Sirolimus for Nosebleeds in HHT: A Phase II Pilot Study

The most common symptom of the hereditary hemorrhagic telangiectasia (HHT) disease is epistaxis. HHT is characterized by vascular (blood vessel) malformations, of the skin and mucus membranes of the nose (telangiectasia), gastrointestinal track, brain, lung and liver.

HHT is an autosomal dominant disease which is found in approximately 1 in 5000 individuals. Epistaxis affects 90% of adults with HHT, negatively affects quality of life and often causes anemia. Recent topical therapeutics trials have been negative and surgical therapies are invasive and offer only temporary benefit at best. Currently there are no highly-effective or approved systemic therapies for HHT-related epistaxis, but this is an area of active research and development. There is considerable in developing and identifying therapies that target the abnormal biology ad mechanisms in HHT, including antiangiogenic therapies, such as bevacizumab. Bevacizumab, however, is associated with significant toxicity, costly and administered intravenously.

Over the past few years, there has been considerable new evidence of the pathways involved in HHT disease and related potential therapeutic targets, including the mTOR pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K-Akt-mTOR and VEGFR2 pathways in endothelial cells. It was recently reported that the mTOR inhibitor, sirolimus, and the receptor tyrosine-kinase inhibitor, nintedanib, synergistically fully blocked, and also reversed, retinal AVMs, in the BMP9/10- immunoblocked neonatal mouse model of HHT. Subsequent unpublished preliminary data demonstrated that sirolimus was more effective than nintedanib at blocking anemia and bleeding in inducible ALK1 knockout HHT mice, and similarly effective to combined sirolimus-nintedanib. As such, sirolimus may provide therapeutic benefit for HHT patients. Human studies have shown "low-dose" sirolimus to be low risk and effective as a treatment for other vascular anomalies.

There is an urgent need for effective therapies for HHT and the chronic bleeding associated with the disease. Preliminary cellular and animal model data have identified sirolimus as a potential new pathway-based therapy in HHT. In addition, sirolimus is an interesting agent, as it is given orally and is available for repurposing. Data from other vascular malformations syndromes suggest that it can be effective in a "low-dose" range, reducing risk of toxicity, but there is only one published case report of sirolimus use in an HHT patient. This phase II pilot study will provide safety data as the primary outcome, and secondarily, efficacy data, outcome measure data and biological exploratory data, to support the planning of a future randomized and placebo -controlled clinical trial of sirolimus for epistaxis in HHT patients.

Sirolimus has been identified as a potential pathway-based therapy for HHT. Pre-clinical research has suggested that the pathogenesis of HHT is as a result of overactive mTOR and VEGFR2 pathway. Sirolimus has been found to work as an mTOR inhibitor to prevent the effects of overactive mTOR that results in arteriovenous malformations in a HHT. One clinical trial that used sirolimus to treat vascular anomalies, found that sirolimus was well tolerated and acted as an effective and safe treatment for most study participants.