VELSIPITY™ Clinical Studies

(etrasimod)

14 CLINICAL STUDIES

The efficacy of VELSIPITY was evaluated in 2 randomized, double-blind, placebo-controlled clinical studies [UC-1 (NCT03945188) and UC-2 (NCT03996369)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response, loss of response, or intolerance to one or more of the following treatment options: oral aminosalicylates, corticosteroids, thiopurines, Janus kinase (JAK) inhibitors, or biologic therapies (e.g., TNF blocker, anti-integrin, anti-IL12/23). UC-1 was a 52-week study and UC-2 was a 12-week study. In both studies, subjects were randomized to VELSIPITY or placebo and continued on treatment for the entire duration of the study.

Disease severity was assessed based on the modified Mayo score (mMS), a 3-component Mayo score (0 to 9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SF), rectal bleeding (RB), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions, and a score of 3 was defined by spontaneous bleeding and ulceration.

Subjects in these studies may have received other concomitant UC therapies including stable daily doses of oral aminosalicylates and/or oral corticosteroids (≤20 mg/day prednisone, ≤9 mg/day budesonide, or equivalent steroid). Concomitant treatment with immunomodulators (e.g., thiopurines, methotrexate), biologic therapies, JAK inhibitors, rectal 5-ASA, or rectal corticosteroids was not permitted.

Endpoints and Results Study UC-1

In UC-1, efficacy was evaluated in 408 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 78 years); 45% were female; and 89% identified as White, 7% as Asian, 2% as Black or African American, 1% as American Indian or Alaska Native, and 1% did not report their racial group. A total of 30% of subjects had prior exposure to biologic/JAK inhibitors and a total of 14% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 68% of subjects were receiving oral aminosalicylates and 31% of subjects were receiving oral corticosteroids.

The coprimary endpoints were the proportion of subjects achieving clinical remission at Week 12 and at Week 52. The secondary endpoints included the proportion of subjects achieving endoscopic improvement, histologic-endoscopic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission (see Table 4).

Table 4: Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-1 at Week 12 and at Week 52
CI = confidence interval
*
Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability).
p <0.001.
§
Endoscopic improvement is defined as ES ≤1 (excluding friability).
Histologic-endoscopic mucosal improvement is defined as ES ≤1 (excluding friability) with Geboes Index score <2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue.
#
Corticosteroid-free clinical remission is defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks prior to Week 52.
Þ
Maintenance of clinical remission is defined as achievement of clinical remission at both Week 12 and Week 52.


Endpoints


Placebo


VELSIPITY

Treatment

Difference*

(95% CI)

Coprimary Endpoints

Clinical Remission at Week 12

   Total population

N = 134

7%

N = 274

27%

20%

(13%, 27%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

10%

N = 194

31%

   Prior biologic/

   JAK inhibitor exposure

N = 41

2%

N = 80

18%

Clinical Remission at Week 52

   Total population

N = 134

7%

N = 274

32%

26%

(19%, 33%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

8%

N = 194

37%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

21%

Week 12 Endpoints

Endoscopic Improvement§

   Total population

N = 134

14%

N = 274

35%

21%

(13%, 29%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

18%

N = 194

39%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

25%

Histologic-Endoscopic Mucosal Improvement

   Total population

N = 134

4%

N = 274

21%

17%

(11%, 23%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

6%

N = 194

24%

   Prior biologic/

   JAK inhibitor exposure

N = 41

0%

N = 80

14%

Week 52 Endpoints

Endoscopic Improvement§

   Total population

N = 134

10%

N = 274

37%

27%

(19%, 34%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

13%

N = 194

40%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

30%

Histologic-Endoscopic Mucosal Improvement

   Total population

N = 134

8%

N = 274

27%

18%

(11%, 25%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

11%

N = 194

28%

   Prior biologic/

   JAK inhibitor exposure

N = 41

2%

N = 80

23%

Corticosteroid-free Clinical Remission#

   Total population

N = 134

7%

N = 274

32%

26%

(19%, 33%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

8%

N = 194

37%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

21%

Maintenance of Clinical RemissionÞ

   Total population

N = 134

2%

N = 274

18%

16%

(11%, 21%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

2%

N = 194

22%

   Prior biologic/

   JAK inhibitor exposure

N = 41

2%

N = 80

10%

The relationship of histologic-endoscopic mucosal improvement at Week 12 or Week 52 to disease progression and longer-term outcomes after Week 52 was not evaluated in Study UC-1.

Clinical Response

A greater proportion of subjects treated with VELSIPITY compared to placebo achieved clinical response, defined as a ≥2 point and ≥30% decrease from baseline in mMS, and a ≥1 point decrease from baseline in RB subscore or an absolute RB subscore ≤1 at Week 12 (62% vs 34%).

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of subjects treated with VELSIPITY compared to placebo achieved endoscopic remission by Week 12 (15% vs 4%), Week 52 (26% vs 6%), and both Week 12 and Week 52 (11% vs 1%).

Endpoints and Results Study UC-2

In UC-2, efficacy was evaluated in 333 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 73 years); 41% were female; and 76% identified as White, 19% as Asian, 2% as American Indian or Alaska Native, 1% as Black or African American, and 2% as multiple racial groups or did not report their racial group. A total of 34% of subjects had prior exposure to biologic/JAK inhibitors and a total of 17% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 66% of subjects were receiving oral aminosalicylates and 28% of subjects were receiving oral corticosteroids.

The primary endpoint was the proportion of subjects achieving clinical remission at Week 12. The secondary endpoints included the proportion of subjects achieving endoscopic improvement and histologic-endoscopic mucosal improvement at Week 12 (see Table 5).

Table 5: Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-2 at Week 12
CI = confidence interval
*
Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability).
p <0.05.
§
Endoscopic improvement is defined as ES ≤1 (excluding friability).
Endoscopic-histologic mucosal improvement is defined as ES ≤1 (excluding friability) with Geboes Index score <2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue.


Endpoints


Placebo


VELSIPITY

Treatment

Difference*

(95% CI)

Clinical Remission

   Total population

N = 112

15%

N = 221

26%

11%

(3%, 20%)

   No prior biologic/

   JAK inhibitor exposure

N = 74

16%

N = 147

30%

   Prior biologic/

   JAK inhibitor exposure

N = 38

13%

N = 74

19%

Endoscopic Improvement§

   Total population

N = 112

19%

N = 221

30%

12%

(3%, 21%)

   No prior biologic/

   JAK inhibitor exposure

N = 74

19%

N = 147

34%

   Prior biologic/

   JAK inhibitor exposure

N = 38

18%

N = 74

23%

Histologic-Endoscopic Mucosal Improvement

   Total population

N = 112

9%

N = 221

16%

8%

(1%, 15%)

   No prior biologic/

   JAK inhibitor exposure

N = 74

11%

N = 147

19%

   Prior biologic/

   JAK inhibitor exposure

N = 38

5%

N = 74

11%

The relationship of histologic-endoscopic mucosal improvement at Week 12 to disease progression and longer-term outcomes after Week 12 was not evaluated in Study UC-2.

Clinical Response

A greater proportion of subjects treated with VELSIPITY compared to placebo achieved clinical response, defined as a ≥2 point and ≥30% decrease from baseline in mMS, and a ≥1 point decrease from baseline in RB subscore or an absolute RB subscore ≤1 at Week 12 (62% vs 41%).

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of subjects treated with VELSIPITY compared to placebo achieved endoscopic remission by Week 12 (17% vs 8%).

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Clinical Studies

14 CLINICAL STUDIES

The efficacy of VELSIPITY was evaluated in 2 randomized, double-blind, placebo-controlled clinical studies [UC-1 (NCT03945188) and UC-2 (NCT03996369)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response, loss of response, or intolerance to one or more of the following treatment options: oral aminosalicylates, corticosteroids, thiopurines, Janus kinase (JAK) inhibitors, or biologic therapies (e.g., TNF blocker, anti-integrin, anti-IL12/23). UC-1 was a 52-week study and UC-2 was a 12-week study. In both studies, subjects were randomized to VELSIPITY or placebo and continued on treatment for the entire duration of the study.

Disease severity was assessed based on the modified Mayo score (mMS), a 3-component Mayo score (0 to 9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SF), rectal bleeding (RB), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions, and a score of 3 was defined by spontaneous bleeding and ulceration.

Subjects in these studies may have received other concomitant UC therapies including stable daily doses of oral aminosalicylates and/or oral corticosteroids (≤20 mg/day prednisone, ≤9 mg/day budesonide, or equivalent steroid). Concomitant treatment with immunomodulators (e.g., thiopurines, methotrexate), biologic therapies, JAK inhibitors, rectal 5-ASA, or rectal corticosteroids was not permitted.

Endpoints and Results Study UC-1

In UC-1, efficacy was evaluated in 408 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 78 years); 45% were female; and 89% identified as White, 7% as Asian, 2% as Black or African American, 1% as American Indian or Alaska Native, and 1% did not report their racial group. A total of 30% of subjects had prior exposure to biologic/JAK inhibitors and a total of 14% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 68% of subjects were receiving oral aminosalicylates and 31% of subjects were receiving oral corticosteroids.

The coprimary endpoints were the proportion of subjects achieving clinical remission at Week 12 and at Week 52. The secondary endpoints included the proportion of subjects achieving endoscopic improvement, histologic-endoscopic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission (see Table 4).

Table 4: Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-1 at Week 12 and at Week 52
CI = confidence interval
*
Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability).
p <0.001.
§
Endoscopic improvement is defined as ES ≤1 (excluding friability).
Histologic-endoscopic mucosal improvement is defined as ES ≤1 (excluding friability) with Geboes Index score <2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue.
#
Corticosteroid-free clinical remission is defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks prior to Week 52.
Þ
Maintenance of clinical remission is defined as achievement of clinical remission at both Week 12 and Week 52.


Endpoints


Placebo


VELSIPITY

Treatment

Difference*

(95% CI)

Coprimary Endpoints

Clinical Remission at Week 12

   Total population

N = 134

7%

N = 274

27%

20%

(13%, 27%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

10%

N = 194

31%

   Prior biologic/

   JAK inhibitor exposure

N = 41

2%

N = 80

18%

Clinical Remission at Week 52

   Total population

N = 134

7%

N = 274

32%

26%

(19%, 33%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

8%

N = 194

37%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

21%

Week 12 Endpoints

Endoscopic Improvement§

   Total population

N = 134

14%

N = 274

35%

21%

(13%, 29%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

18%

N = 194

39%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

25%

Histologic-Endoscopic Mucosal Improvement

   Total population

N = 134

4%

N = 274

21%

17%

(11%, 23%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

6%

N = 194

24%

   Prior biologic/

   JAK inhibitor exposure

N = 41

0%

N = 80

14%

Week 52 Endpoints

Endoscopic Improvement§

   Total population

N = 134

10%

N = 274

37%

27%

(19%, 34%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

13%

N = 194

40%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

30%

Histologic-Endoscopic Mucosal Improvement

   Total population

N = 134

8%

N = 274

27%

18%

(11%, 25%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

11%

N = 194

28%

   Prior biologic/

   JAK inhibitor exposure

N = 41

2%

N = 80

23%

Corticosteroid-free Clinical Remission#

   Total population

N = 134

7%

N = 274

32%

26%

(19%, 33%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

8%

N = 194

37%

   Prior biologic/

   JAK inhibitor exposure

N = 41

5%

N = 80

21%

Maintenance of Clinical RemissionÞ

   Total population

N = 134

2%

N = 274

18%

16%

(11%, 21%)

   No prior biologic/

   JAK inhibitor exposure

N = 93

2%

N = 194

22%

   Prior biologic/

   JAK inhibitor exposure

N = 41

2%

N = 80

10%

The relationship of histologic-endoscopic mucosal improvement at Week 12 or Week 52 to disease progression and longer-term outcomes after Week 52 was not evaluated in Study UC-1.

Clinical Response

A greater proportion of subjects treated with VELSIPITY compared to placebo achieved clinical response, defined as a ≥2 point and ≥30% decrease from baseline in mMS, and a ≥1 point decrease from baseline in RB subscore or an absolute RB subscore ≤1 at Week 12 (62% vs 34%).

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of subjects treated with VELSIPITY compared to placebo achieved endoscopic remission by Week 12 (15% vs 4%), Week 52 (26% vs 6%), and both Week 12 and Week 52 (11% vs 1%).

Endpoints and Results Study UC-2

In UC-2, efficacy was evaluated in 333 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 73 years); 41% were female; and 76% identified as White, 19% as Asian, 2% as American Indian or Alaska Native, 1% as Black or African American, and 2% as multiple racial groups or did not report their racial group. A total of 34% of subjects had prior exposure to biologic/JAK inhibitors and a total of 17% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 66% of subjects were receiving oral aminosalicylates and 28% of subjects were receiving oral corticosteroids.

The primary endpoint was the proportion of subjects achieving clinical remission at Week 12. The secondary endpoints included the proportion of subjects achieving endoscopic improvement and histologic-endoscopic mucosal improvement at Week 12 (see Table 5).

Table 5: Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-2 at Week 12
CI = confidence interval
*
Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).
Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability).
p <0.05.
§
Endoscopic improvement is defined as ES ≤1 (excluding friability).
Endoscopic-histologic mucosal improvement is defined as ES ≤1 (excluding friability) with Geboes Index score <2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue.


Endpoints


Placebo


VELSIPITY

Treatment

Difference*

(95% CI)

Clinical Remission

   Total population

N = 112

15%

N = 221

26%

11%

(3%, 20%)

   No prior biologic/

   JAK inhibitor exposure

N = 74

16%

N = 147

30%

   Prior biologic/

   JAK inhibitor exposure

N = 38

13%

N = 74

19%

Endoscopic Improvement§

   Total population

N = 112

19%

N = 221

30%

12%

(3%, 21%)

   No prior biologic/

   JAK inhibitor exposure

N = 74

19%

N = 147

34%

   Prior biologic/

   JAK inhibitor exposure

N = 38

18%

N = 74

23%

Histologic-Endoscopic Mucosal Improvement

   Total population

N = 112

9%

N = 221

16%

8%

(1%, 15%)

   No prior biologic/

   JAK inhibitor exposure

N = 74

11%

N = 147

19%

   Prior biologic/

   JAK inhibitor exposure

N = 38

5%

N = 74

11%

The relationship of histologic-endoscopic mucosal improvement at Week 12 to disease progression and longer-term outcomes after Week 12 was not evaluated in Study UC-2.

Clinical Response

A greater proportion of subjects treated with VELSIPITY compared to placebo achieved clinical response, defined as a ≥2 point and ≥30% decrease from baseline in mMS, and a ≥1 point decrease from baseline in RB subscore or an absolute RB subscore ≤1 at Week 12 (62% vs 41%).

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of subjects treated with VELSIPITY compared to placebo achieved endoscopic remission by Week 12 (17% vs 8%).

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Health Professional Information

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