Potential participants are eligible to be included in the study only if all of the following criteria apply:
General Inclusion Criteria
  Signed Informed Consent Form
  Signed Assent Form, when appropriate, as determined by the potential participant's age and individual site and country standards
  Age ≥ 18 to ≤ 80 years at the time of signing Informed Consent Form
  Patients aged ≥ 16 to < 18 years may be eligible to participate in the study where locally permissible (e.g., if permitted by local guidelines and regulations). For country-specific requirements, see Appendix 14.
  Bodyweight ≥ 40 kg
Crohn's Disease-Specific Inclusion Criteria
  Confirmed diagnosis of CD with supportive clinical, endoscopic and histopathological evidence
  Moderately to severely active CD, meeting all of the following:
  CDAI ≥ 220 and ≤ 450
  SES-CD of ≥ 6 (or ≥ 4 for isolated ileal disease) confirmed through a centrally read endoscopy performed either:
  During the screening period OR
  Before the screening period (independently of the study), within 4 weeks of randomization, and in patients who already have an established CD diagnosis.

If performed before screening, the SOC endoscopy must have a video recording available and in a format that is suitable for central reading. Use of previous SOC endoscopies for screening is only permitted if performed according to the endoscopy procedural manual/charter specifications. Also, participants must not have had any new CD-related medications initiated in between an SOC endoscopy and randomization. All CD-related concomitant medications must have been stabilized prior to SOC endoscopy (see Table 9).

  Involvement of ileum and/or colon, with at least four colonic segments traversable by an endoscope or a pediatric endoscope, or three segments for patients who have undergone a bowel resection among the following segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum.
  Screening for colorectal cancer (CRC) during or prior to screening for all participants (performed according to local standards).
  For participants with colonic disease lasting for  8 years’ duration or with risk factors for bowel cancer a surveillance ileocolonoscopy must be performed within 12 months prior to screening.
   For all other patients, must be up-to date with CRC surveillance (according to CRC risks and local standards)
  Screening ileocolonoscopy can be used for CRC surveillance (following local guidelines) and results must be available prior to randomization
  Any adenomatous polyps must be completely removed according to routine practice prior to their first dose of study drug.
Reproductive Inclusion Criteria
  For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use an acceptable method of contraception and agree to refrain from egg donation or undergoing fertility treatment during the treatment period and for 95 days after the final dose of afimkibart (see Section 5.3.4).
  A female participant is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state ( 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a female participant with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
  The following are examples of acceptable contraceptive methods: progestogen-only oral hormonal contraception (where inhibition of ovulation is not the primary mode of action), condom (external or internal) with or without spermicide; and cap, diaphragm, or sponge with spermicide. An external condom and an internal condom should not be used together because of risk of failure due to friction.
  The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
Female participants of childbearing potential must refrain from donating eggs or undergoing fertility treatment during this same period.
  For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, as defined below:
  With a female partner of childbearing potential or pregnant female partner, male participants must remain abstinent or use a condom during the treatment period and for 95 days after the final dose of afimkibart to avoid exposing the embryo. Male participants must refrain from donating sperm during this same period.
  The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
Prior Medications Inclusion Criteria
  Must have had at least one of the following treatments in the past with inadequate response, loss of response, and/or intolerance
  Inadequate response is defined as having signs and symptoms of persistently active disease despite completing at least the approved dosing regimen in the product label.
  Intolerance may include, but is not limited to, infusion-related reactions, injection site reactions, rash, serum sickness, hepatic abnormalities, demyelination, congestive heart failure, and infections. There is no minimum requirement for dose or duration if a potential participant was determined to be intolerant to prior treatment.
  Loss of response is defined as the recurrence of signs and symptoms of active disease during approved treatment following prior clinical benefit (discontinuation despite clinical benefit does not qualify as having failed or being intolerant to CD advanced therapy).
  Participants previously exposed to investigational therapies for the treatment of CD must still meet inclusion criteria "Conventional Therapy Failure" or "Advanced Therapy Failure."
Conventional Therapy Failure
  Steroids (e.g., systemic prednisone, oral budesonide)
The following definitions will be used as guidelines for the use of corticosteroids in this trial:
  Corticosteroid refractory: Persistent active disease despite treatment with at least one 4-week induction regimen, including a starting dose of  30 mg of oral prednisone (or equivalent) for at least 2 weeks or IV prednisone for  5 days, or persistently active disease after at least 4 weeks of oral budesonide given 9 mg/day
  Corticosteroid dependent:
  Unable to reduce steroids below the equivalent of prednisone 10 mg/day within 3 months of starting steroids, without recurrent active disease, or
  Relapse within 3 months of stopping steroids
  Corticosteroid intolerant: History of intolerance to corticosteroids (including but not limited to Cushing syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection)
  At least 12 weeks of an immunomodulator, which can include:
   ≥1.5 mg/kg/day of oral azathioprine (AZA) (or per local standard of care)
   ≥ 0.75 mg/kg/day of oral 6-mercaptopurine (6-MP) (or per local standard of care)
  ≥ 15 mg/week of intramuscular or SC methotrexate (MTX)
  Persistent signs and symptoms of active disease despite a 6-TG level of ≥ 230 pmol/8 ≥ 108 RBCs during at least one 12-week regimen of oral AZA or 6-MP at a stable or increasing dose
  History of intolerance to AZA, 6-MP, or MTX (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, TPMT genetic mutation, infection)
  At least 4 weeks of an oral aminosalicylate, which can include a minimum dose of the following:
  2.4 g/day of mesalamine (or per local standard of care)
  4.0 g/day of sulfasalazine (or per local standard of care)
  1.0 g/day of olsalazine (or per local standard of care)
  6.75 g/day of balsalazide (or per local standard of care)
Advanced Therapy Failure
The medications used to qualify the participant for entry into this category include the following therapies (and any relevant biosimilars) approved for the treatment of CD.
  Approved anti-TNF agents, including and not limited to the following:
  At least one 6-week induction regimen of infliximab ( ≥ 5 mg/kg IV at 0, 2, and 6 weeks or per local label) or equivalent biosimilar
  At least one 8-week induction regimen of adalimumab (one 160 mg SC dose followed by one 80 mg SC dose [or one 80 mg SC dose in countries where this dosing regimen is allowed] followed by one 40 mg SC dose at least 2 weeks apart or per local label) or equivalent biosimilar
  Approved anti-integrins, including and not limited to the following:
  At least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2, and 6 weeks or per local label)
  Approved anti-IL-12/IL-23, including and not limited to the following:
  At least one 8-week induction regimen of ustekinumab (a single IV dose using weight-based dosing: 260 mg for participants with body weight > 55 kg; 390 mg for participants with body weight > 55 kg to ≤ 85 kg; 520 mg for participants with body weight > 85 kg or per local label) (single weight-based dose) or equivalent biosimilar
  At least one 8-week induction regimen of risankizumab (600 mg IV at 0, 4, and 8 weeks, or per local label)
  At least one 8-week regimen of mirikizumab (900 mg IV at Weeks 0, 4, and 8 or per local label)
  At least one 8-week induction regimen of guselkumab (200 mg IV at Weeks 0, 4, and 8, or 400mg SC at Weeks 0, 4, and 8, or per local label)
  Approved JAK inhibitors, including and not limited to the following:
  At least one 8-week induction course of upadacitinib (45 mg orally daily or per local label)
  Any newly approved sphingosine-1-phosphate receptor modulators for CD treatment
The “Advanced Therapy Failure” inclusion criteria may also be fulfilled with exposure to investigational advanced therapy, provided that all of the following are met:
  Exposure to the investigational advanced therapy has been confirmed (i.e. the patient has been unblinded)
  The investigational advanced therapy has been approved for the treatment of CD. This approval need not be local.
  The patient completed and failed at least the equivalent of the approved induction dosing regimen, per the investigator’s discretion.

Potential participants are excluded from the study if any of the following criteria apply.
Inflammatory Bowel Disease Exclusion Criteria
•  Participant with a history of
   3 bowel resections
  > 2 missing segments of the following five segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum
•  Diagnosis of short gut or short bowel syndrome
•  Presence of ileostomy, colostomy, or ileo-anal pouch
•  Patients with symptomatic bowel strictures, fulminant colitis, or toxic megacolon
•  Current diagnosis of UC or indeterminate colitis, ischemic colitis, infectious colitis, radiation colitis, or microscopic colitis
•  Presence of abdominal or perianal abscess
•  Presence of rectovaginal, enterovaginal, high output enterocutaneous fistula, enterovesical fistulas, or perianal fistulas with  3 openings and/or the anticipated need for surgery during the study (except surgery for seton placement and/or removal)
•  Current diagnosis or suspicion of primary sclerosing cholangitis

Medical History Exclusion Criteria
•  Lack of peripheral venous access
•  Any major surgery within 6 weeks prior to screening or a major surgery planned during the study
•  Significant uncontrolled medical comorbidity (such as cardiac, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders [excluding CD]), psychiatric, or other condition that in the opinion of the investigator, would confound the study results, compromise patient safety, interfere with the potential participant's provision of informed consent, or compliance with trial procedures.
•  Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 95 days after the final dose of afimkibart.
Female participants of childbearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test on Day 1 prior to initiation of study treatment.
•  Any condition that would preclude endoscopic evaluation
•  Any past or current evidence of cancer of gastrointestinal tract, definite low-grade or high-grade colonic dysplasia.
Adenomas or any other benign neoplasia that are not completely removed are exclusionary. Once completely removed, the participant may be eligible for the study.
•  History of non-gastrointestinal cancer within 5 years prior to screening visit including (e.g., solid tumors, hematologic malignancies, etc.), with the exception of adequately treated non-metastatic basal cell or squamous cell skin cancer or in situ cervical cancer
•  History of alcohol, drug, or chemical abuse < 1 year prior to screening
•  History of blood transfusion within 30 days prior to screening

Infection or Infection Risk Exclusion Criteria
•  Any clinically significant infection < 4 weeks prior to randomization that has not resolved, and/or that required hospitalization, and/or IV antibiotics o Any clinically significant infection that was opportunistic in nature is not permitted within 3 months prior to randomization
•  Evidence of or treatment for Clostridioides difficile (C. difficile; formerly known as Clostridium difficile) as assessed by detection of C. difficile toxin within 30 days prior to randomization (Week 0, Day 1) or other enteric pathogens (as assessed by stool culture/sensitivity and ova and parasite evaluation within 30 days prior to randomization (Week 0, Day 1)
•  Refer to the Laboratory Manual for further guidance and instruction for C. difficile screening. A negative toxin result with a positive PCR test result may reflect infection or colonization, and the Investigator should decide whether PCR positivity reflects infection, in which case treatment should be administered.
•  Any diagnosis of CMV colitis in the past 30 days (including diagnosis during screening)
Laboratory confirmation of CMV from a colon biopsy sample (e.g., tissue immunohistochemistry or tissue PCR, as per local standards) is required during screening evaluation only if clinical suspicion is high and to determine the need for CMV treatment.
•  Confirmation of HIV infection (e.g., positive HIV test) at screening
•  Positive test results for hepatitis B infection at screening, defined as meeting either of the following criteria:
–  Positive hepatitis B surface antigen (HBsAg) test at screening
–  Negative HBsAg test and positive total hepatitis B core antibody (HBcAb) test in combination with quantitative HBV DNA above the lower limit of quantification (refer to laboratory manual for further guidance and instruction for HBV testing)
•  Positive hepatitis C virus (HCV) antibody test during screening with the following exception: o Participants with positive HCV antibody test and quantitative HCV RNA levels below the lower limit of quantification, confirmed by RNA PCR test, will not be excluded provided they have completed a successful course of HCV anti-viral treatment with no HCV recurrence for ≥ 6 months.


•  Participants with latent TB or potentially active TB as defined by positive QuantiFERON TB-Gold test® (QFT), positive purified protein derivative (PPD) skin test or other locally-approved TB enzyme-linked immunosorbent assay (ELISA) tests (e.g., T-SPOT) must agree to comply with testing and management outlined in Section 8.2.4. Also see this section for indeterminate QFT management.
•  Active tuberculosis (TB) infection suggested by positive TB testing, clinical symptoms, and/or chest imaging (X-ray or CT)
•  History of organ transplant
•  Acquired or congenital immunodeficiency

Laboratory Results Exclusion Criteria
•  Clinically significant abnormality on laboratory tests during screening (hematology, serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk in administering study treatment to the potential participant
•  ALT, AST, or ALP ≥ 2.5 x upper limit of normal (ULN), total bilirubin ≥ 1.5 x ULN, or presence of abnormalities in synthetic liver function tests judged to be clinically significant by the investigator.

Patients with an established diagnosis of Gilbert’s syndrome (i.e., with required source documentation showing unconjugated hyperbilirubinemia with no evidence of hemolysis) with total bilirubin levels < 3 x ULN can be included.
•  ANC < 1.5 x 10^9/L (1500/L) with one exception:
– Participants with documented benign ethnic neutropenia (BEN): ANC < 1.3 x 109/L (1300/microliter)

BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al. 2019). BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.
•  Platelet count < 100,000/microliter
•  Hemoglobin < 8 g/dL
•  Absolute lymphocyte count < 500/microliter
•  Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2

•  Prohibited Medications Exclusion Criteria
•  Any of the following related to previous or current treatment:
–  Use of approved CD treatments including approved oral small molecule (e.g., JAK inhibitor) treatments within 2 weeks prior to screening endoscopy (or SOC endoscopy), or approved biologic agents within 8 weeks or 5 half-lives, prior to randomization (Week 0, Day 1) whichever is shorter

•  If there is proper documentation of undetectable drug level measured by a commercially available assay for any of the approved biologics, there is no minimum washout .
  Use of any investigational or experimental therapy within approximately 30 days for non-biologic therapy or 8 weeks for biologic therapy, OR 5 half-lives (whichever is shorter), prior to randomization (Week 0, Day 1)
  Oral prednisone > 20 mg/day (or dose equivalent of other oral corticosteroids) from 2 weeks prior to screening endoscopy (or SOC endoscopy), or intent to receive during the study with the exception for the treatment of an AE
  Any immunosuppressive therapy including B-cell depleting agents (e.g., natalizumab, rituximab) or other lymphocyte depleting agents (e.g., alemtuzumab), or any other immunosuppressive agents (e.g., those where live vaccines are contraindicated) within 1 year prior to screening or intent to receive during the study
  Treatment with IV corticosteroids ≤ 2 weeks prior to screening endoscopy (or SOC endoscopy) or intent to receive during the study, with the exception of a single administration of IV steroid for potential IRR management
  Presence of conditions other than CD (e.g., uncontrolled asthma) that could require treatment with > 20 mg/day of prednisone (or equivalent) during the course of the study
  Treatment with corticosteroid enemas or suppositories and/or topical (rectal) 5-aminosalicyclic acid (5-ASA) preparations ≤ 2 weeks prior to screening endoscopy (or SOC endoscopy) or intent to receive during the study
  Treatment with topical rectal traditional medicine (e.g., Chinese medicine), herbal enemas, or suppositories ≤ 2 weeks prior to screening endoscopy (or SOC endoscopy) or intent to receive during the study
  Treatment with approved CD oral traditional medicine (e.g., Chinese medicine) ≤ 4 weeks prior to screening endoscopy (or SOC endoscopy) or intent to receive during the study.
  Transplant/stem cell therapy at any time prior to randomization (Week 0, Day 1) or intent to receive during the study
  Treatment ≤16 weeks prior to randomization (Week 0, Day 1) with cyclosporine, thalidomide, tacrolimus, sirolimus, or mycophenolate mofetil or intent to receive during the study
  Apheresis ≤ 2 weeks prior to screening endoscopy (or SOC endoscopy) or intent to receive during the study
  Currently receiving total parenteral nutrition
  Continued tube feeding, and/or total parenteral alimentation/nutrition as treatment for CD ≤ 3 weeks prior to randomization or during the study
  Receipt of fecal microbial transplantation within 4 weeks prior to randomization (Week 0, Day 1)
  Current or prior use of anti-TL1A (afimkibart/ RO7790121/ RVT-3101/ PF-06480605) or any type of anti-TL1A therapy
  Receipt of a live or attenuated vaccine  4 weeks prior to screening endoscopy (or SOC endoscopy) or intent to receive during the study;
•  Use of non-live (inactivated) vaccines is allowed.
  Chronic (e.g., > 7 days) nonsteroidal anti-inflammatory drug (NSAID) use;
  Occasional use of NSAIDs and acetaminophen is permitted (e.g., headache, arthritis, myalgias, or menstrual cramps)
•  Aspirin ≤ 325 mg/day is permitted.
  Treatment with immunoglobulin or blood products within 4 weeks prior to screening, or any condition that is likely to require such treatment during the course of the study
  IV antibiotics ≤ 4 weeks prior to randomization (Week 0, Day 1)
  Previous severe allergic reaction (NCI CTCAE v5.0 Grade 3 or higher) or anaphylactic reaction to biologic agents or to any excipients of the study drug

• Gastroenterology

• Roche Laboratories