. 2020 Nov 18;10(4):2045894020941494. doi: 10.1177/2045894020941494

Table 1.

Summary of repurposed or novel therapies investigated in pulmonary arterial hypertension.

Repurposed therapies (n = 72)	Therapies where pulmonary hypertension arguably first indication (n = 11)
7 approved therapies and 65 not approved	8 approved therapies, 2 in development and 1 terminated
Trials in PAH not positive for primary endpoint, terminated early or other results:¹⁷ Terguride: 5-HT receptor antagonist¹⁸ Nilotinib: TK inhibitor (AMN107) NCT01179737 Aspirin and simvastatin: COX and HMG-CoA-reductase inhibitor¹⁹ Atorvastatin: HMG-CoA reductase inhibitor (APATH) Inhaled aviptadil: VI²⁰ Imatinib: TK inhibitor (QTI571; IMPRES) Sorafenib: TK inhibitor²¹ Selonsertib: ASK1 inhibitor (ARROW)²² FK506: calcineurin inhibitor (tacrolimus)²³ Pioglitazone: PPARgamma agonist NCT00825266 Ubenimex: aminopeptidase inhibitor (LIBERTY1/2) NCT02664558/ NCT02736149 Racecadotril: neprilysin inhibitor Anakinra: IL-1 inhibitor Ambrisentan plus spironolactone: ERA plus aldosterone antagonist NCT02253394 Fulvestrant: oestrogen antagonist NCT02911844 Tocilizumab: anti-IL-6 antibody (TRANSFORM-UK) NCT02676947 Selective PDHK 1 and 2 inhibitor (Acros) JTT-251 NCT03789643, withdrawn due to priority change Current ongoing clinical trials:¹⁷ Macitentan and tadalafil and selexipag versus macitentan and tadalafil in combination (TRITON) NCT02558231 Hormonal modulators: Anastrozole: aromatase inhibitor (PHANTOM) NCT03229499 Tamoxifen: oestrogen receptor inhibitor (T3PAH) NCT03528902 DHEA (EDIPHY) NCT03648385 Spironolactone: aldosterone antagonist NCT01712620 rhACE2: GSK2586881 NCT03177603 KAR5585: tryptophan hydroxylase 1 inhibitor NCT02746237 Escitalopram: SSRI NCT00190333 Fluoxetine: SSRI NCT03638908 PB1046: VIP analogue NCT03315507 GPCR pathways: Apelin (EXAP) NCT01590108 Mitochondrial and metabolic adaptations: Ranolazine: sodium channel inhibitor, partial FAO inhibitor NCT01839110 Ranolazine NCT02829034 Trimetazidine: FAO inhibitor NCT02102672 Metformin: biguanide, AMPK activator NCT03617458 Ferinject or CosmoFer: iron infusion NCT01447628 Epigenetic alterations and interaction with metabolic pathways: Olaparib: PARP inhibitor (OPTION) NCT03782818 Apabetalone: BRD4 inhibitor (APPRoAcH-p) NCT03655704 Oxidative stress related pathways: Bardoxolone methyl: IκB kinase and NF-κB inhibitor, Nrf2 activator (LARIAT) NCT02036970 Bardoxolone methyl (CATALYST) NCT02657356 Bardoxolone methyl (RANGER) NCT03068130 CXA-10: nitrated fatty acid compound (PRIMEx) NCT03449524 Inflammatory mediators: Rituximab: anti-CD20 antibody NCT01086540 Elafin: elastase-specific protease inhibitor NCT03522935 Transcriptional factors: ABI-009: mTOR inhibitor NCT02587325 Miscellaneous Carbonic anhydrase (CA) inhibitor: Acetazolamide, NCT02755259 (results not posted), Beta-agonist: Albuterol, APD811 NCT03270332, ongoing Benzbromarone (Medical University Graz) NCT02790450, phase 2 completed, not posted Carbon monoxide NCT01523548, not posted Heart failure: Non-selective beta adrenergic receptor blocker Carvedilol NCT01586156, safety study only²⁴ Bisoprolol²⁵ Nitro fatty acid CXA-10 NCT04053543 Alpha2 receptor agonist Dexmedetomidine NCT 01072643 use cautioned by²⁶ H2 receptor agonist: Famotidine, NCT03554291, funded by NHLBI, study ongoing Selective serotonin reuptake inhibitor: Fluoxetine NCT00942708 Selective thromboxane receptor antagonist Ifetroban NCT02682511, study ongoing Phosphodiesterase 3 inhibitor Milrinone NCT04391478, study ongoing in PPHN L-Glutamine NCT01048905, completed, no results posted Calcium sensitizer Levosimendan,²⁷ not pursued Beta-3 agonist: Mirabegron, NCT02775539 SPHERE-HF, not posted Pulsed nitric oxide (Bellerophon), NCT02725372, primary endpoint not met (stopped for futility) Tryptophan hydroxylase inhibitor Rodatristat RVT-1201 (Altavant), NCT03924154 (ELEVATE-1), terminated as not recruitable Thromboxane synthetase Inhibitor (Boehringer Ingelheim): Terbogrel, NCT02223481, phase 2 terminated due to leg pain,²⁸ Non-selective ETA and ETB receptor antagonist Tezosentan (Idorsia), NCT01077297, terminated due to slow recruitment PDE-5 inhibitor Udenafil (Dong-A), NCT01553721, phase 2 completed²⁹ Pirfenidone, NCT02951429 Nebivolol^25,30 Vasopressin, NCT01370096, paediatric PH, terminated due to slow recruitment	Terminated: Prostacyclin receptor agonist QCC374, NCT02927366, Novartis, due to strategic reasons In development: Growth factor receptors: Sotatercept: activin receptor type 2A fusion protein acting as a ligand trap (SPECTRA) NCT03738150 Sotatercept (phase 2 successfully completed in PAH) Oral IP agonist (UT): Ralinepag, phase 2 completed, UT
Approved repurposed drugs (n = 7): • Beraprost – Japan only^31–33 • Bosentan (Tracleer®)³⁴ • Epoprostenol (Flolan®)³⁵ • Inhaled iloprost (Ventavis®)³⁶ • I.V. iloprost (Ilomedin®) – New Zealand only^37–40 • Sildenafil (Revatio®)⁴¹ • Tadalafil (Adcirca®)⁴²	Approved non-repurposed drugs (n = 8): • Ambrisentan (Letairis®, Volibris®)⁴³ • Macitentan (Opsumit®)⁴⁴ • Riociguat (Adempas®)⁴⁵ • Selexipag (Uptravi®)⁴⁶ • Inhaled treprostinil (Tyvaso®)⁴⁷ • Oral treprostinil (Orenitram®)^48–51 • S.C. treprostinil (Remodulin®)^52,53 • I.V. treprostinil (Remodulin®)⁵⁴

PAH: pulmonary arterial hypertension; TK: tyrosine kinase; IL-1: interleukin-1; PDE-5: phosphodiesterase-5; PH: pulmonary hypertension; S.C.: subcutaneous; I.V.: intravenous.

Note: The information provided in Table 1 was derived from literature search, reviews and clinicaltrials.gov