Glucarpidase (Voraxaze, SERB Pharmaceuticals) significantly improves kidney recovery in patients experiencing nephrotoxicity caused by methotrexate, according to a new study from researchers at Brigham and Women’s Hospital (BWH) analyzing data from more than 700 patients across 28 U.S. cancer centers.
Glucarpidase has been approved by the FDA for the treatment of methotrexate-induced toxicity since 2012, but that approval was based on its known biochemical effects—converting methotrexate into inactive metabolites within 15 minutes of administration—rather than any trial of its clinical efficacy. Due to this evidence gap, there has been widespread variation in glucarpidase regimens used in this setting.
“Glucarpidase is one of the very few potential antidotes available to counteract the high rates of toxicity caused by chemotherapy,” said first author Shruti Gupta, MD, an assistant professor of medicine at Harvard Medical School and the director of onconephrology at BWH and Dana-Farber Cancer Institute, in Boston. “While there have been some clinical studies of glucarpidase, most have been small, observational studies without a control group. Ours is the first comprehensive study to both include a control group and rigorously adjust for confounders.”
The researchers used detailed data from multiple cancer centers to mimic the conditions of a randomized clinical trial. Known as target trial emulation, this approach can estimate the outcomes of a full clinical trial without the attendant costs and extended time, especially for relatively rare events in a specific patient population.
“We worked with dozens of our collaborators across 28 sites to extract granular data from medical records—all by manual chart review—which allowed us to account for key variables in our models. This allowed us to have a high degree of confidence in our findings,” said senior author David E. Leaf, MD, an associate professor of medicine at Harvard Medical School and the director of clinical and translational research in acute kidney injury (AKI) in BWH’s Division of Renal Medicine.
The investigators collected data between 2000 and 2022 from 708 adult patients with methotrexate-induced AKI, including 209 who received glucarpidase within four days after methotrexate exposure and 499 who did not. They compared kidney recovery for the two groups at the time of hospital discharge, based on changes in serum creatinine levels, dialysis dependence and survival. The researchers also analyzed the speed of kidney recovery as well as the incidence of other adverse events, such as liver toxicity and neutropenia.
Patients receiving glucarpidase had a 2.7-fold increase in the chances of kidney recovery compared with those who did not, as well as faster kidney recovery and a lower risk for severe neutropenia or liver toxicity. The drug also has minimal side effects and no known contraindications. “Any adverse reactions tended to be mild subjective symptoms like flushing, and the rates of those were very low,” Dr. Gupta said. “We are not aware of any contraindications for its use.”
Alternative Antidotes Are Limited
There are few other options for treating methotrexate-induced AKI, Dr. Leaf said. “There are standard-of-care prophylactic options, including urinary alkalinization with IV sodium bicarbonate, but despite that we still see high rates of kidney toxicity as well as toxicity to other organs, like the liver and bone marrow. Glucarpidase is unique in that there really is not another antidote that works to promote kidney recovery in this situation.”
Jessica Cupac, PharmD, a hematology/oncology clinical pharmacist at the University of Kentucky Markey Cancer Center, in Lexington, said the new study data will be a big help. “We have been using a glucarpidase protocol for years based on toxicity levels, time from methotrexate administration and evidence of renal dysfunction, and have seen its benefits,” Dr. Cupac said. “But to see the overall clinical benefits confirmed in a published study such as this one is very important; it supports our use of this high-cost medication.”
The study results “won’t change our practice,” she added, “but I do think it could result in more widespread use in other institutions, particularly in community hospitals where it might have been more of a challenge to document that the benefits outweigh the costs in specific situations.”
FDA approval of a drug such as glucarpidase “is only the first step; if people aren’t using the drug, then patients aren’t benefiting from it,” Dr. Leaf agreed. “Our findings offer clinicians evidence-based data supporting glucarpidase.”
The study was funded by BTG International Inc., a SERB Pharmaceuticals Company. Dr. Gupta reported that he was a scientific coordinator for the ASCEND trial (GSK); served as a consultant to Alexion, Proletariat Therapeutics and Secretome; and received research support from AstraZeneca, BTG International Inc., Dana-Farber Cancer Institute’s Wong Foundation, Janssen, and the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (K23DK125672). Dr. Leaf reported receiving research support from BioPorto, BTG International Inc. and Metro International Biotech LLC, and served as a consultant to CardioRenal Systems Inc., Casma Therapeutics, Entrada Therapeutics, MexBrain and Sidereal Therapeutics.
This article is from the March 2025 print issue.