Safety and Efficacy of Andecaliximab in Participants With Moderately to Severely Active Crohn's Disease

• Andecaliximab (Drug), also known as GS-5745: Andecaliximab administered via subcutaneous (SC) injection
• Placebo (Drug): Placebo to match andecaliximab administered via SC injection

Primary outcomes

• Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase [Week 8]: Clinical response was defined as patient-reported outcomes (PRO2) score ≤ 8 at Week 8. PRO2 is the weighted average of the 2 variables of frequency of liquid or very soft stool and abdominal pain, based on 7-day participant diary data. The PRO2 score has a minimum score of 0 and has no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with a missing PRO2 value at the Week 8 analysis visit were imputed as not achieving the Clinical Response.
• Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase [Week 8]: Endoscopic response was defined as ≥ 50% reduction from baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD) at Week 8. The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 60, with higher scores indicating more severe disease. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD value at Week 8 analysis visit were imputed as not achieving Endoscopic Response.

Secondary outcomes

• Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase [Week 8]: Clinical remission was defined as Crohn's Disease Activity Index (CDAI) ≤ 150 at Week 8. CDAI is used as a measure of clinical response and remission. It includes 8 variables of patient-reported symptoms and objective variables: stool count, abdominal pain, general well-being, complications, use of anti-diarrheal medications, presence of abdominal mass, hematocrit values, and weight. It has a minimum range of 0 and no upper bound, with higher scores indicating greater disease activity. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing CDAI score at Week 8 analysis visit were imputed as not achieving CDAI Remission.
• Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase [Week 8]: The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The SES-CD size-of-ulcer subscore ranges from 0 (none) to 3 (very large). Mucosal healing at Week 8 was defined as the size-of-ulcer subscore for segments with non-zero baseline value changes to zero at Week 8 AND the size-of-ulcer subscore for segments with zero value at baseline remain zero at Week 8. Week 8 refers to the analysis window of Day 43 to Day 70 and prior to the first Open-Label dose date. Participants with missing SES-CD size-of-ulcer subscore at Week 8 analysis visit were imputed as not achieving Mucosal Healing.

Sex: All, ages: 18 Years to 75 Years

Key Inclusion Criteria:

* Ability to provide a written informed consent
* Females of childbearing potential must have a negative pregnancy test at screening and baseline
* Documented diagnosis of Crohn's disease with a minimum disease duration of 6 months with involvement of the ileum and/or colon at a minimum
* Moderately to severely active Crohn's disease as defined by a Crohn's Disease Activity Index (CDAI) total score between 220-450 (inclusive) AND with evidence of active disease as measured by ileocolonoscopy
* Within the previous 5 years, demonstrated an inadequate clinical response or intolerance of at least one of the following agents:

  * Corticosteroids
  * Immunomodulators
  * Tumor necrosis factor-alpha (TNFα) antagonists
  * Vedolizumab
* May be receiving the following drugs:

  * Oral 5-aminosalicylate (5-ASA)
  * Oral corticosteroid therapy
  * Antidiarrheals for chronic diarrhea
  * Azathioprine or 6-mercaptopurine (6-MP) or methotrexate
  * Antibiotics for the treatment of Crohn's disease
* Able to comply with the dosing instructions for study drug and able to comply with the study visits and requirements

Key Exclusion Criteria:

* Evidence of abscess at screening
* Extensive colonic resection (subtotal or total colectomy) or history of > 2 small bowel resections
* Ileostomy, colostomy, or symptomatic stenosis of the intestine
* Current use of oral corticosteroids at a dose equivalent to > 30 mg/day of prednisone
* Ulcerative colitis or indeterminate colitis
* Short bowel syndrome
* Stool sample positive for Clostridium difficile (C. difficile) toxin, E. coli, Salmonella, Shigella, Campylobacter or Yersinia
* Treatment with any monoclonal antibody within 4 weeks of screening
* History or evidence of colonic mucosal dysplasia
* HIV, hepatitis B, hepatitis C, or tuberculosis (TB) infection
* Participated in a clinical study with an investigational drug or biologic within the last 30 days
* Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease) that, in the opinion of the investigator, would make the individual unsuitable for the study or would prevent compliance with the study protocol

Note: Other protocol defined Inclusion/ Exclusion criteria may apply.

Participant flow

Outcome results

• Percentage of Participants Achieving Clinical Response (PRO2 Score ≤ 8) at Week 8 of the Double-Blind Phase (Primary), Number, percentage of participants: Andecaliximab 150 mg Every 2 Weeks 17.0 (8.1 to 29.8); Andecaliximab 150 mg Weekly 13.2 (5.5 to 25.3); Andecaliximab 300 mg Weekly 11.3 (4.3 to 23.0); Placebo 14.3 (4.0 to 32.7)
• Percentage of Participants Achieving Endoscopic Response (≥ 50% Reduction From Baseline SES-CD) at Week 8 of the Double-Blind Phase (Primary), Number, percentage of participants: Andecaliximab 150 mg Every 2 Weeks 11.3 (4.3 to 23.0); Andecaliximab 150 mg Weekly 13.2 (5.5 to 25.3); Andecaliximab 300 mg Weekly 7.5 (2.1 to 18.2); Placebo 10.7 (2.3 to 28.2)
• Percentage of Participants Achieving CDAI Remission (CDAI ≤ 150) at Week 8 of the Double-Blind Phase (Secondary), Number, percentage of participants: Andecaliximab 150 mg Every 2 Weeks 20.8 (10.8 to 34.1); Andecaliximab 150 mg Weekly 17.0 (8.1 to 29.8); Andecaliximab 300 mg Weekly 11.3 (4.3 to 23.0); Placebo 21.4 (8.3 to 41.0)
• Percentage of Participants Achieving Mucosal Healing (SES-CD Size-of-Ulcer Subscore = 0) at Week 8 of the Double-Blind Phase (Secondary), Number, percentage of participants: Andecaliximab 150 mg Every 2 Weeks 5.7 (1.2 to 15.7); Andecaliximab 150 mg Weekly 1.9 (0.0 to 10.1); Andecaliximab 300 mg Weekly 1.9 (0.0 to 10.1); Placebo 7.1 (0.9 to 23.5)

Adverse events

Time frame: Double-Blind Phase: First dose of andecaliximab to Week 8; Open-Label Phase (includes adverse events occurring in the Extended Treatment Phase): First dose of open label andecaliximab to the last dose date (maximum: 200 weeks) plus 30 days

Serious adverse events by term

Other adverse events by term

Limitations and caveats: A prespecified topline analysis was performed after the last enrolled subject received the 8-week Double-Blind induction treatment. Based on this review, Gilead terminated the Open-Label and Extended Treatment Phases of study due to lack of efficacy.

• Results publication: Schreiber S, Siegel CA, Friedenberg KA, Younes ZH, Seidler U, Bhandari BR, Wang K, Wendt E, McKevitt M, Zhao S, Sundy JS, Lee SD, Loftus EV. A Phase 2, Randomized, Placebo-Controlled Study Evaluating Matrix Metalloproteinase-9 Inhibitor, Andecaliximab, in Patients With Moderately to Severely Active Crohn's Disease. J Crohns Colitis. 2018 Aug 29;12(9):1014-1020. doi: 10.1093/ecco-jcc/jjy070. PMID 29846530

• Gilead Study Team, Study director, Gilead Sciences

NIH grants: 2015