Recursion's REC-4881 Shows Durable Polyp Reduction in Familial Adenomatous Polyposis Phase 2 Trial
Key Insights
REC-4881, an investigational MEK1/2 (search) inhibitor, demonstrated a 43% median reduction in polyp burden after 12 weeks of treatment in FAP (search) patients, with 75% of evaluable patients showing reductions.
The therapeutic effect persisted 12 weeks after treatment cessation, with 82% of patients maintaining polyp burden reductions and a 53% median decrease from baseline at week 25.
The drug represents the first MEK1/2 (search) inhibitor studied clinically for FAP (search), discovered through Recursion's AI-driven platform that identified MEK1/2 inhibition as a rescue mechanism for APC (search) loss-of-function.
Recursion announced positive Phase 1b/2 data from its ongoing TUPELO trial of REC-4881, an investigational allosteric MEK1/2 (search) inhibitor for familial adenomatous polyposis (search) (FAP (search)). The results demonstrate rapid and durable reductions in polyp burden, marking the first clinical validation of the company's AI-driven drug discovery platform for this rare hereditary cancer syndrome.
Significant Clinical Activity and Durability
In the Phase 2 portion of the study, REC-4881 (4 mg once daily) achieved a median 43% reduction in total polyp burden among 12 efficacy-evaluable patients after 12 weeks of treatment. Notably, 75% of evaluable patients showed reductions in polyp burden during this period.
The therapeutic effect demonstrated remarkable durability. After patients discontinued treatment for an additional 12 weeks, 82% of evaluable patients (9 of 11) maintained reductions at week 25, with a 53% median decrease from baseline. This sustained benefit occurred without continued drug exposure, distinguishing REC-4881 from other investigational agents that have shown approximately 17-29% median reduction in polyp burden after 12 months of continuous treatment.
"The durable polyp burden reduction demonstrated by REC-4881—especially the sustained effect seen at Week 25, 12 weeks after completing therapy—is highly encouraging for the FAP (search) community," said Jessica Stout, D.O., Assistant Clinical Professor at University of Utah School of Medicine (search) and Principal Investigator of the TUPELO study.
Clinical Significance in Upper GI Disease
Beyond total polyp burden reduction, 40% of patients (4 out of 10) achieved a ≥1-point improvement in Spigelman stage—a clinically meaningful measure of upper gastrointestinal disease severity used to assess surveillance and clinical management. This improvement was maintained in 40% of patients at week 25, indicating sustained clinical benefit in upper GI tract disease progression.
AI-Driven Drug Discovery Validation
REC-4881 emerged from Recursion's unbiased phenotypic screening platform, which identified selective MEK1/2 (search) inhibition as a mechanism capable of reversing APC (search) loss-of-function signatures. Using high-content cellular phenomics driven by artificial intelligence, the platform screened thousands of compounds and identified REC-4881 as one of the strongest phenotypic rescue hits, reverting APC-deficient cells toward a healthy state.
"These Phase 2 results mark a meaningful validation of the Recursion OS," said Chris Gibson, Ph.D., Co-Founder and CEO of Recursion. "An unbiased phenotypic insight from our platform and driven by AI—linking MEK1/2 (search) inhibition to APC (search) loss-of-function biology—has now translated into rapid, substantial, and durable reductions in polyp burden in patients."
Based on this AI-driven insight, Recursion in-licensed REC-4881 from Takeda (search), where it had been evaluated in solid tumors, and redirected it as the first MEK1/2 (search) inhibitor advanced clinically for FAP (search).
Natural History Context
To contextualize the single-arm efficacy data, Recursion collaborated with Amsterdam University Medical Center (search) to analyze a registry of approximately 200 FAP (search) patients. Among 55 patients who met TUPELO's key inclusion criteria, 87% experienced annualized increases in polyp burden, 10% remained stable, and only 3% showed modest decreases. The mean increase was 60% and median increase was 28% in annualized polyp burden, underscoring FAP's relentlessly progressive nature.
Safety Profile
REC-4881 demonstrated a safety profile consistent with MEK1/2 (search) inhibition. Across the combined Phase 1b and Phase 2 safety cohorts (n=19), 94.7% of patients reported at least one treatment-related adverse event (TRAE), with the majority being Grade 1 or 2 in severity. The most frequent TRAEs (≥10%) included dermatitis acneiform/rash and blood CPK increase.
Grade 3 TRAEs occurred in 15.8% of patients, with no Grade ≥4 TRAEs reported to date. Treatment modifications were infrequent, with only 2 of 19 patients experiencing dose interruption.
Addressing Critical Unmet Need
FAP (search) is caused by inactivating mutations in the APC (search) gene, leading to hundreds to thousands of gastrointestinal polyps and a near 100% risk of developing colorectal cancer (search) before age 40 if left untreated. With no approved pharmacotherapies, current management relies on intensive surveillance and life-altering surgeries, typically involving colectomy in patients' early twenties.
"Given the near-100% lifetime risk of colorectal cancer (search) and the absence of any approved medical therapies, patients today often face a lifetime of intensive surveillance and life-altering surgeries," noted Dr. Stout. "These Phase 2 results provide a meaningful basis for hope and support the potential for REC-4881 to offer a much-needed non-surgical option for this debilitating, life-long disease."
Approximately 90% of FAP (search) patients develop duodenal adenomas (search), with 6% eventually requiring high-morbidity duodenectomy procedures. The disease affects an estimated >50,000 individuals across the US and EU5 countries.
Regulatory Status and Next Steps
REC-4881 has received Fast Track and Orphan Drug designations from the US FDA, as well as Orphan Drug designation from the European Commission. Recursion plans to expand the trial population from ≥55 to ≥18 years old and further optimize the dosing schedule.
"This program reflects a full validation cycle of the Recursion OS: an unbiased phenotypic signal identifying MEK1/2 (search) inhibition as a rescue mechanism for APC (search) loss-of-function, followed by mechanistic confirmation, clinical translation, and now encouraging human data in a disease with no approved medical therapies," said Najat Khan, Ph.D., Chief R&D and Commercial Officer and incoming President and CEO.
The company intends to engage the FDA in the first half of 2026 to define a potential registration pathway for this first-in-class therapeutic approach to FAP (search).