Pomalidomide Significantly Reduces Bleeding, Improves Quality of Life in Hereditary Hemorrhagic Telangiectasia

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Findings from the Phase II PATH-HHT trial (NCT03910244) show that pomalidomide significantly lowered the Epistaxis Severity Score and improved health-related quality of life in patients with hereditary hemorrhagic telangiectasia (HHT).^1,2

These findings, published by The New England Journal of Medicine, hold promise for patients with HHT, which is the second most common inherited bleeding disorder but does not have any treatments approved by the FDA. The disease impacts approximately one in 3800 individuals, who may have more limited overall survival than the general population, according to the investigators.¹

“HHT-associated bleeding usually worsens over the lifespan of affected patients and results in the need for frequent iron infusions, red-cell transfusions, or both,” the study authors wrote. “Visceral arteriovenous malformations also occur in the lung in approximately 50% of patients with HHT and in the liver in approximately 70% and may also occur in the brain in approximately 20%. These arteriovenous malformations may result in many possible complications including embolic stroke, pulmonary hemorrhage, tissue or brain abscesses, high-output heart failure, hepatic disease, hemorrhagic stroke, and epilepsy. Despite these numerous possible complications, patients distinctly identify bleeding as their most important disease manifestation.”¹

Pomalidomide is a chemotherapy medication that was initially approved by the FDA as an orphan drug in 2013 to treat patients with multiple myeloma, and has since been approved to treat Kaposi sarcoma. A generic version is also available, as the FDA approved the first generic pomalidomide product in 2020.³

The study authors sought to evaluate whether pomalidomide may show efficacy treating HHT with a more favorable safety profile. The randomized, placebo-controlled PATH-HHT trial analyzed the safety and efficacy of pomalidomide in the treatment of HHT.

Investigators randomly assigned patients in a 2:1 ratio, with 95 assigned to the pomalidomide cohort at a dose of 4 mg daily and 49 to assigned receive matching placebo for 24 weeks. The trial’s primary outcome was change in Epistaxis Severity Score from baseline through week 24 in the Epistaxis Severity Score—which ranges from 0 to 10, with higher scores indicating more severe bleeding—and secondary outcomes that included HHT-specific quality-of-life score.

Results showed a baseline mean (±SD) Epistaxis Severity Score of 5.0±1.5, which is consistent with moderate-to-severe epistaxis. After 24 weeks, investigators noted a mean difference in change from baseline in the Epistaxis Severity Score between the pomalidomide cohort and the placebo cohort of −0.94 points (95% confidence interval [CI], −1.57 to −0.31; P=0.004). Further, the mean difference in HHT-specific quality-of-life score changes between both cohorts was −1.4 points (95% CI, −2.6 to −0.3).

“These improvements occurred despite a strong placebo effect that dissipated after discontinuation of the blinded trial regimen,” the study authors wrote. “Additional objective measures, including the incidence of blood transfusion, the quantity of infused iron, levels of hemoglobin and hematocrit, mean corpuscular volume, and mean cellular hemoglobin concentration were all directionally consistent with these outcomes. The benefits of pomalidomide were most apparent over the course of the second 12 weeks of the trial, persisted during the 4 weeks after the end of the treatment period, and were not dependent on HHT genotype or baseline epistaxis severity.”¹

In terms of safety, adverse events more commonly reported by patients administered pomalidomide, which included neutropenia, constipation, and rash. The pomalidomide regimen was permanently discontinued in 16% of patients compared to 2% in the placebo cohort (P=0.01). Dose interruptions occurred in 40% administered pomalidomide compared to 14% (P=0.002) with placebo, and dose reductions occurred in 13% of patients in the pomalidomide cohort compared to 0% (P=0.009) with placebo.

“Although our trial provides evidence of the efficacy and safety of pomalidomide for HHT-related epistaxis, whether similar effects are evident in patients with gastrointestinal bleeding or in patients with pulmonary, liver, or brain arteriovenous malformations is uncertain,” the study authors concluded. “Moreover, defining the mechanisms of action of pomalidomide in HHT will require additional studies. Still, the PATH-HHT trial showed the efficacy of a new agent for the treatment of HHT that may lead to improved quality of life in this population for whom no approved therapies exist.”¹

References

1. Al-Samkari H., et al. Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia.

Published September 18, 2024. N Engl J Med 2024;391:1015-1027. DOI: 10.1056/NEJMoa2312749. Vol. 391 No. 11.

2. Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT). ClinicalTrials.gov. Updated April 25, 2024. Accessed October 4, 2024. https://clinicaltrials.gov/study/NCT03910244

3. Pomalyst FDA approval history. Drugs.com. Updated March 16, 2021. Accessed October 4, 2024. https://www.drugs.com/history/pomalyst.html