CLINICAL DEVELOPMENT PLAN

Isofol has carried out a comprehensive analysis of the available data for arfolitixorin, both from the AGENT study and from other clinical and preclinical studies. Based on current knowledge, the company deems it possible to further improve the efficacy of the drug candidate by using an optimized dosage regimen. The company has therefore decided to carry out a clinical Phase I/II study of arfolitixorin in combination with 5-FU-based cytostatic therapies in treatment-naive mCRC patients. The study aims to generate efficacy and safety data ahead of the continued development and commercialization of the product. 

Regulatory approval to initiate clinical study

In March 2025 the company receives approval from the regulatory authority in Germany, BfArM, to initiate the new clinical trial of the company’s drug candidate arfolitixorin. The study will evaluate the safety and efficacy of a new dosing regimen of arfolitixorin. The main changes compared to the previously phase III study, AGENT, are that arfolitixorin will be given at higher doses and at earlier timepoints relative to the other medicines – adjustments that are expected to lead to higher efficacy as they improve the conditions for arfolitixorin to act synergistically with 5-FU. The study will be conducted in two stages, where the initial phase Ib part will assess the benefit/risk profile of escalating doses. The second part of the trial compares, in line with FDA guidance, the highest dose from phase Ib with one of the lower doses, with efficacy parameters as primary endpoints.

Conclusions from the in-depth analyses

In 2023 and early 2024, Isofol carried out in-depth analyses of the available clinical data and the comprehensive scientific knowledge base for the drug candidate arfolitixorin. The goal was to identify the possible reasons why arfolitixorin did not demonstrate any statistically significant improvement in efficacy compared with the current standard treatment in the AGENT study. As a part of the evaluation, the company – together with external experts – carried out pharmacokinetic simulations to describe the drug’s conversion and metabolism in the body.

The evidence platform gathers the extensive arfolitixorin dataset generated in pre-clinical and clinical studies, and the conclusions can be summarized as follows:

• Arfolitixorin has already shown efficacy in an extensive phase III study
• Higher doses with a new administration regimen are expected to lead to better efficacy
• Higher doses can most likely be given without affecting the safety profile

These conclusions were crucial when we designed the upcoming clinical study with the goal of demonstrating the full potential of arfolitixorin. Briefly put, we will administer arfolitixorin at higher doses and at different injection times, and with the investigational drugs administered in accordance with the protocol. This will enable us to optimize the dose-response relationship and maximize arfolitixorin’s potential to interact with 5-FU so that synergistic efficacy can be achieved.

A pharmacokinetic models and a review of the available safety data also indicated that it is likely possible to administer arfolitixorin at a significantly higher dose than the one evaluated in the AGENT study. The results from a post hoc analysis of the AGENT study and two new preclinical studies of arfolitixorin, which were announced in July 2024, provide additional support for the continued clinical development of the drug candidate. The post hoc analysis indicated that arfolitixorin’s efficacy could have been higher, in some cases statistically significantly higher, than the comparator arm if study protocol compliance had been higher. The preclinical studies, in turn, are based on arfolitixorin’s dose-response relationship and indicated that higher doses of arfolitixorin led to better efficacy.

New on-going clinical study

Based on current knowledge, the company deems it possible to further improve the efficacy of the drug candidate by using an optimized dosage regimen. Isofol therefore plans to carry out a clinical Phase Ib/II study of arfolitixorin as a first-line treatment in combination with 5-FU-based cytostatic therapies in treatment-naive mCRC patients. The study aims to generate efficacy and safety data ahead of the continued clinical development. To achieve an indication of improved efficacy compared with the current standard treatment (5-FU-based cytostatic therapies with leucovorin), comparable analyses will be made against historical controls data.

The study is carried out as a clinical Phase Ib/II study, where the introductory Phase Ib portion will evaluate escalating doses. The highest tolerated dose will then be compared with a lower dose and further evaluated in the following Phase II portion of the study, with a focus on evaluating efficacy. Interim analyses will be carried out in the Phase II portion in order to wind down the arm that potentially demonstrates inferior efficacy and/or toxicity.

In April 2025 the first patient was included and dosed with arfolitixorin. The study is being conducted at Charité – Universitätsmedizin Berlin – one of the world’s top-ranked hospitals.

Last updated 04-28-2025