Introduction
Tofacitinib in ulcerative colitis: clinical trial program
Remission | Full Mayo score ≤ 2, no single subscore > 1 and rectal bleeding subscore = 0 |
Mucosal healing | Endoscopic Mayo subscore = 0 or 1 |
Clinical response | Decrease in full Mayo score of ≥ 3 points and ≥ 30% vs. baseline, which must include a decrease in the subscore for rectal bleeding of ≥ 1 point or an absolute rectal bleeding subscore = 0 or 1 |
Endoscopic remission | Endoscopic Mayo subscore = 0 |
Sustained remission | Remission at weeks 24 and 52 in OCTAVE Sustain in patients already in remission at the beginning of maintenance therapy |
Sustained corticosteroid-free remission | Corticosteroid remission at weeks 24 and 52 in OCTAVE Sustain in patients already in remission at the beginning of maintenance therapy |
Sustained clinical response | Clinical response at weeks 24 and 52 in OCTAVE Sustain in patients already showing clinical response at the beginning of maintenance therapy and sustained clinical response at weeks 24 and 52 |
Treatment failure | Increase in Mayo score of ≥ 3 points vs. baseline in OCTAVE Sustain, which must include an increase in the rectal bleeding subscore of ≥ 1 point and an increase in the endoscopic subscore of ≥ 1 point, i.e. an absolute endoscopic subscore of ≥ 2 following ≥ 8 weeks of treatment in OCTAVE Sustain Patients experiencing treatment failure were excluded from OCTAVE Sustain yet were eligible for participation in OCTAVE Open |
Loss of response | Increase in partial Mayo score of ≥ 2 points vs. baseline in OCTAVE Sustain at 2 consecutive rounds, which must include an increase in the rectal bleeding subscore of ≥ 1 point vs. baseline in OCTAVE Sustain |
OCTAVE Induction 1 | OCTAVE Induction 2 | OCTAVE Sustain | |||||
---|---|---|---|---|---|---|---|
Placebo | Tofacitinib 10 mg b.i. d. | Placebo | Tofacitinib 10 mg b.i. d. | Placebo | Tofacitinib 5 mg b.i. d. | Tofacitinib 10 mg b.i. d. | |
Patients (n) | 122 | 476 | 112 | 429 | 198 | 198 | 197 |
Duration | 8 weeks | 8 weeks | 52 weeks | ||||
Primary endpoint* | Remission at week 8 | Remission at week 8 | Remission at week 52 | ||||
Key secondary endpoints* | Mucosal healing | Mucosal healing | Mucosal healing Sustained corticosteroid-free remission | ||||
Other secondary endpoints* | Clinical response Endoscopic remission | Clinical response Endoscopic remission | Sustained remission Sustained clinical response Endoscopic remission | ||||
Oral corticosteroid application at baseline (in %) | 48 | 45 | 49 | 46 | 51 | 51 | 44 |
Preceding TNF-alpha inhibitor application (in %) | 53 | 53 | 58 | 55 | 47 | 46 | 51 |
Previous failure of (in %) | |||||||
TNF-alpha inhibitor | 53 | 51 | 54 | 52 | 44 | 42 | 47 |
Corticosteroid | 80 | 74 | 74 | 71 | 76 | 73 | 76 |
Immunosuppressive | 68 | 76 | 67 | 70 | 65 | 72 | 72 |
OCTAVE Induction 1 and 2
OCTAVE Sustain
OCTAVE Open
Tofacitinib: efficacy in clinical studies
Efficacy in OCTAVE Induction 1 and 2
Endpointsa | OCTAVE Induction 1 | OCTAVE Induction 2 | ||||
---|---|---|---|---|---|---|
Placebo (n = 122) (in %) | Tofacitinib 10 mg b.i. d. (n = 476) (in %) | P | Placebo (n = 112) (in %) | Tofacitinib 10 mg b.i. d. (n = 429) (in %) | P | |
Remission | 8 | 19 | 0.007 | 4 | 17 | < 0.001 |
Mucosal healing | 16 | 31 | < 0.001 | 12 | 28 | < 0.001 |
Clinical response | 33 | 60 | < 0.001 | 29 | 55 | < 0.001 |
Endoscopic remission | 2 | 7 | 0.04 | 2 | 7 | 0.04 |
Rapid onset of tofacitinib effect
Pretreatment with TNF-alpha inhibitors
Endpointsa Subgroup | OCTAVE Induction 1 | OCTAVE Induction 2 | ||
---|---|---|---|---|
Placebo (n = 122) | Tofacitinib 10 mg b.i. d. (n = 476) | Placebo (n = 112) | Tofacitinib 10 mg b.i. d. (n = 429) | |
Remission | ||||
Previous TNF-alpha inhibitor failure | 1/64 (2%) | 27/243 (11%) | 0/60 (0%) | 26/222 (12%) |
TNF‑alpha inhibitor naïve | 9/58 (16%) | 61/233 (26%) | 4/52 (8%) | 45/207 (22%) |
Mucosal healing | ||||
Previous TNF‑alpha inhibitor failure | 4/64 (6%) | 55/243 (23%) | 4/60 (7%) | 48/222 (22%) |
TNF‑alpha inhibitor naïve | 15/58 (26%) | 94/233 (40%) | 9/52 (17%) | 74/207 (36%) |
Non-response at week 8 of induction treatment
Efficacy in OCTAVE sustain
Endpointsa | OCTAVE Sustain | ||||
---|---|---|---|---|---|
Placebo (n = 198) (in %) | Tofacitinib 5 mg b.i. d. (n = 198) (in %) | Pc | Tofacitinib 10 mg b.i. d. (n = 197) (in %) | P | |
Remission | 11 | 34 | < 0.001 | 41 | < 0.001 |
Mucosal healing | 13 | 37 | < 0.001 | 46 | < 0.001 |
Sustained corticosteroid-free remission | 5 | 35 | < 0.001 | 47 | < 0.001 |
Sustained remission | 10 | 22 | < 0.001 | 25 | < 0.001 |
Clinical response | 20 | 52 | < 0.001 | 62 | < 0.001 |
4 | 15 | < 0.001 | 17 | < 0.001 |
Endpointsa | Placebo (n = 198) | Tofacitinib 5 mg b.i. d. (n = 198) | Tofacitinib 10 mg b.i. d. (n = 197) |
---|---|---|---|
Remission | |||
Previous TNF‑α inhibitor failure | 10/89 (11%) | 20/83 (24%) | 34/93 (37%) |
TNF‑α inhibitor-naïve | 12/109 (11%) | 48/115 (42%) | 46/104 (44%) |
Mucosal healing | |||
Previous TNF‑α inhibitor failure | 11/89 (12%) | 25/83 (30%) | 37/93 (40%) |
TNF‑α inhibitor-naïve | 15/109 (14%) | 49/115 (43%) | 53/104 (51%) |
Efficacy in OCTAVE Open
Sustained response in long-term treatment
Endpointsa | Month 2 | Month 12 | Month 24 | Month 36 |
---|---|---|---|---|
Remission | 131/175 (75%) | 129/175 (74%) | 103/175 (59%) | 103/175 (59%) |
Mucosal healing | 152/175 (87%) | 140/175 (80%) | 119/175 (68%) | 113/175 (65%) |
Clinical response | 159/175 (91%) | 147/175 (84%) | 125/175 (71%) | 117/175 (67%) |
Improvement of clinical response in long-term treatment
Dose escalation in OCTAVE Open after loss of response in OCTAVE Sustain
Time to loss of efficacy after treatment discontinuation and response after treatment resumption
Tofacitinib: safety in clinical studies
General safety profile
Maintenance cohort | Overall cohort | |||
---|---|---|---|---|
Placebo (n = 198) | Tofacitinib 5 mg b.i. d. (n = 198) | Tofacitinib 10 mg b.i.d (n = 196) | All tofacitinib (n = 944) | |
Exposure in PYs | 100 | 146 | 154 | 2441 |
Duration of treatment in days, median (range) | 138 (14–382) | 364 (22–420) | 368 (1–399) | 1529 (36–2422) |
Patients with AEs, n (%) | 149 (75) | 143 (72) | 156 (80) | 780 (83) |
Patients with SAEs, n (%) | 13 (7) | 10 (5) | 11 (6) | 186 (20) |
AEs of special interest
Maintenance cohort | Overall cohort | ||||||
---|---|---|---|---|---|---|---|
Tofacitinib 5 mg b.i. d. (n = 175) | Tofacitinib 10 mg b.i. d. (n = 769) | Per 2022 (n = 944) | |||||
n (%) | IR (95% CI) | n (%) | IR (95% CI) | n (%) | IR (95% CI) | ||
Infections | |||||||
SIs | 8 (5) | 1.25 (0.54–2.46) | 31 (4) | 1.74 (1.18–2.47) | 39 (4) | 1.61 (1.14–2.20) | |
Opportunistic infectionsa,b | 4 (2) | 0.63 (0.17–1.60) | 17 (2) | 0.96 (0.56–1.53) | 21 (2) | 0.87 (0.54–1.33) | |
HZ infections | 13 (7) | 2.8 (1.11–3.55) | 60 (8) | 3.55 (2.71–4.58) | 73 (8) | 3.16 (2.47–3.97) | |
Malignoma | |||||||
Malignoma, excluding non-melanoma skin cancera | 7 (4) | 1.09 (0.44–2.25) | 18 (2) | 1.0 (0.60–1.59) | 25 (3) | 1.03 (0.67–1.52) | |
Non-melanoma skin cancera | 6 (3) | 0.96 (0.35–2.08) | 12 (2) | 0.68 (0.35–1.19) | 18 (2) | 0.75 (0.45–1.52) | |
Cardiovascular events | |||||||
MACEsa | 2 (1) | 0.31 (0.04–1.13) | 2 (0) | 0.11 (0.01–0.4) | 4 (0) | 0.16 (0.04–1.19) | |
Deep vein thrombosis | 0 (0) | 0.0 (0.0–0.57) | 1 (0) | 0.06 (0.0–0.31) | 1 (0) | 0.04 (0.0–0.23) | |
Pulmonary embolism | 0 (0) | 0.0 (0.0–0.57) | 5 (1) | 0.28 (0.09–0.65) | 5 (1) | 0.21 (0.7–0.48) | |
Gastrointestinal tract perforationa | 1 (1) | 0.16 (0.0–0.87) | 1 (0) | 0.06 (0.0–0.31) | 2 (0) | 0.08 (0.01–0.3) | |
Deathsc | 0 (0) | 0.0 (0.0–0.57) | 6 (1) | 0.33 (0.12–0.73) | 6 (1) | 0.25 (0.09–0.54) |
Severe infections
Tuberculosis
Opportunistic infections
Herpes zoster infections
Vaccinations
Hepatitis
Malignoma
Non-melanoma skin cancer
Major adverse cardiovascular events
Venous thromboembolic events (VTEs) under tofacitinib
VTE risk under tofacitinib in RA
Indication | Deep vein thrombosis IR (95% CI) | Pulmonary embolism IR (95% CI) | Arterial thromboembolic event IR (95% CI) | |||
---|---|---|---|---|---|---|
Tofacitinib 5 mg b.i. d. | Tofacitinib 10 mg b.i. d. | Tofacitinib 5 mg b.i. d. | Tofacitinib 10 mg b.i. d. | Tofacitinib 5 mg b.i. d. | Tofacitinib 10 mg b.i. d. | |
RA (n = 7964) | 0.17 (0.09–0.27) | 0.15 (0.09–0.22) | 0.12 (0.06–0.22) | 0.13 (0.08–0.21) | 0.32 (0.22–0.46) | 0.38 (0.28–0.49) |
PsO (n = 3663)a | 0.06 (0.00–0.36) | 0.06 (0.02–0.15) | 0.13 (0.02–0.47) | 0.09 (0.04–0.19) | 0.52 (0.22–1.02) | 0.22 (0.13–0.35) |
PsA (n = 783) | 0.00 (0.00–0.28) | 0.13 (0.00–0.70) | 0.08 (0.00–0.43) | 0.00 (0.00–0.46) | 0.31 (0.08–0.79) | 0.38 (0.08–1.11) |