Current and emerging pharmacotherapies for hereditary hemorrhagic telangiectasia

ABSTRACT

Introduction: Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler- Weber syndrome, is a multisystemic vascular rare disease characterized by localized angiodysplasia. It is an inherited autosomal dominant disease. The estimated prevalence is around 1 in 5,000. Epistaxis is the most frequent manifestation, increasing from the 4th decade of life on. Many patients show severe nose bleeds which seriously interfere with the quality of life. Epistaxes are due to telangiectases on the nasal mucosa,

Areas covered: This review includes our own experience of years researching to find therapeutic agents in HHT. Our strategy has been drug repurposing, or second use of already known drugs. In this context, the use of antifibrinolytics, modulators of hormonal receptors (SERMs), anti-oxidant agents, immunosuppresants and anti-angiogenic agents, tested under preclinical conditions.

Expert opinion: Out of different approaches used to decrease bleeding in HHT, effective drugs currently used in the medical practice are: antifibrinolytics, and SERMs, both raloxifene and bazedoxifene, designated as orphan drugs for the EMA (European Medicine Agency). However, the emerging field of antiangiogenesis is very promising, and we hope that in a short time, topical treatment by sprays or creams will be available.

KEYWORDS:

• HHT
• Endoglin
• ACVLR1/ALK1
• antifibrinolytic
• immunosuppressant agents
• SERMs anti-angiogenic agents
• antioxidant agents
• VEGF
• FGF

Article highlights

• There is no definite treatment for bleedings derived from HHT however, several drugs that improve the health condition and quality of life of HHT patients are currently available.

• As a rare disease, HHT is a chronic condition which needs a chronic treatment within the lifespan, and therefore the therapeutic agents should have minimal side effects, and be cost-effective.

• There are several strategies to decrease the mucosa-derived bleeds, either from nose or gastro-intestinal tract.

• Antifibrinolysis, is a first line of pharmacological treatment when no risks of thromboembolism exist. Its use may be effective for several years.

• The selective modulators of estrogen receptors (SERMs) are therapeutic agents increasing ENG and ALK1, proteins haploinsufficient in HHT. Among them, raloxifene hydrochloride, and bazedoxifene acetate have been considered as orphan drugs.

• Antiangiogenesis is a good strategy to decrease the excessive abnormal vasculature in mucosa. For nose bleeds, topical treatment with beta-blockers could be used for a long term without side effects. To this purpose, propranolol and timolol, should be formulated as gels or sprays.

• For gastrointestinal bleeding, it is necessary systemic treatment. In the case of propranolol, it could be appropriate for hypertensive patients. When blood pressure is normal, propranolol should be administered under the cardiologist supervision.

• New antiangiogenic topical drugs are currently being investigated, and we hope to have available soon, alternative compounds administered by spray for nose bleeds.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This study has been supported by grants from Ministerio de Economia y Competitividad of Spain (SAF2011-23475 and SAF2014-52374-R) to LM Botella; and “Rare diseases networking in biomedical research” (CIBERER). CIBERER is an initiative of the Instituto de Salud Carlos III (ISCIII).