Introduction
Icotrokinra (JNJ-2113) is a first-in-class targeted oral peptide that selectively blocks IL-23 receptor (IL-23R) activation. We evaluated the efficacy and safety of icotrokinra in adult participants with moderately to severely active ulcerative colitis (UC) in a phase 2b, randomized, double-blind, placebo-controlled, treat-through, 28-week, dose-ranging study (ANTHEM-UC).
Aims & Methods
Eligible participants with moderately to severely active UC defined as a modified Mayo score (mMS) of 5–9 (inclusive) and a Mayo endoscopy subscore (MES) ≥2 and history of inadequate response or intolerance (IR) to TNFα blockers, vedolizumab, ustekinumab, JAK inhibitors, or S1P modulators (BIO/JAKi/S1Pi-IR) or IR to corticosteroids (CS), azathioprine, or mercaptopurine were randomized 1:1:1:1 to once-daily (qd) oral icotrokinra 100 mg, 200 mg, 400 mg, or placebo (PBO). At randomization, participants were stratified by BIO/JAKi/S1Pi-IR status (yes/no) and MES (2 or 3).
The primary endpoint was clinical response at Week 12 (W12); secondary endpoints were clinical remission, symptomatic remission, endoscopic improvement, and histologic-endoscopic mucosal improvement (HEMI) at W12. The study was powered to detect a treatment difference between icotrokinra 400 mg and PBO for the primary endpoint; it was not powered for secondary endpoints.
Results
Overall, 252 participants were randomized and received study medication (primary analysis population: mean age, 41.6 y; male 58.3%; mean UC duration, 7.8 y; mean mMS, 6.63; mMS > 7 [severe], 31.9%; MES = 3 [severe], 58.7%; baseline CS use, 37.3%; BIO/JAKi/S1Pi-IR, 43.3%). Baseline demographic and disease characteristics were generally similar across groups.
All icotrokinra doses met the primary endpoint, demonstrating superiority to PBO for clinical response at W12 (Table). Relative to PBO, significantly greater proportions of participants achieved clinical remission, symptomatic remission, and endoscopic improvement at W12 in the icotrokinra 400 mg group, with clinically meaningful differences for HEMI at W12 in the icotrokinra 400 mg group. Clinically meaningful differences were observed for icotrokinra 100 mg and 200 mg vs PBO at W12 across secondary endpoints. All icotrokinra doses demonstrated separation from PBO for symptomatic remission as early as W4.
Across the PBO and 100 mg, 200 mg, and 400 mg icotrokinra groups, respectively, similar proportions of participants reported ≥1 AEs (50.8%, 50.0%, 45.2%, 46.0%), SAEs (4.8%, 0%, 3.2%, 1.6%), serious infections (1.6%, 0%, 0%, 0%), and AEs leading to discontinuation of study agent (7.9%, 0%, 6.5%, 1.6%) through W12. No opportunistic infections, tuberculosis, malignancies, clinically important hepatic disorders, MACE, or deaths were reported in icotrokinra treatment groups through W12.
| Placebo
N = 63
| Icotrokinra
400 mg qd
N = 63
| Icotrokinra
200 mg qd
N = 62
| Icotrokinra
100 mg qd
N = 64
|
Primary endpoint
|
Clinical responsea at W12
| 27.0%
| 63.5%
Δ 36.3%
CI: 20.5, 52.1
p<0.001*
| 58.1%
Δ 30.8%
CI: 14.4, 47.3
p<0.001*
| 54.7%
Δ 27.7%
CI: 11.4, 43.9
p<0.001*
|
Secondary endpoints
|
Clinical remissionb at W12
| 11.1%
| 30.2%
Δ 19.2%
CI: 5.6, 32.8
p=0.006*
| 24.2%
Δ 13.0%
CI: –0.2, 26.3
p=0.054
| 21.9%
Δ 10.9%
CI: –1.8, 23.6
p=0.092
|
Symptomatic remissionc at W12
| 19.0%
| 46.0%
Δ 26.9%
CI: 11.2, 42.5
p<0.001*
| 41.9%
Δ 22.7%
CI: 7.0, 38.4
p=0.005 †
| 53.1%
Δ 34.1%
CI: 18.4, 49.8
p<0.001 †
|
Endoscopic improvementd at W12
| 14.3%
| 36.5%
Δ 22.4%
CI: 8.4, 36.4
p=0.002*
| 33.9%
Δ 19.7%
CI: 5.4, 34.1
p=0.007 †
| 26.6%
Δ 12.4%
CI: –1.1, 26.0
p=0.072
|
Histologic-endoscopic mucosal improvement (HEMI)e at W12
| 11.1%
| 28.6%
Δ 17.6%
CI: 4.3, 31.0
p=0.009 †
| 25.8%
Δ 14.8%
CI: 1.6, 28.0
p=0.028 †
| 15.6%
Δ 4.8%
CI: –6.8, 16.4
p=0.419
|
* Significant p-value based on the testing procedure; † nominal p-value <0.05 based on the testing procedure
Data presented as percentage of participants attaining the endpoint, with adjusted treatment difference (Δ), 95% confidence interval (CI) for the adjusted treatment difference, and p-value versus placebo. Adjusted treatment differences, 95% CIs, and p-values were based on the common risk difference by use of Mantel-Haenszel stratum weights and the Sato variance estimator, using stratification factors of BIO/JAKi/S1Pi-IR status (Yes or No) and Mayo endoscopy subscore (MES) (moderate [2] or severe [3]).
a. Clinical response: a decrease from baseline in modified Mayo score by ≥30% and ≥2 points with either a ≥1-point decrease from baseline in rectal bleeding subscore or a rectal bleeding subscore of 0 or 1
b. Clinical remission: stool frequency subscore of 0 or 1, rectal bleeding subscore of 0, and MES of 0 or 1
c. Symptomatic remission: stool frequency subscore of 0 or 1 and rectal bleeding subscore of 0
d. Endoscopic improvement: MES of 0 or 1
e. Histologic-endoscopic mucosal improvement (HEMI): histologic remission (absence of neutrophils from the mucosa [both lamina propria and epithelium], no crypt destruction, and no erosions, ulcerations, or granulation tissue according to the Geboes grading system) AND endoscopic improvement (MES of 0 or 1)
|
Conclusion
Icotrokinra, the first-in-class targeted oral peptide that selectively blocks IL-23R activation, demonstrated efficacy and a favorable safety profile in participants with moderately to severely active UC.
Disclosure
Maria T. Abreu: consultant/advisory board member for AbbVie, Arena Pharmaceuticals (now Pfizer), Bristol Myers Squibb, Celsius Therapeutics, Gilead, Johnson & Johnson, Lilly, Pfizer, Prometheus Biosciences, UCB; lecture fees from Alimentiv, Johnson & Johnson, Prime, WebMD Global LLC
Britta Siegmund: consultant for AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Johnson & Johnson, Landos, Materia Prima, PredictImmune, Pfizer, Takeda; speaker fees from AbbVie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MSD, Ferring, Galapagos, Johnson & Johnson, Pfizer, Takeda; grant from Pfizer
Minhu Chen: research grants and steering committee advisor for Johnson & Johnson; lecture fees from AbbVie, China Medical System Holding Limited, Johnson & Johnson, Takeda
Karen Chachu: advisory board for Johnson & Johnson; consultant for OptumRx
Edouard Louis: educational and research grants from AbbVie, Celltrion, Falk, Fresenius-Kabi, Johnson & Johnson, Pfizer, Takeda; speaker fees from AbbVie, BMS, Celltrion, Ferring, Fresenius-Kabi, Galapagos, Johnson & Johnson, Pfizer, Takeda; advisory board for AbbVie, BMS, Celgene, Eli Lilly, Ferring, Johnson & Johnson, Pfizer, Takeda; consultant for AbbVie, Aboleris, Biokuris, Thabor
Katsuyoshi Matsuoka: speaker fees from Johnson & Johnson, Abbvie, Takeda, Pfizer, Gilead, Eli Lilly, Mitsubishi Tanabe Pharma, EA Pharma, Mochida, Kyorin, Zeria, Nippon Kayaku; research support from AbbVie, Mitsubishi Tanabe Pharma, EA Pharma, Mochida, Kyorin, Zeria, Nippon Kayaku, JIMRO; advisor to Johnson & Johnson, AbbVie, Takeda, Pfizer, Gilead, Eli Lilly, EA Pharma, Mochida, Kyorin, Bristol Myers Squibb, Celltrion Healthcare
Jimmy Limdi: speaker/consultancy fees from AbbVie, Abivax, Arena, BioHit, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Takeda; research support from Galapagos, Takeda
Grazyna Rydzewska: speaker and consultant fees from AbbVie, AlfaSigma, AstraZeneca, Bayer, Biocodex, Bristol Myers Squibb, Ferring, Johnson & Johnson, Lilly, PRO.MED.Pl, Recordati, Sanprobi, SOBI, Takeda; travel/accomodation meeting expenses from AbbVie, Ferring, Takeda
Edward V. Loftus, Jr.: consulting for AbbVie, Abivax, Astellas, Avalo Therapeutics, Biocon, Bristol-Myers Squibb, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Johnson & Johnson, Merck, Morphic, Ono, Takeda, TR1X Bio; research support from AbbVie, Genentech, Gilead, Gossamer Bio, Johnson & Johnson, Merck, Takeda; shareowner of Exact Sciences, Moderna.
Vipul Jairath: consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Johnson & Johnson, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; speaker fees from AbbVie, Ferring, Bristol Myers Squibb, Fresenius Kabi, Galapagos, Johnson & Johnson, Pfizer, Shire, Takeda
Lindsey Surace, Ngozi Erondu, Edmund Arthur, Nicole Houck, Mary Ellen Frustaci, Bin Zou: employee and shareholder of Johnson & Johnson
