Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding
Abstract
:1. Introduction
2. General Care and Control of Anemia
3. Therapeutic Pathways/Strategies of Pharmacological Treatments for HHT
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- Strategy 1. Although HHT does not result from a clotting failure, the use of antifibrinolytics to restore the balance between coagulation versus fibrinolysis would help to promote a quicker coagulation and to stabilize the fibrin network. Among the antifibrinolytics used for epistaxis treatment, tranexamic acid (TA) and ε-aminocaproic acid (AC) stand out [23,24].
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- Strategy 2. HHT is associated with haploinsufficiency in ENG or ALK1 genes, therefore stimulating their protein expression is thought to revert the HHT phenotype. At this point, raloxifene hydrochloride and bazedoxifene acetate, two specific estrogen receptor modulators (SERMs), have proven efficiency and safety, and have been designated as orphan drugs for HHT (2010 EU/3/10/730 and 2014 EU/3/14/1367; respectively) [25,26].
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- Strategy 3. Antiangiogenic therapies tackle the excess of abnormal vasculature present on the nasal mucosa in HHT. Therefore, bevacizumab (BZ) (Avastin®), a humanized monoclonal antibody against the main angiogenic factor, the vascular endothelial growth factor (VEGF), has been widely used and tested on HHT. Its systemic administration has improved hepatic function, delaying the liver transplant [27] but it has not shown consistent results when tested to decrease epistaxis events by topical spray administration [28,29].
3.1. Strategy 1. Antifibrinolysis: ε-Aminocaproic and Tranexamic Acids
3.2. Strategy 2. Upregulating ENG and ACVRL1
3.2.1. Hormonal Therapy: Specific Estrogen Receptor Modulators (SERMs)
3.2.2. Immunosuppressor Tacrolimus (FK506)
3.2.3. N-Acetylcysteine
3.3. Strategy 3. Antiangiogenesis
3.3.1. Anti-VEGF and Tyrosine Kinase Inhibitors (TKI)
3.3.2. Non-Selective Adrenergic β-blockers
3.3.3. Antiangiogenesis by FGF Ligand Blocking
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AC | Aminocaproic acid |
ACVRL1/ALK1 | Activin Receptor-Like Kinase 1 |
AVM | Arteriovenous Malformation |
BMP9 | Bone Morphogenetic Protein 9 |
BZ | Bevacizumab |
CM | Capillary Malformation |
CYP2D6 | Cytochrome P450 2D6 |
ECs | Endothelial Cells |
EMA | European Medicine Agency |
ENG | Endoglin |
EPHB4 | Ephrin Type-B Receptor 4 |
ER | Estrogen Receptor |
ESS | Epistaxis Severity Score |
FDA | Food and Drug Administration |
FGF | Fibroblast Growth Factor |
FK506 | Tacrolimus |
GI | Gastrointestinal |
HHT | Hereditary Hemorrhagic Telangiectasia |
iKO | inducible Knockout |
JPHT | Juvenile Polyposis/HHT |
MADH4/Smad4 | Mothers Against Decapentaplegic Homolog 4 |
mRNA | messenger Ribonucleic Acid |
NAC | N-acetylcysteine |
OLT | Orthotopic Liver Transplant |
OPG | Osteoprotegerin |
PDGF | Platelet Derived Growth Factor |
RANK | Receptor Activator of Nuclear Factor κ B |
RANK-L | Receptor Activator of Nuclear Factor κ B Ligand |
RASA1 | RAS P21 Protein Activator 1 |
SERMs | Selective Estrogen Receptor Modulator |
TA | Tranexamic Acid |
TFRE | Transcription Factor Regulatory Element |
TGF-β | Transforming Growth Factor β |
VEGF | Vascular Endothelial Growth Factor |
VM | Venous Malformation |
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1 | Decrease hemorrhages stabilizing the fibrin network with antifibrinolytics |
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2 | Stimulate ENG and ALK1 transcription to increase protein expression to partially overcome haploinsufficiency |
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3 | Decrease the abnormal excessive vasculature of the nose mucosa through antiangiogenesis |
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Trial Registration # | Country | Phase | Title | Intervention | Number of Patients | Trial Design | Outcome | Start Date | Status |
---|---|---|---|---|---|---|---|---|---|
EudraCT 2010-020545-26 | IT | 2 | Bevacizumab, an anti-angiogenic monoclonal antibody effective for prevention of hemorrhage in patients with HHT: possible regression of visceral arteriovenous malformations | Bevacizumab | 18 | Single-arm, controlled | Frequency of Epistaxis | 2008 | O |
EudraCT 2008-006755-44 | FR | 2 | METAFORE: Maladie de Rendu-Osler: Etude de l’Efficacité et de la tolérance du Bevacizumab utilisé pour le traitement des formes hépatiques sévères. Etude de phase II | Bevacizumab | 25 | Information not available | Effect on cardiac output in patients with severe liver damage | 2009 | O |
NCT02389959 | US | 4 | Intranasal Bevacizumab for HHT-Related Epistaxis | Bevacizumab | 40 | Two-arm, randomized, double-blind, placebo-controlled | Improvement in ESS | 2014 | R |
NCT02287558 | US | 1 | Pomalidomide in HHT and Transfusion-Dependent Vascular Ectasia: a Phase I Study | Pomalidomide | 9 | Single-arm, open-label | Transfusion requirement measure | 2015 | R |
NCT04167085 | US | 4 | NOrth American Study for the Treatment of Recurrent epIstaxis With DoxycycLine: The NOSTRIL Trial | Doxycycline | 24 | Two-arm, randomized, double-blind, crossover | Frequency of epistaxis | 2017 | A |
NCT02963129 | AR | 3 | Treatment of Nasal Staphylococcus Aureus Colonization in Patients With HHT | Mupirocin | 40 | Two-arm, randomized, triple-blind, placebo | Nosebleed by Sadick scale | 2017 | U |
NCT03981562 | CA | 2 | Vitamin D and HHT | Vit D | 60 | Three-arm, randomized, double-blind, placebo | Change in ESS | 2018 | R |
EudraCT z017-003272-31 | NL | 2 | Efficacy and safety of oral itraconazole in the reduction of epistaxis severity in HHT | Itraconazole | 25 | Single-arm, open-label | Change in epistaxis severity | 2018 | O |
NCT03397004 | CA | 2 | Doxycycline for HHT | Doxycycline Hyclate | 30 | Two-arm, randomized, double-blind, placebo-controlled, crossover | Reduction in epistaxis (nose bleeding) severity over 96 weeks | 2018 | R |
NCT04113187 | FR | 3 | Propranolol for Epistaxis in HHT a Patients | Propranolol | 38 | Two-arm, double-blind | Cumulative duration of epistaxis (in minutes) | 2019 | NR |
NCT04139018 | US | 2 | Timolol Gel for Epistaxis in HHT | Timolol Gel | 30 | Two-arm, double-blind, randomized controlled | ESS | 2019 | R |
NCT03910244 | US | 2 | Pomalidomide for the Treatment of Bleeding in HHT | Pomalidomide | 159 | Two-arm, placebo-controlled, double-blind | Change in ESS | 2019 | R |
NCT03850730 | US | 1–2 | Pazopanib for the Treatment of Epistaxis in HHT | Pazopanib | 30 | Single-arm, open-label | Percent change in epistaxis duration in minutes | 2019 | NR |
NCT03850964 | US | 2–3 | Pazopanib Effects on Bleeding in HHT | Pazopanib | 45 | Two-arm, double-blind, placebo controlled | Change in epistaxis duration in minutes | 2019 | NR |
EudraCT 2019-003585-40 | NL | NA | An uncontrolled, open label pilot-study assessing the efficacy in reducing bleeding severity, and the safety of oral tacrolimus in patients with HHT | Tacrolimus | 20 | Uncontrolled, single-arm, open-label | Change in the epistaxis and/or gastrointestinal severity | 2019 | O |
EudraCT 2019-002593-31 | FR | 2 | Efficacy of Nintedanib per os as a treatment for epistaxis in HHT disease. A national, randomized, multicenter phase II study EPICURE | Nintedanib | 60 | Two-arm, double-blind, randomized controlled, placebo | Frequency of Epistaxis | 2019 | O |
EudraCT 2018-004179-11 | NL | 2 | Effectiveness of Somatostatin Analogues in patients with HHT and symptomatic gastrointestinal bleeding, the SAIPAN-trial: a multicenter, randomized, open-label, parallel group, superiority trial | Somatostatin Analogues | 38 | Two-arm, open-label, randomized controlled | Decreasing the transfusion requirements | 2019 | O |
ACTRN 12619001020178 | AU | 2 | A pilot study assessing the effectiveness of oral Propranolol in preventing epistasis in patients with HHT | Propranolol | 15 | Single-arm, open-label, non-randomized | Change in Epistasis | 2019 | NR |
NCT03954782 | FR | 2 | Efficacy of Nintedanib Per os as a Treatment for Epistaxis in HHT Disease | Nintedanib | 60 | Two-arm, triple-blind, randomized | Epistaxis duration assessed on epistaxis grids completed by the patients | 2020 | O |
Trial Registration # | Country | Phase | Title | Intervention | Number of Patients | Trial Design | Outcome (Summary of Statistically Significant Outcomes) | Start Date | Status | Link to Results |
---|---|---|---|---|---|---|---|---|---|---|
NCT00004327 | US | 2 | Phase II Pilot Study of Octreotide, a Somatostatin Octapeptide Analog, for Gastrointestinal Hemorrhage in Hormone-Refractory HHT and Senile Ectasia | Octreotide | 8 | Information not available | - | 1995 | C | - |
NCT00004654 | US | 3 | Phase III Randomized, Placebo-Controlled, Crossover Study of Soy Protein Isolate for HHT | Soy protein | 60 | Randomized | - | 1996 | C | - |
NCT01031992 | GE | 3 | Tranexamic Acid and Epistaxis in HHT | Tranexamic acid | 23 | Two-arm, double-blind, controlled | No changes in hemoglobin levels. Significant reduction in ESS | 2002 | C | Article [32] |
NCT00375622 | IL | 2 | Anti-Estrogen Therapy for HHT A Double-Blind Placebo-Controlled Clinical Trial | Tamoxifen | 25 (60) * | Double-blind, placebo-controlled | Significant reduction in ESS (frequency and severity). | 2005 | C | Article [33] |
NCT00355108 | FR | 3 | ATERO: A Randomized Study with Tranexamic Acid in Epistaxis of Rendu Osler Syndrome | Tranexamic acid | 118 (170) * | Single-arm, double-blind, randomized, crossover | Significant decrease in the duration of epistaxis | 2006 | C | Article [34] |
NCT00389935 | US | 2 | Thalidomide Reduces Arteriovenous Malformation Related Gastrointestinal Bleeding | Thalidomide | 14 | Single-arm, open-label | - | 2006 | C | - |
NCT00588146 | US | 2 | Phase 2 Study of PEG-Intron in HHT | Pegylated IFN-α2B | 10 | Two-arm, open-label, randomized | Adverse events plus discontinuation of the study supply | 2007 | T | Trial file |
NCT01397695 | US | 2 | Topical Bevacizumab for the Management of Recurrent Epistaxis in Patients with HHT | Bevacizumab | 20 | Single-arm, open-label, non-randomized | - | 2009 | T | Trial file |
NCT01402531 | US | 2 | Submucosal Bevacizumab for the Management of Recurrent Epistaxis in Patients with HHT | Bevacizumab | 10 | Single-arm, open-label, non-randomized | - | 2010 | T | Trial file |
EudraCT2009-018049-19 | AT | 2 | A randomized double-blind placebo-controlled trial of intranasal submucosal bevacizumab in hereditary hemorrhagic telangiectasia | Bevacizumab | 30 | Two-arm, double-blind, randomizedcontrolled | - | 2010 | C | - |
NCT01408030 | US | 2 | North American Study of Epistaxis in HHT (NOSE) | Bevacizumab- Estriol- Tranexamic Acid | 121 | Four-arm, double-blind, placebo-controlled, randomized | No significant differences on epistaxis frequency | 2011 | C | Article [28] |
NCT01408732 | US | 1 | Office-sclerotherapy for Epistaxis Due to HHT | Sclerotherapy with sodium tetradecyl sulfate | 18 | Two-arm, open-label, randomized-controlled | No significant differences on severity of epistaxis | 2011 | C | Trial file |
NCT01485224 | IT | 2 | Efficacy of Thalidomide in the Treatment of HHT | Thalidomide | 31 | Single-arm, open-label, non-randomized | 100% showed a complete or partial response to epistaxis | 2011 | C | Article [35] |
NCT01314274 | AT | 2 | Intranasal Submucosal Bevacizumab for Epistaxis in HHT | Bevacizumab | 15 | Two-arm, double-blind, randomized, placebo-controlled | No significant differences on epistaxis frequency | 2011 | C | Article [36] |
NCT01507480 | FR | 1 | The ELLIPSE Study: A Phase-1 Study Evaluating the Tolerance of Bevacizumab Nasal Spray to Treat Epistaxis in HHT | Bevacizumab | 42 | Single-arm, double-blind, randomized, placebo-controlled | Bevacizumab nasal spray is safe | 2011 | C | Article [37] |
EudraCT 2011-004096-36 | IT | 2 | Efficacy of thalidomide in the treatment of severe recurrent epistaxis in HHT | Thalidomide | 31 | Single-arm, non-controlled | - | 2011 | C | - |
NCT01908543 | UK | NA | Iron Deficiency and HHT | Ferrous sulphate | 3 | Single-arm, open-label | - | 2013 | T | Article [38] |
NCT01752049 | CA | NA | Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept | Timolol maleate | 5 | Two-arm, double-blind, placebo-controlled | - | 2013 | C | - |
EudraCT 2013-004204-19 & NCT02157987 | FR | 1-2 | Treatment of HHT of the Nasal Mucosa by Intranasal Bevacizumab: Search for Effective Dose | Bevacizumab | 30 | Four-arm, double-blind, randomized, controlled | - | 2014 | C | - |
NCT02638012 | CA | NA | Prospective Pilot Study of Floseal for the Treatment of Anterior Epistaxis in Patients With HHT | Floseal | 10 | Two-arm, open-label, non-randomized | No statistically significant difference noted in ESS | 2015 | C | Article [39] |
NCT02204371 | US & CA | 2 | Evaluation of Pazopanib on Bleeding in Subjects with HHT | Pazopanib | 7 | Two-arm, open-label, non-randomized | No statistically significant difference noted in ESS | 2015 | T | Trial file |
EudraCT 2015-000385-55 & NCT02484716 | FR | 2 | Efficacy of a Timolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)—(TEMPO) | Timolol | 58 | Two-arm, double-blind, randomized | No statistically significant difference noted in ESS | 2015 | C | Article [40] |
EudraCT 2016-003982-24 | ES | 4-2 | A phase IV-II, single-center, open, single arm treatment, low level of intervention, to assess the efficacy clinical trial and safety of intranasal administration of ethamsylate in the treatment of HHT, during for 4 weeks | Ethamsylate | 12 | Single-arm, open-label, non-randomized | Statistically significant difference noted in ESS | 2016 | C | Article [31] |
EudraCT 2016-001340-19 & NCT02874326 | NL | 2 | Octreotide in Patients With GI Bleeding Due to Rendu-Osler-Weber | Octreotide LAR | 15 | Single-arm, open-label | The median number of RBC units needed decreased significantly. | 2016 | C | Article [41] |
NCT03152019 | FR | 2 | Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hemorrhagic Hereditary Telangiectasia (HHT) (TACRO) | Tacrolimus | 50 | Two-arm, double-blind, randomized | No statistically significant difference noted in ESS | 2017 | C | Article [42] |
Active Substance | Date | EU-Designated Number | Sponsor | Degree of Evidence Clinical Trial |
---|---|---|---|---|
Etamsylate | 11/2018 | EU/3/10/18/2087 | CSIC, Spain | EudraCT: 2016–003982–24 |
Thalidomide | 02/2017 | EU/3/17/1845 | PlumeStars, S.R.L., Italy | Several clinical trials, Table 3 |
Bevacizumab | 12/2014 | EU/3/14/1390 | Dupuis-Girod, France | Several clinical trials, Table 3 |
Bazedoxifene | 11/2014 | EU/3/14/1367 | CSIC, Spain | Observational study, 5 patients |
Raloxifene | 06/2010 | EU/3/10/730 | CSIC, Spain | Observational study, 19 patients |
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Albiñana, V.; Cuesta, A.M.; de Rojas-P, I.; Gallardo-Vara, E.; Recio-Poveda, L.; Bernabéu, C.; Botella, L.M. Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding. J. Clin. Med. 2020, 9, 1766. https://doi.org/10.3390/jcm9061766
Albiñana V, Cuesta AM, de Rojas-P I, Gallardo-Vara E, Recio-Poveda L, Bernabéu C, Botella LM. Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding. Journal of Clinical Medicine. 2020; 9(6):1766. https://doi.org/10.3390/jcm9061766
Chicago/Turabian StyleAlbiñana, Virginia, Angel M. Cuesta, Isabel de Rojas-P, Eunate Gallardo-Vara, Lucía Recio-Poveda, Carmelo Bernabéu, and Luisa María Botella. 2020. "Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding" Journal of Clinical Medicine 9, no. 6: 1766. https://doi.org/10.3390/jcm9061766