Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy

Figures & data

Figure 1 Change in PVR from baseline to week 17, per protocol analysis.

Note: Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal. Oct 2012, 40 (4) 874–880; DOI: 10.1183/09031936.00137511.²⁸
Abbreviations: PVR, pulmonary vascular resistance; TE, treatment effect; CL, confi dence limit.

Figure 2 In the GRIPHON clinical trial, the primary composite endpoint included all-cause mortality, disease progression, or worsening of PAH resulting in hospitalization, initiation of parental prostanoid therapy, or long-term oxygen therapy or the need for lung transplantation or atrial septostomy.

Notes: A treatment effect in favor of selexipag was observed (hazard ratio 0.60, P<0.001). From N Engl J Med, Sitbon O, Channick R, Chin KM, et al, Selexipag for the treatment of pulmonary arterial hypertension, 373, 2522–2533. Copyright © (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.²⁹
Abbreviation: PAH, pulmonary arterial hypertension.

Table 1 Adverse events reported during the GRIPHON clinical trial

	Placebo (n=577) (%)	Selexipag (n=575) (%)	P-value
Headache	189 (33)	375 (65)	<0.001
Diarrhea	110 (19)	244 (42)	<0.001
Nausea	107 (19)	193 (34)	<0.001
Pain in jaw	36 (6)	148 (26)	<0.001
Worsening of PAH	206 (36)	126 (22)	<0.001
Vomiting	49 (9)	104 (18)	<0.001
Pain in extremity	46 (8)	97 (17)	<0.001
Dyspnea	121 (21)	92 (16)	0.03
Myalgia	34 (6)	92 (16)	<0.001
Dizziness	85 (15)	86 (15)	0.96
Peripheral edema	104 (18)	80 (14)	0.06

Notes: Events reported by ≥15% in either group are listed. From N Engl J Med, Sitbon O, Channick R, Chin KM, et al, Selexipag for the treatment of pulmonary arterial hypertension, 373, 2522–2533. Copyright © (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.²⁹

Abbreviation: PAH, pulmonary arterial hypertension.

Figure 3 Mean (standard deviation) plasma concentration versus time profiles of selexipag and its metabolite ACT-333679 in healthy subjects.

Notes: (A) Following selexipag 800 μg at steady state (morning dose of day 11; n=84). (B) Following selexipag 1,600 μg at steady state (morning dose of day 23; n=58).

Table 2 Clinical trials evaluating oral prostanoid and nonprostanoid IP receptor agonists in the treatment of PAH

Trial	Study drug	n	Weeks	Background PAH therapy	Primary endpoint: treatment effect	Secondary endpoints
ALPHABET^Citation12	Beraprost	130	12	None	6MWD: 25 meters, P=0.04	Improvement in Borg dyspnea index versus placebo; no significant difference in functional class, hemodynamics or disease progression
Beraprost study group^Citation13	Beraprost	116	52	None	Disease progression: placebo 17% versus beraprost 29%, P=0.254	No significant difference in 12-month peak VO2, 6MWD, Borg dyspnea index, WHO functional class or hemodynamics
FREEDOM-C^Citation15	Treprostinil	350	16	100%	6MWD: 11 meters, P=0.07	Improvement in dyspnea fatigue index score; no significant difference in clinical worsening, functional class, Borg dyspnea score
FREEDOM-C2^Citation16	Treprostinil	310	16	100%	6MWD: 10 meters, P=0.09	No significant difference in clinical worsening, Borg dyspnea score, NT-proBNP, functional class, CAMPHOR
FREEDOM-M^Citation17	Treprostinil	349	12	None	6 MWD: 26 meters, P=0.01	No significant difference in Borg dyspnea score, functional class or symptoms of PAH
Selexipag phase 2 study^Citation28	Selexipag	43	17	100%	ΔPVR: −30%, P<0.01	Improvement in cardiac index; no significant difference in Borg dyspnea score, NT-proBNP, 6MWD
GRIPHON^Citation29	Selexipag	1,156	64–71	80%	Disease progression: HR 0.6, P<0.001	Improvement in 6MWD (12 meters, P<0.01) and NT-proBNP, no significant difference in proportion with worsening functional class

Abbreviations: CAMPHOR, Cambridge Pulmonary Hypertension Outcome Review; HR, hazard ratio; IP, prostacyclin; MWD, minute walk distance; NT-proBNP, N-terminal probrain natriuretic peptide; PVR, pulmonary vascular resistance; PAH, pulmonary arterial hypertension; VO2, peak oxygen consumption; WHO, World Health Organization.

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