Phase 3 Trial of eRapa in Patients With Familial Adenomatous Polyposis

This Phase 3 clinical trial is testing whether eRapa — an enteric-coated formulation of rapamycin (sirolimus) designed for intermittent dosing — can slow the progression of Familial Adenomatous Polyposis (FAP), a hereditary condition caused by APC gene mutations that leads to hundreds of colorectal polyps and near-certain colon cancer if untreated. Rapamycin works partly by inhibiting mTOR, a master regulator of cell growth, and by activating autophagy — the cellular 'self-cleaning' process that degrades damaged proteins and organelles. The trial is randomized and placebo-controlled, meaning neither participants nor investigators know who receives the active drug until the study ends, which is the gold standard for testing efficacy. Participants take eRapa or placebo once daily on alternating weeks — a dosing schedule intended to preserve autophagy induction while minimizing immunosuppressive side effects — continuing until disease progresses. Outcomes include polyp burden in the GI tract measured by endoscopy every six months, overall disease progression, safety, and patient-reported quality of life. FAP currently has no approved pharmacological agent proven to halt polyp progression long-term, making this one of the first Phase 3 rapalog trials in a hereditary GI cancer syndrome. If successful, this trial could establish mTOR inhibition and autophagy induction as a viable chemoprevention strategy in a high-risk population.

• Primary efficacy endpoint: whether eRapa slows disease progression versus placebo in FAP patients — results are not yet available as the trial is actively recruiting with an estimated completion date of May 2026.
• The study will quantify change in GI polyp number and burden via endoscopy at baseline and every 6 months, providing one of the most rigorous pharmacological polyp-burden datasets in FAP to date.
• Safety and tolerability of the every-other-week intermittent dosing regimen of rapamycin will be systematically characterized, addressing a key translational question about whether pulsed mTOR inhibition reduces adverse effects compared to continuous dosing.

This is a Phase 3, randomized, double-blind, placebo-controlled trial sponsored by Rapamycin Holdings Inc. (NCT06950385), currently recruiting participants diagnosed with Familial Adenomatous Polyposis. Participants are randomized to receive oral eRapa (enteric-coated rapamycin) or matched placebo once daily every other week, continuing until disease progression, withdrawal, or death. Clinic visits occur every 3 months and endoscopic assessment of GI polyp burden is conducted at baseline and every 6 months thereafter; sample size and specific dosing levels have not been publicly disclosed in the available record.

As an active recruiting trial, no efficacy or safety outcome data are yet available, so all findings noted here are prospective and based on trial design only — confidence in outcome-level conclusions is low. The every-other-week dosing schedule, while mechanistically motivated, has not been validated head-to-head against continuous rapamycin dosing in FAP, meaning the optimal regimen remains uncertain. The trial does not appear to include pharmacodynamic biomarkers of autophagy flux (e.g., LC3-II, p62) in its publicly described endpoints, which limits mechanistic interpretation of any clinical benefit. A key next experiment would be a parallel biomarker substudy measuring autophagy induction in colonic mucosa biopsies to confirm that the intermittent dosing regimen achieves the intended cellular mechanism in the target tissue.

This trial sits at the translational apex of the mTOR-autophagy axis explored across multiple articles in this corpus. It directly extends [§62], which characterizes PI3K/AKT/mTOR pathway suppression as a mechanism for reducing cancer cell proliferation, by moving mTOR inhibition into a Phase 3 setting in a defined hereditary cancer syndrome. The trial also parallels [§92], another randomized trial testing an autophagy-modulating agent (hydroxychloroquine) in combination with targeted therapy in a GI malignancy, highlighting a shared strategy of leveraging autophagy dysregulation as a therapeutic vulnerability in colorectal cancer contexts. The mechanistic rationale for autophagy induction as a tumor-suppressive intervention in the GI tract is further supported by [§63], which maps the crosstalk between autophagy pathways and colorectal cancer progression — providing a biological framework for why restoring autophagic flux in FAP polyp epithelium may reduce adenoma burden. Together, these articles frame the eRapa trial as the highest-evidence test yet of whether pharmacological autophagy induction can translate preclinical and mechanistic insights into clinical chemoprevention in a cancer-predisposition syndrome.

• Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory
  Direct methodological parallel: both are randomized controlled trials testing autophagy-modulating agents (rapamycin vs. hydroxychloroquine) in GI cancer contexts, enabling comparison of clinical trial design and tolerability strategies across rapalogs and autophagy inhibitors.
• Mechanism of Inonotus hispidus in suppressing renal cell carcinoma proliferation via regulation of the PI3K/AKT/mTOR pathway
  Shares the PI3K/AKT/mTOR mechanistic axis — this preclinical study of mTOR pathway suppression in renal cell carcinoma provides the molecular context for why mTOR inhibition in FAP polyp epithelium is biologically plausible.
• The Mechanistic Crosstalk between Probiotics, ncRNAs, and Autophagy: Implications for Colorectal Cancer Precision Medicine
  Directly relevant disease context: this article maps autophagy-ncRNA-microbiome interactions in colorectal cancer and offers a complementary mechanistic lens for understanding how autophagy modulation might alter polyp progression in FAP.
• Metformin-phytochemical combination therapy in metabolic dysfunction-associated steatotic liver disease: mechanistic insights and therapeutic potential
  Examines combinatorial mTOR-pathway modulation via metformin and phytochemicals in metabolic liver disease, providing a useful comparison for pulsed versus continuous mTOR inhibition strategies and their autophagy-induction profiles.
• Mammalian Lysophagy: mechanisms and pathophysiological implications
  Covers mammalian lysophagy mechanisms downstream of mTOR signaling — understanding lysosomal quality control is essential context for interpreting how rapamycin-induced autophagy may clear pre-neoplastic cellular debris in FAP polyp tissue.