Table 2.
Clinical trials of anti-CCR9 therapy in IBD.
| Compound | Entry criteria | Cohort size | Organisation | Primary endpoint | Potential expedients |
|---|---|---|---|---|---|
| A) Phase II (PROTECT) | |||||
| CCX282-B (oral) |
Inclusion:
Moderate to severe Crohn’s disease - CDAI 250450 - Fasting CRP > 7.5 mg/L Exclusion: - Fluctuating dosages of immunosuppression 4 weeksa - > 20 mg prednisolone (or equivalent) 4 w previouslya - Anti-TNFα or anti-α4 integrin treatment 12 w previouslya |
- Placebo twice daily (n = 144) - 250 mg CCX282-B once daily (n = 98) - 250 mg CCX282-B twice daily (n = 96) - 500 mg CCX282-B once daily (n = 97) |
Induction phase; 12 w
- Measuring CR at 8 and 12 w Active (open-label) period; 4 w - Eligible participants received CCX282-B (250 mg twice daily) Maintenance period; 36 w - Subjects with clinical response following active period re-randomised to receive placebo or CCX282-B (250 mg twice daily) |
Induction period
CDAI to ≤ 70 by 8 w - Placebo: 49% - 250 mg o.d.: 52% - 250 mg b.d.: 48% - 500 mg: 60% P = N.S.; all comparisons Maintenance period Sustained CDAI ≤.70 - Placebo: 31% - 250 mg b.d.: 47% P = 0.012 |
CDAI ≤ 70 by 12 w
- Placebo vs 500 mg: 47% vs 61%; P = 0.039 CDAI decrease by ≥ 100 points by 12 w - Placebo vs 500 mg: 40% vs 55%; P = 0.029 Mean change in CDEIS at 12 w - Placebo: - 3.0 - 250 mg o.d.: - 8.7 - 250 mg b.d.: 2.0 - 500 mg: - 10.8 P = 0.049 for 500 mg vs placebo |
| B) Phase III (SHIELD-1)54 | |||||
| CCX282-B (oral): - Vercirnon |
Inclusion:
Moderate to severe Crohn’s disease - CDAI 220450 - Active inflammationb - Inadequate response to immunosuppression Exclusion: - Fluctuating dosages of immunosuppressiona - > 20 mg prednisolone (or equivalent) - No concurrent dependence on anti-TNFα therapy during trial - EC, abdominal or pelvic fistulas with abscess |
- Placebo once daily (n = 203) - 500 mg CCX282-B once daily (n = 203) - 500 mg CCX282-B twice daily (n = 202) |
Induction phase only |
CDAI dec. ≥100 by 12 w
- Placebo: 25% - 500 mg o.d.: 27% - 500 mg b.d.: 27% P = N.S.; all comparisons |
CDAI dec. ≥ 100 by 12 w in patients with colitis
- Placebo: 13% - 500 mg o.d.: 25% - 500 mg b.d.: 29% p < 0.05; for 500 mg b.d. vs placebo |
| C) Phase II55,56 | |||||
| CCR9-targeted leukapheresis |
Inclusion:
UC; moderate to severe activity - Mayo score 6–11 - Prednisolone ≤ 20 mg daily (stable dose at least 2 w) - Naïve to anti-TNFα antibodies |
- Placebo (n = 9) - Treatment (n = 14) |
Alternate day leukapheresis
(5 sessions; 10 days) |
Reduction of CCR9
+
HLA-DR
hi
monocytes
- 11% to 12% (P = 0.469) vs 14% to 10% (P = 0.039); placebo vs treatment groups, respectively |
Dec. in overall Mayo score:
8.0 to 6.3 (P = 0.125) vs 8.8 to 5.7 (P = 0.016); placebo vs treatment groups, respectively |
IBD, inflammatory bowel disease; CRP, C-reactive protein; EC, enterocutaneous; TNF, tumour necrosis factor; CDAI,Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of Severity; w, weeks; m, months; UC, ulcerative colitis; N.S., not significant; dec., decrease; o.d., once daily; b.d., twice daily.
aBefore randomisation.
bBy endoscopic assessment or a CRP ≥.3 mg/L or faecal calprotectin > 200 µg/g in stool.