Table 2.

Investigated Therapies in HHT and CCM Disease Models and Clinical Trials

DiseaseTherapeutic StrategyCompoundPreclinical Evidence for Use (Mode of Action)Clinical ResultsClinical Trial Identifier
HHTAntiangiogenic (anti-VEGF)BevacizumabBMP9/BMP10 inhibit VEGF48,139RecruitingNCT02389959
High levels of circulating VEGF97,141METAFORE study completed142,143NCT00843440
Prevention/reduction of AVMs in HHT mouse models76,136,137,144ELLIPSE study completed145NCT01507480
Study completed146NCT01314274
Study completed147NCT02106520
Bevavizumab, estriol, tranexamic acidStudy completed. No benefit with any of the drugs148NCT01408030
PazopanibAmeliorates anemia and GI bleeding in Alk1-iKO mouse model149Study completed. No published results yetNCT02204371
Anti-inflammatory/antiangiogenicThalidomideReduces vascularization in rabbit cornea.150 Reduces VEGF, migration, and tube formation151Study completed. Reduces number of epistaxis, telangiectasis, and transfusions152NCT01485224
Increases pericyte coverage in neonatal Eng-null mouse retina, improves epistaxis frequency in HHT153Study completed. No published results yetNCT00389935
Antifibrinolytic agentTranexamic acidCompetitive inhibitor of plasminogen; reduces conversion into plasmin; reduces nose bleeds.154,155 Increases expression and activity of ALK1 and endoglin in ECs156ATERO study completed. Decreased duration of epistaxis157NCT00355108
Significant reduction of nosebleeds158NCT01031992
β-BlockerPropanololReduces blood flow; angiogenesis inhibitor159Apoptotic and profibrinolytic effects159NA
TimololTopic application reduces epistaxis160Active study not recruiting. TEMPO studyNCT02484716
AntiestrogenTamoxifenSelective estrogen receptor modulator; reduces epistaxis in patients with HHT161Improved bleeding score in frequency and severity161NCT00375622
RaloxifeneIncreases expression of Eng/ALK1 in ECs; improved EC function (eg, migration)162NA
ImmunomodulatorInterferon-αReduction in EC migration and proliferation163Early study termination because of discontinued drug supplyNCT00588146
TacrolimusIncreases expression of ALK1 and endoglin164Not open for recruitment yetNCT03152019
CCMReceptor tyrosine kinase inhibitorSorafenibReduces vascular density165NAFDA approved
TGF-βRI inhibitorLY-364947, SB-431542Reduces pSmad, EndMT markers, and vascular lesion burden5NANA
BMPRI inhibitorDMH1Reduces vascular lesion burden and leakage5NANA
HMG CoA reductase inhibitorSimvastatinBlocks geranylgeranylation of RhoA, inhibits permeability,166 and reduces lesion burden167,168Study completed. No published results yetNCT01764451
AtorvastatinPreserves EC integrity169Not open for recruitment yetNCT02603328
Rock1/2 inhibitorFasudilInhibits actin stress fibers, MLC phosphorylation, permeability, and reduces vascular lesion burden168,170,171NANA
β-catenin- and Klf4-driven transcriptionSulindac sulfone (exisulind)Rescues adherens junctions, inhibits EndMT, and reduces lesion burden7NANA
Vitamin D3Rescues cell-to-cell junctions, actin stress fibers, transcellular resistance, and inhibits vascular lesion burden172NANA
Superoxide inhibitorTempolRescues cell-to-cell junctions, actin stress fibers, transcellular resistance, and inhibits vascular lesion burden172NANA
Erk5 inhibitorsXMD8-92, XMD17-105Inhibits the expression of Klf2 and Klf4 and lesion burden134,173NANA
Mek5 inhibitorBIX 02189Inhibits the expression of Klf2 and Klf4 and Erk5 phosphorylation134,173NANA
Angiopoietin-2 inhibitorANGPT2-neutralizing antibodyRescues cell-to-cell junctions and barrier functions, reduces lesion burden, Ccm3-EC-KO specific174NANA
  • AVM indicates arteriovenous malformation; BMP, bone morphogenetic protein; CCM, cerebral cavernous malformation; DMH1, dorsomorphin; EC, endothelial cell; FDA, Food and Drug Administration; GI, gastrointestinal; HHT, hereditary hemorrhagic telangiectasia; MLC, myosin light chain; NA, not available; TGF-β, transforming growth factor-β; and VEGF, vascular endothelial growth factor.