REC-4881 for Familial Adenomatous Polyposis

(TUPELO Trial)

Recruiting at 12 trial locations

Overseen By Recursion Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Recursion Pharmaceuticals Inc.

Must not be taking: NSAIDs, Omega-3, Corticosteroids, others

Disqualifiers: Cancer, Desmoid tumors, Eye abnormality, others

Compensation: Varies

Number of Visits: Unknown

67 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called REC-4881 for individuals with Familial Adenomatous Polyposis (FAP), a condition where many polyps form in the digestive tract, potentially leading to cancer if untreated. The trial aims to determine if REC-4881 can manage the disease more effectively than a placebo (a pill with no active medicine). Participants will receive either a 4mg or 8mg dose of REC-4881 or a placebo. The trial seeks individuals who have undergone surgery to remove part of their colon due to FAP and have polyps in the remaining digestive tract. As a Phase 1 trial, this research focuses on understanding how REC-4881 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

You will need to stop using non-steroidal anti-inflammatory drugs (NSAIDs), omega-3 fatty acids, oral corticosteroids, strong CYP3A inhibitors or inducers, and strong BCRP or MRP2 inhibitors before starting the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that REC-4881 has been tested in patients with Familial Adenomatous Polyposis (FAP) and has yielded promising results. In a previous study, patients taking REC-4881 experienced an average 43% reduction in polyp growth after 13 weeks, suggesting the treatment might be effective.

Ongoing studies are examining how well patients tolerate REC-4881. Although detailed safety information from these studies isn't provided, the continuation of the trial suggests the treatment is likely considered safe enough for further testing. As this is an early-phase trial, researchers are closely monitoring the treatment for any possible side effects.

Overall, while specific side effects aren't listed, REC-4881 appears to be relatively well-tolerated so far. Participants interested in this trial should know that safety is a key focus, and researchers will carefully record and address any adverse events. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for FAP?

Unlike the standard treatments for familial adenomatous polyposis, which often involve surgical interventions or NSAIDs like sulindac to manage polyp growth, REC-4881 is a novel oral medication that offers a new approach. Researchers are excited about REC-4881 because it could potentially target the underlying mechanisms of polyp formation at a molecular level, something current treatments don't specifically address. With its unique formulation available in both 4mg and 8mg doses, REC-4881 is designed to be taken once daily, offering a convenient and potentially more effective way to manage this condition.

What evidence suggests that this trial's treatments could be effective for Familial Adenomatous Polyposis?

Studies have shown that REC-4881 can significantly reduce the number of polyps in people with Familial Adenomatous Polyposis (FAP). In a recent study, patients taking 4 mg of REC-4881 daily experienced an average 43% reduction in their polyps after just 13 weeks. This trial will evaluate REC-4881 at different dosages, including 4 mg and 8 mg, to further assess its effectiveness. Although most patients had positive results, at least one case showed less effectiveness, indicating the need for more research. Overall, these findings suggest that REC-4881 might be a promising option for people with FAP. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

Adults over 18 with Familial Adenomatous Polyposis (FAP) who've had a colectomy can join this trial. They must not use strong CYP3A affecting drugs, NSAIDs (except low-dose aspirin), or have had recent cancer treatments. Those with certain GI diseases or difficulty swallowing pills are excluded.

Inclusion Criteria

Have provided written informed consent to participate in the study

I am 55 years old or older.

My blood counts are normal.

Exclusion Criteria

I am currently being treated for desmoid tumors.

I haven't taken any FAP-targeted drugs in the last 8 weeks.

Has received treatment with other investigational agents prior to Study Day 1

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive either REC-4881 4mg or placebo once daily post-colectomy/proctocolectomy

43 days

Treatment Part 2

Participants receive escalating doses of REC-4881 (4mg, 8mg, or 12mg) to determine the RP2D

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• REC-4881

Trial Overview The study tests REC-4881 against a placebo in people with FAP to see if it's effective and safe. It's conducted at multiple centers and includes two parts, focusing on patients who've undergone colon surgery due to their condition.

How Is the Trial Designed?

Group I: REC-4881 8 mg (Part 2) Experimental Treatment 1 Intervention

Participants will receive REC-4881 8 mg administered orally QD.

Group II: REC-4881 4 mg (Part 2) Experimental Treatment 1 Intervention

Participants will receive REC-4881 4 mg administered orally QD.

Group III: REC-4881 4 mg (Part 1) Experimental Treatment 1 Intervention

Participants will receive REC-4881 4 milligrams (mg) administered orally and then, following 14-28 days, participants will begin QD dosing for another 14 days.

Group IV: Placebo (Part 1) Placebo Group 1 Intervention

Participants will receive a single dose of placebo administered orally and then, following 14-28 days, participants will begin once daily (QD) dosing for another 14 days.

Who Is Running the Clinical Trial?

Recursion Pharmaceuticals Inc.

Lead Sponsor

Trials

6

Recruited

450+

Published Research Related to This Trial

In a Phase II pilot study involving 15 patients with familial adenomatous polyposis (FAP), low-dose rectal sulindac therapy led to complete adenoma reversion in 87% of patients after 48 weeks, demonstrating its efficacy in managing this condition.

The treatment was well-tolerated with minimal side effects, and significant reductions in proliferation indices of adenomatous tissue were observed, suggesting that rectal sulindac may be a promising alternative to surgical procedures for FAP management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal anti-inflammatory drug regimen in reversing adenomas exceeding 33 months. Winde, G., Schmid, KW., Schlegel, W., et al.[2019]

In a randomized trial involving 112 subjects with familial adenomatous polyposis, the combination of celecoxib (CXB) and diflouromethylornithine (DFMO) showed a moderate synergy in reducing adenoma burden, but no significant difference in adenoma count compared to celecoxib alone after 6 months.

The study found that while fatigue was a significant adverse event associated with celecoxib, there were no major cardiovascular risks or DFMO-related ototoxicity observed, indicating a relatively safe profile for the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Lynch, PM., Burke, CA., Phillips, R., et al.[2016]

A new staging and intervention classification system for familial adenomatous polyposis (FAP) was developed, showing high agreement among 26 expert reviewers in assessing polyp stages and recommending interventions, which is crucial for future clinical trials.

The high concordance rate (ρ = 0.710) indicates that this system can reliably measure treatment outcomes, although cases with significant disagreement may need special consideration before being included in clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A proposed staging system and stage-specific interventions for familial adenomatous polyposis. Lynch, PM., Morris, JS., Wen, S., et al.[2020]

Familial adenomatous polyposis (FAP) is a genetic condition that leads to the early development of numerous polyps in the colon and rectum, with an incidence of 1 in 10,000 newborns, and can result in cancer if not monitored and treated.

The condition is primarily caused by mutations in the APC tumor suppressor gene, and a DNA Bank has been established in Poland to study FAP, collecting samples from 600 families to better understand the genetic factors involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Familial adenomatous polyposis of the colon. Plawski, A., Banasiewicz, T., Borun, P., et al.[2022]

Two family members with attenuated familial adenomatous polyposis (AFAP) were found to have a novel mutation in the APC gene, which is linked to the development of colorectal polyps.

Both patients successfully managed their condition with sulindac, showing significant regression of colorectal polyps over two years, despite initially refusing colectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Germline Mutation in Exon 15 of the APC Gene in Attenuated Familial Adenomatous Polyposis: A Report of Two Cases. Jahng, J., Yoon, SJ., Park, H.[2021]

In a study involving six patients with familial adenomatous polyposis (FAP), treatment with the COX-2 inhibitor meloxicam led to a significant increase in COX-2 expression in adenomas, suggesting a potential effect on tumor biology.

The treatment also resulted in a down-regulation of the APC gene, a key player in the Wnt signaling pathway, indicating that meloxicam may influence important cancer-related pathways in FAP patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of COX-2 and Wnt pathway genes in adenomas of familial adenomatous polyposis patients treated with meloxicam. Dobbie, Z., Muller, PY., Heinimann, K., et al.[2018]

Patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) require frequent endoscopic surveillance and may need prophylactic colectomy to prevent colorectal cancer, with ongoing management focusing on both colorectal and upper gastrointestinal adenomas.

Recent advancements allow for endoscopic treatment of premalignant lesions in the upper gastrointestinal tract, shifting the focus from solely diagnostic surveillance to active intervention, while research into chemopreventive agents aims to further reduce polyp burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of familial adenomatous polyposis and MUTYH-associated polyposis; new insights. Aelvoet, AS., Buttitta, F., Ricciardiello, L., et al.[2022]

In a Phase III trial involving 106 children with familial adenomatous polyposis (FAP), celecoxib treatment resulted in a lower rate of colorectal polyps and a longer time to disease progression compared to placebo, with 12.7% of celecoxib patients showing disease progression versus 25.5% in the placebo group.

Celecoxib was well-tolerated, with similar rates of adverse events between the treatment and placebo groups, although three patients on celecoxib experienced serious adverse events, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Children's International Polyposis (CHIP) study: a randomized, double-blind, placebo-controlled study of celecoxib in children with familial adenomatous polyposis. Burke, CA., Phillips, R., Berger, MF., et al.[2020]

Citations

1. ir.recursion.com ir.recursion.com/news-releases/news-release-details/preliminary-phase-1b2-data-rec-4881-familial-adenomatous

Preliminary Phase 1b/2 Data for REC-4881 in Familial ... 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- ...

2. clinicaltrialvanguard.com clinicaltrialvanguard.com/news/rec-4881-fap-study-shows-reduced-polyp-burden/

Rec-4881 FAP Study Shows Reduced Polyp Burden A 43% reduction in polyp burden at just 13 weeks suggests REC-4881 could significantly alter disease management and improve patient outcomes.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05552755

NCT05552755 | Evaluate REC-4881 in Patients With FAP This is a Phase 1b/2, trial to evaluate efficacy, safety, pharmacokinetics and pharmacodynamics of REC-4881 in participants with Familial Adenomatous Polyposis ...

4. facingourrisk.org facingourrisk.org/research-clinical-trials/study/288/testing-the-safety-and-action-of-the-investigational-drug-rec-4881-in-people-with-familial-adenomatous-polyposis-fap

Testing the Safety And Action of the Investigational Drug ... This study is looking at how safe and effective the research drug REC-4881 is for treating polyps in people with Familial Adenomatous Polyposis (FAP).

5. seekingalpha.com seekingalpha.com/article/4814775-recursion-hold-rating-based-on-initial-rec-4881-fap-treatment-data

Recursion: "Hold" Rating Based On Initial REC-4881 FAP ... REC-4881 demonstrated significant polyp reduction in most FAP patients, yet one non-responder raises questions about its future potential. I ...

6. ir.recursion.com ir.recursion.com/news-releases/news-release-details/recursion-present-preliminary-clinical-data-ongoing-phase-1b2

Recursion to Present Preliminary Clinical Data from the ... This multicenter, open-label study assesses the efficacy, safety, and pharmacokinetics of REC-4881 in this patient population.

7. ddw.digitellinc.com ddw.digitellinc.com/p/s/ongoing-phase-1b2-trial-of-the-allosteric-mek12-inhibitor-rec-4881-as-monotherapy-in-familial-adenomatous-polyposis-fap-preliminary-safety-and-efficacy-data-11698

ONGOING PHASE 1B/2 TRIAL OF THE ALLOSTERIC MEK1/2 ... ... 4881 AS MONOTHERAPY IN FAMILIAL ADENOMATOUS POLYPOSIS (FAP): PRELIMINARY SAFETY AND EFFICACY DATA. Date. May 4, 2025. Explore related products in the following ...