Safety and tolerability of spesolimab in patients with ulcerative colitis

Figures & data

Table 1. Clinical trials of intravenous spesolimab as induction therapy in patients with ulcerative colitis.

ClinicalTrials.gov identifier [reference] Sponsor’s study ID	Study 1 NCT03482635 [29] 1368–0005	Study 2 NCT03123120 [30] 1368–0010	Study 3 NCT03100864 [31] 1368–0004
Objectives	Dose-finding, efficacy, safety: To confirm the clinical activity of spesolimab as induction therapy in patients with moderate-to-severe, active UC who had failed previous biologic treatments, and to identify an effective and safe dose	Efficacy, safety: To define the safety and efficacy of induction of mucosal healing by spesolimab as add-on therapy in patients with mild-to-moderate, active UC and persisting endoscopic activity despite TNF-α inhibitor treatment	Mechanism of action: Primary: To understand the mode of action of spesolimab in patients with moderate-to-severe active UC Secondary: To explore the clinical effect, safety, and tolerability (incl. immunogenicity) of spesolimab treatment
Study design	Randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase II trial comparing three dose groups of spesolimab with placebo over 12 weeks, followed by a 12-week safety follow-up	Randomized (2:1), double-blind, placebo-controlled, parallel-group, exploratory phase IIa trial over 12 weeks, followed by a 24-week safety follow-up	Open-label, single-arm, phase IIa exploratory trial over 12 weeks, followed by a 16-week safety follow-up
Patient population	Moderate-to-severe UC; previous biologics have failed	Mild-to-moderate UC; receiving TNF-α inhibitor therapy	Moderate-to-severe UC; biologic-naïve or TNF-α inhibitor-experienced but not failed
Endpoints	Primary: Proportion of patients with clinical remission at Week 12 Secondary: Primary safety data were analyzed up to Week 12	Primary: Endoscopic improvement (MCS mESS ≤1) at Week 12 Secondary: Identification of TEAEs Safety data were analyzed descriptively based on AEs, SAEs, and laboratory values ADAs were reported descriptively	Primary: Identification of the total number of deregulated genes (post treatment vs baseline), analyzed by gene expression Secondary: To explore clinical effect, safety, and tolerability (incl. immunogenicity) of spesolimab treatment
No. patients enrolled: actual/planned	98/160	22/30	8/10
Spesolimab dosage schedule	300 mg single dose at Week 0, or 450 mg or 1,200 mg q4w at Weeks 0, 4, and 8	1,200 mg q4w	1,200 mg q4w
Comparator	Placebo	Placebo	None

ADA, anti-drug antibody; AE, adverse event; ID, identification; MCS, Mayo Clinic Score; mESS, modified endoscopic subscore; q4w, every 4 weeks; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TNF, tumor necrosis factor; UC, ulcerative colitis.

Table 2. Baseline demographics and clinical characteristics in clinical trials of intravenous spesolimab in patients with ulcerative colitis.

	Study 1 (1368–0005)		Study 2 (1368–0010)		Study 3 (1368–0004)
	Spesolimab (300 mg single dose, 450 mg q4w, or 1,200 mg q4w) (n = 75)	Placebo (n = 23)	Spesolimab (1,200 mg q4w) (n = 14)	Placebo (n = 8)	Spesolimab (1,200 mg q4w) (n = 8)
Female, n (%)	25 (33.3)	11 (47.8)	4 (28.6)	1 (12.5)	3 (37.5)
BMI, median (range)	24.3 (17.1–54.3)	24.4 (17.7–43.7)	25.8 (20.1–29.9)	23.8 (22.2–34.5)	21.2 (15.2–24.3)
Race, n (%)
American Indian or Alaska Native	1 (1.3)	0	0	0	0
Asian	10 (13.3)	4 (17.4)	0	0	0
Black or African American	2 (2.7)	1 (4.3)	0	0	0
White	62 (82.7)	18 (78.3)	13 (92.9)	8 (100)	8 (100)
Multiple	0	0	1 (7.1)	0	0
Ethnicity, n (%)
Not Hispanic or Latinx	74 (98.7)	23 (100)	14 (100)	8 (100)	8 (100)
Hispanic or Latinx	1 (1.3)	0	0	0	0
Age, years, median (range)	44.0 (19–73)	40.0 (20–73)	47.5 (25–54)	47.0 (29–60)	35.0 (23–76)
Smoking status, n (%)
Never	38 (50.7)	15 (65.2)	7 (50.0)	4 (50.0)	2 (25.0)
Former	33 (44.0)	8 (34.8)	6 (42.9)	4 (50.0)	5 (62.5)
Current	4 (5.3)	0	1 (7.1)	0	1 (12.5)
Time since first diagnosis of UC, years, median (range)	7.2 (1.0–49.0)	8.3 (1.0–37.0)	6.6 (2.0–18.0)	15.7 (2.0–30.0)	2.4 (0.0–17.0)
Previous surgery for UC*, n (%)	0	0	0	1 (12.5)^†	1 (12.5)^‡
Extra-intestinal manifestations, n (%)	19 (25.3)	7 (30.4)	5 (35.7)	0	1 (12.5)
Total MCS, median (range)	9.0 (4–12)	10.0 (6–12)	6.5 (4–10)	6.5 (4–10)	9.0 (6.0–12.0)
mESS, n (%)
2	11 (14.7)	3 (13.0)	3 (21.4)	2 (25.0)	3 (37.5)
3	64 (85.3)	20 (87.0)	11 (78.6)	6 (75.0)	4 (50.0)
Total IBDQ score, median (range)	121.0 (60–205)	113.0 (51–175)	159.0 (102–204)	175.5 (90–209)	nd
CRP, mg/L, mean (SD)	12.7 (24.3)	15.7 (25.1)	4.2 (7.6)	4.3 (5.0)	11.5 (11.0)
FCP, mg/kg, mean (SD)	3,114.0 (4,942.1)	4,180.3 (5,329.5)	1,550.5 (2,528.4)	1,294.6 (1,724.6)	1,859.9 (1,510.8)

*Previous surgery for UC could include any type of surgery related to UC, but not in contradiction with the exclusion criteria (i.e. extensive colonic resection, subtotal or total colectomy); endoscopic procedures could be classified as ‘surgery.’

^†The type of previous surgery for this patient was not specified.

^‡The investigator reported colonoscopy as previous surgery for UC.

BMI, body mass index; CRP, C-reactive protein; FCP, fecal calprotectin; IBDQ, Inflammatory Bowel Disease Questionnaire; MCS, Mayo Clinic Score; mESS, modified endoscopic subscore; nd, no data; q4w, every 4 weeks; SD, standard deviation; UC, ulcerative colitis.

Table 3. Concomitant and historical ulcerative colitis medications up to Week 12 in clinical trials of intravenous spesolimab in patients with ulcerative colitis.

	Study 1 (1368–0005)		Study 2 (1368–0010)		Study 3 (1368–0004)
n (%)	Spesolimab (300 mg single dose, 450 mg q4w, or 1,200 mg q4w) (n = 75)	Placebo (n = 23)	Spesolimab (1,200 mg q4w) (n = 14)	Placebo (n = 8)	Spesolimab (1,200 mg q4w) (n = 8)
Concomitant UC medications*	63 (84.0)	22 (95.7)	14 (100)	8 (100)	6 (75.0)
Corticosteroids	37 (49.3)	10 (43.5)	6 (42.9)	0	2 (25.0)
Prednisolone	15 (20.0)	3 (13.0)	0	0	0
Prednisone	14 (18.7)	4 (17.4)	6 (42.9)	0	0
Non-corticosteroids	52 (69.3)	19 (82.6)	14 (100)	8 (100)	6 (75.0)
TNF-α inhibitors
Infliximab	0	0	12 (85.7)	7 (87.5)	0
Adalimumab	0	0	2 (14.3)	0	0
Immunomodulators
Azathioprine	8 (10.7)	4 (17.4)	3 (21.4)	2 (25.0)	0
Aminosalicylates
Mesalazine	43 (57.3)	16 (69.6)	7 (50.0)	7 (87.5)	0
Rescue UC medication^†	9 (12.0)	3 (13.0)	2 (14.3)	2 (25.0)	3 (37.5)
Initiation of new therapy	8 (10.7)	3 (13.0)	2 (14.3)	2 (25.0)	3 (37.5)
Prednisone	4 (5.3)	1 (4.3)	1 (1.7)		0
Historical UC medications^‡	75 (100)	23 (100)	13 (92.9)	7 (87.5)	5 (62.5)
TNF-α inhibitors
Infliximab	49 (65.3)	18 (78.3)	3 (21.4)	1 (12.5)	1 (12.5)
Adalimumab	35 (46.7)	11 (47.8)	1 (7.1)	0	0
Golimumab	20 (26.7)	6 (26.1)	1 (7.1)	1 (12.5)	0
Immunomodulators
Azathioprine	39 (52.0)	11 (47.8)	6 (42.9)	6 (75.0)	1 (12.5)
Ciclosporin	2 (2.7)	3 (13.0)	0	0	0
Aminosalicylates
Mesalazine	45 (60.0)	17 (73.9)	12 (85.7)	4 (50.0)	0
Integrin-receptor inhibitors
Vedolizumab	43 (57.3)	15 (65.2)	0	0	0
Corticosteroids
Prednisone	36 (48.0)	9 (39.1)	11 (78.6)	4 (50.0)	1 (12.5)
Budesonide	19 (25.3)	8 (34.8)	4 (28.6)	2 (25.0)	1 (12.5)
Mercaptopurine	11 (14.7)	2 (8.7)	1 (7.1)	0	0
Beclometasone dipropionate	11 (14.7)	1 (4.3)	1 (7.1)	0	0
Methylprednisolone	8 (10.7)	2 (8.7)	0	0	1 (12.5)
Hydrocortisone acetate	2 (2.7)	2 (8.7)	2 (14.3)	1 (12.5)	0
Blinded therapy	4 (5.3)	3 (13.0)	0	0	0

Threshold for inclusion: individual medication usage reported in ≥10% and ≥2 patients overall, up to Week 12.

Categories are not an exhaustive list because of the small sample sizes.

*Medication received during the study for UC.

^†Medication received during the study for UC in case of non-response.

^‡Medication for UC received before patient inclusion in the study. In Study 1, as required by the inclusion criteria, all patients had used ≥1 biologic as historical medication.

q4w, every 4 weeks; TNF, tumor necrosis factor; UC, ulcerative colitis.

Table 4. Overall summary of adverse events in clinical trials of intravenous spesolimab in patients with ulcerative colitis.

	Study 1 (1368–0005)		Study 2 (1368–0010)		Study 3 (1368–0004)
n (%)	Spesolimab (300 mg single dose, 450 mg q4w, or 1,200 mg q4w) (n = 74)	Placebo (n = 23)	Spesolimab (1,200 mg q4w) (n = 15)*	Placebo (n = 7)	Spesolimab (1,200 mg q4w) (n = 8)
Any AE	48 (64.9)	15 (65.2)	13 (86.7)	5 (71.4)	8 (100)
Severe AE (RCTC grade 3 or 4)	7 (9.5)	4 (17.4)	1 (6.7)	1 (14.3)	2 (25.0)
Investigator-defined, drug-related AE	16 (21.6)	2 (8.7)	3 (20.0)	1 (14.3)	6 (75.0)
AE leading to discontinuation of study treatment	6 (8.1)	2 (8.7)	2 (13.3)	1 (14.3)	2 (25.0)
SAEs	7 (9.5)	4 (17.4)	1 (6.7)	1 (14.3)^†	2 (25.0)
Resulted in death	0	0	0	0	0
Was life-threatening	1 (1.4)	0	0	0	0
Required or prolonged hospitalization	6 (8.1)	2 (8.7)	0	1 (14.3)	2 (25.0)
Other medically important	1 (1.4)	2 (8.7)	1 (6.7)	1 (14.3)	0
TEAEs (system organ class; preferred term)
Gastrointestinal disorders	20 (27.0)	5 (21.7)	6 (40.0)	1 (14.3)	3 (37.5)
Worsening of UC	12 (16.2)	1 (4.3)	3 (20.0)	1 (14.3)	1 (12.5)
Infections and infestations	19 (25.7)	2 (8.7)	4 (26.7)	2 (28.6)	7 (87.5)
Nasopharyngitis	5 (6.8)	0	3 (20.0)	1 (14.3)	4 (50.0)
Nausea	1 (1.4)	1 (4.3)	2 (13.3)	0	0
Skin and subcutaneous tissue disorders	13 (17.6)	2 (8.7)	4 (26.7)	2 (28.6)	2 (25.0)
Skin rash	5 (6.8)	0	0	1 (14.3)	1 (12.5)
Acne	1 (1.4)	0	2 (13.3)	0	1 (12.5)
Eczema	1 (1.4)	0	2 (13.3)	0	0
Eye disorders	0	0	0	0	2 (25.5)
Eye inflammation	0	0	0	0	2 (25.5)
Nervous system disorders	8 (10.8)	1 (4.3)	5 (33.3)	1 (14.3)	2 (25.0)
Headache	4 (5.4)	0	4 (26.7)	1 (14.3)	2 (25.0)
Blood and lymphatic system disorders	5 (6.8)	6 (26.1)	0	0	1 (12.5)
Anemia	1 (1.4)	6 (26.1)	1 (6.7)	0	1 (12.5)
UDAECs (system organ class; preferred term)
Any UDAEC	10 (13.5)	2 (8.7)	3 (20.0)	1 (14.3)	3 (37.5)
Infusion or systemic hypersensitivity reactions, including anaphylactic reactions	10 (13.5)	1 (4.3)	2 (13.3)	1 (14.3)	2 (25.0)
Rash	5 (6.8)	0	0	1 (14.3)	1 (12.5)
Eczema	1 (1.4)	0	2 (13.3)	0	0

Threshold for inclusion: AEs reported in ≥10% and ≥2 patients overall on the preferred term level up to Week 12.

Categories are not an exhaustive list because of the small sample sizes.

*One patient assigned to placebo accidentally received one dose of spesolimab and is analyzed in the spesolimab group in the safety analyses.

^†A patient may have had SAE(s) with multiple seriousness criteria.

AE, adverse event; q4w, every 4 weeks; RCTC, Rheumatology Common Toxicity Criteria; SAE, serious adverse event; TEAE, treatment-emergent adverse event; UC, ulcerative colitis; UDAEC, user-defined adverse event category.

Table 5. Serious adverse events in clinical trials of intravenous spesolimab in patients with ulcerative colitis.

	Study 1 (1368–0005)		Study 2 (1368–0010)		Study 3 (1368–0004)
n (%)	Spesolimab (300 mg single dose, 450 mg q4w, or 1,200 mg q4w) (n = 74)	Placebo (n = 23)	Spesolimab (1,200 mg q4w) (n = 15)*	Placebo (n = 7)	Spesolimab (1,200 mg q4w) (n = 8)
Serious AEs	7 (9.5)	4 (17.4)	1 (6.7)	1 (14.3)	2 (25.0)
Gastrointestinal disorders	5 (6.8)	1 (4.3)	0	1 (14.3)	1 (12.5)
Worsening of UC	5 (6.8)	1 (4.3)	0	1 (14.3)	1 (12.5)
Injury, poisoning, and procedural complications	1 (1.4)	2 (8.7)	0	0	0
Infusion-related reaction	1 (1.4)^†	1 (4.3)^†	0	0	0
Femur fracture	0	1 (4.3)	0	0	0
Blood and lymphatic system disorders	1 (1.4)	1 (4.3)	0	0	0
Anemia	0	1 (4.3)	0	0	0
Iron deficiency anemia	1 (1.4)	0	0	0	0
Infections and infestations	0	1 (4.3)	0	1 (14.3)	1 (12.5)
Clostridioides difficile colitis	0	1 (4.3)	0	0	0
Diverticulitis	0	0	0	0	1 (12.5)
Rectal abscess	0	0	0	1 (14.3)	0
Neoplasms benign, malignant, and unspecified (incl. cysts and polyps)	0	0	1 (6.7)	0	0
Adenocarcinoma of colon	0	0	1 (6.7)	0	0

Categories are not an exhaustive list because of the small sample sizes.

*One patient assigned to placebo accidentally received one dose of spesolimab and is analyzed in the spesolimab group in the safety analyses.

^†Assessed by the study investigator as drug related: the patient randomized to the spesolimab group received the planned 300 mg IV single dose on Day 1, with no AE reported during that dose or before the next administration. As planned, the second administration on Day 33 was placebo, reflecting the randomized treatment with single-dose spesolimab. The infusion-related reaction started approximately 25 minutes after the start of the placebo infusion. The reaction was reported by the investigator as being life-threatening: the patient experienced swollen lips, chest tightness with difficulty breathing a decrease in systolic blood pressure (from 110 to 74 mmHg), and blurred vision. No other symptoms were reported. The study drug was discontinued, and the patient recovered.

AE, adverse event; IV, intravenous; q4w, every 4 weeks; UC, ulcerative colitis.

ClinicalTrials.gov. NCT03482635. BI655130 (spesolimab) induction treatment in patients with moderate-to-severe ulcerative colitis. [cited 2021 Dec 16] Available from: https://www.clinicaltrials.gov/ct2/show/NCT03482635.

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ClinicalTrials.gov. NCT03123120. A study in patients with mild or moderate ulcerative colitis who take a TNF inhibitor. The study investigates whether bowel inflammation improves when patients take BI 655130 in addition to their current therapy. [cited 2021 Dec 16] Available from: https://www.clinicaltrials.gov/ct2/show/NCT03123120.

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ClinicalTrials.gov. NCT03100864. This study tests how BI 655130 works in patients with active ulcerative colitis. The study also tests how well BI 655130 is tolerated and whether it helps the patients. [cited 2021 Dec 16] Available from: https://www.clinicaltrials.gov/ct2/show/NCT03100864.

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