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Preliminary Phase 1b/2 Data for REC-4881 in Familial Adenomatous Polyposis (FAP) Demonstrates Reduced Polyp Burden

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Recursion (RXRX) announced promising preliminary results from its Phase 1b/2 TUPELO trial of REC-4881, an investigational MEK1/2 inhibitor for Familial Adenomatous Polyposis (FAP). The study showed a median 43% reduction in polyp burden at Week 13 in Phase 2 patients (n=6). Five out of six patients (83%) experienced polyp reductions ranging from 31% to 82%, though one patient showed a 595% increase. The drug demonstrated an acceptable safety profile, with mostly Grade 1-2 adverse events and no Grade ≥4 events reported. FAP, affecting approximately 50,000 individuals across the US and EU5, currently has no FDA-approved treatments. REC-4881 has received Fast Track and Orphan Drug designations from both U.S. FDA and European Commission.
Recursion (RXRX) ha annunciato risultati preliminari promettenti dalla sua sperimentazione di Fase 1b/2 TUPELO su REC-4881, un inibitore sperimentale di MEK1/2 per la Poliposi Adenomatosa Familiare (FAP). Lo studio ha mostrato una riduzione mediana del 43% del carico di polipi alla settimana 13 nei pazienti di Fase 2 (n=6). Cinque pazienti su sei (83%) hanno registrato una riduzione dei polipi compresa tra il 31% e l'82%, mentre un paziente ha mostrato un aumento del 595%. Il farmaco ha evidenziato un profilo di sicurezza accettabile, con eventi avversi principalmente di grado 1-2 e nessun evento di grado ≥4 riportato. La FAP, che colpisce circa 50.000 persone tra USA e EU5, non ha attualmente trattamenti approvati dalla FDA. REC-4881 ha ottenuto le designazioni Fast Track e Orphan Drug sia dalla FDA statunitense che dalla Commissione Europea.
Recursion (RXRX) anunció resultados preliminares prometedores de su ensayo de Fase 1b/2 TUPELO con REC-4881, un inhibidor experimental de MEK1/2 para la Poliposis Adenomatosa Familiar (FAP). El estudio mostró una reducción mediana del 43% en la carga de pólipos en la Semana 13 en pacientes de Fase 2 (n=6). Cinco de seis pacientes (83%) experimentaron reducciones en los pólipos que variaron entre el 31% y el 82%, aunque un paciente mostró un aumento del 595%. El medicamento demostró un perfil de seguridad aceptable, con eventos adversos principalmente de grado 1-2 y sin eventos de grado ≥4 reportados. La FAP, que afecta aproximadamente a 50,000 personas en EE. UU. y EU5, actualmente no cuenta con tratamientos aprobados por la FDA. REC-4881 ha recibido las designaciones Fast Track y Orphan Drug tanto de la FDA estadounidense como de la Comisión Europea.
Recursion(RXRX)는 가족성 선종성 용종증(FAP)을 위한 MEK1/2 억제제 후보물질 REC-4881의 1b/2상 TUPELO 임상시험에서 유망한 예비 결과를 발표했습니다. 연구 결과, 2상 환자(n=6)에서 13주차에 용종 부담 중앙값 43% 감소가 관찰되었습니다. 6명 중 5명(83%)은 31%에서 82% 사이의 용종 감소를 경험했으나, 한 명의 환자는 595% 증가를 보였습니다. 해당 약물은 주로 1~2등급 부작용이 보고되었으며, 4등급 이상의 부작용은 없어서 허용 가능한 안전성 프로파일을 나타냈습니다. FAP는 미국과 EU5 지역에서 약 5만 명이 영향을 받으며, 현재 FDA 승인 치료제가 없습니다. REC-4881은 미국 FDA와 유럽위원회로부터 빠른 심사(Fast Track) 및 희귀의약품(Orphan Drug) 지정도 받았습니다.
Recursion (RXRX) a annoncé des résultats préliminaires prometteurs de son essai de phase 1b/2 TUPELO avec REC-4881, un inhibiteur expérimental de MEK1/2 pour la polypose adénomateuse familiale (FAP). L'étude a montré une réduction médiane de 43 % de la charge en polypes à la semaine 13 chez les patients de phase 2 (n=6). Cinq patients sur six (83 %) ont présenté des réductions de polypes allant de 31 % à 82 %, bien qu'un patient ait montré une augmentation de 595 %. Le médicament a démontré un profil de sécurité acceptable, avec principalement des événements indésirables de grade 1-2 et aucun événement de grade ≥4 rapporté. La FAP, qui touche environ 50 000 personnes aux États-Unis et dans les cinq pays de l'UE, ne dispose actuellement d'aucun traitement approuvé par la FDA. REC-4881 a reçu les désignations Fast Track et Orphan Drug de la FDA américaine et de la Commission européenne.
Recursion (RXRX) gab vielversprechende vorläufige Ergebnisse aus der Phase 1b/2 TUPELO-Studie mit REC-4881 bekannt, einem experimentellen MEK1/2-Inhibitor für familiäre adenomatöse Polyposis (FAP). Die Studie zeigte eine median 43%ige Reduktion der Polypenlast in Woche 13 bei Patienten der Phase 2 (n=6). Fünf von sechs Patienten (83%) erfuhren Polypenreduktionen zwischen 31% und 82%, während ein Patient eine Zunahme von 595% zeigte. Das Medikament zeigte ein akzeptables Sicherheitsprofil mit überwiegend Nebenwirkungen der Grade 1-2 und keinen berichteten Ereignissen ≥ Grad 4. FAP betrifft etwa 50.000 Personen in den USA und den EU5-Ländern und hat derzeit keine von der FDA zugelassenen Behandlungen. REC-4881 erhielt sowohl von der US-amerikanischen FDA als auch von der Europäischen Kommission die Fast Track- und Orphan-Drug-Status.
Positive
  • Significant 43% median reduction in polyp burden at Week 13, surpassing other investigational agents (20-30% in 6 months)
  • Strong response rate with 83% of patients showing polyp reduction between 31-82%
  • 50% of patients achieved ≥1-point improvement in Spigelman stage
  • Generally acceptable safety profile with majority of adverse events being Grade 1-2
  • Fast Track and Orphan Drug designations from both FDA and European Commission
Negative
  • One patient (17%) showed substantial polyp burden increase of 595% from baseline
  • 16% of patients experienced Grade 3 adverse events
  • 3 out of 19 patients discontinued treatment
  • One patient progressed from Stage II to Stage IV in Spigelman staging

Insights

Recursion's REC-4881 shows promising 43% median polyp reduction in FAP patients at 13 weeks, though extreme response variability raises questions.

The preliminary data from Recursion's TUPELO trial provides compelling early evidence for REC-4881 in Familial Adenomatous Polyposis (FAP), a disease with no current FDA-approved treatments despite its near 100% lifetime risk of colorectal cancer if left untreated.

The 43% median reduction in polyp burden at just 13 weeks is particularly noteworthy when compared to historical benchmarks of 20-30% reduction at 6 months with other investigational agents. However, the heterogeneity in patient responses is striking - while 5 of 6 patients (83%) showed meaningful reductions between 31-82%, one patient experienced a concerning 595% increase in polyp burden.

The 50% rate of improvement in Spigelman staging (measuring upper GI disease severity) further supports potential clinical benefit, though again with mixed results as one patient progressed from Stage II to IV.

From a safety perspective, the profile appears consistent with MEK inhibitor class effects. The predominantly Grade 1-2 adverse events, with Grade 3 events in 16% of patients and no Grade 4+ events, suggests general tolerability. The presence of decreased left ventricular ejection fraction (LVEF) as a common event warrants cardiac monitoring in future studies.

For the estimated 50,000 FAP patients across the US and EU5, these preliminary results offer hope, but the extremely small sample size (n=6) and significant response variability necessitate cautious interpretation pending more robust data from the ongoing trial.

Recursion's REC-4881 shows promising early efficacy for FAP, exceeding benchmarks with 43% polyp reduction, but small sample size limits conclusions.

Recursion's preliminary TUPELO trial results represent a potential breakthrough for a rare disease with significant unmet need. The 43% median reduction in polyp burden after just 13 weeks of treatment with REC-4881 appears superior to historical benchmarks (20-30% at 6 months) for other investigational agents in FAP.

The regulatory advantages of Fast Track and Orphan Drug designations from both FDA and European Commission could accelerate development timelines and provide market exclusivity if eventually approved. This positions REC-4881 favorably in the treatment landscape for this orphan indication affecting approximately 50,000 patients across major markets.

However, investors should carefully weigh the extremely small efficacy dataset (n=6 patients) and the concerning outlier with dramatic disease worsening (595% increase in polyp burden). This heterogeneity introduces uncertainty about consistent benefit across the broader patient population.

From a safety perspective, the profile appears manageable with predominantly Grade 1-2 events. The 16% rate of Grade 3 events and absence of Grade 4+ toxicities suggest a tolerable profile, supported by the relatively low discontinuation rate (3 of 19 patients).

What's particularly notable is how Recursion identified this approach using their AI-powered Recursion OS platform by analyzing cellular models of APC gene loss. This technology-driven discovery model demonstrates potential value beyond this specific indication and validates their overall platform approach.

While these data likely justify continued development, they remain too preliminary to significantly de-risk the program, with much depending on whether the efficacy signals persist in larger patient cohorts with longer follow-up.

  • In the Phase 2 open-label study, REC-4881 (4 mg QD) led to a median 43% reduction (n=6 patients) in polyp burden at the Week 13 assessment at time of data cutoff.
  • Five of six patients (83%) experienced reductions in polyp burden ranging from 31% to 82%, however, one patient showed a substantial increase from baseline.
  • At Week 13, 50% of patients (3 out of 6) achieved ≥1-point improvement in Spigelman stage, a measure of upper GI disease severity.
  • The early safety profile of REC-4881 was generally consistent with that of prior MEK1/2 inhibitors; among 19 patients across Phase 1b and 2, most treatment-related adverse events were Grade 1 or 2, with Grade 3 events in 16% of patients and no Grade ≥4 TRAEs reported to date.

SALT LAKE CITY, May 04, 2025 (GLOBE NEWSWIRE) -- Recursion (Nasdaq: RXRX), a clinical-stage TechBio company decoding biology to radically improve lives, today announced preliminary safety and efficacy results from its ongoing Phase 1b/2 TUPELO trial of REC-4881, an investigational, allosteric MEK1/2 inhibitor in development for Familial Adenomatous Polyposis (FAP). These data were presented in a late-breaking oral presentation at Digestive Disease Week (DDW) 2025 in San Diego, California.

FAP is a rare, inherited disorder caused by mutations in the APC gene, leading to the growth of hundreds to thousands of gastrointestinal polyps and a near 100% lifetime risk of colorectal cancer if left untreated. Despite this significant burden, there are currently no FDA-approved treatments. FAP affects an estimated 50,000 individuals across the US and EU5 (France, Germany, Italy, Spain, and the UK). REC-4881 has received Fast Track and Orphan Drug designations from the U.S. FDA, as well as Orphan Drug designation from the European Commission.

As of the March 17, 2025 data cutoff in the open-label Phase 2 portion of the TUPELO trial, treatment with REC-4881 (4 mg QD) led to a preliminary median 43% reduction to date in polyp burden at the Week 13 assessment among six efficacy-evaluable patients. Other investigational agents in separate studies have reported 20-30% polyp burden reduction in 6 months1. Five of the six patients (83%) experienced reductions in polyp burden ranging from 31% to 82%, while one patient (17%) showed a substantial increase of 595% from baseline. Additionally, three of six patients (50%) achieved a ≥1-point reduction in Spigelman stage; one patient had no change, one progressed from Stage II to IV, and one had no baseline stage but was classified as Stage II at Week 13.

Across the combined Phase 1b and ongoing Phase 2 cohorts (n=19 safety-evaluable patients), REC-4881 demonstrated an early safety profile generally consistent with that of prior MEK1/2 inhibitors. Seventy-nine percent (15 of 19) of patients experienced at least one treatment-related adverse event (TRAE), the majority of which were Grade 1 or 2 in severity. Grade 3 TRAEs occurred in 16% of patients, with no Grade ≥4 events reported to date. In Phase 1b, the most frequent TRAEs (≥20%) were acneiform rash, diarrhea, and decreased left ventricular ejection fraction (LVEF), while in Phase 2, the most common events were acneiform rash, blood creatine phosphokinase (CPK) increase, and diarrhea. Overall, treatment modifications were infrequent, with 3 of 19 patients discontinuing treatment, 1 patient each requiring dose interruption or modification.

"For patients with FAP, who face increased risk of colorectal and small bowel cancer and a lifetime of invasive interventions, the preliminary polyp burden reduction at a median of >43% seen with REC-4881 1in just three months of treatment is highly encouraging," said Dr. Jewel Samadder, Gastroenterologist at Mayo Clinic and Principal Investigator of TUPELO, "These early results offer a much-needed glimpse of hope for this underserved population."

"For patients with FAP, who currently lack FDA-approved treatment options, Recursion's AI-powered Recursion OS platform identified a promising approach through MEK 1/2 inhibition," said Najat Khan, PhD, Chief R&D Officer and Chief Commercial Officer at Recursion. "By analyzing cellular models of APC gene loss, we uncovered a potential first-in-disease treatment and are excited to share our preliminary findings."

About the TUPELO Trial Design (REC-4881)
The Phase 1b/2 TUPELO trial is evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of REC-4881 monotherapy in patients with Familial Adenomatous Polyposis (FAP).

The Phase 1b portion was a randomized, double-blind, placebo-controlled safety run-in designed to assess the safety, tolerability, and PK of REC-4881 at 4 mg QD for 14 days in FAP patients aged 18 years and older. A total of five patients received REC-4881, and two received placebo. Following the safety review, the eligibility criteria were amended to enroll only patients aged ≥55 years in Phase 2, in an effort to reduce treatment-related adverse events (TRAEs) consistent with MEK1/2 inhibition.

In the ongoing Phase 2 portion, participants must have a confirmed germline APC mutation and be ≥55 years old. Efficacy is assessed via upper and lower endoscopy at baseline, Week 13 (W13, on-treatment), and Week 25 (W25, off-treatment). The primary efficacy endpoint is percent change from baseline in polyp burden.

The Efficacy Evaluable Population includes patients who had measurable disease at baseline, received ≥75% of the study drug, and completed at least one post-baseline endoscopic assessment. Disease staging is evaluated using the Spigelman system for the upper gastrointestinal tract and the InSiGHT classification for the lower GI tract.

Efficacy
In the interim Phase 2 analysis, REC-4881 (4 mg QD) demonstrated a preliminary median 43% reduction in polyp burden at Week 13 among efficacy-evaluable post-colectomy FAP patients aged ≥55 years (n=6). Other investigational agents in separate studies have reported 20-30% polyp burden reduction in 6 months1. Three of six patients (50%) achieved a >50% reduction in polyp burden at the Week 13 (on-treatment) assessment. Of these, two patients maintained a >30% reduction at the Week 25 (off-treatment) assessment, 12 weeks after completing therapy. One patient who reached Week 25 did not undergo the endoscopic evaluation. The distribution of polyp burden changes across all patients is shown in Figure 1.

At Week 13, three of six patients achieved a ≥1-point reduction in Spigelman stage, a validated measure of upper gastrointestinal disease severity; one patient had no change, one progressed from Stage II to IV, and one had no baseline stage but was classified as Stage II at Week 13.

At the time of data cutoff, three additional patients had been enrolled in the 8 mg QD dose cohort. All three were found to have no measurable disease (zero polyp burden) at baseline endoscopy and were therefore not considered efficacy evaluable.

Figure1

Figure 1: Waterfall plot showing percent change from baseline in total polyp burden at Week 13 (end of treatment) for efficacy-evaluable patients receiving REC-4881 (4 mg QD).

Safety
In the preliminary Phase 1b safety and Phase 2 dose-finding/dose-expansion cohorts of the TUPELO trial, the majority of treatment-related adverse events (TRAEs) were Grade 1 or 2, with Grade 3 TRAEs observed in 16% of patients and no Grade ≥4 TRAEs reported to date. Among the 19 safety-evaluable patients that received REC-4881 across both phases, the most frequent TRAEs (≥20%) in Phase 1b were acneiform rash, diarrhea, and decreased left ventricular ejection fraction (LVEF). In the ongoing Phase 2 portion, the most commonly reported TRAEs (≥20%) have been acneiform rash, elevated blood creatine phosphokinase (CPK), and diarrhea. Rash and decreased left ventricular ejection fraction (LVEF), both observed in this study, are consistent with the reported safety profile of MEK1/2 inhibitors.

Grade 3 TRAEs included rash, increased C-reactive protein (CRP), and decreased LVEF—each occurring in one patient (6%), all within the 4 mg dose cohort. A single patient in the Phase 1b cohort experienced a Grade 3 LVEF decrease, which was transient and resolved following dose interruption. No patients in Phase 1b discontinued treatment due to a TRAE. Three patients in Phase 2 discontinued treatment due to TRAEs. A full summary of adverse events is provided in Figure 2.

Figure2

Figure 2. Summary of Adverse Events Across Phase 1b and Phase 2 of the TUPELO Trial

Next Steps
Patient enrollment in the TUPELO trial is ongoing. Recursion plans to conduct additional efficacy and safety analyses anticipated in the second half of 2025.

About REC-4881
REC-4881 is an orally bioavailable, non-ATP-competitive allosteric small molecule MEK 1/2 inhibitor. The platform analyzed cellular models of APC gene loss—the root cause of FAP—to identify compounds that suppress the disease-inducing effects of APC mutations.

About Recursion
Recursion (NASDAQ: RXRX) is a clinical stage TechBio company leading the space by decoding biology to radically improve lives. Enabling its mission is the Recursion OS, a platform built across diverse technologies that continuously generate one of the world’s largest proprietary biological and chemical datasets. Recursion leverages sophisticated machine-learning algorithms to distill from its dataset a collection of trillions of searchable relationships across biology and chemistry unconstrained by human bias. By commanding massive experimental scale — up to millions of wet lab experiments weekly — and massive computational scale — owning and operating one of the most powerful supercomputers in the world, Recursion is uniting technology, biology and chemistry to advance the future of medicine. Recursion is headquartered in Salt Lake City, where it is a founding member of BioHive, the Utah life sciences industry collective. Recursion also has offices in Toronto, Montréal, New York, London, Oxford area, and the San Francisco Bay area. Learn more at www.Recursion.com, or connect on X (formerly Twitter) and LinkedIn.

Forward-Looking Statements
This document contains information that includes or is based upon "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995, including, without limitation, those regarding the potential efficacy of REC-4881, including the potential to be a first-in-disease treatment; the timing of and outcomes of the TUPELO clinical trial; the effects of our platform on trial outcomes; the potential size of the market opportunity for our drug candidates; Recursion’s leadership of the TechBio space; the Recursion OS and other technologies; and all other statements that are not historical facts. Forward-looking statements may or may not include identifying words such as “plan,” “will,” “expect,” “anticipate,” “intend,” “believe,” “potential,” “continue,” and similar terms. These statements are subject to known or unknown risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements, including but not limited to: challenges inherent in pharmaceutical research and development, including the timing and results of preclinical and clinical programs, where the risk of failure is high and failure can occur at any stage prior to or after regulatory approval due to lack of sufficient efficacy, safety considerations, or other factors; our ability to leverage and enhance our drug discovery platform; our ability to obtain financing for development activities and other corporate purposes; the success of our collaboration activities; our ability to obtain regulatory approval of, and ultimately commercialize, drug candidates; our ability to obtain, maintain, and enforce intellectual property protections; cyberattacks or other disruptions to our technology systems; our ability to attract, motivate, and retain key employees and manage our growth; inflation and other macroeconomic issues; and other risks and uncertainties such as those described under the heading “Risk Factors” in our filings with the U.S. Securities and Exchange Commission, including our Annual Report on Form 10-K for the Fiscal Year Ended December 31, 2024. All forward-looking statements are based on management’s current estimates, projections, and assumptions, and Recursion undertakes no obligation to correct or update any such statements, whether as a result of new information, future developments, or otherwise, except to the extent required by applicable law.

Media Contact
Media@Recursion.com 

Investor Contact
Investor@Recursion.com 

Photos accompanying this announcement are available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/d025ef61-3451-47e1-9dc6-8fe910b4ef6d

https://www.globenewswire.com/NewsRoom/AttachmentNg/b64bdf18-73b8-4f07-b38d-a96478162b1b

1 Steinberg et al 2000 NEJM and Burke et al 2024 Gastroenterology


FAQ

What were the key results of RXRX's Phase 1b/2 trial for REC-4881 in FAP patients?

The trial showed a median 43% reduction in polyp burden at Week 13, with 83% of patients experiencing reductions between 31-82%. The drug demonstrated an acceptable safety profile with mostly Grade 1-2 adverse events.

How many patients discontinued treatment in Recursion's REC-4881 FAP trial?

3 out of 19 patients discontinued treatment, with 1 patient each requiring dose interruption or modification.

What is the market potential for RXRX's REC-4881 in FAP treatment?

FAP affects approximately 50,000 individuals across the US and EU5, with currently no FDA-approved treatments. REC-4881 has received Fast Track and Orphan Drug designations.

What were the main side effects reported in RXRX's REC-4881 Phase 1b/2 trial?

The most common treatment-related adverse events included acneiform rash, diarrhea, decreased left ventricular ejection fraction, and blood creatine phosphokinase increase, mostly Grade 1-2 in severity.

How does REC-4881's efficacy compare to other investigational FAP treatments?

REC-4881 showed a 43% median polyp reduction in 13 weeks, while other investigational agents have reported 20-30% polyp burden reduction in 6 months.
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