SUMMARY: Hereditary Hemorrhagic Telangiectasia (HHT) is an Autosomal Dominant inherited disorder caused by mutations in regulators of angiogenesis. Also known as Osler-Weber-Rendu syndrome, HHT is the second most common inherited bleeding disorder after Von Willebrand Disease, with an estimated prevalence of 1 in 5000. HHT presents with a triad of recurrent epistaxis with iron deficiency anemia, mucocutaneous telangiectasias, and visceral arteriovenous malformations (AVMs) and in more severe cases, patients may experience life-threatening hemorrhage, stroke, or high-output heart failure, requiring hospitalizations, with a negative impact on Quality of Life (QOL). HHT is caused by disruptions in angiogenesis signaling, resulting in impaired vascular development. Three genes in the Transforming Growth Factor-beta (TGF-β) signaling pathway have been implicated and they include Endoglin (ENG), activin A receptor ligand type I (ACVRL1 or ALK-1), and SMAD family member 4 (MADH4 or SMAD4).
Small non-randomized studies suggested that systemic antiangiogenic agent Bevacizumab or immunomodulatory drugs with antiangiogenic properties such as Thalidomide, Lenalidomide, and Pomalidomide may be effective in treating HHT. There are presently no FDA approved therapies for HHT.
PATH-HHT is a randomized, placebo-controlled, multicenter clinical trial, conducted in the US to determine the safety and efficacy of Pomalidomide, for bleeding in HHT. In this study, 144 patients (N=144) diagnosed with HHT were randomly assigned in a 2:1 ratio to receive either Pomalidomide 4 mg orally daily or a matching placebo, for a duration of six months. Pomalidomide, instead of another immunomodulatory drug, was chosen due to its favorable safety profile. Eligibility criteria included a confirmed HHT diagnosis per Curaçao Diagnostic Criteria, documented anemia, and an Epistaxis Severity Score (ESS) of 3 or more over the prior 3 months. Epistaxis Severity Score (ESS) was developed to self- describe epistaxis severity from 0-10, with 10 representing the most severe epistaxis. Mild is ESS of 1-4, moderate is ESS of 4-7 and Severe is ESS of 7-10. The mean age was 59 years and 48% were female. Among the 134 patients who agreed to genetic testing, ENG mutations were detected in 37%, ACVRL1 in 51%, and SMAD4 in 1%. Patients had a mean ESS of 5 at baseline, and mean daily epistaxis duration of 16 minutes. In the preceding 6 months, 84% of patients had required iron infusions and 19% required blood transfusions. More than a third of the patients also had GI bleeding, and 40% had pulmonary AVMs. The Primary endpoint of the study was the change in Epistaxis Severity Score (ESS), from baseline to the end of the six-month treatment period. Secondary endpoints included changes in the average daily self-reported duration of epistaxis from the 4 weeks preceding the baseline visit to weeks 20-24 of treatment, the amount of parenteral iron infused or blood transfused, and change in Quality-of-Life (QOL) measurements, including an HHT-specific QOL score.
The results of this study showed that treatment with Pomalidomide led to a significant reduction in epistaxis severity compared to placebo. The mean ESS decreased by -1.84 in the Pomalidomide group versus -0.89 in the placebo group at 24 weeks (P=0.003). This benefit was seen as early as week 12. Additionally, patients treated with Pomalidomide reported greater improvements in Quality of Life (QOL) related to HHT. The HHT-specific QOL score (ranges from 0-16 with higher scores indicating more limitations) also decreased more in the Pomalidomide group versus the placebo group at 24 weeks (P=0.015). Adverse events were more common in the Pomalidomide group and included mild to moderate neutropenia (45% versus 10%), constipation/diarrhea (60% versus 37%), and rash (36% versus 10%).
It was concluded from this largest HHT study that treatment with Pomalidomide demonstrated a significant and highly clinically relevant reduction in epistaxis, as well as an improvement in the HHT-specific QOL score. Pomalidomide holds promise as a therapeutic option for patients with HHT, addressing an unmet medical need, in managing this challenging genetic disorder. Additional studies may identify biomarkers predicting responses to Pomalidomide.
PATH-HHT, a Double-Blind, Randomized, Placebo-Controlled Trial in Hereditary Hemorrhagic Telangiectasia Demonstrates That Pomalidomide Reduces Epistaxis and Improves Quality of Life. Al-Samkari H, Kasthuri RS, Iyer V, et al. Blood (2023) 142 (Supplement 2): LBA-3. https://doi.org/10.1182/blood-2023-191983.
