Evaluation of MORF-057 Efficacy and Safety in Adults with Moderately to Severely Active Crohn's Disease: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-508158-24-00
Protocol: MORF-057-203
Sponsor: Morphic Therapeutic Inc.

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Diseases & Conditions

Crohn's disease

Objectives

The primary objective of this study is to evaluate the effect of **MORF-057** on endoscopic response at Week 14 in adults with moderately to severely active Crohn's disease. This is clinically relevant as endoscopic response is a critical indicator of disease activity and treatment efficacy in Crohn's disease, providing insights into the potential of MORF-057 to induce mucosal healing.

Secondary objectives include:

To evaluate the effect of MORF-057 on clinical response as determined using the Crohn's Disease Activity Index (CDAI) at Week 14.
To evaluate the effect of MORF-057 on CDAI clinical remission at Week 14.
To assess the safety and tolerability of MORF-057.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic potential and safety profile of MORF-057, which is essential for determining its viability as a treatment option for Crohn's disease.

Participants

The clinical trial involves a total of **93 participants** diagnosed with **moderately to severely active Crohn's Disease**. The study population includes both male and female subjects, aged between 18 to 85 years. Participants were selected based on their ability to fully engage in all aspects of the study, as determined by the investigator. The trial includes individuals who have demonstrated an inadequate response, loss of response, or intolerance to previous treatments such as corticosteroids, immunosuppressants, or advanced therapies for Crohn's Disease. Participants are required to maintain stable doses of certain medications and adhere to specific washout periods for prior therapies. Lifestyle considerations include maintaining a body mass index (BMI) of at least 18.0 at screening. The trial population is not limited to any specific dietary or physical activity requirements, but participants must agree to follow contraception guidelines during and after the study period. The study also includes a vulnerable population, ensuring comprehensive representation within the trial.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety and efficacy of two active dose regimens of MORF-057 in adults with moderately to severely active **Crohn's disease**. The trial will involve participants aged 18 to 85 years who meet specific inclusion criteria, including a confirmed diagnosis of Crohn's disease for at least three months prior to screening. The primary objective is to assess the effect of MORF-057 on endoscopic response at Week 14, with the primary endpoint being the proportion of participants achieving an endoscopic response as determined by the Simple Endoscopic Score-CD (SES-CD). Secondary endpoints include clinical response and remission rates, as well as safety assessments through the monitoring of treatment-emergent adverse events and changes in laboratory parameters.

The trial is expected to commence recruitment on June 21, 2024, and conclude by March 25, 2028. Participants will be involved in the study for a maximum treatment period of 104 weeks. The study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria, such as a Crohn's Disease Activity Index (CDAI) score of 220 to 450 and an SES-CD score of ≥6. Follow-up visits will occur at regular intervals to monitor the participants' response to the treatment and any adverse events. The end-of-study visit will assess the final outcomes and ensure the safety of the participants as they transition out of the study.

Participants will be randomly assigned to receive either the MORF-057 IR Capsule or a placebo, both administered orally. The expected length of participant involvement is contingent upon adherence to the study protocol, with conditions for early termination including significant adverse events or non-compliance with the study requirements. Participants must agree to specific guidelines regarding the use of concomitant medications and contraception during the study period. The trial will ensure that all participants provide informed consent and comply with the study's requirements and restrictions.

Treatment

The clinical trial involves the administration of **MORF-057**, an investigational medication, in the form of an immediate-release (IR) capsule. The active substance, **MORF-057**, is of chemical origin and is provided 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 165.6 grams over the course of the study. The treatment period extends up to 104 weeks. The dosing schedule and participant compliance are monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the MORF-057 IR capsule in appearance and is also administered orally. The use of a placebo allows for the assessment of the efficacy and safety of MORF-057 by providing a baseline for comparison. The placebo does not contain any active pharmaceutical ingredients and serves to maintain the blinding of the study.

Efficacy

The efficacy of MORF-057 in the treatment of moderately to severely active **Crohn's Disease** will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the proportion of participants achieving an endoscopic response, as determined by the Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 14. This endpoint will provide a quantitative measure of the drug's impact on the intestinal mucosa, a critical factor in evaluating treatment success.

Secondary efficacy endpoints include the proportion of participants achieving a clinical response and clinical remission, both assessed using the Crohn's Disease Activity Index (CDAI) at Week 14. These endpoints will help determine the broader clinical benefits of MORF-057, including symptom relief and disease management. The CDAI is a well-established tool for evaluating disease activity in Crohn's Disease, providing a comprehensive assessment of patient symptoms and overall health status.

Data collection for these endpoints will occur at specified timepoints, with Week 14 being a critical juncture for both primary and secondary efficacy assessments. The use of validated scales such as the SES-CD and CDAI ensures that the efficacy evaluations are robust and scientifically sound. The analysis of these endpoints will involve comparing the outcomes between the treatment and placebo groups to determine the therapeutic effect of MORF-057.

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).
Has a body mass index (BMI) ≥18.0 at Screening.
For the study Treatment Period and at least 90 days after receiving the last dose of MORF-057, male participants must agree not to donate sperm. For the study Treatment Period and at least 28 days after receiving the last dose of MORF-057, 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 the protocol.
Participant has had a diagnosis of CD supported by signs/symptoms, endoscopy, and histology for at least 90 days prior to Screening. Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the Investigator, must be available.
Moderately to severely active CD was confirmed during the Screening Period with the following criteria: a) A CDAI score of 220 to 450 inclusive b) An SES-CD score of ≥6. If disease is isolated to the ileum, the requirement will be an SES-CD score ≥4. c) Additional inflammatory markers hs-CRP>5 mg/L and/or fecal calprotectin >250 µg/g.
Average daily stool score ≥4 points and/or an average daily abdominal pain score of ≥2 points.
Demonstrated an inadequate response, loss of response, or intolerance to at least one of the following treatments (including corticosteroids, immunosuppressants, and/or advanced therapies for CD) in the opinion of the Investigator: a. Corticosteroids b. Immunosuppressants (e.g., azathioprine, 6-mercaptopurine, or methotrexate) c. Advanced therapies for CD (e.g., biologic agents, JAK inhibitors, or applicable investigational products [including blinded study treatments in placebo-controlled trials, however, if participants can document that they received only placebo, they will be considered advanced therapy naïve]).
Meets the following washout criteria of prior CD therapy relative to study Day 1: a. TNF-α antagonists: at least 5 half-lives; b. IL-12/IL-23 antagonists, including ustekinumab: at least 5 half-lives; c. IL-23 antagonists, including risankizumab, guselkumab or mirikizumab: as least 5 half-lives; d. JAK inhibitors, including tofacitinib or upadacitinib: at least 1 week.
If the participant has been receiving any of the non-prohibited medications for CD 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 completion of the Induction Period. a. Oral 5-aminosalicylates (not exceeding 4.8 g per day): at least 2 weeks prior to Screening ileocolonoscopy; b. Oral corticosteroids (not exceeding prednisone 20 mg/day, budesonide 9 mg/day, beclomethasone dipropionate 5 mg/day, methylprednisolone 24 mg/day, or equivalent): at least 2 weeks prior to Screening ileocolonoscopy; c. 6-Mercaptopurine (any stable dose): at least 4 weeks prior to Screening ileocolonoscopy; d. Azathioprine (any stable dose): at least 4 weeks prior to Screening ileocolonoscopy; e. Methotrexate (any stable dose): at least 4 weeks prior to Screening ileocolonoscopy.
In the opinion of the Investigator, the participant can fully participate in all aspects of this clinical study.
A participant is eligible to participate if he/she agrees to abide by the guidelines 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 90 days after receiving the last dose of MORF-057: • Agrees to abstain 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 a male condom, with female partner use of an additional contraceptive method; 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 together with a barrier method used by her or her male partner during the study Treatment Period and for at least 28 days after receiving the last dose of MORF-057.

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Exclusion Criteria

Diagnosed with indeterminate colitis, microscopic colitis, ischemic colitis, radiation colitis, or UC, or has clinical findings suggestive of UC.
Currently requires or is anticipated to require surgical intervention for CD during the study duration.
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.
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, in consultation with the Sponsor Medical Monitor, 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 known 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, white blood cell [WBC] count, or platelet count) or coagulation results at Screening, as evidenced by the ranges provided below: a. Hemoglobin level <8.0 g/dL; b. Absolute WBC count <3.0x10^9/L; c. Absolute lymphocyte count <0.5x10^9/L or >5.5x10^9/L; d. Absolute neutrophil count <1.2x10^9/L; e. Platelet count <100x10^9/L or 1000x10^9/L; f. International normalized ratio >1.5.
Has positive findings on a Subjective Progressive Multifocal Leukoencephalopathy (PML) Checklist during Screening or prior to the administration of the first dose of study drug on study Day 1.
Clinically significant abnormal urinalysis results, as deemed by the Investigator or designee.
Abnormal organ function at Screening, as evidenced by the following: a. Alanine transaminase (ALT) or aspartate transaminase (AST) >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/1.73 m^2 as calculated using the Modification of Diet in Renal Disease (MDRD) equation (National Kidney Foundation), receiving dialysis, or being listed for or has received a renal transplant c. Total bilirubin ≥1.5×ULN unless the patient has documented diagnosis of Gilbert’s syndrome and other diseases that can present with hyperbilirubinemia have been ruled out.
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.
Has a potentially active bacterial, viral, or parasitic pathogenic enteric infection, including Clostridioides difficile (C. difficile); has hepatitis B or C virus, or human immunodeficiency virus (HIV); had an infection requiring hospitalization or intravenous antimicrobial therapy, or an opportunistic infection within 90 days 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. A diagnostic test for TB performed within 30 days prior to Screening or during the Screening Period that is positive, as defined below: • Two consecutive positive interferon gamma release assay (IGRA) tests or 2 consecutive indeterminate IGRA tests OR • A purified protein derivative (PPD) skin test ≥5 mm b. A chest X-ray or imaging per local guidelines within 90 days prior to Screening where active or latent pulmonary TB cannot be excluded.
Crohn’s disease isolated to the oral cavity, stomach, duodenum, jejunum, or perianal region, without colonic or ileal involvement.
Extensive bowel resection (>100 cm), and/or more than 3 resections, and/or known diagnosis of short bowel syndrome.
Currently receiving total parenteral nutrition, tube feeding, or a formula diet.
Has current evidence of un-resected colonic dysplasia or un-resected adenomatous colonic polyps, stoma, ileostomy, or colostomy at Screening.
Has any of the following known complications of CD: • abscess (abdominal or perianal) • impassable fibrotic strictures • symptomatic bowel strictures or obstruction • fulminant colitis • toxic megacolon • intra-abdominal or enterocutaneous fistula.
Treatment with cyclosporine, mycophenolate, tacrolimus, thalidomide, or sirolimus within 30 days or 5 half-lives (whichever is shorter) prior to study Day 1.
Will require treatment with nonsteroidal anti-inflammatory drugs, including but not limited to ibuprofen, naproxen, indomethacin, and celecoxib, during the study. (However, participants may take aspirin for cardio-protection at a dose indicated per local guidelines but not exceeding 325 mg per day.)
Any previous treatment with vedolizumab or other licensed or investigational integrin pathway inhibitors.
Experiencing toxicities from prior therapy with Grade >1 within 1 week prior to first dose of study drug.
Fecal microbiota transplantation within 90 days prior to Screening.
Participant needs to continue treatment with a moderate-to-strong CYP3A inducer or inhibitor and, therefore, will be unable to do a washout period of at least 14 days or 5 half-lives (whichever is longer) prior to study Day 1.
Participant needs to continue treatment with an organic anion transporter polypeptide-1B (OATP1B) inhibitor, a P-gp inhibitor, or a narrow therapeutic substrate for P-gp or BCRP, and, therefore, will be unable to do a washout period of at least 14 days or 5 half-lives (whichever is longer) 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.
Previous exposure 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 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	Recruiting	21 Jun 2024	4
Bulgaria	Not Yet Recruiting	21 Jun 2024	7
Croatia	Recruiting	21 Jun 2024	6
Czechia	Recruiting	21 Jun 2024	27
Estonia	Not Yet Recruiting	21 Jun 2024	3
France	Recruiting	21 Jun 2024	3
Germany	Recruiting	21 Jun 2024	16
Hungary	Recruiting	21 Jun 2024	15
Italy	Recruiting	21 Jun 2024	15
Latvia	Recruiting	21 Jun 2024	4