Introduction
ANTHEM-UC is a Phase 2b, randomized, double-blind, placebo (PBO)-controlled, dose-ranging study evaluating icotrokinra, a first-in-class investigational targeted oral peptide, in adults with moderately to severely active ulcerative colitis. As previously reported, all doses of once-daily icotrokinra achieved the primary endpoint (clinical response at Week 12) and demonstrated clinically meaningful improvements in secondary clinical, endoscopic, and histologic endpoints at Week 12 with durable improvement through Week 28. Here we report the efficacy of icotrokinra across additional exploratory endoscopic and histologic endpoints from ANTHEM-UC.
Aims & Methods
Participants (pts) had a modified Mayo score of 5–9 inclusive, a Mayo endoscopy subscore (MES) ≥2, and prior inadequate response or intolerance (IR) to advanced therapies (ADT-IR) or IR to corticosteroids, azathioprine, or mercaptopurine. Pts were randomized 1:1:1:1 to once-daily oral icotrokinra 100 mg, 200 mg, 400 mg, or PBO with stratification by ADT-IR status (Y/N) and MES (2 or 3). Pts meeting inadequate response criteria at Week 16 were treatment adjusted (PBO pts switched to icotrokinra 400 mg and icotrokinra pts had a sham adjustment) and were considered nonresponders at Week 28. Analyses of histologic improvement, histologic remission, endoscopic remission, and the composite of histologic remission & clinical remission (see table for definitions) at Weeks 12 and 28 were prespecified and considered exploratory.
Results
At Week 12, compared with PBO, greater proportions of pts in the icotrokinra 100, 200, and 400 mg groups achieved endoscopic remission, histologic remission, histologic improvement, and histologic remission & clinical remission (Table). The 400 mg dose group demonstrated the greatest numerical differences versus PBO at Week 12. At Week 28, pts in all icotrokinra dose groups showed clinically meaningful (≥10%) improvements compared with PBO across all endpoints (excepting the 200 mg group for endoscopic remission). Relative to Week 12, the proportions of pts in histologic improvement, histologic remission, endoscopic remission, and histologic remission & clinical remission generally continued to increase at Week 28 across icotrokinra dose groups.
Endpoint
| Placebo
(N=63)
| Icotrokinra
100 mg
(N=64)
| Icotrokinra
200 mg
(N=62)
| Icotrokinra
400 mg
(N=63)
|
Histologic improvementa at Week 12
| 23.8%
| 35.9%
Δ 12.6
(-2.7, 27.8)
| 35.5%
Δ 12.0
(-3.5, 27.5)
| 39.7%
Δ 16.1
(0.6, 31.6)
|
Histologic remissionb at Week 12
| 19.0%
| 31.3%
Δ 12.7
(-1.8, 27.3)
| 33.9%
Δ 15.1
(0.2, 30.0)
| 36.5%
Δ 17.7
(2.8, 32.6)
|
Endoscopic remissionc at Week 12
| 3.2%
| 4.7%
Δ 1.6
(-5.1, 8.3)
| 12.9%
Δ 9.7
(0.4, 19.1)
| 14.3%
Δ 11.0
(1.9, 20.2)
|
Histologic remissionb &
clinical remissiond at Week 12
| 9.5%
| 14.1%
Δ 4.8
(-6.3, 15.9)
| 17.7%
Δ 8.2
(-3.8, 20.2)
| 25.4%
Δ 16.1
(3.2, 28.9)
|
Histologic improvementa at Week 28
| 14.3%
| 54.7%
Δ 40.8
(25.9, 55.7)
| 45.2%
Δ 30.8
(15.6, 46.1)
| 54.0%
Δ 39.8
(25.0, 54.5)
|
Histologic remissionb at Week 28
| 12.7%
| 53.1%
Δ 40.9
(26.3, 55.4)
| 41.9%
Δ 29.3
(14.3, 44.3)
| 49.2%
Δ 36.6
(22.0, 51.2)
|
Endoscopic remissionc at Week 28
| 4.8%
| 26.6%
Δ 22.0
(10.2, 33.8)
| 11.3%
Δ 6.6
(-2.7, 16.0)
| 17.5%
Δ 12.7
(2.2, 23.2)
|
Histologic remissionb &
clinical remissiond at Week 28
| 9.5%
| 32.8%
Δ 23.5
(10.1, 36.8)
| 27.4%
Δ 17.9
(4.7, 31.2)
| 28.6%
Δ 19.2
(5.9, 32.5)
|
Data presented as percentage of participants attaining the endpoint, with adjusted treatment difference (Δ) and (95% CI). Adjusted treatment differences and 95% CIs were based on the common risk difference by use of Mantel-Haenszel stratum weights and the Sato variance estimator, using stratification factors of inadequate response/intolerance to advanced therapies for ulcerative colitis (Yes or No) and baseline Mayo endoscopy subscore (2 or 3).
Analyses performed in all randomized participants who received ≥1 dose of study medication. Participants with intercurrent events of ostomy or colectomy, prohibited changes in UC medication, discontinuation of study intervention for any reason except those due to major disruptions (e.g., COVID-19 related reasons or regional crisis, excluding COVID-19 infection), or (for the Week 28 endpoints) meeting Week 16 inadequate response criteria were considered nonresponders, as were participants who had missing data for the endpoint.
a. Histologic improvement: neutrophil infiltration in <5% of crypts [Geboes Grade 3 ≤1], no crypt destruction [Geboes Grade 4=0], and no erosions, ulcerations, or granulation tissue [Geboes Grade 5=0].
b. Histologic remission: absence of neutrophils from the mucosa (both lamina propria and epithelium) [Geboes Grades 2B and 3=0], no crypt destruction [Geboes Grade 4=0], and no erosions, ulcerations, or granulation tissue [Geboes Grade 5=0].
c. Endoscopic remission: Mayo endoscopy subscore of 0.
d. Clinical remission: stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1. |
Conclusion
In ANTHEM-UC, participants with moderately to severely active ulcerative colitis experienced meaningful improvements in stringent, objective histologic and endoscopic outcomes at Week 12 that continued to improve through Week 28 with once-daily oral icotrokinra.
Disclosure
Britta Siegmund: consultant for AbbVie, Abivax, AltruBio, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Johnson & Johnson, Materia Prima, MSD, Pfizer, Takeda, Wedbush Securities; speaker fees from AbbVie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MD Education, MSD, Galapagos, Johnson & Johnson, Pfizer, Tr1X Bio; grant from Pfizer
Jimmy K. Limdi: speaker/consultancy fees from AbbVie, Abivax, Arena, BioHit, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Takeda; research support from Galapagos, Takeda
Edward V. Loftus, Jr.: consulting for AbbVie, Abivax, Astellas, Avalo Therapeutics, Biocon, Bristol-Myers Squibb, Celltrion Healthcare, Eli Lilly, Genentech, Gilead, HanAll Biopharma, Iota Biosciences, Iterative Health, Johnson & Johnson, Merck, Morphic, Ono, Shattuck Labs, Spyre Therapeutic, Takeda, TR1X Bio; research support from AbbVie, Gilead, Johnson & Johnson, Merck, Takeda, TR1X Bio; shareowner of Exact Sciences, Moderna
Vipul Jairath: consulting fees from AbbVie, Alimentiv, Asieris, Astra Zeneca, Attovia, Biomebank, Boehringer Ingelheim, Caldera Therapeutics, Calluna, Celltrion, Domain Therapeutics, Eli Lilly, Enthera, Ensho, Exeliom Biosciences, Ferring Ventures, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Granite Bio, Johnson & Johnson, Merck, Metacrine, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pandion, Pendopharm, Pfizer, Prometheus Biosciences, Roche, Salvina, Sanofi, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Thabor Therapeutics, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma; speaker’s fees from AbbVie, Ferring, Eli Lilly, Pfizer, Takeda
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
Minhu Chen: research grants and steering committee advisor for Johnson & Johnson; lecture fees from AbbVie, China Medical System Holding Limited, Johnson & Johnson, Takeda
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
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/accommodation meeting expenses from AbbVie, Ferring, Takeda
Karen Chachu: advisory board for Johnson & Johnson; consultant for OptumRx
Lindsey Surace, Ngozi Erondu, Martha Zeeman, Joyce Zhan, Mary Ellen Frustaci: employee and shareholder of Johnson & Johnson
