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Pulmonary Vascular Disease |

Individualized Dosing of Selexipag Based on Tolerability in the GRIPHON Study Shows Consistent Efficacy and Safety in Patients With Pulmonary Arterial Hypertension (PAH) FREE TO VIEW

Richard Channick; Kelly Chin; Lilla Di Scala; Aline Frey; Ralph Preiss; Sean Gaine; Nazzareno Galiè; Hossein Ardeschir Ghofrani; Marius Hoeper; Irene Lang; Vallerie McLaughlin; Lewis Rubin; Gérald Simonneau; Olivier Sitbon; Victor Tapson
Author and Funding Information

Massachusetts General Hospital, Boston, MA; University of Texas Southwestern Medical Center, Dallas, TX; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland; Istituto di Malattie dell’Apparato Cardiovascolare, University of Bologna, Bologna, Italy; University of Giessen and Marburg Lung Center, Giessen, Germany; Department of Respiratory Medicine, Hannover Medical School and German Center of Lung Research, Hannover, Germany; Medical University of Vienna, Department of Internal Medicine II, Division of Cardiology, Allgemeines Krankenhaus, Vienna, Austria; University of Michigan Health System Division of Cardiovascular Medicine, Ann Arbor, MI; Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA: Hôpital Universitaire de Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, Paris, France; Cedars-Sinai Medical Center, Los Angeles, CA


Chest. 2015;148(4_MeetingAbstracts):961A. doi:10.1378/chest.2256760
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Abstract

SESSION TITLE: Pulmonary Arterial Hypertension Posters II

SESSION TYPE: Original Investigation Poster

PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM

PURPOSE: Selexipag is an oral, selective IP receptor agonist targeting the prostacyclin pathway. In the randomized, controlled, event-driven GRIPHON study in patients with PAH, selexipag, when titrated to an individualized highest tolerated dose, reduced the risk of a morbidity/mortality event (primary endpoint) up to the end of treatment by 40% vs placebo (PBO); hazard ratio (HR) 0.60; 99%CI: 0.46-0.78; log-rank p<0.0001. Here, we further examine GRIPHON study data according to selexipag dose.

METHODS: Patients (18-75 years) were randomized 1:1 to selexipag or PBO. Study drug was titrated weekly, in 200 mcg b.i.d. increments, to an individualized highest tolerated dose (maximum 1600 mcg b.i.d.). The individualized maintenance dose (IMD) was defined as the dose to which each patient was exposed for the longest duration. Based on their IMD, patients were assigned to pre-specified dose groups; low (200, 400 mcg b.i.d.), medium (600, 800, 1000 mcg b.i.d.) or high (1200, 1400, 1600 mcg b.i.d.). HRs for the effect of selexipag vs PBO on the primary endpoint were calculated using Cox regression models.

RESULTS: In total, 1156 patients were randomized to selexipag (n=574) or PBO (n=582). Of those randomized to selexipag, 133 (23%), 180 (31%) and 246 (43%) were in the low-, medium- and high-dose groups, respectively. The effect of selexipag on the primary endpoint was consistent across dose groups; HR (95%CI; log-rank p-value) vs overall PBO was 0.60 (0.41-0.88; p=0.0038), 0.53 (0.38-0.72; p<0.0001) and 0.64 (0.49-0.82; p=0.0002) in the low-, medium- and high-dose groups, respectively. Median treatment duration, weeks (range), was 52 (1-217), 71 (3-183) and 79 (7-200) in the respective low-, medium- and high-dose groups, and 64 (1-192) in overall PBO. The IMD did not appear to be influenced by baseline characteristics including background PAH therapy, functional class or body mass index. The most frequent adverse events observed with selexipag in all IMD dose groups were headache, diarrhea, nausea and jaw pain.

CONCLUSIONS: Patients' baseline characteristics did not appear to influence the highest tolerated dose of selexipag. The approach to individually titrate selexipag based on tolerability resulted in consistent efficacy and safety in patients with PAH.

CLINICAL IMPLICATIONS: The GRIPHON study data indicate that an individualized dose regimen based on tolerability is safe and efficacious in patients with PAH.

DISCLOSURE: Richard Channick: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Grant monies (from industry related sources): Actelion Pharmaceuticals Ltd, Grant monies (from industry related sources): Bayer Healthcare Pharmaceuticals, Grant monies (from industry related sources): United Therapuetics Kelly Chin: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Giliead Sciences Inc, Grant monies (from industry related sources): Actelion Pharmaceuticals Ltd, Grant monies (from industry related sources): Geno Pharmaceuticals, Grant monies (from industry related sources): Giliead Sciences Inc, Grant monies (from industry related sources): NIH Lilla Di Scala: Employee: Actelion Pharmaceuticals Ltd Aline Frey: Employee: Actelion Pharmaceuticals Ltd Sean Gaine: Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Other: Actelion Pharmaceuticals Ltd Nazzareno Galiè: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly and Company, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer Inc Hossein Ardeschir Ghofrani: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Ergonex Pharma GmbH, Consultant fee, speaker bureau, advisory committee, etc.: Gilead Sciences Inc, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Merck & Co Inc, Consultant fee, speaker bureau, advisory committee, etc.: Novartis Corporation, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer Inc, Grant monies (from industry related sources): Actelion Pharmaceuticals Ltd, Grant monies (from industry related sources): Bayer Healthcare Pharmaceuticals, Grant monies (from industry related sources): Ergonex Pharma GmbH, Grant monies (from industry related sources): Pfizer Inc Marius Hoeper: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer Inc Irene Lang: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly and Company, Consultant fee, speaker bureau, advisory committee, etc.: Encysive Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Gilead Sciences Inc, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Novartis Corporation , Consultant fee, speaker bureau, advisory committee, etc.: Pfizer Inc, Consultant fee, speaker bureau, advisory committee, etc.: Schering, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Grant monies (from industry related sources): Actelion Pharmaceuticals Ltd, Grant monies (from industry related sources): Bayer Healthcare Pharmaceuticals Vallerie McLaughlin: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Gilead Sciences Inc, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Grant monies (from industry related sources): Actelion Pharmaceuticals Ltd, Grant monies (from industry related sources): Bayer Healthcare Pharmaceuticals Ralph Preiss: Employee: Actelion Pharmaceuticals Ltd Lewis Rubin: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Arena Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Geno Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Gilead Sciences Inc, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics Gérald Simonneau: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly and Company, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Novartis Corporation , Consultant fee, speaker bureau, advisory committee, etc.: Pfizer Inc, Grant monies (from industry related sources): Actelion Pharmaceuticals Ltd Olivier Sitbon: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly and Company, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer Inc, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Grant monies (from industry related sources): Actelion Pharmaceuticals Ltd, Grant monies (from industry related sources): Bayer Healthcare Pharmaceuticals, Grant monies (from industry related sources): Eli Lilly and Company, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Pfizer Inc Victor Tapson: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Pharmaceuticals, Consultant fee, speaker bureau, advisory committee, etc.: Daiichi Sankyo, Consultant fee, speaker bureau, advisory committee, etc.: Gilead Sciences Inc, Consultant fee, speaker bureau, advisory committee, etc.: Janssen Pharmaceutica, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics

This abstract will discuss clinical data for selexipag, a selective prostacyclin IP receptor agonist. Selexipag has completed Phase III clinical trials and in December 2014 a registration dossier for selexipag was submitted to the EMA and FDA for the treatment of patients with pulmonary arterial hypertension.


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