Introduction
Objective: Tumor necrosis factor–like cytokine 1A (TL1A) regulates pro-inflammatory cytokines and fibrosis. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases incorporating a precision approach with a predictive genetic-based diagnostic (Dx) tool. This placebo-controlled, double-blind phase 2 study assessed efficacy and safety of PRA023 induction treatment in adults with moderately to severely active ulcerative colitis (UC).
Aims & Methods
Patients with a modified Mayo score (mMS) of 4 to 9, centrally read endoscopy subscore of ≥2, rectal bleeding subscore of ≥1, and history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced therapies (≤4 advanced agents from ≤3 classes allowed) were eligible. Patients were stratified by prior biologic exposure and Dx status and randomized 1:1 to placebo or intravenous PRA023 (1000 mg on day 1, 500 mg at weeks 2, 6, and 10). The primary endpoint was clinical remission per mMS at week 12. Analyses of ranked secondary endpoints were multiplicity-controlled.
Results
Of the 135 patients, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week induction period. Baseline characteristics were similar. A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5% PRA023 vs 1.5% placebo, ∆25.0%, p<0.0001) at week 12 (Table 1). All ranked secondary endpoints for cohort 1 significantly favored drug relative to placebo, including symptomatic remission (19.1% PRA023 vs 6.0% placebo, ∆13.1%, p=0.02), mucosal healing (30.8% PRA023 vs 3.5% placebo, ∆27.3%, p<0.0001), and IBDQ response (82.4% PRA023 vs 49.3% placebo, ∆33.1%, p<0.0001; Table 1). Exposure to prior advanced therapy, antidrug antibody status, and concomitant therapy did not have a major effect on efficacy. Statistically significant reductions in symptom scores (partial Mayo score) were observed in patients receiving PRA023 as early as week 2. C-reactive protein and fecal calprotectin levels were significantly reduced throughout the treatment period with PRA023 compared to placebo. An enhanced treatment effect was observed for the prespecified Dx+ subgroup, with 37.5% for both placebo-adjusted clinical remission and endoscopic improvement. The rates of treatment-emergent adverse events (AEs) were similar between the 2 arms with no serious AEs or AEs leading to study drug discontinuation in the PRA023 arm. There were no safety signals identified from the study.
Table 1: Primary and Secondary Efficacy Endpoints
| | Placebo (N=67)
N (%) | PRA023 (N=68)
N (%) | Placebo-adjusted treatment effect
% (95% CI) | P-value |
| Clinical remission | 1 (1.5) | 18 (26.5) | 25.0 (13.9–36.6) | <0.0001 |
| Endoscopic improvement | 4 (6.0) | 25 (36.8) | 30.8 (17.4–43.2) | <0.0001 |
| Clinical response | 15 (22.4) | 45 (66.2) | 43.8 (27.4–56.9) | <0.0001 |
| Symptomatic remission | 4 (6.0) | 13 (19.1) | 13.1 (1.8–24.6) | 0.0223 |
| Mucosal healing | 2 (3.5)* | 20 (30.8)† | 27.3 (14.3–39.6) | <0.0001 |
| Histologic improvement | 10 (17.5)* | 30 (46.2)† | 28.6 (12.1–42.9) | 0.0009 |
| Histologic-endoscopic mucosal improvement | 2 (3.5)* | 20 (30.8)† | 27.3 (14.3–39.6) | <0.0001 |
| Inflammatory Bowel Disease Questionnaire response | 33 (49.3) | 56 (82.4) | 33.1 (17.2–46.8) | <0.0001 |
P values for testing the treatment difference are based on Cochran–Mantel–Haenszel test adjusted for prior biologic exposure status and Dx status. *n=56; †n=56.
Conclusion
PRA023 was effective with favorable tolerability for the induction of clinical remission and endoscopic improvement in moderately to severely active UC. A phase 3 study will be conducted to confirm these findings. The enhanced treatment effect in the Dx+ subgroup from cohort 1 is being further evaluated in the Dx+ expansion cohort 2.
Disclosure
BES has served as a consultant for or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Connect Biopharma, Cytoki Pharma, Eli Lilly and Company, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, Genentech, GSK, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kallyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, and Viela Bio and has received stock options from Ventyx Biosciences.
LPB has served as a consultant for or has received fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Eli Lilly and Company, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, Hikma, Index Pharmaceuticals, Inotrem, Janssen, MSD, Mylan, Oppilan Pharma, OSE Immunotherapeutics, Nestlé, Norgine, Roche, Pandion Therapeutics, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, sterna biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tillotts Pharma, and Vifor; has received grants from AbbVie, Fresenius Kabi, MSD, and Takeda; and has stock options from CTMA.
SD has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor and lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
DTR has served as a consultant for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Chronicles, Corp/Syneos, ClostraBio, Connect Biopharma, Eco R1, Eli Lilly and Company, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido, Pfizer, Prometheus Biosciences, Reistone Biopharma, Seres Therapeutics, Takeda, Target RWE, and Trellus Health and has received grant support from Takeda, Helmsley Charitable Trust, and the Gastro-Intestinal Research Foundation.
SV has received grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda and consulting and/or speaking fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr. Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, Johnson & Johnson, Eli Lilly and Company, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma, and Zealand Pharma.
OL, AL, DDN, and JDL are employees and shareholders of Prometheus Biosciences.
AWK has nothing to disclose.
JL has received speaker fees from AstraZeneca, MSD, Janssen, and Gilead and research grants from Johnson & Johnson.
RK has received grants from Janssen and Takeda.
JK has received consultation fees, research grants, or honoraria from AbbVie, Egis, Janssen, Nestlé, Nutricia, and Takeda.
CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma, BIOJAMP, Bristol Myers Squibb, Celltrion Healthcare, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Prometheus Biosciences, Roche, and Sanofi; speaker's fees from AbbVie, Amgen, AVIR Pharma, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; and research support from Ferring and Pfizer.
TER has been a speaker for Takeda Pharmaceuticals, Janssen, Pfizer, Bristol Myers Squibb, and Abbvie; has served on advisory boards for AbbVie, Ardelyx, Arena, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Ferring, Genentech/Roche, Gilead, Intercept, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Sanofi, and Takeda; and has been a shareholder for Iterative Scopes.
RP has been a consultant for Abbott, AbbVie, Abivax, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly and Company, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB; has received speakers fees from AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; and has served on advisory boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Ventyx.
BGF has served as a consultant for AbbVie, AbolerIS Pharma, AgomAb, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital Advisors, Atomwise, BIOJAMP, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics, Bristol Myers Squibb/Celgene, Connect Biopharma, Cytoki, Disc Medicine, Duality, EcoR1 Capital, Eli Lilly and Company, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Bio, GSK, Hinge Bio, HotSpot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAK Academy, Janssen, Japan Tobacco, Kaleido, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo Biopharma, Orphagen, Pandion Pharma, Pendopharm, Pfizer, Prometheus Therapeutics, PlayToKnow AG, Progenity, Protagonist Therapeutics, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts Pharma, Ventyx Biosciences, VHsquared, Viatris, Ysios, Ysopia, Zealand Pharma; on the speaker’s bureau for AbbVie, Janssen, and Takeda; and on advisory boards for AbbVie, Amgen, AMT, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Genentech/Roche, Janssen, MiroBio, Origo BioPharma, Pfizer, Prometheus, REDX, Sanofi, Takeda, Tillotts Pharma, Teva, Progenity, Index, EcoR1 Capital, Morphic, GSK, and Axio Research.
ST has received consulting fees from Robarts Clinical Trials and Prometheus Biosciences and owns stock in Prometheus Biosciences; is a member of steering committees of Janssen, AbbVie, Boehringer Ingelheim, Gilead, Celgene, and Bristol Meyers Squibb; has received speaker honoraria from AbbVie, Takeda, Janssen, Ferring, Pfizer, and Celltrion; and has served on advisory committees of Janssen, Takeda, AbbVie, Eli Lilly, Pfizer, Gilead, Galapagos, and Roche.
DPBM has received consulting fees from Prometheus Biosciences, Prometheus Laboratories, Gilead Sciences, Boehringer-Ingelheim, Pfizer, Prometheus Laboratories, Takeda, Palatin Technologies, and owns stock in Prometheus Biosciences.
