FDA Grants Fast Track Status to Arfolitixorin for Metastatic Colorectal Cancer

The FDA has granted a fast track designation to arfolitixorin as a potential therapeutic option for patients with metastatic colorectal cancer.

The FDA has granted a fast track designation to arfolitixorin as a potential therapeutic option for patients with metastatic colorectal cancer (mCRC), according to an announcement from Isofol Medical AB.1

Arfolitixorin is comprised of [6R]-MTHF, which is the active substance in the folate-based prodrug leucovorin. The agent does not require multistep metabolic activation and could produce higher, and less inter- and intraindividually variable, concentrations of [6R]-5, 10-methylene-THF (MTHF) vs leucovorin.2

In the phase 3 AGENT trial (NCT03750786), the safety and efficacy of arfolitixorin, [6R]-MTHF acid is being compared with that of leucovorin, both in combination with 5-fluorouracil (5-FU), oxaliplatin, and bevacizumab (Avastin), in the frontline treatment of patients with mCRC.3,4

“We are thrilled that the FDA has granted fast track designation to our lead candidate arfolitixorin. This serves as a strong external validation of arfolitixorin’s potential to benefit patients with this devastating disease,” Ulf Jungnelius, chief executive officer of Isofol Medical AB, stated in a press release. “Our next clinical milestone is reaching 300 progression-free survival [PFS] events in the phase 3 AGENT study which means that data can be deblended so that we can analyze and present top-line results in the first half of 2022.”

The multicenter, parallel-group, phase 3 trial enrolled patients with colorectal adenocarcinoma, nonresectable mCRC planned for frontline therapy with 5-FU, oxaliplatin, and bevacizumab. Patients needed to be at least 18 years of age, have at least 1 measurable lesion, a life expectancy of more than 4 months, an ECOG performance status of 0 or 1, a hemoglobin of greater than 100 g/L, an absolute neutrophil count of greater than 1.5 x 109/L, and thrombocytes of higher than 100 x 109/L.

Study participants will be randomized 1:1 to receive either arfolitixorin plus 5-FU, oxaliplatin (ARFOX), and bevacizumab or leucovorin plus 5-FU, oxaliplatin (modified FOLFOX-6), and bevacizumab. Treatment was given until progressive disease.

The primary end point of the trial is overall response rate, and key secondary end points include progression-free survival and duration of response. Other end points include overall survival, quality of life, safety and tolerability, and number of curative metastasis resections. Exploratory end points include pharmacokinetic measurements and level of gene expression of folate relevant genes in tumor cells.

“The fast track designation will enable us to engage more frequently with the FDA to optimally plan for the continued development of arfolitixorin and potentially make it the first novel drug to improve the standard of care in mCRC in over 40 years,” Jungnelius added.


  1. Isofol Medical AB (publ) receives FDA fast track designation for arfolitixorin in advanced colorectal cancer (mCRC). News release. Isofol Medical AB (publ); November 23, 2021. Accessed November 24, 2021. https://prn.to/3nPjKZt
  2. Arfolitixorin – a new drug candidate for colorectal cancer. Isofol Medical AB (publ) website. Accessed November 24, 2021. https://bit.ly/3r8yKn6
  3. A study to compare the efficacy of arfolitixorin versus leucovorin in combination with 5 fluorouracil, oxaliplatin, and bevacizumab in patients with advanced colorectal cancer (AGENT). ClinicalTrials.gov. Updated September 5, 2021. Accessed November 24, 2021. https://clinicaltrials.gov/ct2/show/NCT03750786
  4. Lenz H-J, Gibbs P, Stintzing S, et al. AGENT: an open-label phase III study of arfolitixorin versus leucovorin in modified FOLFOX-6 for first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2020;38(suppl 4):TPS268. doi:10.1200/JCO.2020.38.4_suppl.TPS268