Moderate-to-Severe Crohn′s Disease

 To assess the effect of BMS-986165 on endoscopic remission at Week 12 (Day 85)  To assess the effect of BMS-986165 on clinical response at end of the Induction Period (Week 12 [Day 85])  To assess the effect of BMS-986165 on clinical response through the end of the Maintenance Period (Week 52 [Day 365])  To assess the effect of BMS-986165 on clinical remission through the end of the Maintenance Period (Week 52 [Day 365])  To endoscopically assess the effect of BMS-986165 on gut mucosal disease activity through Week 52  To assess the effect of BMS-986165 on deep remission through Week 52

BMS-986165

BMS-986165

capdule

3

The proposed study is a Phase 2 randomized, double-blind placebo-controlled study to assess the
safety and efficacy of 3 dosing regimens of BMS-986165 in subjects with moderate-to-severe CD.
Three doses of BMS-986165 will be compared to placebo in the induction and maintenance of
clinical remission (average daily score for abdominal pain ≤ 1 and number of very soft (loose or
mushy) or liquid (watery) stools (Bristol Stool Scale [BSS; see APPENDIX 18] Type 6 or 7 only)
≤ 3 on the patient [or subject] reported outcome [PRO] based on the frequency of very soft (loose
or mushy) or liquid (watery) stools and abdominal pain components of the Crohn’s Disease
Activity Index [CDAI PRO-2], and both not worse than baseline) and endoscopic response (at
least a 50% improvement from baseline in the Simple Endoscopic Score for Crohn’s Disease
[SES-CD]) in subjects with moderately to severely active CD.

Inclusion Criteria
1) Signed Written Informed Consent
a) Willing to participate in the study and sign the ICF.
b) Willing and able to complete all study-specific procedures and visits.
2) Type of Subject and Target Disease Characteristics
a) Documented diagnosis of CD of at least 3 months’ duration, with colitis, ileitis, or
ileocolitis, confirmed by:
 Source: Medical records with report of an ileocolonoscopy (full colonoscopy with the
intubation of terminal ileum) which shows features consistent with CD, as determined
by the procedure-performing physician, AND
 Source: Medical record documentation of a histopathology report showing features
consistent with CD, as determined by the local pathologist.
Note: If no previous confirmation of diagnosis is available or if previous diagnosis is not
deemed conclusive, at time of baseline endoscopy, histology must be performed and read
locally to confirm diagnosis of CD before proceeding to randomization.
b) Must have active moderate-to-severe CD, as defined by:
 CDAI score of 220 to 450 AND
 PRO-2: Average daily score for abdominal pain ≥ 2 OR average daily number of very
soft (loose) or liquid (watery) stools (BSS Type 6 or 7 only; see APPENDIX 18) ≥ 4,
as collected in a 7-day diary, AND
 Evidence of active inflammation in at least 1 of the 5 ileocolonic segments (based on
central reading) with total SES-CD ≥ 6 or SES-CD ≥ 4 if only isolated ileitis is present
on baseline endoscopy
c) Must have had an inadequate response, loss of response, or intolerance to a standard
treatment course of 1 or more of the following standard of care medications as below:
 Oral aminosalicylates: (eg, mesalamine, sulfasalazine, olsalazine, balsalazine) at or
above the approved label dose for induction therapy for at least 6 weeks
 Oral CS: Prednisone 20 mg/day or equivalent for at least 2 weeks, and/or 2 failed
attempts to taper oral CS below prednisone or equivalent 10 mg daily
 IV Corticosteroids: hydrocortisone ≥ 400 mg/day or equivalent for at least 1 week
 Immunomodulators: (AZA ≥ 2 mg/kg/day, 6-MP ≥ 1 mg/kg/day, MTX ≥ 25 mg/week,
or documentation of a therapeutic concentration of 6 thioguanine nucleotide) for at least
12 weeks
 Biologics: (eg, infliximab, adalimumab, certolizumab pegol, vedolizumab,
natalizumab) as defined in APPENDIX 4. Subjects can be included if treatment with a
biologic was stopped due to primary or secondary nonresponse (responded initially but
then lost response with continued therapy), or were intolerant to treatment, as defined
in APPENDIX 4.
d) This study permits the rescreening of a subject that has been deemed as ineligible (screen
failure) during the Screening Period (ie, subject has not been randomized/has not been
treated; Section 6.5). If re-enrolled, the subject must be re-consented (ie, re-signing of the ICF) and rescreened (if outside the 28-day Screening Period window). Only
1 re-enrollment per subject is permissible.
3) Age and Reproductive Status
a) Men and women aged 18 to 75 years inclusive at the time of screening
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic
gonadotropin) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration
of treatment with study treatment(s) (BMS-986165 or placebo) plus 5 half-lives of study
treatment (3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post
treatment completion
e) WOCBP who are not heterosexually active are exempt from contraceptive requirements,
and still must undergo pregnancy testing as described in this section
f) Investigators shall counsel WOCBP and men who are sexually active with WOCBP, on
the importance of pregnancy prevention and the implications of an unexpected
pregnancy. Investigators shall advise on the use of highly effective methods of
contraception, (APPENDIX 5) which have a failure rate of < 1% when used consistently
and correctly.
g) Men who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception (APPENDIX 5) for the duration of treatment with study
treatment BMS-986165 or placebo plus 5 half-lives of the study treatment (3 days) after
the final dose of study treatment.
h) Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive requirements,
and still must undergo pregnancy testing as described in this section.
i) Male subjects must be willing to refrain from sperm donation during the entire duration
of treatment plus 5 half-lives of study treatment (3 days) after the final dose of study
treatment.

Exclusion Criteria
1) Target Population
a) Severe or fulminant colitis that is likely to require surgery or hospitalization
b) Presence of a diagnosis of alternative forms of colitis (infectious, inflammatory including
ulcerative colitis, malignant, toxic, indeterminate, etc.) other than CD
c) Presence of a stoma, gastric or ileoanal pouch, previous proctocolectomy or total
colectomy, symptomatic, obstructive disease such as stenosis or obstructive strictures,
abscess or suspected abscess, pouchitis, short bowel syndrome, or history of bowel
perforation
d) History of intra-abdominal abscess within the last 60 days
 Previous intra-abdominal abscess that has been drained and successfully treated with a
local standard course of antimicrobial therapy is permitted (The course must be
completed at least 60 days prior to Day 1)
e) History of diverticulitis within the last 60 days
 Previous diverticulitis that has been successfully treated with a local standard course of
antimicrobial therapy is permitted. (The course must be completed at least 60 days prior
to Day 1)
f) Receiving tube feeding, defined formula diets, or total parenteral alimentation
g) Current colonic dysplasia or past colonic dysplasia that has not been definitively treated
h) History of infectious (bacterial, viral, fungal, parasitic, etc.) colitis within past 30 days;
must be fully treated to rescreen
i) Use of therapeutic enema or suppository, other than required for ileocolonoscopy, within
7 days prior to screening or during the Screening Period
j) Prior treatment with specific lymphocyte-depleting agents, such as alemtuzumab,
rituximab, and other agents such as ustekinumab, are prohibited within 12 months prior to
the first dose of study treatment during the Induction Period. Please note that lack of
response to ustekinumab (as well as other anti-12/23 p40 antibodies) or anti-IL-23 p19
antibodies are criteria for exclusion (also see exclusion criterion 3b)
k) Receipt of either lymphocyte apheresis or selective monocyte, granulocyte apheresis (eg,
Cellsobra®) is prohibited within 12 months prior to the first dose of study treatment during
the Induction Period
l) Previous exposure to BMS-986165 in any study
m) Previous stem cell transplantation
n) Previous treatment with investigational agents within 12 weeks or 5 half-lives (whichever
is longer) prior to the first dose of study treatment during the Induction Period
2) Other Medical Conditions and History
a) Women who are pregnant or breastfeeding
b) Any major illness/condition or evidence of an unstable clinical condition (eg, renal,
hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, psychiatric),
or local active infection/infectious illness) that, in the investigator’s judgment, will
substantially increase the risk to the subject if he or she participates in the study
c) Any major surgery within the last 30 days before the first dose of study treatment, or any
surgery planned during the course of the study
d) Potential subjects with the following characteristics will be excluded from the study:
 History of any kind of bowel resection within 6 months or any other intra-abdominal
surgery within 3 months prior to baseline
 History of any surgical procedure requiring general anesthesia, other than required for
ileocolonoscopy, within 30 days prior to the first dose of study treatment, or is
planning to undergo surgery during the study period
 History of bleeding disorders or recent use of anti-platelet or anti-thrombotic agents
that in the investigator’s judgment preclude safely performing endoscopic procedures
and biopsy within the timeframe outlined in the study protocol
 Currently on any therapy for chronic infection (eg, pneumocystis, cytomegalovirus,
herpes simplex, herpes zoster, invasive bacterial or fungal infections, or atypical
mycobacteria)
 History of congenital or acquired immunodeficiency
 Known active infection, or any major episode of infection requiring hospitalization or
treatment with parenteral (intramuscular or IV) antimicrobial agents (eg, antibiotics,
antiviral, antifungal, or antiparasitic agents) within 30 days of the first dose of study
treatment, or completion of oral antimicrobial agents within 2 weeks of the first dose
of study treatment
 Previous history of herpes zoster, herpes simplex, or influenza infection within
12 weeks before the first dose of study treatment or a history of
disseminated/complicated herpes zoster infection (multidermatomal involvement,
ophthalmic zoster, central nervous system involvement, or post-herpetic neuralgia)
 Cancer or history of cancer or lymphoproliferative disease within the previous 5 years
(other than adequately treated cutaneous basal cell or squamous cell carcinoma or
resected cervix carcinoma in situ with no evidence of recurrence)
 Class III or IV congestive heart failure, as classified by the New York Heart
Association (NYHA) Functional Classification or any recent onset of heart failure
resulting in NYHA Class III/IV symptoms
 Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) and/or
any history of significant cerebrovascular disease (eg, stroke, cerebral hemorrhage,
transient ischemic attack) within 24 weeks before screening
 Administration of a live vaccine within 90 days or an inactivated vaccine within
30 days before the first dose of study treatment administration. Heat-killed, or
otherwise inactivated or protein vaccines (eg, influenza and pneumococcal vaccines)
may be received at any time on study. Furthermore, live vaccines should not be used
during the study and within the 2 months following last dose, and any other
inactivated vaccines (eg, tetanus, etc.) should be used according to local guidelines
during the treatment period.
 Current or recent (within 3 months before the first dose) gastrointestinal disease,
including gastrointestinal surgery, that could impact the absorption of study
treatment, or current or recent (within 6 months before the first dose) gastrointestinal
resections
e) Female subjects with a breast cancer screen suspicious for malignancy, and in whom the
possibility of malignancy cannot be reasonably excluded after additional clinical,
laboratory, or other diagnostic evaluations
f) Significant blood loss (> 500 mL) or blood transfusion within 4 weeks of study treatment
administration
g) Inability to tolerate oral medication
h) Inability to undergo venipuncture and/or tolerate venous access
i) Recent (within 6 months of study treatment administration) drug or alcohol abuse, as
defined by the Diagnostic and Statistical Manual of Mental Disorders IV (APPENDIX 8)
j) Any other sound medical, psychiatric and/or social reason as determined by the investigator
3) Prior/Concomitant Therapy.
a) Inability to comply with restrictions and prohibited treatments, as listed in Section 7.7
b) Lack of response (if known) to previous treatment with agents that are approved or were
used in a clinical trial, that target the same pathway as BMS-986165 such as anti-12/23 p40
antibodies (such as ustekinumab or briakinumab) or anti-IL-23p19 antibodies (such as
guselkumab, risankizumab, tildrakizumab, brazikumab [MEDI2070], and mirikizumab
[LY3074828])
c) Other investigational agents must be discontinued at least 12 weeks or 5 half-lives prior to
the first dose of study treatment, whichever is longer
4) Physical and Laboratory Test Findings
a) Evidence of organ dysfunction or any clinically significant deviation from normal in
physical examinations, vital signs, ECG, chest x-ray, or clinical laboratory determinations
beyond what is consistent with the target population
b) Evidence of active or latent tuberculosis (TB), as follows:
 History of active TB prior to the screening visit, regardless of completion of adequate
treatment
 Has signs or symptoms of active TB as judged by the investigator
 A chest x-ray obtained during the Screening Period or anytime within 6 months before
screening, with documentation, with evidence of current active or old active pulmonary
TB
 Latent TB infection (LTBI) defined as positive IFN-gamma release assay (IGRA) such as
QuantiFERON®-TB Gold, QuantiFERON®-TB Gold Plus, or T-Spot® at screening, or
other diagnostic test in the absence of clinical manifestations
Note: such subjects may be eligible if (1) there are no current signs or symptoms of
active TB and (2) the subject has received adequate documented treatment for LTBI
within 5 years of screening OR has initiated prophylactic treatment for LTBI per
local guidelines and is rescreened now after 1 month of treatment. The subject must
agree to complete a locally recommended course of treatment for LTBI to continue
in the study.
 An indeterminate IGRA result at screening with no signs or symptoms of active TB
Note: A subject with an indeterminate IGRA test result must be retested for
confirmation. If the second result is again indeterminate, the subject will be
excluded from the study. If the second result is positive, the subject should be
treated as having LTBI. If the second result is negative, the subject may be eligible
provided no other exclusion criterion for TB is met.
c) Hepatitis C virus (HCV), hepatitis B virus (HBV), or human immunodeficiency virus
(HIV) infection as demonstrated by a positive blood screen for HCV antibody (anti-HCV),
hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), or HIV-1 and -
2 antibodies; subjects who have been vaccinated for HBV (ie, hepatitis B surface antibody
[anti-HB]-positive) are not excluded. Note: Testing for anti-HBs is not requested (APPENDIX 9). Note: Subjects who are newly found to be HIV-positive should be
directed to appropriate follow-up.
d) Clinically significant abnormalities on chest x-ray or ECG
e) Clinically significant abnormalities in laboratory testing including:
 Serum alanine aminotransferase (ALT) > 2× upper limit of normal (ULN)
 Serum aspartate aminotransferase (AST) > 2× ULN
 Serum total bilirubin > 2× ULN
 Alkaline phosphatase > 2.5× ULN
 Serum creatinine > 2× ULN
 Hemoglobin level < 9 g/dL
 Absolute white blood cell count < 3000/mm3
 Absolute lymphocyte count < 500/mm3
 Neutrophil count < 1000/mm3
 Platelet count < 100,000/mm3
f) Positive stool culture for enteric pathogens (not including flora that are considered
commensal within a study region) at screening visit; subjects may rescreen 30 days after
completion of a standard treatment course with antimicrobial agents without recurrence of
clinical symptoms
g) Stool positive for Clostridium difficile (C. difficile) toxin at screening visit; subjects may
be rescreened 30 days after completion of an institutional standard-of-care course with
antibiotics without documented evidence of recurrence of clinical symptoms
h) Any other significant laboratory abnormalities that, in the opinion of the investigator, might
place the subject at unacceptable risk for participation in this study
5) Allergies and Adverse Drug Reaction
a) History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. If applicable to national or local
legislation: history of being admitted to an institution under an administrative or court order
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infectious disease) illness
c) Inability to comply with the study protocol