC, and other clinical outcomes in Chinese patients with PAH or CTEPH. Trial registration number PATENT-1: NCT00810693, Results; CHEST-1 NCT00855465, Results.