A Phase II clinical trial has revealed that pomalidomide, a drug previously approved for multiple myeloma, significantly reduces bleeding and improves the quality of life for individuals with hereditary hemorrhagic telangiectasia (HHT). The findings, published in The New England Journal of Medicine, offer a potential new treatment for this rare bleeding disorder that currently lacks FDA-approved therapies.
HHT affects approximately 1 in 5,000 people and is characterized by abnormal blood vessel formation, leading to frequent and severe nosebleeds, gastrointestinal bleeding, and potential complications in organs like the lungs, liver, and brain. The PATH-HHT trial (NCT03910244) was designed to evaluate the safety and efficacy of pomalidomide in treating HHT-related bleeding.
PATH-HHT Trial Details
The randomized, placebo-controlled trial enrolled 144 adult participants with moderate to severe nosebleeds. Participants were randomly assigned in a 2:1 ratio to receive either 4 mg of pomalidomide daily (n=95) or a matching placebo (n=49) for 24 weeks. The primary outcome was the change in Epistaxis Severity Score (ESS) from baseline to week 24, while secondary outcomes included HHT-specific quality-of-life scores.
Significant Reduction in Bleeding Severity
Results from the trial indicated a significant reduction in bleeding severity among patients treated with pomalidomide. The mean difference in change from baseline in the Epistaxis Severity Score between the pomalidomide and placebo groups was -0.94 points (95% CI, -1.57 to -0.31; P=0.004). Additionally, the mean difference in HHT-specific quality-of-life score changes between the two groups was -1.4 points (95% CI, -2.6 to -0.3), indicating a clinically meaningful improvement in quality of life.
According to Hanny Al-Samkari, MD, the Peggy S. Blitz Endowed Chair in Hematology/Oncology at Massachusetts General Hospital, the trial demonstrates the clear safety and efficacy of pomalidomide to treat bleeding in HHT, giving these patients a much-needed effective treatment option.
Safety and Tolerability
While pomalidomide was generally well-tolerated, some patients experienced adverse events. The most common side effects reported in the pomalidomide group included neutropenia, constipation, and rash. The pomalidomide regimen was permanently discontinued in 16% of patients, compared to 2% in the placebo group (P=0.01). Dose interruptions occurred in 40% of patients receiving pomalidomide versus 14% in the placebo group (P=0.002), and dose reductions were required in 13% of pomalidomide-treated patients compared to 0% in the placebo group (P=0.009).
Implications for HHT Treatment
The study authors noted that the benefits of pomalidomide were most apparent during the second 12 weeks of the trial and persisted for four weeks after the treatment period ended. These effects were independent of HHT genotype or baseline epistaxis severity.
Keith McCrae, M.D., professor of molecular medicine at the Cleveland Clinic, who led the research team, speculates that pomalidomide works by blocking the growth of abnormal blood vessels, potentially causing them to have a more normal structure or thicker walls, making them less fragile. Further study is needed to fully elucidate the mechanisms of action.
Andrei Kindzelski, M.D., Ph.D., program officer at the National Heart, Lung, and Blood Institute (NHLBI), emphasized the broader implications of these findings, noting that malformed blood vessels in organs such as the lung, liver, and brain can lead to hemorrhagic stroke, bleeding in the lungs, or heart failure in more severe forms of HHT. A treatment like this could be lifesaving for such patients.
Future Research Directions
Additional studies are needed to define the mechanisms of action of pomalidomide in HHT and to determine if the drug could have similar effects in patients with gastrointestinal bleeding or other HHT complications. Despite these uncertainties, the PATH-HHT trial provides evidence of the efficacy and safety of a new agent for the treatment of HHT, potentially leading to improved quality of life for this patient population.
