Oral hymecromone decreases hyaluronan in human study participants
Joelle I. Rosser, … , Carlos E. Milla, Paul L. Bollyky
Joelle I. Rosser, … , Carlos E. Milla, Paul L. Bollyky
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e157983. https://doi.org/10.1172/JCI157983.
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Clinical Research and Public Health Inflammation Article has an altmetric score of 32

Oral hymecromone decreases hyaluronan in human study participants

Abstract

BACKGROUND Hyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODS We conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTS Hymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSION After 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATION ClinicalTrials.gov NCT02780752.FUNDING Stanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.

Authors

Joelle I. Rosser, Nadine Nagy, Riya Goel, Gernot Kaber, Sally Demirdjian, Jamie Saxena, Jennifer B. Bollyky, Adam R. Frymoyer, Ana E. Pacheco-Navarro, Elizabeth B. Burgener, Jayakumar Rajadas, Zhe Wang, Olga Arbach, Colleen E. Dunn, Anissa Kalinowski, Carlos E. Milla, Paul L. Bollyky

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Figure 1

CONSORT diagram of study enrollment.

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CONSORT diagram of study enrollment. Open-label, single-center, nonrando...
Open-label, single-center, nonrandomized, dose-response study of hymecromone in healthy adults. Participants were assigned to receive hymecromone at 1200 mg/d, 2400 mg/d, or 3600 mg/d. First, participants were assigned to 1 of 2 study arms: 2400 mg/d or 3600 mg/d; participants were assigned to dose arms in a sequential manner until 6 participants were enrolled in each arm. Second, participants were invited to reenroll to complete either 1 or 2 additional dose arms. The first 6 individuals who volunteered to reenroll for 2 additional doses were first assigned to the high-dose arm opposite of what they received in the first enrollment and then received 1200 mg/d for their third enrollment. Additional individuals who volunteered to reenroll for 1 additional dose were assigned to the 1200 mg/d arm.