FRα: A Clinically Validated Target for Broad Oncology Indications

Folate Receptor alpha (FRα) is a highly promising and clinically validated target protein for cancer therapy. It is known to be overexpressed on the surface of various epithelial tumor cells—specifically in over 90% of ovarian and endometrial cancer patients and approximately 86% of TNBC patients—while exhibiting minimal expression in normal healthy cells. This makes FRα an ideal target for selective cancer treatment.

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Lead Development Program: Idetrexed

Idetrexed is the only small-molecule FRα-targeted inhibitor that selectively accumulates in cancer cells overexpressing FRα. It works by inhibiting Thymidylate Synthase (TS), an essential enzyme for DNA synthesis, thereby blocking cancer cell proliferation.

Compared to other antifolate drugs, Idetrexed has a significantly lower binding affinity to the Reduced Folate Carrier (RFC), which is expressed in normal cells. As a result, it demonstrates superior selectivity for cancer cells with high FRα expression. Once absorbed by cancer cells, Idetrexed inhibits TS, leading to DNA synthesis blockade and inducing cancer cell death—all while sparing healthy cells and minimizing off-target toxicity.

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Mechanism of Action of Idetrexed

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Clinical Development Status and Key Results

Idetrexed successfully completed a Phase 1 clinical trial (CCR3941 Study) in ovarian cancer patients. The study enrolled a total of 109 patients and demonstrated a favorable safety profile. Most adverse events observed during the trial were mild and manageable, with no dose-limiting toxicities (DLTs) reported. Notably, Idetrexed did not exhibit the hematologic toxicity or vision-related side effects commonly associated with other Thymidylate Synthase inhibitors or FRα-targeted antibody-drug conjugates (ADCs), highlighting its superior safety profile.

In terms of efficacy, among platinum-resistant high-grade serous ovarian cancer (HGSOC) patients with moderate to high FRα expression, Idetrexed achieved an Objective Response Rate (ORR) of 36% (9 out of 25 patients). In contrast, the ORR in patients with low or no FRα expression was only 7.7%, clearly demonstrating that Idetrexed’s efficacy is highly dependent on FRα expression levels.

Given that current chemotherapy options for platinum-resistant ovarian cancer typically achieve an ORR of only 10–15%, the results from Idetrexed’s Phase 1 trial suggest it could offer a new and superior treatment option for these patients. Based on these promising findings, Algok Bio is preparing to initiate a Phase 2 clinical trial in the second half of 2025, exploring Idetrexed as a monotherapy for indications including endometrial cancer and TNBC.

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Combination Therapy Strategy: Synergy with Olaparib (IDOL Study)

In addition to its potential as a monotherapy, Idetrexed has demonstrated strong synergistic effects when combined with other anti-cancer agents. Preclinical studies have shown that combining Idetrexed with Olaparib, a PARP inhibitor, enhances anti-cancer efficacy by more than 20-fold compared to Olaparib alone.

Building on this data, Algok Bio has partnered with the UK’s Institute of Cancer Research (ICR) to conduct the IDOL Study, a Phase Ib/II clinical trial evaluating the combination of Idetrexed and Olaparib. The trial aims to optimize combination dosing, assess safety, and establish early efficacy in ovarian cancer patients. Patient dosing is scheduled to begin in the first half of 2025.