Nintedanib as a novel treatment option in hereditary haemorrhagic telangiectasia

Kovacs-Sipos, Evelin; Holzmann, David; Scherer, Thomas; Soyka, Michael

doi:10.1136/bcr-2017-219393

Cited by 13 publications

(10 citation statements)

References 7 publications

(11 reference statements)

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“…The tyrosine kinase inhibitor Nintedanib, which targets the platelet-derived growth factor, fibroblast growth factor and vascular endothelial growth factor receptors, has been used in one HHT2 patient following the diagnosis of Interstitial Pulmonary Fibrosis [47] with encouraging results. His Epistaxis Severity Score significantly decreased.In France, we are implementing a multicenter, randomized, drug versus placebo study to evaluate efficacy of Nintedanib treatment per os on epistaxis duration in HHT patients with moderate to severe epistaxis (NCT03954782).…”

Section: Main Textmentioning

confidence: 99%

Future treatments for hereditary hemorrhagic telangiectasia

Robert

Desroches-Castan

Bailly

et al. 2020

Orphanet J Rare Dis

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Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations of ACVRL1 or ENG genes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the gene SMAD4 which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, recent progress has been made using drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway with the use of bevacizumab (anti-VEGF antibody). Furthermore, several exciting high-throughput screenings and preclinical studies have identified new molecular targets directly related to the signaling pathways affected in the disease. These include FKBP12, PI3-kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients.

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Section: Main Textmentioning

confidence: 99%

Future treatments for hereditary hemorrhagic telangiectasia

Robert

Desroches-Castan

Bailly

et al. 2020

Orphanet J Rare Dis

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“…Several receptor tyrosine kinase (RTK) inhibitors that target VEGFR2 are FDA/EMA approved; one of these, pazopanib, showed beneficial effects in ALK1-deficient mice (39) and in a cohort of patients with HHT (40). A recent case study reported that nintedanib (Nin, BIBF 1120), a VEGFR2-targeting RTK inhibitor that is approved for idiopathic pulmonary fibrosis (IPF) treatment, produced marked reductions in epistaxis and skin telangiectasias in a patient affected by both HHT and IPF (41). Nin is of particular interest compared with other classical RTK inhibitors because it has a narrow spectrum of inhibition and is associated with minimal adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Ruíz¹,

Zhao²,

Chandakkar³

et al. 2020

Journal of Clinical Investigation

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Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs-including in HHT patient blood outgrowth ECs-and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.

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“…BZ is used (off-label) for antiangiogenic strategy in HHT patients with severe bleeding or symptomatic liver AVMs, in order to reduce bleedings and excessive number of abnormal mucosa vessels. TKIs (pazopanib, nintenadib, sunitinib or buparlisib) and thalidomide have also been used or are planned to be used in clinical trials [ 22 , 83 , 101 , 102 ] ( Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…Initially, patients will be monitored for 24 weeks: 12-weeks of oral treatment plus 12-weeks of follow-up. Theoretically, nintedanib, as a non-specific/wide range TKI, should allow a reduction of epistaxis in HHT [ 83 ].…”

Section: Therapeutic Pathways/strategies Of Pharmacological Treatmmentioning

confidence: 99%

Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding

Albiñana

Cuesta

Rojas-P

et al. 2020

JCM

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The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at “ground zero” to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT.

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Nintedanib as a novel treatment option in hereditary haemorrhagic telangiectasia

Cited by 13 publications

References 7 publications

Future treatments for hereditary hemorrhagic telangiectasia

Future treatments for hereditary hemorrhagic telangiectasia

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding

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