Modufolin (arfolitixorin) / Isofol Medical, Solasia - LARVOL DELTA

A Clinical Study of Arfolitixorin in Patients With mCRC (clinicaltrials.gov) - P1/2 | N=90 | Recruiting | Sponsor: Isofol Medical AB | Trial completion date: Mar 2029 ➔ Dec 2029 | Trial primary completion date: Mar 2028 ➔ Nov 2028 | N=60 ➔ 90

Enrollment change • Trial completion date • Trial primary completion date • Colorectal Cancer • Oncology • Solid Tumor • BRAF

A Clinical Study of Arfolitixorin in Patients With mCRC (clinicaltrials.gov) - P1/2 | N=60 | Recruiting | Sponsor: Isofol Medical AB | N=90 ➔ 60

Enrollment change • Colorectal Cancer • Oncology • Solid Tumor

Phase 1b/2 study of arfolitixorin in combination with 5-fluorouracil (5FU), oxaliplatin, and bevacizumab as first-line therapy for metastatic colorectal cancer (mCRC) (AACR 2026) - P1/2, P3 | "Background: Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is a direct-acting folate in development that may enhance treatment outcomes in patients with mCRC by bypassing the multi-step metabolic activation required by leucovorin (LV), the most commonly used folate agent. Further details will be made available following finalization of protocol updates. Patient enrolment is ongoing as of December 2025."

Clinical • Combination therapy • Metastases • P1/2 data • Colorectal Cancer • Oncology • Solid Tumor

A Phase 1b/2 study of arfolitixorin as part of 5-fluorouracil-based treatment regimens in the first-line treatment of metastatic colorectal cancer (clinicaltrials.gov) - P1/2 | N=90 | Recruiting | Sponsor: Isofol Medical AB | N=60 ➔ 90

Enrollment change • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Phase 1b/2 study of arfolitixorin in combination with 5-fluorouracil (5FU), oxaliplatin, and bevacizumab as first-line therapy for metastatic colorectal cancer (mCRC). (ASCO-GI 2026) - P1/2, P3 | "Background: Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is a direct-acting folate in development that may enhance treatment outcomes in patients with mCRC by bypassing the multi-step metabolic activation required by leucovorin (LV), the most commonly used folate agent. Sebastian Stintzing et al. at the ESMO Congress 2025 (Final Publication Number: 908eTiP) and is reused here with permission."

Clinical • Combination therapy • Metastases • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Deoxyuridine as a surrogate marker of thymidylate synthase inhibition contributes to a multivariable model predicting 5-FU/LV response in metastatic colorectal cancer. (PubMed, Cancer Treat Res Commun) - "The method used enables simultaneous analysis of multiple compounds within a tumor homogenate. Measuring dUr in homogenates before and after folate modulation, prior to initiation of FLV-based chemotherapy, could help predict tumor response and guide the choice between LV and ARF for optimal folate support."

Journal • Colorectal Cancer • Oncology • Solid Tumor • TYMS

Phase Ib/II study of arfolitixorin in combination with 5-fluorouracil (5FU), oxaliplatin, and bevacizumab as first-line therapy for metastatic colorectal cancer (mCRC) (ESMO 2025) - P3 | "Background Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is a direct-acting folate in development that may enhance treatment outcomes in patients with mCRC by bypassing the multi-step metabolic activation required by leucovorin (LV), the most commonly used folate agent. Legal entity responsible for the study Isofol Medical AB. Funding Isofol Medical AB."

Clinical • Combination therapy • Metastases • P1/2 data • Colorectal Cancer • Oncology • Solid Tumor

Cytotoxicity of arfolitixorin versus leucovorin (LEU) with 5-fluorouracil (5FU) and oxaliplatin in colorectal cancer (CRC) patient-derived tumoroids (PDTs) (ESMO-GI 2025) - P3 | "In a phase 3 study with bevacizumab (NCT03750786), ARFOX (arfolitixorin, 5FU, oxaliplatin) was unexpectedly comparable, not superior, to standard mFOLFOX6 (LEU, 5FU, oxaliplatin) in patients with advanced metastatic CRC (mCRC). Arfolitixorin showed potent, concentration-dependent cytotoxic effects, synergistic and additive, that increased 5FU-oxaliplatin activity in PDTs more than LEU. These findings have supported a new phase 1b/2 clinical trial in mCRC, ultimately aiming to improve the standard of care for patients."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • CD133 • PROM1

A Multi-Modal Graph Neural Network Framework for Parkinson's Disease Therapeutic Discovery. (PubMed, Int J Mol Sci) - "Among the top hits were compounds such as dithiazanine, ceftolozane, DL-α-tocopherol, bromisoval, imidurea, medronic acid, and modufolin. These findings provide mechanistic insights into PD pathology and demonstrate that a polypharmacology approach can reveal repurposing opportunities for existing drugs. Our results highlight the potential of network-based deep learning frameworks to accelerate the discovery of multi-target therapies for PD and other multifactorial neurodegenerative diseases."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

Isofol includes first patient in a clinical phase Ib/II study of arfolitixorin (Isofol Medical Press Release) - "Isofol Medical AB...announces that the first patient has been included in the clinical phase Ib/II study of the drug candidate arfolitixorin as a new potential treatment of metastatic colorectal cancer....The study will be conducted in two stages, where the initial phase Ib part will assess the benefit/risk profile of escalating doses in a new dosing regimen that is expected to increase the efficacy further as compared to previously conducted trials."

Trial status • Colorectal Cancer

A Clinical Study of Arfolitixorin in Patients With mCRC (clinicaltrials.gov) - P1/2 | N=60 | Recruiting | Sponsor: Isofol Medical AB | Not yet recruiting ➔ Recruiting

Enrollment open • Colorectal Cancer • Oncology • Solid Tumor

A Clinical Study of Arfolitixorin in Patients With mCRC (clinicaltrials.gov) - P1/2 | N=60 | Not yet recruiting | Sponsor: Isofol Medical AB

New P1/2 trial • Colorectal Cancer • Oncology • Solid Tumor

Isofol announces the presentation of a post-hoc analysis of the phase III study AGENT at the 2025 ASCO GI symposium (Isofol Medical Press Release) - P3 | N=490 | AGENT (NCT03750786) | Sponsor: Isofol Medical AB | "Results from the analysis, in which the expert committee excluded patients who were not treated in compliance with the study protocol, show a numerical difference in objective response rate (ORR) in favor of arfolitixorin based on a remaining group of 225 patients...The study further pointed out regional differences. In North America, the incremental efficacy of arfolitixorin was significant (arfolitixorin: 85.7% ORR; leucovorin: 45.5% ORR; p<0.017; based on 47 patients). Notably, in all regions excluding Japan, arfolitixorin showed a 15.9 percentage points statistically significant higher response rate compared to leucovorin (arfolitixorin: 62.1% ORR; leucovorin: 46.2% ORR; p<0.026; based on 172 patients)."

P3 data • Colorectal Cancer

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. (ASCO-GI 2025) - P3 | " In a randomized, multicenter, multinational, phase III study, patients were randomized to receive either arfolitixorin (n=245) or leucovorin (n=245) with 5-fluorouracil (5-FU), oxaliplatin and bevacizumab as a first-line treatment. In the AGENT trial, 46% of the included patients met per protocol compliance for treatment handling. In this cPP population, there was a non-significant, but clinically relevant, increase in the overall response rate in the arfolitixorin compared to the leucovorin arm. Notably, in all regions excluding Japan, the overall response rate was higher for arfolitixorin, with statistical significance."

Clinical • Compliance • Metastases • P3 data • Retrospective data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Isofol and its partner Solasia plan to expand the upcoming clinical trial of arfolitixorin to Japan (Isofol Medical Press Release) - "Isofol Medical AB...today announces that its partner Solasia Pharma K.K. (Solasia) has made a directional decision to include Japanese patients in the phase II part of the upcoming phase Ib/II trial of arfolitixorin in metastatic colorectal cancer...Isofol and its Japanese license partner Solasia are strongly committed to developing arfolitixorin as a new potential treatment for colorectal cancer. Isofol has submitted a clinical trial application, CTA, to the German regulatory agency, BfArM, for an upcoming clinical phase Ib/II trial and is expected to initiate the first part of the trial in the first half of 2025....Alongside the initiation of the first part of the clinical trial (phase Ib), which is conducted at Charité – Universitätsmedizin Berlin in Europe, Isofol and Solasia have agreed to engage in joint preparations for the second part of the study (phase II). The aim is to enroll patients in Japan in 2026."

New P1/2 trial • Colorectal Cancer

Isofol provides an operational update during investor meeting (Isofol Medical Press Release) - "Isofol Medical AB...will provide an operational update during today’s investor meeting. The company will present its evidence platform that forms the basis for the upcoming clinical study with drug candidate arfolitixorin, the intended study design for the phase Ib/II study, as well an update on the commercial potential of arfolitixorin...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....The design and preliminary endpoints will be presented at the investor meeting."

Clinical protocol • New P1/2 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Isofol announces that an investigator-initiated study of arfolitixorin has been published in BJC Reports (Isofol Medical Press Release) - P1/2 | N=30 | Modelle 001 (NCT04126655) | "Isofol Medical...announces that the investigator-initiated Modelle study, evaluating the effect of the drug candidate arfolitixorin at tissue level, has been published in the scientific journal BJC Reports...Modelle is an investigator-initiated study conducted at Sahlgrenska University Hospital in collaboration with Norrlands University Hospital and co-financed by Isofol...The study evaluated different doses of arfolitixorin and its ability to enhance the tumor-inhibiting effect of 5-FU-based chemotherapy. The effect was measured as inhibition of thymidylate synthase (TS), an enzyme that drives tumor cell growth and is thus an important target in cancer treatment....The results showed that giving arfolitixorin resulted in significantly higher concentrations of the active substance in liver metastatic tissue compared to the given dose of the standard of care treatment leucovorin. Further, an increased inhibition of TS was shown..."

P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Increased potentiation of 5-fluorouracil induced thymidylate synthase inhibition by 5,10-methylenetetrahydrofolate (arfolitixorin) compared to leucovorin in patients with colorectal liver metastases; The Modelle-001 Trial. (PubMed, BJC Rep) - "The Modelle-001 Trial demonstrated significantly higher levels of MeTHF in metastases following Arfo compared to LV. This resulted in a greater increase TS inhibition in metastases although not statistically significant."

Journal • Colorectal Cancer • Oncology • Solid Tumor • TYMS

Isofol announces that an abstract has been accepted for presentation at ASCO GI 2025 (Isofol Medical Press Release) - "Isofol Medical AB...announces that an abstract with results from a post hoc-analysis of the company’s Phase III-study AGENT has been accepted by ASCO GI, which takes place in San Francisco, US, between January 23-25th, 2025....The results show the importance of adherence to the study protocol and that a higher protocol compliance would likely increase the efficacy of arfolitixorin and thus, as previously communicated, support the company’s new development plan."

Retrospective data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Late Breaking Abstract concerning arfolitixorin will be presented at ENA 2024 today (Isofol Medical Press Release) - "The poster describes a dose-dependent cytotoxic effect and increased activity of arfolitixorin at higher doses in combination with 5-FU...The studies evaluated the effect of arfolitixorin and leucovorin in combination with 5-FU based chemotherapy in patient-derived colorectal cancer tumoroids. The results show that arfolitixorin displays a potent, dose-dependent cytotoxic effect and increased activity in 5-FU-treated tumoroids that, at higher doses, is higher than with today’s standard treatment leucovorin. The effect was most marked in the tumoroids that were most resistant to 5-FU....'The conclusions from the preclinical studies support our hypothesis of a suboptimal arfolitixorin dose regime in the phase III clinical trial AGENT. This contributed to not achieving a sufficiently high efficacy to establish superiority to leucovorin in the ITT population.'"

Preclinical • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Dose-dependent cytotoxicity of arfolitixorin, a direct-acting folate, versus leucovorin with 5-fluorouracil in patient-derived colorectal cancer tumoroids (PDTs) (EORTC-NCI-AACR 2024) - P3 | "In the Phase 3 study ISO-CC-007 (NCT03750786), ARF showed efficacy comparable to LEU, however, the primary endpoint of demonstrating superiority was not achieved, possibly due to the dose being suboptimal for a cellular response.Material and methods The activity of 5FU, LEU, levoleucovorin (LLEU), ARF, and combinations thereof, were assessed in a panel of two CRC cell lines and 20 PDTs. These findings support that suboptimal dosage in the ISO-CC-007 trial contributed to insufficient efficacy. Further clinical development at higher doses could enhance the standard of care for patients, and a Phase 1/2 clinical trial based on this approach is currently being planned."

Clinical • Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Isofol announces that a Late Breaking Abstract has been accepted by ENA 2024 (Isofol Medical Press Release) - "Posters qualified for Late Breaking Abstracts at ENA are, according to the congress guidelines, those that describe the latest advances that will change daily clinical practice....The abstract was produced in cooperation with Oncosyne AS and Akershus University Hospital in Oslo, Norway, and is based on the preclinical studies that were conducted earlier this year, whose conclusions support the company’s clinical development plan."

Late-breaking abstract • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Isofol strengthens the outlook for further extending the patent protection of its drug candidate arfolitixorin (Isofol Medical Press Release) - "Isofol Medical AB...announces positive outcomes of a preliminary patentability report on a new international product patent application for arfolitixorin, submitted under the PCT (Patent Cooperation Treaty). If granted, the patent could significantly strengthen and prolong arfolitixorin’s intellectual property protection internationally...The application, which has been filed under the Patent Cooperation Treaty, covers pharmaceutical compositions comprising arfolitixorin in the form of stable lyophilizates for use in clinical settings....The ensuing patents will have an expected expiry in the mid- 2040s, and span across Isofol’s key markets, including but not limited to the United States, Europe and Japan. Given its scope, potential geographic coverage and long duration, this patent is deemed to be of high importance for Isofol and its partners."

Patent • Patent expiry • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

ISOFOL ANNOUNCES NEW PRECLINICAL DATA SUPPORTING THE PREVIOUSLY COMMUNICATED CLINICAL DEVELOPMENT PLAN FOR ARFOLITIXORIN (Isofol Medical Press Release) - "Isofol Medical AB...today announces results from two preclinical studies that support the dose-response relationship for arfolitixorin. These positive data further strengthen the hypothesis behind the design of the clinical Phase Ib/II study in patients with colorectal cancer that Isofol plans to conduct in collaboration with one of Europe’s leading university hospitals, Charité – Universitätsmedizin Berlin...The preclinical studies were conducted by Oncosyne AS in collaboration with Akershus University Hospital in Oslo, and at the Surgical Oncology Laboratory (SOL) at Sahlgrenska University Hospital in Gothenburg, respectively. Both studies show that increased doses of arfolitixorin in combination with 5-FU lead to significantly higher efficacy. The studies also investigated the addition of PLP (the active form of vitamin B6) and with the analysis methods applied, neither found any additive efficacy in combination with arfolitixorin."

Clinical protocol • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

ISOFOL ANNOUNCES A POST HOC PER-PROTOCOL ANALYSIS OF THE AGENT STUDY, FURTHER SUPPORTING ARFOLITIXORIN’S CONTINUED CLINICAL DEVELOPMENT (Isofol Medical Press Release) - P3 | N=490 | AGENT (NCT03750786) | Sponsor: Isofol Medical AB | "Isofol Medical AB...announced today that an external committee of experts has performed a post hoc per-protocol analysis of the clinical phase III study AGENT that shows new results in favor of arfolitixorin...Results from the analysis, in which the expert committee excluded patients who were not treated in compliance with the study protocol, show a numerical difference in objective response rate (ORR) in favor of arfolitixorin (arfolitixorin: 59.3 % ORR; leucovorin: 51.5 % ORR; p<0.23). Thus, the study shows a non-significant difference between the arms in favor of arfolitixorin of 7.8 percentage points based on a remaining group of 225 patients....The conclusions from the per-protocol post hoc analysis will support the design of the phase Ib/II study that is expected to be initiated before the end of 2024 and the upcoming dialogues with relevant authorities."

Clinical protocol • New P1/2 trial • P3 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor