A Phase 2b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of 3 Active Dose Regimens of MORF-057 in Adults with Moderately to Severely Active Ulcerative Colitis (EMERALD-2)

Trial ID: 2022-500953-17-00
Protocol: MORF-057-202
Sponsor: Morphic Therapeutic Inc.

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Diseases & Conditions

Colitis ulcerative

Objectives

The primary objective of this study is to evaluate the effects of **MORF-057** on clinical remission at Week 12 in adults with moderately to severely active ulcerative colitis. This is clinically relevant as achieving clinical remission is a critical goal in the management of ulcerative colitis, aiming to improve patient outcomes and quality of life.

Secondary objectives include: - Secondary Efficacy: To evaluate the effects of MORF-057 on clinical response at Week 12. - Exploratory Efficacy: To evaluate the effects of MORF-057 on clinical remission and response at Week 52, MCS remission and response at Weeks 12 and 52, histologic remission and improvement at Weeks 12 and 52, endoscopic improvement and remission at Weeks 12 and 52, mucosal healing and improvement at Weeks 12 and 52, symptomatic response at Weeks 2 and 6, Partial MCS response at Week 6, time to symptomatic response by Week 12, non-endoscopic biomarkers of inflammation at Weeks 12 and 52, patient-reported outcomes at Weeks 12 and 52, corticosteroid-free remission at Week 52, and the need for UC-related hospitalizations and surgeries. Additionally, the long-term histologic and endoscopic effects of MORF-057 will be evaluated at Week 104. - Safety: To assess the safety and tolerability of MORF-057. - Pharmacokinetics: To characterize the PK of MORF-057. - Exploratory Pharmacodynamics: To characterize the PD of MORF-057 in peripheral blood.

Participants

The clinical trial involves a total of **126 participants** diagnosed with **moderately to severely active ulcerative colitis**. The study population includes both male and female subjects, aged between 18 and 85 years. Participants were selected based on their ability to provide informed consent and their compliance with the study's requirements. The trial includes individuals who have demonstrated an inadequate response, loss of response, or intolerance to previous treatments for ulcerative colitis, such as oral aminosalicylates, corticosteroids, immunosuppressants, or advanced therapies. Participants are required to have a body mass index (BMI) of at least 18.0 at screening. The study population is characterized by a diverse age range and includes individuals who are capable of adhering to the study's guidelines, including those related to contraception and medication washout periods. The trial does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's effects across different demographic groups.

Plans and Procedures

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the safety and efficacy of three active dose regimens of **MORF-057** in adults with moderately to severely active **ulcerative colitis**. The trial aims to assess the effects of MORF-057 on clinical remission at Week 12, with the primary endpoint being the proportion of participants in clinical remission as determined using the Modified Mayo Clinic Score (mMCS). The study is expected to last until November 30, 2026, with participant recruitment having commenced on March 15, 2023.

Participants will be involved in the study for a maximum treatment period of 52 weeks. The trial 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 85 years of age, with a confirmed diagnosis of ulcerative colitis for at least three months prior to screening. Participants must demonstrate an inadequate response, loss of response, or intolerance to at least one prior treatment for ulcerative colitis.

Study visits are structured to ensure comprehensive monitoring and data collection. The screening visit will involve assessments to confirm the diagnosis and severity of ulcerative colitis, as well as to ensure compliance with the study's inclusion criteria. Follow-up visits will occur at regular intervals to evaluate the primary and secondary endpoints, including clinical response and remission rates at Weeks 12 and 52. The end-of-study visit will finalize data collection and assess long-term outcomes.

Participant involvement may be terminated early if they experience treatment-emergent serious adverse events or if they fail to comply with the study protocol. The trial is designed to maintain participant safety and data integrity, with stringent criteria for continuation and withdrawal. The study will utilize MORF-057 IR Capsules and a placebo, both administered orally, with a maximum daily dose of 400 mg. The trial's design and procedures are aligned with regulatory standards to ensure robust and reliable results.

Treatment

The clinical trial involves the administration of **MORF-057**, an investigational medication formulated as an immediate-release capsule. The active substance, MORF-057, is of chemical origin and is developed by Morphic Therapeutic, Inc. The pharmaceutical form of the medication is a capsule, intended for **oral use**. The maximum daily dose of MORF-057 is 400 mg, with a total maximum dose of 145.6 grams over the course of the study. The treatment period extends up to 52 weeks. The study aims to evaluate the safety and efficacy of three active dose regimens of MORF-057 in adults with moderately to severely active **ulcerative colitis**.

The trial also includes a **placebo** group, which receives a capsule that is unauthorised and contains no active substance. The placebo is designed to match the MORF-057 capsule in appearance to maintain the double-blind nature of the study. The placebo is administered orally, following the same dosing schedule as the active treatment groups. This allows for a controlled comparison to assess the true efficacy and safety of MORF-057. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

Efficacy

The efficacy of MORF-057 in the treatment of moderately to severely active **Ulcerative Colitis** will be assessed through a series of primary, secondary, and exploratory endpoints. The primary efficacy endpoint is the proportion of participants achieving clinical remission at Week 12, as determined by the Modified Mayo Clinic Score (mMCS). This score is a composite of the Mayo endoscopic subscore (MES), stool frequency subscore, and rectal bleeding subscore.

Secondary efficacy will be evaluated by the proportion of participants with a clinical response at Week 12, also using the mMCS. Exploratory efficacy endpoints include the proportion of participants in clinical remission and response at Week 52, as well as various other measures such as histologic and endoscopic remission and improvement, assessed at Weeks 12, 52, and 104. These assessments will utilize tools such as the Robarts Histopathology Index (RHI), Nancy Histopathology Index (NI), and Continuous Geboes Score.

Additional exploratory endpoints include changes from baseline in high sensitivity C-reactive protein (hs CRP) levels, fecal calprotectin levels, and the Inflammatory Bowel Disease Questionnaire (IBDQ) Score at Weeks 12 and 52. The study will also monitor the proportion of participants achieving corticosteroid-free remission at Week 52 and the percentage requiring UC-related hospitalization or surgery at Weeks 12 and 52.

Data collection will occur at specified timepoints, including Weeks 2, 6, 12, 52, and 104, using validated scales and laboratory tests to ensure accurate and reliable measurement of efficacy parameters. The analysis will focus on the proportion of participants meeting the defined criteria for each endpoint, providing a comprehensive evaluation of MORF-057's efficacy in this patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female, 18 to 85 years of age, inclusive, at the time of signing the Informed Consent Form (ICF).
Participant has had diagnosis of UC supported by signs/symptoms, endoscopy, and histology for at least 3 months prior to Screening. Moderately to severely active UC was determined during the Screening Period with the following criteria: an mMCS of 5 to 9 (inclusive), with an MES ≥2 (confirmed by central reader)
Has evidence of UC extending at least 15 cm from the anal verge
Demonstrated an inadequate response, loss of response, or intolerance to at least one of the following treatments (including oral aminosalicylates, corticosteroids, immunosuppressants, and/or advanced therapies for UC) in the opinion of the Investigator : Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, or balsalazide), Corticosteroids, Immunosuppressants (e.g., azathioprine, 6 mercaptopurine, or methotrexate), Advanced therapies for UC (e.g., biologic agents, JAK antagonists, or sphingosine-1-phosphate [S1P] receptor agonists)
Meets the following washout criteria of prior UC therapy relative to study Day 1: a. TNF antagonists: at least 8 weeks b. IL-12/IL-23 antagonists, including ustekinumab: at least 8 weeks c. JAK antagonists, including tofacitinib or upadacitinib: at least 1 week d. S1P receptor agonists, including ozanimod: at least 4 weeks
If the participant has been receiving any of the non-prohibited medications for UC listed below, he/she must discontinue use at least 5 half-lives before study Day 1 or must agree to maintain stable doses of these concomitant medications starting from the time specified below until the end of the SFU Period, with the exception of tapering oral corticosteroid dose after 12 weeks of being in the trial. a. Oral 5-Aminosalicylates (not exceeding 4.8 g per day): at least 2 weeks prior to study Day 1 b. Oral corticosteroids (not exceeding prednisone 30 mg/day, budesonide 9 mg/day, beclomethasone dipropionate 5 mg/day, methylprednisolone 24 mg/day, or equivalent; at least 2 weeks prior to study Day 1 c. 6-Mercaptopurine (any stable dose): at least 12 weeks prior to study Day 1 d. Azathioprine (any stable dose): at least 12 weeks prior to study Day 1 e. Methotrexate (any stable dose): for at least 12 weeks prior to study Day 1
If the participant has had UC for over 7 years, he/she must have had a full colonoscopy in the last 2 years or must agree to have a full colonoscopy (rather than sigmoidoscopy) with appropriate colon cancer surveillance biopsies at Screening
In the opinion of the Investigator, the participant can fully participate in all aspects of this clinical study
Has a body mass index (BMI) ≥18.0 at Screening
A participant is eligible to participate if he/she agrees to abide by the guidelines set forth in this protocol regarding contraception requirements a. A male participant is eligible to participate if he agrees to the following during the study Treatment Period and for at least 28 days after receiving the last dose of MORF-057: • Abstains from heterosexual intercourse as his preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR • Agrees to use contraception/barrier methods as detailed below: o Agrees to use a male condom, with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant. b. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: • Is a woman of non-childbearing potential OR • Is a woman of childbearing potential and agrees to use a contraceptive method that is highly effective with a failure rate of <1% per year during the study Treatment Period and for at least 28 days after receiving the last dose of MORF-057
For the study Treatment Period and at least 14 days after receiving the last dose of MORF-057, male participants must agree not to donate sperm and female participants must agree not to donate eggs (ova, oocytes).
Capable of giving signed informed consent,which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

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Exclusion Criteria

Diagnosed with indeterminate colitis, microscopic colitis, ischemic colitis, radiation colitis, or Crohn’s disease or has clinical findings suggestive of Crohn’s disease
Has current evidence of un-resected colonic dysplasia or un-resected adenomatous colonic polyps or evidence of toxic megacolon, abdominal abscess, symptomatic colonic stricture, fistula, stoma, ileostomy, or colostomy at Screening
Currently requires or is anticipated to require surgical intervention for UC during the study
Has had a surgical procedure requiring general anesthesia within 30 days prior to Screening or is planning to undergo major surgery during the study period
Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, demyelinating, or neurodegenerative disease. For questions about whether this applies to a specific case, consult with the Medical Monitor
Has positive findings on a PML subjective symptom checklist during Screening or prior to the administration of the first dose of study drug on study Day 1
Has a potentially bacterial, viral or parasitic pathogenic enteric infection, including Clostridiodes difficile; has hepatitis B or C virus, or HIV; had an infection requiring hospitalization or intravenous antimicrobial therapy, or an opportunistic infection within 3 months prior to Screening; had any infection requiring oral antimicrobial therapy within 2 weeks prior to Screening; or has a history of more than 1 episode of herpes zoster or any episode of disseminated herpes zoster infection
Has active tuberculosis (TB), as evidenced by any of the following: •A diagnostic test for TB performed within 30 days prior to Screening or during the Screening Period that is positive, as defined below: positive interferon gamma release assay (IGRA) test (e.g., QuantiFERON® or T-SPOT® TB test) or 2 consecutive indeterminate IGRA tests OR A purified protein derivative (PPD) skin test ≥5 mm •A chest X-ray or imaging per local guidelines within 3 months prior to Screening where active or latent pulmonary TB cannot be excluded
Has a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result during the Screening Period. Testing for SARS-CoV-2 is required only per local regulations. Participants who have a positive test result can be randomized after a subsequent negative test result during the Screening Period.
Had any vaccination (including live virus vaccinations) within 3 weeks prior to study Day 1.
Has a concurrent, clinically significant, serious, unstable comorbidity (such as uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder) that, in the judgement of the Investigator, would compromise compliance with the protocol, interfere with interpretation of the study results, or pre-dispose participants to safety risks
Has a known primary or secondary immunodeficiency
Has a history of myocardial infarction, unstable angina, transient ischemic attack, decompensated heart failure requiring hospitalization, congestive heart failure (New York Heart Association Class 3 or 4), uncontrolled arrhythmias, cardiac revascularization, uncontrolled hypertension, or uncontrolled diabetes within 6 months of Screening
Has a history of left ventricular ejection fraction (LVEF) <50%
Has a clinically significant abnormal ECG at Screening, including a QT interval corrected through use of Fridericia’s formula (QTcF) ≥450 ms for males and ≥470 ms for females
Abnormal hematology (hemoglobin level, WBC count, or platelet count) or coagulation results at Screening, as evidenced by the ranges: a.Hemoglobin level <8.0 g/dL b.Absolute WBC count <3.0 × 10^9/L c.Absolute lymphocyte count <0.5 × 10^9/L d.Absolute lymphocyte count >5.5 x 10^9/L e.Absolute neutrophil count <1.2 × 10^9/L f.Platelet count <100 × 10^9/L or >1000 × 10^9/L g.International normalized ratio >1.5. Participants with an international normalized ratio >1.5 due to anticoagulant therapy (e.g., warfarin) may only be enrolled after a consultation with the Medical Monitor.
Clinically significant abnormal urinalysis results, as deemed by the Investigator or designee
Abnormal organ function at Screening, as evidenced by: a.Alanine aminotransferase or aspartate aminotransferase >2.0 × upper limit of normal (ULN) b.Chronic kidney disease stages 4 and 5, defined as having a glomerular filtration rate <30 mL/min/1.73m2 as calculated using the Modification of Diet in Renal Disease equation, receiving dialysis, or being listed for or has received a renal transplant c.Total bilirubin ≥1.5 × ULN
History of active malignancy in the 5 years preceding study Day 1, except in cases of basal cell skin cancer, squamous cell skin cancer, or other in-situ malignancies that have been excised and resolved and the participant was deemed clear of cancer after appropriate follow-up. Participants with a history of malignancy or those at high risk for malignancy may only be enrolled after a consultation with the Medical Monitor.
Treatment with cyclosporine, mycophenolate, tacrolimus, or sirolimus within 30 days or 5 half-lives (whichever is shorter) prior to study Day 1
Any previous treatment with vedolizumab or other licensed or investigational integrin inhibitors
Experiencing toxicities from prior therapy with Grade >1 within 1 week prior to first dose of study drug
Fecal microbiota transplantation within 3 months prior to Screening
Participant needs to continue treatment with a moderate-to-strong CYP3A4 inducer or inhibitor and, therefore, will be unable to do a washout period of at least 30 days or 5 half-lives (whichever is shorter) prior to study Day 1
Participant needs to continue treatment with a moderate-to-strong organic anion transporter polypeptide-1B inhibitor and, therefore, will be unable to do a washout period of at least 14 days or 5 half-lives (whichever is shorter) prior to study Day 1.
Concurrent participation in any other interventional study
Received any investigational therapy within 30 days or 5 half-lives (whichever is longer) prior to study Day 1
Known allergies/hypersensitivity to any component of the study drug and/or previous exposure to MORF-057 and/or a known hypersensitivity to drugs with a similar mechanism to MORF-057
Females who are pregnant or lactating or who are planning on becoming pregnant during the course of the study
Current or recent history of alcohol dependence or illicit drug use that, in the opinion of the Investigator, may interfere with the participant’s ability to comply with the study procedures
Mental or legal incapacitation or a history of clinically significant psychiatric disorders at the time of the Screening Visit that would impact the ability to participate in the trial according to the Investigator
Unable to attend study visits or comply with procedures

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	15 Mar 2023	9
Bulgaria	Not Recruiting	15 Mar 2023	7
Czechia	Not Recruiting	15 Mar 2023	6
Estonia	Not Recruiting	15 Mar 2023	6
France	Not Recruiting	15 Mar 2023	8
Germany	Not Recruiting	15 Mar 2023	8
Hungary	Not Recruiting	15 Mar 2023	15
Italy	Not Recruiting	15 Mar 2023	9
Latvia	Not Recruiting	15 Mar 2023	3
Lithuania	Not Recruiting	15 Mar 2023	6