FOG-001 Is Safe, Yields Antitumor Activity in Desmoid Tumors

FOG-001, a first-in-class direct β-catenin-TCF4 inhibitor, exhibited a manageable safety profile and antitumor activity that was clinically meaningful in patients with desmoid tumors, according to data from a phase 1/2 study (NCT05919264) presented at the 2025 ESMO Congress.^1,2

FOG-001 displayed a manageable safety profile in patients with desmoid tumors (n = 12). Any grade treatment-related adverse effects (TRAEs) occurred in 83.3% of patients across all dose levels, whereas grade 3 or higher TRAEs occurred in 16.7% of patients.¹ Common TRAEs that occurred in patients at any grade were fatigue (58.3%), alopecia (50%), increased aspartate aminotransferase (ALT) levels (41.7%), nausea (41.7%), and increased alanine aminotransferase (AST) levels (33.3%). Grade 3 or higher TRAEs included increased AST and increased ALT levels, both of which occurred in 8.3% of patients. No patients experienced grade 4 or higher TRAEs, discontinued treatment due to TRAEs, or had high-grade gastrointestinal or skin toxicity.

Preliminary efficacy findings from the trial showed that in patients who received FOG-001 with more than one post-baseline scan (n = 5), 80% achieved objective responses regardless of prior gamma secretase inhibitor (GSI) exposure or whether they harbored APC or CTNNB1 mutations.

In patients who were response-evaluable with 1 or more post-baseline scans (n = 10), all experienced some level of tumor reduction from baseline, and they had a disease control rate of 100% at first scan.

"These data support further development of FOG-001 in patients with desmoid tumors and suggest that FOG-001 directly addresses the underlying mechanism of disease through inhibition of β-catenin," lead study author Gregory Cote, MD, PhD, said in a presentation of the data.

Cote is a clinician investigator and associate professor both at Mass General Research Institute; an associate physician of medicine-hematology and medical oncology at Massachusetts General hospital; and an associate professor of medicine at Harvard Medical School in Boston.

What was the rationale and design of the trial?

Investigators of the trial aimed to develop a more suitable for treatment patients with desmoid tumors beyond systemic therapy options that indirectly target relevant mutations. Cote explained that Wnt/β-catenin pathway activating mutations (WPAMs), such as APC and CTNNB1, are highly prevalent in this patient population.

In November 2025, the FDA granted fast track designation to FOG-001 as a treatment for desmoid tumors.³ The designation was supported by the safety and preliminary efficacy data presented for the trial.

The first-in-human, multicenter, open-label, dose-escalation study is enrolling patients who have histologically confirmed select advanced solid tumors, including desmoid tumors with aggressive fibromatosis.^1,2 Patients also need to have an ECOG performance status of 0 or 1 and adequate organ and bone marrow function.²

If patients have a history of bone metastasis, evidence of vertebral compression or non-traumatic bone fractures within the last 12 months, uncontrolled inflammatory bowel disease, or inadequate cardiac function they are not enrolled.

Patients with desmoid tumors were enrolled across different dose levels, dose level 2 (DL2) (n = 1), dose level 4 (DL4) (n = 9), and dose level 6 (DL6) (n = 2), which were doses of 72 mg/m², 240 mg/m², and 480 mg/m², respectively.¹ Doses were administered intravenously in continuously 28-day cycles.²

FOG-001’s safety and tolerability was the primary end point of the trial, whereas the secondary endpoint of the trial evaluated antitumor activity.¹

Baseline characteristics in the desmoid tumor cohort revealed that patients had a median age of 32.5 years (range, 20-53), and most patients were male (83.3%). Most patients had CTNNB1 WPAMs (83.3%), less had APC WAPMs (8.3%), or WAPM status was not available (8.3%). Location of tumors for patients were mostly extra-abdominal (91.7%), whereas less were intra-abdominal (8.3%). Patients had a median of 2 prior surgeries (range, 0-6), which were either systemic, surgery, or radiation at respective rates of 91.7%, 16.7%, and 8.3%. Moreover, the median number of prior systemic therapies was 1.5 (range, 0-5), which were either nirogacestat (Ogsiveo; 75%), sorafenib (Nexavar; 50%), cytotoxic chemotherapy (41.7%), or other systemic therapies (25%). The median target lesion size per RECIST criteria was 95.5 mm (range, 37-250)

What were the additional data from the trial?

TRAEs at any grade occurred in 100%, 77%, and 100% in patients receiving FOG-001 at DL2, DL4, and DL6, respectively. Grade 3 or higher TRAEs occurred in 100% of patients receiving FOG-001 at DL6, whereases such TRAEs did not occur in any patients at other dose levels. Alopecia (100%) was the only TRAE to occur in patients at DL2, while fatigue (55.6%), alopecia (33.3%), increased AST (33.3%), and nausea (44.4%) occurred in patients at DL4. At DL6, all patients experienced TRAEs like fatigue, alopecia, increased AST and ALT levels, and hypoaldosteronism.

References

1. Cote GM, Cecchini M, Papadopoulos KP, et al. A phase I/II trial of FOG-001, a first-in-class direct β-catenin:TCF4 inhibitor - safety and preliminary antitumor activity in patients with desmoid tumors. Ann Oncol. 2025;36(suppl 2):S1435-S1436. doi:10.1016/j.annonc.2025.08.3
2. FOG-001 in locally advanced or metastatic solid tumors. ClinicalTrials.gov. Updated October 24, 2025. Accessed November 12, 2025. https://clinicaltrials.gov/study/NCT05919264
3. Parabilis Medicines receives FDA fast track designation for FOG-001, the first and only direct inhibitor of the β -catenin:TCF interaction, for the treatment of desmoid tumors. News release. Parabilis Medicines. November 12, 2025. Accessed December 16, 2025. https://parabilismed.com/press-release/parabilis-medicines-receives-fda-fast-track-designation-for-fog-001-the-first-and-only-direct-inhibitor-of-the-%ce%b2-catenintcf-interaction-for-the-treatment-of-desmoid-tumors/