ARFOLITIXORIN

The drug candidate that can boost the effect of chemotherapy

Isofol’s folate-based drug candidate arfolitixorin ([6R]-MTHF) has the potential to be established as a key component in today’s standard treatment of several forms of solid tumors. A clinical study in patients with colorectal cancer is now being conducted as a first step. To optimize the efficay of the first-line treatment, 5-FU-based chemotherapy, it is administered together with folate-based drugs that, after degradation in the body, are converted to the active metabolite [6R]-MTHF. This active metabolite increases the tumor cell-killing effect of 5-FU and simultaneously reduces the production of one of the building blocks that tumor cells need to multiply. The body’s conversion of currently available folate-based drugs to the active metabolite is a multi-step process. Treating patients with the metabolite in its pure form, eliminating the need for conversion, could therefore bring significant benefits.

Isofol’s patented drug candidate arfolitixorin, composed of the active metabolite [6R]-MTHF, is the world’s first and only direct-acting folate-based drug candidate.
In a comparative clinical study in the early development phase (ISO-CC-002), Isofol has statistically verified that patients with colorectal cancer showed at least three to four times higher levels of [6R]-MTHF in the tumor when treated with arfolitixorin compared to current folate-based treatments. When arfolitixorin was administered together with 5-FU in the treatment of colorectal cancer, the tumor-killing effect was enhanced and more cancer cells died.

The Evidence Platform support continued development

Phase III study AGENT

Arfolitixorin has previously been evaluated in the randomized, controlled global, multicenter phase III study AGENT, which compared the efficacy and safety of arfolitixorin with the current folate-based drug leucovorin. Both substances were used in combination with 5-FU, oxaliplatin and bevacizumab in patients with metastatic colorectal cancer in first-line treatment. The study, which was initiated in 2018, was the first in approximately 20 years to evaluate a meaningful alternative to today’s standard treatment for the vast majority of patients with metastatic colorectal cancer and included around 90 clinics in the US, Canada, Europe, Australia and Japan and a total of nearly 490 patients. In August 2022, top-line results from the AGENT study were presented, showing that arfolitixorin was not statistically significantly superior to the control arm, and the study was subsequently halted.

Conclusions from the AGENT study

When data from the AGENT study were analyzed, it was found that:
• The selected dose and administration regimen consisting of two 60 mg bolus likely resulted in a blood concentration of arfolitixorin that was too low to deliver a sufficiently high amount of active substance into the tumor.
• The selected dose was lower than that used in the standard treatment control group, which compromised the validity of the comparison between the groups.
• The dose of arfolitixorin was administered late in relation to 5-FU. An earlier dose would likely maximize the potential for arfolitixorin to act synergistically with 5-FU and thereby provide greater efficacy.
Furthermore, in 2024, an external expert group conducted a post hoc, per-protocol analysis of the AGENT study, commissioned by Isofol. It was noted that compliance with the study protocol was low, mainly with regard to the time interval between the administration of 5-FU bolus and arfolitixorin and the duration of the 5-FU injections, which may have affected the outcome.
Results from the analysis, where the expert committee excluded patients who were not treated according to the study protocol, show that arfolitixorin, even with the suboptimal dose regimen used in the AGENT study, provided better efficacy than standard treatment in most of the study regions ¹. In addition, pharmacokinetic modeling and a review of available safety data showed that it is likely feasible to administer arfolitixorin at a higher dose than in the AGENT study and that a different dose and administration regimen could probably improve the efficacy of the drug candidate.

Positive assessment of the data collected

To summarize the conclusions in the extensive data package available for arfolitixorin, the following can be mentioned:
• Arfolitixorin has already shown efficacy at a level comparable to the control group in the extensive global phase III AGENT study.
• The dose-response relationship shown in previous preclinical studies indicates that higher doses may lead to better efficacy based on. Furthermore, an adjustment of the dosing time should be able to further optimize the efficacy as it increases the possibilities for synergistic effects between arfolitixorin and 5-FU.
• According to PK simulations and safety data from previously conducted clinical studies, higher doses can probably be administered without affecting the safety profile.
Based on these conclusions, a new study program is now being conducted where a new dosage regimen is tested and protocol compliance is optimized. The design of the new program is based on the large data package generated so far, which constitutes a strong evidence platform that strengthens Isofol’s confidence in being able to show positive results.

New clinical study in 2025

To demonstrate the clinical potential of arfolitixorin, Isofol will conduct a new phase Ib/II study, with the aim of determining the optimal dosage regimen with regard to tolerability and efficacy. The study design was approved in March 2025 and will include patients with advanced (metastatic) colorectal cancer and will initially be conducted in collaboration with the leading academic hospital Charité – Universitätsmedizin Berlin, Germany.
In parallel with the first part of the study being conducted at Charité, Isofol and its license partner Solasia will carry out joint preparations for the second part of the study with the goal of recruiting patients in Japan in 2026. The inclusion of Japanese patients not only expands the study with additional participants but also enhances the diversity of the patient population, creating a stable foundation for subsequent regulatory processes in Japan and other geographic markets.

Source: 1) Poster ASCO-GI 2025; Titel “The importance of treatment handling and compliance on overall response rate in a phase III study of metastatic colorectal cancer: Post-hoc per protocol analyses of the AGENT trial”. Author; Pivodic et al, 2025

Last updated 04-15-2025