Evaluation of the Efficacy and Safety of Oral 1,3,5-Tris(6-Methylpyridin-2-yloxy)benzene in Moderate to Severe Ulcerative Colitis: A Phase 2 Randomized Controlled Trial

Trial ID: 2022-503005-38-00
Protocol: NX-13-201/M25-484
Sponsor: Landos Biopharma Inc.

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Diseases & Conditions

Colitis ulcerative

Objectives

The primary objective of this study is to assess the **clinical activity** of oral NX-13 compared to placebo in participants with moderate to severe **Ulcerative Colitis**. This evaluation is clinically relevant as it aims to determine the efficacy of NX-13 in managing symptoms and improving the condition of patients suffering from this chronic inflammatory bowel disease.

Secondary objectives include evaluating the following aspects:

**Safety and tolerability** of the treatment, which is crucial for understanding the risk-benefit profile of NX-13.
**Clinical remission**, which refers to the absence of symptoms, indicating the effectiveness of the treatment in achieving a symptom-free state.
**Clinical response**, assessing the degree of improvement in clinical symptoms.
**Endoscopic response**, which involves evaluating changes in the mucosal appearance through endoscopy.
**Endoscopic remission**, indicating the absence of visible inflammation during endoscopy.
**Endoscopic-histologic mucosal improvement**, assessing both endoscopic and histological changes in the mucosa.
**Symptomatic remission**, focusing on the resolution of symptoms experienced by the patient.

These secondary objectives provide a comprehensive understanding of the treatment's impact on both clinical and endoscopic parameters, contributing to a holistic evaluation of NX-13's therapeutic potential.

Participants

The clinical trial involves a total of **10 participants** diagnosed with **Ulcerative Colitis**. The study population includes both male and female subjects, aged between **18 to 75 years**. Participants were selected based on their ability to provide informed consent and comply with study requirements, including attending visits and maintaining e-diaries. The trial includes individuals with moderate to severe disease activity who have had an inadequate response to, loss of response to, or intolerance of conventional, biologic, or advanced therapies. Participants are required to have undergone a surveillance colonoscopy within 12 months prior to randomization to rule out dysplasia. Lifestyle considerations such as diet and physical activity are not specified. The trial population includes vulnerable individuals, and both genders are represented, with specific contraceptive requirements for women of childbearing potential and men to prevent conception during and after the trial period.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the clinical activity and safety of oral NX-13 in participants with moderate to severe **ulcerative colitis**. The trial is structured in a multiple-dose, multicenter Phase 2 induction study with a long-term extension. The primary objective is to assess the clinical activity of oral NX-13 compared to placebo, with the primary endpoint being the change from baseline in the Modified Mayo Score (MMS) at Week 12. Secondary endpoints include safety and tolerability, clinical remission, clinical response, endoscopic response, endoscopic remission, endoscopic-histologic mucosal improvement, and symptomatic remission.

The trial is expected to last until August 21, 2025, with recruitment starting on September 4, 2023. Participants will be involved for a maximum treatment period of 52 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be between 18 and 75 years of age, have a confirmed diagnosis of ulcerative colitis for at least three months, and demonstrate moderate to severe disease activity. Participants must also have an inadequate response or intolerance to certain conventional, biologic, or advanced therapies.

Participants may be terminated early from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The study employs a double-blind design, ensuring that neither the participants nor the investigators know which treatment the participants receive, thereby minimizing bias. The investigational product, NX-13, is administered orally in tablet form, with a maximum daily dose of 750 mg. The trial is conducted under the sponsorship of Landos Biopharma Inc., with NX-13 being the test product and a matching placebo used as the control. The study aims to provide valuable insights into the efficacy and safety of NX-13 for treating moderate to severe ulcerative colitis.

Treatment

The clinical trial involves the administration of **NX-13**, an experimental medication formulated as a **tablet**. The active substance in NX-13 is **1,3,5-tris(6-methylpyridin-2-yloxy)benzene**, a chemical entity developed by Landos Biopharma Inc. The medication is administered orally, with a maximum daily dose of 750 mg and a total maximum dose of 273 g over a treatment period of up to 52 weeks. The trial aims to evaluate the clinical activity and safety of NX-13 in participants with moderate to severe **ulcerative colitis**.

In addition to the experimental treatment, the study includes the use of an **NX-13 Matching Placebo**. The placebo is designed to mimic the appearance and administration route of the NX-13 tablet, ensuring the double-blind nature of the trial. The placebo is administered orally, following the same dosing schedule as the experimental medication, to maintain consistency in the treatment regimen across all study participants.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the clinical activity of oral NX-13 compared to placebo in participants with moderate to severe **Ulcerative Colitis**. The primary endpoint is the change from baseline in the Modified Mayo Score (MMS) at Week 12. This score is a composite index used to assess disease activity in Ulcerative Colitis, incorporating stool frequency, rectal bleeding, and endoscopic findings.

Secondary endpoints include several measures of clinical and endoscopic outcomes at Week 12. These include the proportion of participants achieving clinical remission, defined as an MMS of 2 or less, and clinical response, characterized by a reduction of at least 2 points and 30% from baseline in MMS, with a decrease of at least 1 point in the rectal bleeding subscore (RBS) or an RBS of 1 or less. Endoscopic response and remission will be evaluated by the proportion of participants with an endoscopic subscore (ES) of 1 or less and 0, respectively. Additionally, endoscopic-histologic mucosal improvement will be assessed by the proportion of participants with an ES of 1 or less and a Geboes score of less than 2.0. Symptomatic remission will be determined by the proportion of participants with an RBS of 0 and a stool frequency subscore (SFS) of 0, or an SFS of 1 with a baseline SFS of 2 or more.

The efficacy parameters will be measured at baseline and at Week 12, using validated scales and clinical assessments. Data collection will involve clinical evaluations, patient-reported outcomes, and laboratory tests to ensure comprehensive assessment of the treatment's impact on disease activity. The analysis will focus on comparing the changes in these parameters between the treatment and placebo groups to determine the efficacy of NX-13 in managing moderate to severe Ulcerative Colitis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

18 to 75 years of age at time of informed consent
Able to give informed consent, attend, and comply with study visits and e-diaries
Diagnosed with UC ≥ 3 months prior to screening. The diagnosis of UC must be confirmed by endoscopic and histologic evidence. The endoscopy and histology report should be present in source documents; however, if not available, the screening endoscopy and histology report may serve as such.
Received a surveillance colonoscopy (performed according to local standard) within 12 months prior to the planned randomization date to rule out dysplasia in individuals with pancolitis > 8 years duration or individuals with left sided colitis > 12 years duration. Individuals without a surveillance colonoscopy within the prior 12 months will have a colonoscopy at screening (i.e., in place of the screening proctosigmoidoscopy). Any adenomatous polyps must be removed according to routine practice prior to the study participant’s first dose of investigational product.
Moderate to severe disease activity, characterized by all of the following (see Section 7.3.1 for details): • MMS ≥ 5 defined as follows: • ES ≥ 2 within 14 days prior to randomization • RBS ≥ 1
An inadequate response to, loss of response to, or intolerance of at least 1 of the following therapies, as defined below (see Section 12.9 for details): Conventional therapy classes: • Oral 5-ASA compounds plus systemic glucocorticosteroids/glucocorticoids • Systemic glucocorticosteroids/glucocorticoids • Thiopurines Biologic therapy classes: • Anti-TNF monoclonal antibodies or biosimilars • Anti-integrin monoclonal antibodies • Anti-IL-12/23 monoclonal antibodies Advanced therapy classes: • JAK inhibitors • S1P receptor modulators
Eligible male participants must either: • Be surgically sterile (i.e., vasectomy) for ≥ 3 months (≥ 90 days) before screening; or • Agree to the following, from the time of randomization until at least 30 days after last dose of investigational product: o Agree to use a condom with spermicide when sexually active with a female partner who was not using a highly effective method of birth control o Agree not to participate in a conception process (i.e., active attempt to impregnate, sperm donation, or in vitro fertilization)
Eligible female participants must be: • Nonpregnant, evidenced by a urine dipstick pregnancy test within 24 hours prior to randomization, and • Nonlactating
Eligible female participants of non-childbearing potential must be surgically sterile or postmenopausal (defined as ≥ 1 year without menses). • Women must be surgically sterile for at least 6 months before screening as confirmed by medical history. Surgical procedures are tubal ligation performed laparoscopically, hysterectomy, and/or bilateral oophorectomy; or other procedures if sponsor agrees. • A postmenopausal state is defined as no menses for ≥ 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.
Women of childbearing potential (WOCBP) must: • Agree to use birth control methods that are considered highly effective: o Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal o Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable o Intrauterine device (IUD) o Intrauterine hormone-releasing system (IUS) o Bilateral tubal occlusion o Vasectomized partner o Sexual abstinence Note: Contraceptive measures such as Plan B (used after unprotected sex) are not considered highly effective methods of contraception for this study • Agree not to participate in a conception process (i.e., active attempt to become pregnant, egg donation, in vitro fertilization) for at least 30 days after the last dose of investigational product

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Exclusion Criteria

Severe extensive colitis as evidenced by: • Physician judgment that the participant is likely to require hospitalization for medical care or surgical intervention of any kind for UC (e.g., colectomy) within the 12 weeks after randomization • Current evidence of fulminant colitis, toxic megacolon or recent history (within 6 months prior to screening) of toxic megacolon, or bowel perforation
Diagnosis of Crohn’s disease (CD) or indeterminate colitis, or the presence or history of a fistula consistent with CD
Inadequate response to an induction course of more than 2 classes of biologics (e.g. TNF alpha, integrin or IL-12/23) approved for UC
Diagnosis of microscopic colitis, ischemic colitis, or radiation colitis
History of active bacterial, viral, fungal, or mycobacterial infectious colitis requiring oral antibiotic/anti-infective treatment within 4 weeks prior to screening.
Infection requiring hospitalization or intravenous (IV) antimicrobial therapy within 8 weeks prior to screening
Presence of indefinite dysplasia or UC-associated dysplasia on colonoscopy or FS, or a history of UC-associated dysplasia
History of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy; or is planning bowel surgery
History of spontaneous gastrointestinal (GI) perforation (other than appendicitis or mechanical injury), diverticulitis, or at significantly increased risk of GI perforation per the investigator’s judgment
Hospitalization for exacerbation of UC requiring IV steroids (i.e., UC flare) within 12 weeks prior to screening (a single dose of IV steroids is acceptable)
Treatment with cyclosporine, tacrolimus, sirolimus, methotrexate, or mycophenolate mofetil within 4 weeks prior to screening.
Thiopurine washout is required to be completed within 6 weeks prior to screening.
Treatment with a biologic agent (e.g., infliximab, vedolizumab) within 6 weeks or 5 elimination half-lives (whichever is less) prior to screening. For anti-IL-12/23 (p19 or p40 subunits) (e.g., ustekinumab) a total of 12 weeks (6 weeks prior to screening and 6 weeks of screening) or 5 elimination half-lives (whichever is less) of washout.
Treatment with an advanced oral UC therapy (e.g., JAK inhibitor, S1P modulator) within 4 weeks prior to screening
Treatment with IV glucocorticosteroids/glucocorticoids, rectal glucocorticosteroids/ glucocorticoids, rectal or topical 5-ASA, or enema within 2 weeks prior to screening
Treatment with oral prednisone at a daily dose of > 20 mg (or equivalent) or active oral glucocorticosteroids/ glucocorticoids , e.g., budesonide at a daily dose of > 9 mg or equivalent, within 30 days prior to screening. If receiving systemically active oral glucocorticosteroids/ glucocorticoids , must be on a stable dose for at least 14 days prior to screening.
Confirmed or suspected infection of the intestinal tract, including positive Clostridioides difficile stool test at screening
Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at screening
Have current hepatitis C infection or test positive for hepatitis C virus (HCV) at screening
Have known infection with human immunodeficiency virus as confirmed by medical history
Live virus vaccination within 4 weeks prior to randomization (Note: no currently available vaccine for SARS-CoV-2 is a live virus vaccine)
Fecal microbial transplantation within 30 days prior to screening
Known primary or secondary immunodeficiency
Previously received stem cell transplantation
Has been a previous recipient of an organ transplant, which requires continued immunosuppression
Any surgical procedure requiring general anesthesia within 4 weeks prior to randomization, or planned elective surgery during the study
History of malignant neoplasms or carcinoma within 5 years prior to screening (except basal cell and in situ squamous cell carcinomas of the skin that have been fully excised and resolved)
Requirement for regular dosing of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) or inducers (e.g., rifampin, phenytoin, carbamazepine) or CYP2C19 inhibitors (e.g., fluconazole, fluoxetine, fluvoxamine, ticlopidine) or inducers (e.g., rifampin).
Current or recent history of alcohol dependence or recreational drug use that, in the opinion of the investigator, may interfere with the individual’s ability to comply with the study procedures
Mental or legal incapacitation at the time of screening or a history of clinically significant psychiatric disorders that would impact the individual’s ability to participate in the study, according to the investigator
Any concurrent clinically significant medical condition that, in the judgment of the investigator, may pose an unacceptable risk to the participant, including any known hypersensitivity to the drug product or any of its excipients
Participants with evidence of active or latent infection with Mycobacterium tuberculosis (TB) or participants with this history who have not completed a generally accepted full course of treatment (with completion of this treatment at least 6 months prior to start of screening) are excluded. All other participants must have either the Mantoux (purified protein derivative [PPD]) tuberculin skin test or interferon gamma release assay (IGRA) performed. See Section 12.7 for details.
Unable to comply with study activities (e.g., swallow 3 whole tablets per day without crushing, breaking, or chewing)
Concurrent participation in any other investigational study, or individuals who have received any investigational therapy within 4 weeks or 5 elimination half-lives (whichever is longer) prior to screening
Women who are pregnant, breastfeeding, or contemplating pregnancy, from the time of informed consent until at least 30 days after the last dose of investigational product.
Estimated absolute glomerular filtration rate of < 30 mL/minute
Liver transaminases (ALT, AST) > 1.5× ULN at screening
Total bilirubin > 1.5× ULN at screening, or > 2.0× ULN for individuals with Gilbert’s syndrome
Hemoglobin < 9g/dL (< 5.6 mmol/L) at screening
Individuals who are investigational site staff members or relatives of those site staff members or are Sponsor or CRO employees directly involved in the conduct of the study