A Phase 2b Study to Evaluate MORF-057 in Adults with Moderately to Severely Active UC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Morphic Therapeutic Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

23 Mar 2023 → ongoing

Decision date (initial)

2023-02-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Morphic Therapeutic, Inc.

External identifiers

EU CT number

2022-500953-17-00

WHO UTN

U1111-1283-7075

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Pharmacokinetic, Efficacy, Therapy

To evaluate the effects of MORF-057 on clinical remission at Week 12

Secondary objectives 5

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

Conditions and MedDRA coding

Moderately to severely active ulcerative colitis

Study design 6 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Male or female, 18 to 85 years of age, inclusive, at the time of signing the Informed Consent Form (ICF).
2. 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)
3. Has evidence of UC extending at least 15 cm from the anal verge
4. 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)
5. 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
6. 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
7. 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
8. In the opinion of the Investigator, the participant can fully participate in all aspects of this clinical study
9. Has a body mass index (BMI) ≥18.0 at Screening
10. 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
11. 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).
12. Capable of giving signed informed consent,which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

Exclusion criteria 32

1. Diagnosed with indeterminate colitis, microscopic colitis, ischemic colitis, radiation colitis, or Crohn’s disease or has clinical findings suggestive of Crohn’s disease
2. 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
3. Currently requires or is anticipated to require surgical intervention for UC during the study
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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.
10. Had any vaccination (including live virus vaccinations) within 3 weeks prior to study Day 1.
11. 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
12. Has a known primary or secondary immunodeficiency
13. 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
14. Has a history of left ventricular ejection fraction (LVEF) <50%
15. 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
16. 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.
17. Clinically significant abnormal urinalysis results, as deemed by the Investigator or designee
18. 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
19. 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.
20. Treatment with cyclosporine, mycophenolate, tacrolimus, or sirolimus within 30 days or 5 half-lives (whichever is shorter) prior to study Day 1
21. Any previous treatment with vedolizumab or other licensed or investigational integrin inhibitors
22. Experiencing toxicities from prior therapy with Grade >1 within 1 week prior to first dose of study drug
23. Fecal microbiota transplantation within 3 months prior to Screening
24. 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
25. 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.
26. Concurrent participation in any other interventional study
27. Received any investigational therapy within 30 days or 5 half-lives (whichever is longer) prior to study Day 1
28. 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
29. Females who are pregnant or lactating or who are planning on becoming pregnant during the course of the study
30. 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
31. 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
32. Unable to attend study visits or comply with procedures

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary Efficacy: Proportion of participants in clinical remission at Week 12 as determined using the Modified Mayo Clinic Score (mMCS). The mMCS is a composite of the following subscores: - Mayo endoscopic subscore (MES) - Mayo Clinic Score (MCS) stool frequency subscore - MCS rectal bleeding subscore

Secondary endpoints 23

1. Secondary Efficacy: Proportion of participants with clinical response at Week 12 as determined using the mMCS
2. Exploratory Efficacy: Proportion of participants in clinical remission at Week 52 as determined using the mMCS
3. Exploratory Efficacy: Proportion of participants with clinical response at Week 52 as determined using the mMCS
4. Exploratory Efficacy: Proportion of participants in MCS remission at Weeks 12 and 52. MCS is a composite of the following subscores: MES; MCS stool frequency subscore ; MCS rectal bleeding subscore; MCS Physician’s Global Assessment (PGA)
5. Exploratory Efficacy: Proportion of participants with MCS response at Weeks 12 and 52
6. Exploratory Efficacy: - Proportion of participants in histologic remission at Weeks 12 and 52 as determined using the Robarts Histopathology Index (RHI) Score - Proportion of participants in histologic remission at Weeks 12 and 52 as determined using the Nancy Histopathology Index (NI) - Proportion of participants in histologic remission at Weeks 12 and 52 as determined using the Continuous Geboes Score
7. Exploratory Efficacy: Proportion of participants with histologic improvement at Weeks 12 and 52 as determined using the RHI
8. Exploratory Efficacy: Proportion of participants with endoscopic improvement at Weeks 12 and 52 as determined using the MES
9. Exploratory Efficacy: Proportion of participants in endoscopic remission at Weeks 12 and 52 as determined using the MES
10. Exploratory Efficacy: Proportion of participants in endoscopic remission as determined using the MES and histologic remission as determined using the RHI at Weeks 12 and 52
11. Exploratory Efficacy: Proportion of participants with endoscopic improvement as determined using the MES and a histologic improvement as determined using the RHI at Weeks 12 and 52
12. Exploratory Efficacy: Proportion of participants with symptomatic response at Weeks 2 and 6 as determined using the Partial mMCS. Partial mMCS is a composite of the following subscores:MCS stool frequency subscore; MCS rectal bleeding subscore
13. Exploratory Efficacy: Proportion of participants with Partial MCS response at Week 6. Partial MCS is a composite of the following subscores: MCS stool frequency subscore; MCS rectal bleeding subscore; MCS PGA
14. Exploratory Efficacy: Time to symptomatic response by Week 12 as determined using the Partial mMCS
15. Exploratory Efficacy: - Change from baseline to Weeks 12 and 52 in high sensitivity C reactive protein (hs CRP) levels - Change from baseline to Weeks 12 and 52 in fecal calprotectin levels
16. Exploratory Efficacy: Change from baseline to Weeks 12 and 52 in Inflammatory Bowel Disease Questionnaire (IBDQ) Score
17. Exploratory Efficacy: Proportion of participants in corticosteroid free remission at Week 52, as determined using the mMCS, among the participants who were on a stable dose of corticosteroids at baseline
18. Exploratory Efficacy: Percentage of participants requiring UC related hospitalization or surgery at Weeks 12 and 52
19. Exploratory Efficacy: • Proportion of participants in histologic remission at Week 104 as determined using the RHI • Proportion of participants in histologic remission at Week 104 as determined using the NI • Proportion of participants in histologic remission at Week 104 as determined using the Continuous Geboes Score • Proportion of participants with histologic improvement at Week 104 as determined using the RHI
20. Exploratory Efficacy: • Proportion of participants with endoscopic improvement at Week 104 as determined using MES • Proportion of participants in endoscopic remission at Week 104 as determined using MES • Proportion of participants in endoscopic remission as determined using MES and histologic remission as determined using RHI at Week 104 • Proportion of participants with endoscopic improvement as determined using MES and a histologic improvement as determined using RHI at Week 104
21. Safety: Frequencies and proportions for treatment emergent serious adverse events (TESAEs), and TEAEs leading to study drug discontinuation.
22. Pharmacokinetics: MORF-057 concentration in plasma
23. Exploratory Pharmacodynamics: - α4β7 receptor occupancy in blood over time - α4β1 receptor occupancy in blood over time - Change from baseline over time in blood CCR9 messenger ribonucleic acid (mRNA) - Change from baseline over time in blood lymphocyte subsets

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Morphic Therapeutic Inc.

Sponsor organisation

Morphic Therapeutic Inc.

Address

Lilly Corporate Center

City

Indianapolis

Postcode

46285-0001

Country

United States

Scientific contact point

Organisation

Morphic Therapeutic Inc.

Contact name

Lilly Clinical Trials Information Desk

Public contact point

Organisation

Morphic Therapeutic Inc.

Contact name

Lilly Clinical Trials Information Desk

Third parties 11

Sponsor responsibilities

Article 77 compliance

Morphic Therapeutic Inc.

Contact point sponsor

Morphic Therapeutic Inc.

Article 77 implementation

Morphic Therapeutic Inc.

Locations

13 EU/EEA countries · 53 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 144 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications