Introduction
Most clinical trials of systemic ulcerative colitis (UC) therapies exclude patients (pts) with isolated proctitis, who are considered a more treatment-refractory population, creating a need for clinical evidence. Etrasimod is an investigational, oral, once-daily, selective sphingosine 1‑phosphate (S1P)1,4,5 receptor modulator in development for the treatment of moderately to severely active UC. The phase 3 etrasimod ELEVATE UC trials included pts with isolated proctitis (< 10 cm rectal involvement), provided they met all other eligibility criteria.1
Aims & Methods
This post hoc analysis assessed predefined efficacy and safety outcomes in subgroups of pts with isolated proctitis and more extensive colitis (proctosigmoiditis/left-sided colitis/pancolitis). In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), pts (aged 16–80 years) with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo. ELEVATE UC 52 comprised a 12-week (wk) induction period followed by a 40-wk maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-wk induction period. Clinical endpoints were assessed in pts with isolated proctitis (data pooled from both trials) and in pts with more extensive colitis (individual trial data). Sustained and corticosteroid-free clinical remission were assessed at Wk 52 (ELEVATE UC 52 only). Bowel urgency Numeric Rating Scale (NRS) was assessed at Wks 12 and 52. Safety was assessed up to Wk 52.
Results
This analysis included 64 (pooled; Wk 12) and 36 (ELEVATE UC 52; Wk 52) pts with isolated proctitis, and 397 (ELEVATE UC 52; Wks 12 and 52) and 326 (ELEVATE UC 12; Wk 12) pts with more extensive colitis. Similar proportions of pts with isolated proctitis achieved the predefined efficacy endpoints vs those with more extensive colitis (Table). Pts with isolated proctitis receiving etrasimod had similar improvements in urgency NRS scores vs those with more extensive colitis (mean change from baseline: Wk 12, -2.8 vs -2.9 [both trials]; Wk 52, -5.0 vs -4.1). Safety in pts with isolated proctitis was generally similar to that in the overall trial population.1
| Table. Achievement of prespecified efficacy endpoints among pts with isolated proctitisa and those with more extensive colitis in the etrasimod ELEVATE UC trials (full analysis set) |
|---|
Endpoint
| Pts with isolated proctitis
| Pts with more extensive colitis
|
ELEVATE UC 12 + ELEVATE UC 52
| ELEVATE UC 52 | ELEVATE UC 12 |
Wk 12
| PBO, n (%)
[N=22]
| Etrasimod 2 mg QD, n (%)
[N=42]
| Percentage difference from PBOb
| PBO, n (%)
[N=135]
| Etrasimod 2 mg QD, n (%)
[N=262]
| Percentage difference from PBOb
| PBO, n (%)
[N=103]
| Etrasimod 2 mg QD, n (%)
[N=223]
| Percentage difference from PBOb
|
Clinical remissionc
Clinical responsed
Symptomatic remissione
Endoscopic improvementf
Endoscopic improvement-histological remissiong
| 3 (13.6)
9 (40.9)
5 (22.7)
5 (22.7)
3 (13.6)
| 18 (42.9)
30 (71.4)
22 (52.4)
22 (52.4)
16 (38.1)
| 45.5***
35.2*
44.2***
41.3**
40.7**
| 10 (7.4)
48 (35.6)
30 (22.2)
20 (14.8)
7 (5.2)
| 68 (26.0)
162 (61.8)
118 (45.0)
93 (35.5)
55 (21.0)
| 18.5***
26.0***
22.7***
20.6***
16.0***
| 16 (15.5)
43 (41.7)
31 (30.1)
21 (20.4)
9 (8.7)
| 57 (25.6)
141 (63.2)
108 (48.4)
71 (31.8)
36 (16.1)
| 9.9*
21.0***
18.0**
11.4*
7.4*
|
Wk 52, ELEVATE UC 52
| PBO, n (%)
[N=9]
| Etrasimod 2 mg QD, n (%)
[N=27]
| Percentage difference from PBOb
| PBO, n (%)
[N=135]
| Etrasimod 2 mg QD, n (%)
[N=262]
| Percentage difference from PBOb
| N/A |
Clinical remissionc
Clinical responsed
Symptomatic remissione
Endoscopic improvementf
Endoscopic improvement-histological remissiong
Sustained clinical remissionh
Corticosteroid-free clinical remissioni
| 1 (11.1)
3 (33.3)
1 (11.1)
3 (33.3)
3 (33.3)
1 (11.1)
1 (11.1)
| 12 (44.4)
15 (55.6)
15 (55.6)
14 (51.9)
8 (29.6)
8 (29.6)
12 (44.4)
| 44.4***
32.3
53.6***
29.5
-2.3
35.7***
44.4***
| 10 (7.4)
32 (23.7)
27 (20.0)
16 (11.9)
12 (8.9)
3 (2.2)
9 (6.7)
| 82 (31.3)
128 (48.9)
112 (42.7)
99 (37.8)
71 (27.1)
46 (17.6)
82 (31.3)
| 24.0***
25.2***
22.8***
26.0***
18.4***
15.5***
24.8***
|
*p<0.05; **p<0.01; ***p<0.001 (nominal p values are reported without adjustment for multiple comparisons)
aPts with isolated proctitis at baseline (defined as < 10 cm of rectal involvement) met all other eligibility criteria for inclusion (MMS 4–9, ES ≥ 2 [centrally read] and RBS ≥1)
bTreatment comparisons and 2-sided p values were obtained using the Cochran–Mantel–Haenszel method within each subgroup, adjusting to study stratification (for pooled data only), naïvety to prior biologic/Janus kinase inhibitor therapy, baseline corticosteroid use and baseline disease activity (MMS 4–6 or 7–9). Difference (%) is for etrasimod minus PBO and is based on estimated common risk difference using Mantel–Haenszel weights
cClinical remission was defined as an SFS=0 (or =1 with a ≥ 1-point decrease from baseline), RBS=0 and ES ≤ 1 (excluding friability)
dClinical response was defined as a ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS ≤ 1
eSymptomatic remission was defined as an SFS=0 (or =1 with a ≥ 1-point decrease from baseline) and an RBS=0
fEndoscopic improvement was defined as a score of ≤ 1 (excluding friability)
gEndoscopic improvement-histologic remission was defined as an ES ≤ 1 (excluding friability) with histologic remission as measured by a Geboes Index score < 2.0
hSustained clinical remission was defined as clinical remission at both Wks 12 and 52
iCorticosteroid-free remission was defined as remission at Wk 52 with no use of corticosteroids for at least the last 12 study wks immediately before Wk 52
ES, endoscopic subscore; MMS, modified Mayo score; N, total number of patients; n, number of patients with evaluable data within each category; N/A, not applicable; PBO, placebo; pt, patient; RBS, rectal bleeding subscore; SFS, stool frequency subscore; QD, once daily; UC, ulcerative colitis; wk, week
|
Conclusion
Etrasimod treatment had similar efficacy in pts with isolated proctitis and in those with more extensive colitis. Prospective confirmation in larger pt cohorts with isolated proctitis is necessary. Safety was consistent with the overall population.1
References
- Sandborn WJ et al. Lancet 2023: Epub ahead of print
Disclosure
LPB: research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma, Amgen, Applied MolecularTransport, Arena, Biogen, BMS, Celltrion, CONNECTBiopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG ImageAnalysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
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