8-K: Recursion's REC-4881 Shows Durable Polyp Reduction in FAP Trial

Recursion Pharmaceuticals announced positive Phase 1b/2 TUPELO trial data for REC-4881, demonstrating rapid and durable reductions in polyp burden for familial adenomatous polyposis patients.

Summary

• REC-4881 (4 mg QD) achieved a 43% median reduction in total polyp burden after 12 weeks of treatment in 75% of evaluable patients (n=12).
• The effect was durable, with 82% of evaluable patients (9 of 11) maintaining a 53% median reduction from baseline at Week 25, 12 weeks after stopping therapy.
• 40% of patients (4 out of 10) achieved a 1-point improvement in Spigelman stage, a measure of upper GI disease severity.
• The safety profile of REC-4881 is consistent with MEK1/2 inhibition, with most treatment-related adverse events (TRAEs) being Grade 1 or 2, and Grade 3 events occurring in 15.8% of patients (n=19), with no Grade 4 TRAEs reported.
• Natural history analysis of untreated FAP patients showed an 87% annualized polyp-burden increase, 10% stable, and 3% modest decrease, underscoring the progressive nature of the disease.
• REC-4881 is the first MEK1/2 inhibitor studied clinically for FAP, a disease affecting approximately 50,000 patients in the US and EU5 with no approved medical therapies.

Sentiment

Score: 9

Explanation: The filing reports highly positive Phase 1b/2 clinical trial results for REC-4881 in FAP, demonstrating rapid and durable polyp burden reduction and a favorable safety profile. The data significantly outperforms natural disease progression and other reported investigational agents, validating the company's AI-driven platform and addressing a high unmet medical need. This represents a major step forward for the program and the company.

Positives

• REC-4881 demonstrated rapid clinical activity with a 43% median reduction in total polyp burden after 12 weeks of treatment.
• A significant majority (75%) of evaluable patients showed reductions in polyp burden.
• The treatment effect was durable, with 82% of patients maintaining a 53% median reduction in polyp burden 12 weeks after stopping therapy.
• 40% of patients achieved a clinically meaningful 1-point improvement in Spigelman stage.
• The safety profile is consistent with the known class effects of MEK1/2 inhibitors, with a low incidence of severe adverse events (15.8% Grade 3, no Grade 4).
• The results validate Recursion's AI-driven discovery platform (Recursion OS) in identifying novel therapeutic candidates.
• REC-4881 has received Fast Track and Orphan Drug designations from the US FDA, and Orphan Drug designation from the European Commission.

Negatives

• 94.7% of patients reported at least one treatment-related adverse event (TRAE), though most were Grade 1/2.
• 21.1% (4 of 19) patients discontinued treatment due to TRAEs, including 1 for diarrhea (G1), 1 for retinopathy (G2), 1 for rash (G2), and 1 for hypertension (G2).
• 10.5% (2 of 19) patients experienced dose interruption due to TRAEs.

Risks

• Challenges inherent in pharmaceutical research and development, including the high risk of failure in preclinical and clinical programs due to lack of sufficient efficacy, safety considerations, or other factors.
• Ability to leverage and enhance the drug discovery platform.
• Ability to obtain financing for development activities and other corporate purposes.
• Success of collaboration activities.
• Ability to obtain regulatory approval of, and ultimately commercialize, drug candidates.
• Ability to obtain, maintain, and enforce intellectual property protections.
• Cyberattacks or other disruptions to technology systems.
• Ability to attract, motivate, and retain key employees and manage growth.
• Inflation and other macroeconomic issues.

Future Outlook

Recursion plans to engage the FDA in the first half of 2026 to define a potential registration pathway for REC-4881. The company also intends to expand the TUPELO trial population to include patients aged 18 to 55 and further optimize the dosing schedule. They will continue follow-up for evaluation of durability.

Management Comments

• "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 community." Jessica Stout, D.O., Principal Investigator of the TUPELO study.
• "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." Jessica Stout, D.O.
• "These Phase 2 results mark a meaningful validation of the Recursion OS... This is a powerful example of how even the earliest versions of the Recursion OS can uncover therapeutic opportunities in diseases with no approved pharmacotherapy options." Chris Gibson, Ph.D., Co-Founder and CEO of Recursion.
• "This program reflects a full validation cycle of the Recursion OS... REC-4881, an allosteric MEK1/2 inhibitor, represents a first precision-medicine approach for the causal biology of FAP." Najat Khan, Ph.D., Chief R&D and Commercial Officer and incoming President and CEO.

Industry Context

Familial Adenomatous Polyposis (FAP) is a rare, hereditary colorectal cancer syndrome with a near 100% lifetime risk of colorectal cancer if untreated. Currently, there are no approved pharmacotherapies, leaving patients with intensive surveillance and life-altering surgeries like colectomy and duodenectomy. REC-4881, as the first MEK1/2 inhibitor clinically investigated for FAP, addresses a significant unmet medical need for approximately 50,000 patients in the US and EU5. The durable polyp reduction and Spigelman stage improvements observed in the TUPELO trial suggest a potential non-surgical therapeutic option, which would be a major advancement in a field dominated by invasive procedures.

Comparison to Industry Standards

• Other investigational agents currently under evaluation in separate studies generated approximately 17-29% median reduction in polyp burden after 12 months of treatment, with no off-treatment durability reported (e.g., Biodexa press release, June 24, 2024).
• REC-4881 demonstrated a 43% median reduction after only 12 weeks of treatment and a 53% median reduction maintained 12 weeks off-treatment, indicating superior efficacy and durability compared to these reported benchmarks.
• Natural history analysis showed 87% of untreated FAP patients experienced an annualized increase in polyp burden, with an average increase of 60% and median increase of 28%, highlighting the progressive nature of the disease and the significance of REC-4881's reduction.

Management Changes

Stakeholder Impact

• Shareholders: Positive clinical data could lead to increased investor confidence and potential share price appreciation due to advancement of a key pipeline asset and validation of the Recursion OS platform.
• Patients (FAP): Offers significant hope for a non-surgical, effective medical therapy to manage a debilitating, life-long disease with no approved pharmacotherapies, potentially improving quality of life and reducing the need for invasive surgeries.
• Employees: Validation of the Recursion OS platform could boost morale and reinforce the company's strategic direction in AI-driven drug discovery.
• Regulatory Authorities: The company plans to engage the FDA to define a registration pathway, indicating progress towards potential market approval.

Next Steps

• Engage the FDA in the first half of 2026 to define a potential registration pathway for REC-4881.
• Expand the TUPELO trial population to include patients aged 18 to 55.
• Further optimize the dosing schedule for REC-4881.
• Continue follow-up for evaluation of durability.

Key Dates

Recommendation

The positive Phase 1b/2 results for REC-4881 in FAP are highly compelling, demonstrating rapid, substantial, and durable reductions in polyp burden that significantly outperform both the natural progression of the disease and reported results from other investigational agents. The validation of Recursion's AI-driven OS platform with these clinical outcomes is a major de-risking event for the company's broader pipeline. Given the high unmet medical need in FAP and the potential for REC-4881 to be a first-in-class non-surgical option, this data suggests a strong commercial opportunity and significant value creation. The Fast Track and Orphan Drug designations further streamline the regulatory path. While development risks remain, the current data provides a robust foundation for continued advancement and warrants a strong buy recommendation for long-term investors.

Keywords

Familial Adenomatous Polyposis, FAP, REC-4881, MEK1/2 inhibitor, Polyp Burden Reduction, Clinical Trial, Phase 1b/2, TUPELO trial, Recursion Pharmaceuticals, RXRX, AI-driven drug discovery, Orphan Drug, Fast Track, Oncology, Gastroenterology