Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension

Figures & data

Figure 1 Physiopathological mechanisms of pulmonary arterial hypertension.

Abbreviations: ↑, increase in; ECs, endothelial cells; EGF, epidermal growth factor; FGF, fibroblast growth factor IL, interleukin; PDGF, platelet-derived growth factor RAAS, renin–angiotensi–-aldosterone system; SMCs, smooth muscle cells; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide.

Table 1 Summary of Clinical Trials Data of New Potential Drugs in the Treatment of PAH

	Clinical Trials.gov	Study Design	Study Duration	Inclusion Criteria	Primary Outcome	Secondary Outcomes	Status	Results	REF
Therapies targeting BMPR2 signaling
Tacrolimus	NCT01647945	Phase II, single-center, double-blind, randomized	16-weeks	PAH	Safety	Clinical events 6MWDT NT-proBNP Echo changes	Terminated	No significant change in 6MWDT and echo parameters	[^Citation51]
Therapies targeting Inflammation and Immunity
Tocilizumab	NCT02676947 (TRANSFORM-UK)	Phase II, open-label	6 months	PAH	Safety changes in PVR	6MWDT NT-proBNP WHO FC QOL Numbers of AEs	Completed	Results not reported
Anakinra	NCT03057028	Pilot study, open-label, single-group	14 days	PAH	Peak VO2	CRP, IL-6 NT-proBNP	Completed	No change in Peak VO2 Improvement of QOL	[^Citation91]
Bardoxolone	NCT02036970 (LARIAT)	Phase II, double-blind, randomized	16 weeks	WHO PH Groups I, III or V PH	Changes in 6MWDT	–	Completed	Improvement in 6MWDT	[^Citation106]
	NCT02657356 (CATALYST)	Phase III, double-blind, randomized	24 weeks	CTD-PAH	Changes in PVR	–	Completed	Results not reported
	NCT03068130 (RANGER) extended study in patients previously enrolled in Bardoxolone trial	Phase III, single group assignment, open-label extension	Long-term	PAH	Long-term safety	–	Active	NA
DMF (dimethyl fumarate)	NCT02981082	Phase I, double-blind, randomized, placebo controlled	24 weeks	SSc-PAH	6MWDT	Time to clinical worsening, BORG Dyspnea Index (BDI), oxidative stress markers, BNP	Terminated	Results not reported
Rituximab	NCT01086540	Phase II, double-blind, placebo controlled, multicenter	24 weeks	SSc-PAH	6MWDT	PVR, 6MWDT, time to clinical worsening, DLCO change, number of AEs, mortality	Completed	No significant change in 6MWDT	[^Citation110]
Therapies targeting tyrosine kinases (TK) signaling pathway
Imatinib	NCT00477269	Phase II, double-blind, placebo-controlled, multicenter	24 weeks	PAH	Safety 6MWDT	Changes in WHO class, invasive hemodynamics	Completed	No significant change in 6MWDT PVR improved	[^Citation118,Citation120]
	NCT00902174 (IMPRES)	Phase III, Phase II, double-blind, placebo-controlled	24 weeks	PAH	6MWDT	Number of clinical worsening events, Invasive hemodynamics	Completed	Significant change in 6MWDT PVR improved	[^Citation121]
	NCT01117987 (IMPRES extension)	Single group assignment, extension	Long term	PAH	Safety (# AEs)	6MWDT Incidence of Clinical worsening	Completed	6MWDT improvement was maintained	[^Citation121]
Nilotinib	NCT01179737	Phase II, double blind, placebo controlled	24 weeks	PAH	PVR	6MWDT # AEs	Terminated	Terminated due to serious AEs
Sorafenib	NCT00452218	Phase Ib, open-label exploratory, single-center	16 weeks	PAH	6MWD	Efficacy, WHO FC, RHC, Treadmill	Completed	Results not reported Cardiac safety concerns
Therapies targeting mitochondrial dysfunction
DCA (dichloroacetate)	NCT01083524	Phase I, open-label, two-center	16 weeks	PAH	Safety	PVR, 6MWDT, RV size/fction by MRI, NT-proBNP Lung/RV metabolism	Completed	Improvement PA pressures, PVR and lung metabolism	[^Citation162]
Ranolazine	NCT01757808	Phase I, double-blind, placebo controlled	12 weeks	PAH	PVR	Change in CPET, in RV parameters, 6MWDT, AEs	Completed	Safe No HD improvement	[^Citation172]
	NCT01174173	Phase III	12 weeks	PAH	6MWDT, QOL, angina sxs	RHC parameters, RV function (echo)	Completed		[^Citation173]
	NCT01839110	Phase IV, double-bind, placebo controlled	26 weeks	PAH	Change in RVEF	–	Completed	Results not reported	[^Citation174]
Selonsertib	NCT02234141 (ARROW)	Phase II, dose-ranging, double-blind, placebo-controlled	24 weeks	PAH	PVR	Invasive HD, 6MWDT, BDI, NT-proBNP, QOL, TTCW, RV echo parameters	Completed	No PVR improvement
Trimetazidine	NCT02102672	Phase II, randomized, crossover	12 weeks	PAH	RV parameters (echo)	6MWDT, BDI, BNP, galactin-3, TTCW	Unknown
	NCT03273387	Phase II, double-blind, placebo-controlled	12 weeks	PAH	RVEF (MRI)	Functional capacity by SF-36	Completed	Results not reported
Therapies targeting oxidative stress signaling pathway
Inhaled Nitrite	NCT01431313	Phase II, open-label, parallel-dose study	16 weeks	PAH	PVR	TTCW	Terminated	Results not reported
Coenzyme Q10	NCT01148836	Non-randomized, open-label, single-center	12 weeks	PAH	Echo parameters	RBCs, Hb, Htc, MCH	Completed	No change in echo parameters, 6MWDT or biomarkers
Therapies targeting extracellular matrix
Elafin	NCT03522935	Phase 1, dose escalation, double-blind	5 weeks	Normal healthy subjects	Safety (# Aes)	PK/PD	Active, recruiting	–
Therapies targeting metabolism
Metformin	NCT03617458	Phase II, 2×2 factorial randomized, blinded	12 weeks	PAH	6MWDT Change in WHO FC	Weight, BMI, BDI, QOL, estradiol, BNP, RV echo parameters, mortality, hospitalization	Active, recruiting	–
Therapies targeting neurohormonal modulation pathway
Carvedilol	NCT01586156 (PAHTCH)	Parallel assignment, blinded, placebo controlled	24 weeks	PAH	Cardiac glucose uptake	RVSP (echo) 6MWDT NT-proBNP	Completed	No change of RV function, no change in 6MWDT	[^Citation277]
Bisoprolol	NCT01246037	Crossover, placebo-controlled, blinded, single	52 weeks	PAH	RVEF (MRI) Safety	Exercise capacity Pressure volume loop	Terminated	No benefit RVEF unchanged Decreased in 6MWDT and CI	[^Citation278]
rhACE2 (GSK2586881)	NCT03177603	Phase II, open-label, dose escalation	4 weeks	PAH	PVR CO Mean PA	# AEs, labs, Ang II, NT-proBNP, nitrite	Completed	No reduction in PVR
Spironolactone	NCT02253394	Phase II, crossover	12 weeks	PAH	Peak VO2	-	Terminated	Only 2 participants enrolled
	NCT01712620	Parallel assignment, blinded, placebo-controlled	24 weeks	PAH	6MWDT	Peak VO2, RV function, biomarkers	Recruiting	–
Therapies targeting endogeneous vasoactive peptides pathway
VIP	NCT03556020	Phase II, double-blind, placebo-controlled	24 weeks	PAH	# AEs PVR Vital signs, EKG	6MWDT, NT-proBNP, invasive HD, BDI, WHO FC, incidence of CW, PK/PD	Recruiting	–
Therapies targeting the serotonin system signaling pathway
Escitalopram	NCT00190333	Phase III, double-blind, placebo-controlled	16 weeks	PAH	6MWDT	Invasive HD, NYHA, Dyspnea Scale, QOL, safety	Completed	Results not reported
Fluoxetine	NCT00942708	Phase II, single group assignment, open-label	12 weeks	PAH	PVR	6WDT Depression Scale	Completed	Results not reported
Therapies targeting estrogen signaling pathway
Anastrozole	NCT01545336	Phase II, double-blind, placebo-controlled	12 weeks	PAH	Estradiol levels TAPSE	6MWDT	Completed	↓40% Estradiol 6MWDT improvement	[^Citation369]
	NCT03229499 (PHANTOM)	Phase II, double-blind, placebo-controlled	52 weeks	PAH	6MWDT	RV function, NT-proBNP, biomarkers, QOL, TTCW, AEs	Recruiting	–
Tamoxifen	NCT03528902	Phase II, single-center, double-blind, placebo-controlled	24 weeks	PAH	TAPSE	6MWDT, QOL, BNP, Hb A1c	Recruiting	–
DHEA	NCT03648385 (EDIPHY)	Phase II, double-blind, placebo-controlled	18 weeks	PAH	RV function (echo)	RVEF, NT-proBNP, sex hormone levels, 6MWDT, QOL, # AEs	Recruiting	–
Fulvestrant	NCT02911844	Phase II, single group, open-label, single-center	9 weeks	PAH	Estradiol levels, TAPSE, 6MWDT, NT-proBNP	–	Completed	6MWDT improvement No change in TAPSE
Therapies targeting iron deficiency
Ferric carboxymaltose	NCT01447628	Phase II, crossover, double-blind	12 weeks	PAH	PVR Exercise capacity	Peak VO2, cardiac MRI, 6MWDT, WHO FC, NT proBNP, QOL, Safety	Completed	Results not reported
Oral FeS04	NCT01446848	Single-group, open-label	12 weeks	IPAH	Serum ferritin	6MWDT, death, hospitalization, erythropoietin, TF sat, RVSP, AEs	Completed	Results not reported
Therapies targeting DNA damage
Olaparib	NCT03782818 (OPTION)	Phase 1, single-group, open-label	24 weeks	PAH	# AEs	6MWDT, WHO FC, NT-proBNP, QOL	Recruiting	–

Abbreviations: 6MWDT, 6-minute walk distance test; AEs, adverse events; Ang II, angiotensin II; BDI, BORG Dyspnea Index; BNP, brain natriuretic peptide; CI, cardiac index; CW, clinical worsening; FC, functional class; N/A, not available; HD, hemodynamics; PK/PD, pharmacokinetics/pharmacodynamics; PVR, pulmonary vascular resistance; REF, reference; RVEF, right ventricular ejection fraction; RVSP, right ventricular systolic pressure; SSc-PAH, systemic sclerosis-PAH; TF, transferrin; QOL, quality of life; TTCW, time to clinical worsening; VO₂, oxygen consumption; WHO, World Health Organization.

Figure 2 Schematic of BMP signaling pathway signaling implicated in PAH pathogenesis. BMP9 and BMP10 present in the circulation initiate signaling by binding and bringing together BMPR2 and ALKI. BMPR2 phosphorylated ALK1 which then propagate the signal through phosphorylation of SMAD 1/5/8. Subsequently, SMAD 4 forms a complex with SMAD 1/5/8, which translocates to the nucleus regulating the expression of target genes.

Abbreviations: ASK1, apoptosis signal regulating kinase 1; P, phosphate.

Figure 3 Growth factors and tyrosine kinases (TK) signaling pathway.

Abbreviations: ↑, increase in; ↓, decrease in; PDGFR2, platelet-derived growth factor receptor type 2; VEGFR2, vascular endothelial growth factor type 2; BCR, breakpoint cluster region; ABL, abelson 1 kinase.

Figure 4 RhoA/Rho-kinase signaling pathway. Wthin PAEcs and PASMCs, Rho-Rho kinase can be activated by several pathological mediators, including angiotensin II (Ang II), endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT). Rho-Rho kinase activation leads to inhibition of myosin light chain phosphatase (MLCPh) and subsequently vasoconstriction. Rho-Rho kinase also contributes to endothelial dysfunction through negative regulation of endothelial nitric oxide synthase (eNOS) and phosphatidylinositol 3-kinase (PI3K) activity causing reduced NO bioavailability.

Abbreviations: ↓, decrease in; 5-HT, 5-hydroxytryptamine; Ang II, angiotensin II; ET-1, endothelin-1; eNOS, endothelial nitric oxide synthase; MLCPh, myosin light-chain phosphatase; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase.

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