A Phase 2, Multi-Center, Platform Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics with Multiple Therapies in Participants with Active Crohn’s Disease or Active Ulcerative Colitis (ASCEND-IBD)

The primary objective of this study is to evaluate the safety and tolerability of investigational therapies following the Induction Phase in participants with active Crohn's disease or active ulcerative colitis. In prospective observer-blinded endpoint intervention-specific appendices, the primary objective is to assess the proportion of participants achieving endoscopic response in Crohn's disease or endoscopic improvement in ulcerative colitis at the end of the Induction Phase. In randomized placebo-controlled intervention-specific appendices, the primary objective is to assess the proportion of participants achieving clinical remission at the end of the Induction Phase. These endpoints are clinically relevant as they evaluate both mucosal healing and symptomatic control, which are key therapeutic targets in inflammatory bowel disease management.

The secondary objectives include:

• Assessment of the proportion of participants with clinical remission at the end of the Induction Phase in prospective observer-blinded endpoint intervention-specific appendices

• Assessment of the proportion of participants with endoscopic response in Crohn's disease or endoscopic improvement in ulcerative colitis at the end of the Induction Phase in randomized placebo-controlled intervention-specific appendices

• Assessment of the proportion of participants with symptomatic remission at the end of the Induction Phase

• Assessment of the proportion of participants with clinical response at the end of the Induction Phase

• Assessment of the proportion of participants with endoscopic and clinical response at the end of the Induction Phase in Crohn's disease only

• Assessment of the proportion of participants with histologic response at the end of the Induction Phase in ulcerative colitis only

• Assessment of the proportion of participants with histologic remission at the end of the Induction Phase in ulcerative colitis only

• Assessment of the proportion of participants with histologic-endoscopic mucosal improvement at the end of the Induction Phase in ulcerative colitis only

• Characterization of the change in endoscopy score from Day 1 to the end of the Induction Phase

• Characterization of the change in histology score from Day 1 to the end of the Induction Phase

• Assessment of the pharmacokinetics of the investigational drug

The clinical trial enrolled a total of **1 participant** diagnosed with either **ulcerative colitis** or **Crohn's disease**. The study population included both male and female participants aged **18 to 80 years**. Eligible participants were required to have **moderately to severely active disease**, with those with ulcerative colitis demonstrating appropriate disease activity levels and those with Crohn's disease meeting specific **Crohn's Disease Activity Index (CDAI)** criteria and **Simple Endoscopic Score for Crohn's Disease (SES-CD)** consistent with moderate to severe activity as determined by central reading. Participants were selected based on documented diagnosis of their respective condition and having experienced **insufficient response and/or intolerance** to prior treatments including corticosteroids, immunosuppressants, and/or approved advanced therapies. All participants were required to meet specific drug stabilization requirements prior to enrollment. Female participants of childbearing potential were required to have a negative serum pregnancy test at screening, with additional contraceptive requirements applicable per individual study protocols. The trial population included vulnerable populations as defined by regulatory standards.

This is a Phase 2, multi-center, platform study designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of multiple therapies in participants with active Crohn's disease or active ulcerative colitis. The study employs two distinct design approaches depending on the intervention-specific appendix (ISA): prospective observer-blinded endpoint ISAs and randomized placebo-controlled ISAs. The investigational medicinal products include MT-501 administered as film-coated tablets via oral use, along with matching placebo for MT-501 film-coated tablets. The active substance MT-501 is of chemical origin.

The primary objective of the trial is to evaluate safety and tolerability following the Induction Phase. For prospective observer-blinded endpoint ISAs, the study aims to assess the proportion of participants with endoscopic response in Crohn's disease or endoscopic improvement in ulcerative colitis at the end of the Induction Phase. For randomized placebo-controlled ISAs, the primary objective is to assess the proportion of participants achieving clinical remission at the end of the Induction Phase. Secondary objectives include evaluation of clinical remission, endoscopic response or improvement, Patient-Reported Outcome-2 (PRO-2) remission, clinical response, and changes in disease activity scores such as Simple Endoscopic Score for Crohn's Disease (SES-CD) and Mayo Endoscopic Score (MES). Additional secondary endpoints assess histologic response, histologic remission, and changes in various histopathology scores including Global Histopathology Activity Score (GHAS), Robarts Histopathology Index (RHI), Geboes score, and Nancy Histology Index (NHI). Descriptive summaries of pharmacokinetics of the investigational drug will also be evaluated.

Eligible participants must be between 18 and 80 years of age. For ulcerative colitis, participants must have moderately to severely active disease and meet drug stabilization requirements. For Crohn's disease, participants must have documented diagnosis with moderately to severely active disease as defined by Crohn's Disease Activity Index (CDAI), and SES-CD consistent with moderate to severe activity per central reading. All participants must have had insufficient response and/or intolerance to corticosteroids, immunosuppressants, and/or an approved advanced therapy for ulcerative colitis or Crohn's disease. Female participants must be of non-childbearing potential or have a negative serum pregnancy test at screening if of childbearing potential, with additional birth control requirements applying for each ISA. Participants must be able to provide written informed consent and comply with study requirements.

The primary endpoints include the proportion of participants reporting treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events leading to discontinuation, and markedly abnormal laboratory values. For prospective observer-blinded endpoint ISAs, primary efficacy endpoints are the proportion of participants with endoscopic response in Crohn's disease or endoscopic improvement in ulcerative colitis at the end of the Induction Phase. For randomized placebo-controlled ISAs, the primary efficacy endpoint is the proportion of participants achieving clinical remission at the end of the Induction Phase.

The estimated recruitment start date is October 30, 2025, with an estimated study end date of May 7, 2027. The overall trial duration encompasses the recruitment period, treatment phases, and follow-up assessments as specified in the master protocol and individual ISAs.

The experimental medication **MT-501** is administered as a **film-coated tablet** formulated for **oral use**. MT-501 contains a chemical active substance and is manufactured by Mirador Therapeutics, Inc. Two formulations of MT-501 film-coated tablets are utilized in this clinical trial, both designated as test products. The specific dosage amounts, frequency of administration, and duration of treatment during the **Induction Phase** are evaluated as part of the study protocol to assess safety, tolerability, efficacy, **pharmacokinetics**, and **pharmacodynamics** in participants with active **Crohn's disease** or active **ulcerative colitis**.

A **placebo** for MT-501 is included in the trial as a comparator treatment for randomized placebo-controlled intervention-specific arms. The placebo is formulated as film-coated tablets to match the appearance of the active MT-501 medication, thereby maintaining blinding integrity throughout the study. The placebo contains no active pharmaceutical ingredient and serves as a control to enable assessment of the therapeutic effect of MT-501. Administration of the placebo follows the same route and schedule as the experimental medication to ensure consistency in study conduct.

The trial employs a platform study design incorporating both prospective observer-blinded endpoint intervention-specific arms and randomized placebo-controlled intervention-specific arms. **Clinical remission** and **endoscopic response** or **endoscopic improvement** are evaluated at the end of the Induction Phase as primary efficacy endpoints. Participant compliance monitoring and adherence to the prescribed dosing schedules are integral components of the study to ensure accurate assessment of treatment outcomes and safety profiles across all study arms.

Efficacy will be assessed through multiple endpoints evaluated at the end of the Induction Phase. For **Crohn's disease** participants, the primary efficacy endpoint is the proportion of participants with endoscopic response, while for **ulcerative colitis** participants, it is the proportion with endoscopic improvement. In Randomized Placebo-Controlled Investigation Sub-studies, the primary endpoint is the proportion of participants achieving clinical remission at the end of the Induction Phase. Safety will be evaluated by monitoring the proportion of participants reporting treatment-emergent adverse events, serious adverse events, adverse events leading to discontinuation, and markedly abnormal laboratory values.

Secondary efficacy endpoints include the proportion of participants with clinical remission, the proportion with Patient-Reported Outcome-2 remission, and the proportion with clinical response at the end of the Induction Phase. For **Crohn's disease**, additional secondary endpoints include the proportion of participants with endoscopic and clinical response, as well as endoscopic response alone. For **ulcerative colitis**, secondary endpoints include the proportion of participants with histologic response, histologic remission, and histologic-endoscopic mucosal improvement. Changes in disease activity scores will be assessed, including changes in Simple Endoscopic Score for Crohn's Disease from Day 1 to end of Induction Phase for **Crohn's disease** participants, and changes in Mayo Endoscopic Score for **ulcerative colitis** participants. Histopathology changes will be evaluated using the Global Histopathology Activity Score and Robarts Histopathology Index for **Crohn's disease**, and the Geboes score, Robarts Histopathology Index, and Nancy Histology Index for **ulcerative colitis**. Descriptive summaries of pharmacokinetics of the investigational drug will also be provided.