Dose-Ranging Phase 2b Study of ABX464 in Moderate to Severe Ulcerative Colitis

Reduction from baseline in Modified Mayo Score (MMS)

MMS is a composite score of UC disease activity based on the following 3 subscores:

1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal).
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed).
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration).

The overall MMS ranges from 0 to 9 where higher scores represent more severe disease.

Number of participants who achieved clinical remission per Modified Mayo Score at Week 8

MMS is a composite score of UC disease activity based on the following 3 subscores:

1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal).
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed).
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration).

The overall MMS ranges from 0 to 9 where higher scores represent more severe disease.

Clinical remission is defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1 (modified to exclude friability)

Number of participants who achieved clinical remission per Modified Mayo Score at Week 16

MMS is a composite score of UC disease activity based on the following 3 subscores:

1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal).
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed).
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration).

The overall MMS ranges from 0 to 9 where higher scores represent more severe disease.

Clinical remission is defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1 (modified to exclude friability)

Clinical response is defined as a reduction in MMS of at least 2 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub-score of greater than or equal to 1 point or absolute rectal bleeding sub-score of less than or equal to 1 point.

Clinical response is defined as a reduction in MMS of at least 2 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub-score of greater than or equal to 1 point or absolute rectal bleeding sub-score of less than or equal to 1 point.

Endoscopic improvement is defined as an endoscopic subscore of 0 or 1 (excluding friability)

Endoscopies were assessed by a blinded central reader and scored according to the following scale:

0 = Normal or inactive disease;

1. = Mild disease (erythema, decreased vascular pattern);
2. = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions);
3. = Severe disease (spontaneous bleeding, ulceration).

A higher endoscopic score indicates more severe disease.

Endoscopic improvement is defined as an endoscopic subscore of 0 or 1 (excluding friability)

Endoscopies were assessed by a blinded central reader and scored according to the following scale:

0 = Normal or inactive disease;

1. = Mild disease (erythema, decreased vascular pattern);
2. = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions);
3. = Severe disease (spontaneous bleeding, ulceration).

A higher endoscopic score indicates more severe disease.

Mucosal healing is defined as endoscopic remission (overall mucosal appearance at endoscopy subscore=0) and histological remission (Geboes score <2.0 based on rectal biopsy).

The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration).

The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.

A higher score is associated with higher disease activity.

Mucosal healing is defined as endoscopic remission (overall mucosal appearance at endoscopy subscore=0) and histological remission (Geboes score <2.0 based on rectal biopsy).

The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration).

The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.

A higher score is associated with higher disease activity.

Participants recorded stool frequency using an electronic subject diary on a daily basis. The stool frequency subscore (SFS) ranges from 0 to 3 according to the following scale:

Score 0: Normal number of stools Score 1: 1 to 2 stools per day more than normal Score 2: 3 to 4 stools per day more than normal Score 3: 5 or more stools per day more than normal

Decreasing score indicates improvement.

Participants recorded rectal bleeding in an electronic subject diary on a daily basis. Rectal bleeding score (RBS) is taken as the worst subscore of the three most recent scores within 7 days prior to the visit.

The rectal bleeding subscore ranges from 0 to 3 according to the following scale:

Score 0: No blood seen Score 1: Streaks of blood with stool less than half the time Score 2: Obvious blood with stool most of the time Score 3: Blood alone passed A lower score represents an improvement in rectal bleeding.

Partial Modified Mayo Score (pMMS) Change from baseline

The pMMS is a composite score of UC disease activity based on the following 2 subscores:

1. Stool frequency subscore (SFS), scored from 0 (normal number of stools per day) to 3 (5 or more stools per day more than normal).
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed).

The overall pMMS score ranges from 0 to 6 with higher scores representing more severe disease.

Fecal Calprotectin (FC) is a non-invasive surrogate marker of inflammation in the small intestine and levels below 250 ug/g is associated with mucosal healing.

FC levels were measured using enzyme-linked immunosorbent assay (ELISA) and/or a validated quantitative rapid test. Outcome will be measured based on a reduction in FC relative to baseline values.

CRP is an acute-phase protein which provides an objective criterion of inflammatory activity. CRP has a short half-life (19 hours) and therefore rises early after the onset of inflammation and rapidly decreases after resolution of the inflammation. It is induced by interleukin-6, TNF-alpha and other pro-inflammatory cytokines that are produced within the intestinal lamina propria. Outcome will be measured based on a reduction in CRP relative to baseline values.

Absolute quantification (QuantaSoft Pro) of the miR-124 copy number was performed at Week 8 and Week 16 using droplet digital PCR technology (ddPCR) on whole blood samples.

"0" in the placebo column means "no signal", so BLQ (Below the level of quantification).

Serum samples from participants who received ABX464 (25, 50 or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57, and Day 113).

IL6 was measured using the 8-plex assay on the ELLA Platform (Biotechne). All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n)

The post baseline values are calculated as follow: post-baseline IL-6 values - Day 1 IL-6 values/Day 1 IL-6 values)*100

Endoscopic remission is defined as an endoscopic subscore of 0.

Endoscopies were assessed by a blinded central reader and scored according to the following scale:

0 = Normal or inactive disease;

1. = Mild disease (erythema, decreased vascular pattern);
2. = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions);
3. = Severe disease (spontaneous bleeding, ulceration).

A higher score represents more severe disease.

Endoscopic remission is defined as an endoscopic subscore of 0.

Endoscopies were assessed by a blinded central reader and scored according to the following scale:

0 = Normal or inactive disease;

1. = Mild disease (erythema, decreased vascular pattern);
2. = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions);
3. = Severe disease (spontaneous bleeding, ulceration).

A higher score represents more severe disease.

Serum samples from patients who received ABX464 (25, 50 or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57, and Day 113).

IL10 was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n)

The post baseline values are calculated as follow: post-baseline IL-10 values - Day 1 IL-10 values/Day 1 IL-10 values)*100

Serum samples from patients who received ABX464 (25, 50, or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57 and Day 113).

IL1beta was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n)

The post baseline values are calculated as follow: post-baseline IL-1B values - Day 1 IL-1B values/Day 1 IL-1B values)*100

Serum samples from patients who received ABX464 (25, 50, or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57 and Day 113 TNF-alpha was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n)

The post baseline values are calculated as follow: post-baseline TNFα values - Day 1 TNFα values/Day 1 TNFα values)*100

Infiltrate/Histopathology (Rectal/Sigmoidal Biopsies) using the Robarts Histopathology Index (RHI) Week 8 and Week 16 biopsies will be compared to biopsies at baseline to assess the disease evolution at a tissue level, based on the Robarts Histological Index.

The score ranges from 0 (no disease activity) to 33 (severe disease activity) is based on evaluation of 4 parameters: chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in the epithelium and erosion and ulceration.

A higher score indicates more severe disease.

The Geboes score is composed of 6 major grades that assess different aspects of the biopsy findings, with each grade having its own score range:

1. Structural Changes (Grade 0): Range: 0 (No changes) to 3 (Severe changes)
2. Chronic Inflammation (Grade 1): Range: 0 (No inflammation) to 3 (Severe inflammation)
3. Lamina Propria Neutrophils (Grade 2): Range: 0 (None) to 3 (Severe infiltration of neutrophils)
4. Neutrophils in the Epithelium (Grade 3): Range: 0 (None) to 3 (Severe neutrophil infiltration)
5. Crypt Destruction (Grade 4): Range: 0 (No destruction) to 3 (Severe crypt destruction)
6. Erosion and Ulcers (Grade 5): Range: 0 (None) to 3 (Severe erosion/ulceration)

Subscales are summed across all 6 grades, final total score between 0 and 18 :

• 0-5: Minimal or no inflammation
• 6-10: Mild inflammation
• 11-15: Moderate inflammation
• 16-18: Severe inflammation or damage A higher score indicates more severe disease

Serum samples from participants who received ABX464 (25, 50 or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57, and Day 113).

IL6 was measured using the 8-plex assay on the ELLA Platform (Biotechne). All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n) The post baseline values are calculated as follow: post-baseline IL-6 values - Day 1 IL-6 values/Day 1 IL-6 values)*100

Serum samples from patients who received ABX464 (25, 50 or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57, and Day 113).

IL10 was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n)

The post baseline values are calculated as follow: post-baseline IL-10 values - Day 1 IL-10 values/Day 1 IL-10 values)*100

Serum samples from patients who received ABX464 (25, 50, or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57 and Day 113).

IL1beta was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n)

The post baseline values are calculated as follow: post-baseline IL-1B values - Day 1 IL-1B values/Day 1 IL-1B values)*100

Serum samples from patients who received ABX464 (25, 50, or 100 mg) or placebo were collected during 5 visits (Day 1, Day 8, Day 29, Day 57 and Day 113 TNF-alpha was measured using the 8-plex assay on the ELLA Platform. All samples were tested in duplicate at the minimum required dilution.

Baseline (Day 1) values are calculated as below: x1/arithmetic mean of baseline values x 100, where the arithmetic mean is defined by (x1 + x2+...+xn)/n (summing all baseline values and dividing by the total number of values n)

The post baseline values are calculated as follow: post-baseline TNFα values - Day 1 TNFα values/Day 1 TNFα values)*100