BTG Pharmaceuticals Statement on NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Recommendation for Use of Glucarpidase (Voraxaze®) and MTXPK.org

West Conshohocken, PA, June 22, 2023 (GLOBE NEWSWIRE) -- BTG Pharmaceuticals, a SERB company, highlights the recent updates to the National Comprehensive Cancer Network (NCCN) Guidelines for Acute Lymphoblastic Leukemia, B-Cell Lymphomas, Pediatric Acute Lymphoblastic Leukemia, and Pediatric Aggressive Mature B-Cell Lymphomas. ^i-iv

The updated guidelines:

• Describe the currently accepted approach in the event a patient receiving high-dose methotrexate (HDMTX) experiences delayed elimination due to renal impairment.
• Strongly recommend glucarpidase when plasma MTX concentrations are two standard deviations above the mean expected MTX plasma concentration as determined by MTXPK.org, or if the 36-hour plasma MTX level is above 30 μM, 42-hour level is above 10 μM, or 48-hour level is above 5 μM.
• Explain that optimal administration of glucarpidase is within 48 to 60 hours from the start of MTX infusion.
• Include important safety information related to glucarpidase use:
  • Leucovorin should be dosed on pre-glucarpidase plasma MTX concentration and should be continued for at least 2 days following glucarpidase administration. However, since leucovorin is a substrate for glucarpidase, it should not be administered within two 2 hours prior to or following glucarpidase.
  • Measurements of plasma MTX levels after glucarpidase by standard immunoassay methods do not distinguish MTX from its metabolites and may overestimate the true MTX concentration.

“The updated guidelines will help ensure that healthcare professionals understand the current best practice for managing delayed methotrexate elimination due to acute kidney injury, and can identify, and appropriately treat patients at risk of methotrexate toxicity,” said Suzanne Ward, PharmD, MBA, Senior Director of Medical Strategy for BTG Pharmaceuticals. “The updates also bring attention to MTXPK.org, an online tool designed to help clinicians understand the pharmacokinetics of high-dose methotrexate, especially with regard to delayed clearance.”

“The inclusion of MTXPK.org in several NCCN Guidelines is an important milestone for our team after launching this free, open-access tool in 2019. We are pleased to be able to provide a user-friendly tool for clinicians managing patients receiving HDMTX for them to understand whether their patients are eliminating methotrexate as expected,” said Laura Ramsey, PhD, who led the creation of MTXPK.org and is an Associate Professor at Cincinnati Children’s Hospital Medical Center.

High-dose methotrexate, defined as a dose higher than 500 mg/m², is used to treat a range of adult and childhood cancers, including, osteosarcoma, acute lymphoblastic leukemia, and primary central nervous system lymphoma. Acute kidney injury due to high-dose methotrexate is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Voraxaze^® is a carboxypeptidase indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose administered) due to impaired renal function.

About Methotrexate Toxicity

Methotrexate is a potent anticancer agent used in high doses (>500 mg/m²) to treat osteosarcoma, lymphomas, and lymphoblastic leukemia. Because methotrexate is primarily cleared by the kidneys, high doses can impair kidney function and lead to delayed methotrexate elimination. Exposure to elevated concentrations of methotrexate for minutes to hours may lead to acute renal toxicity and other serious systemic adverse reactions. In clinical studies, patients treated with Voraxaze^® experience rapid and sustained reductions in plasma MTX concentrations. ^{v, vi}

About MTXPK.org

MTXPK.org is a free, open-access tool designed to help clinicians understand the pharmacokinetics of high-dose methotrexate, especially with regard to delayed clearance. It uses a pharmacokinetic model for the dose of methotrexate to display the concentration vs time curve for an individual patient overlaid upon the population-predicted curve for that dose. The original model was based on >30,000 methotrexate concentrations in pediatric acute lymphoblastic leukemia patients treated on the Nordic Society of Pediatric Hematology & Oncology trials and required dose, infusion time, height, weight and serum creatinine. This model was validated in adults and children with a variety of doses, infusion times and ancestries.^vii

About BTG Pharmaceuticals

BTG, a SERB company, is dedicated to helping healthcare providers treat patients with critical conditions, focusing on emergency care and rare diseases. For over 30 years we have helped treat complex and life-threatening conditions; supporting clinicians, healthcare systems and governments while offering hope to patients and their families. As a fully integrated company, we have the experience and capabilities to acquire, develop, and manufacture our medicines to the highest standards, and make them available worldwide through our secure supply chain. Learn more at serb.com.

NCCN Warranty Statement:

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

References:

1. National Comprehensive Cancer Network. Acute Lymphoblastic Leukemia (Version 1.2023). Accessed June 5, 2023. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf.
2. National Comprehensive Cancer Network. B-Cell Lymphomas (Version 4.2023). Accessed June 5, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.
3. National Comprehensive Cancer Network. Pediatric Acute Lymphoblastic Leukemia (Version 2.2023). Accessed June 5, 2023. https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf.
4. National Comprehensive Cancer Network. Pediatric Aggressive Mature B-Cell Lymphoma (Version 1.2023). Accessed June 5, 2023. https://www.nccn.org/professionals/physician_gls/pdf/ped_b-cell.pdf.
5. Widemann BC, Balis FM, Kim A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. 2010;28(25):3979-3986.
6. 2013 Annual Meeting of the North American Congress of Clinical Toxicology (NACCT). Clin Toxicol. 2013;51(7):575-724.
7. MTXPK.org: A clinical decision support tool evaluating high‐dose methotrexate pharmacokinetics to inform post‐infusion care and use of glucarpidase. Taylor ZL, Mizuno T, Punt N, Baskaran B, Navarro Sainz A, Shuman W, Felicelli N, Vinks AA, Heldrup J, Ramsey LB. Clin Pharmacol Ther. 2020 Sep;108(3):635-643. doi: 10.1002/cpt.1957. Epub 2020 Jul 18. PMID: 32558929. https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1957.

Voraxaze^® US indication and limitations of use

• Voraxaze^® is a carboxypeptidase indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function
• Limitations of Use: Voraxaze^® is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate

Important safety information
Warnings and precautions

Serious Hypersensitivity Reactions

• Serious hypersensitivity reactions, including anaphylactic reactions, may occur. Serious hypersensitivity reactions occurred in less than 1% of patients

Monitoring Methotrexate Concentration/Interference with Assay

• Methotrexate concentrations within 48 hours following Voraxaze^® administration can only be reliably measured by a chromatographic method due to interference from metabolites. Measurement of methotrexate concentrations within 48 hours of Voraxaze^® administration using immunoassays results in an overestimation of the methotrexate concentration

Adverse reactions

• In clinical trials, the most common related adverse events (occurring in >1% of patients) were paresthesia, flushing, nausea and/or vomiting, hypotension and headache

Drug interactions

• Voraxaze^® can decrease leucovorin concentration, which may decrease the effect of leucovorin rescue unless leucovorin is dosed as recommended, and may also reduce the concentrations other folate analogs or folate analog metabolic inhibitors

Please see full Prescribing Information.

Chris Sampson SERB Pharmaceuticals +44 7773 251 178 chris.sampson@serb.com