Introduction
Despite therapeutic advances, many patients with Crohn’s disease (CD) develop disease refractory to systemic therapies (STs; biologics and novel oral agents), with diminishing efficacy after each treatment. We previously reported results from the DUET-CD study of JNJ-78934804 (JNJ-4804), the first fixed-dose, co-antibody therapy with guselkumab (GUS) and golimumab (GOL) targeting the complementary IL-23 and TNF pathways. In DUET-CD, JNJ-4804 showed substantial and clinically meaningful benefit vs GUS and GOL monotherapies in the subpopulation of participants (pts) with CD refractory to ≥2 ST mechanisms (anti-TNFs, anti-IL-12/23s, anti-IL-23p19s, anti-integrins, and JAK inhibitors). Here, we present additional efficacy and safety data from this subpopulation.
Aims & Methods
In this Phase 2b, randomized, double-blind, dose-ranging, active- and placebo (PBO)-controlled, parallel-group, multicenter study, pts were randomized 1:2:2:2:2:2 to PBO, GUS, GOL, or JNJ-4804 (low-, mid-, or high-dose). Co-primary endpoints were clinical remission (CR) at W48 and endoscopic response at W48. Key endpoints at W48 included endoscopic remission, deep remission, and corticosteroid-free CR. Fecal calprotectin concentrations over time were also evaluated.
Results
In pts with CD refractory to ≥2 ST mechanisms, those receiving high-dose JNJ-4804 showed clinically meaningful improvements in W48 CR and endoscopic response vs GOL (Δ27.3 and Δ21.2, respectively), GUS (Δ21.2, Δ11.7), and PBO (Δ39.4, Δ35.0; Table), with efficacy across key endpoints exceeding both monotherapies. Mean change from baseline at W48 in fecal calprotectin was also greater with high-dose JNJ-4804 vs the other groups (Table). Exposure-adjusted safety event rates with JNJ-4804 in the subpopulation were overall similar to or lower than PBO, GOL, or GUS; adverse event (AE) rates [number of events] per 100 pt-years were 606.0 [124] (PBO), 695.1 [312] (GOL), 798.8 [311] (GUS), and 585.6 [293] (JNJ-4804 high dose). Respective serious AE rates were 24.4 [5], 44.6 [20], 20.5 [8], and 24.0 [12]. AEs leading to treatment discontinuation were lower with JNJ-4804 (high dose: 10.0 [5]) vs other groups (PBO: 53.8 [11]; GOL: 29.0 [13]; GUS: 23.1 [9]). Across groups, there were no deaths and serious infection rates were low (PBO: 4.9 [1], GOL: 2.2 [1], GUS: 7.7 [3], JNJ-4804 high dose: 2.0 [1]).
| Key endpoints at Week 48 in the subpopulation of participants with CD that was refractory to 2 or more systemic therapy mechanisms |
|---|
aClinical remission was defined as a CDAI score of <150. Endoscopic response was defined as a >50% improvement from baseline in SES-CD or an SES-CD ≤2, as assessed by central endoscopy reading. Corticosteroid-free (60-day) clinical remission was defined as clinical remission with no corticosteroids received for at least 60 days. Endoscopic remission was defined as an SES-CD ≤4, with at least a 2-point reduction from baseline and no subscore greater than 1 on any individual component. Deep remission was defined as achieving both clinical remission and endoscopic remission.
bParticipants were considered not to have met the Week 48 endpoint from that timepoint onward if any of the following occurred prior to Week 48: CD-related surgery (except minor procedures such as drainage of a superficial abscess or seton placement); prohibited change in CD medication; treatment escalation due to inadequate response at Week 24; discontinuation of study treatment due to lack of efficacy or an AE of worsening CD; discontinuation of study treatment due to COVID-19 infection or any other reason. Participants who discontinued study treatment for COVID-19-related reasons (excluding COVID-19 infection) had their observed data used, if available.
cMissing data imputation: After accounting for the conditions in footnote b, participants with a missing CDAI score (for clinical remission, corticosteroid-free clinical remission, and deep remission) or SES-CD (for endoscopic response, endoscopic remission, and deep remission) were considered not to have met the endpoint.
dWald CIs were based on normal approximation. In cases of rare events, the exact confidence limits were provided.
eThe Mantel-Haenszel estimate of the common risk difference and the 95% CI using Mantel-Haenszel stratum weights and the Sato variance estimator were used for obtaining the adjusted differences and associated 95% CIs for pairwise comparisons of each JNJ-4804 treatment group with the comparator treatment group.
fAs-observed, log transformed data, excluding inadequate responder data after treatment escalation at Week 24
AE=adverse event, CD=Crohn’s disease, CDAI=Crohn’s Disease Activity Index, CI=confidence interval, GOL=golimumab, GUS=guselkumab, IQR=interquartile range, IR=inadequate response or intolerance, MOA=mechanism of action, PBO=placebo, SES-CD=Simple Endoscopic Score for Crohn’s Disease. |
Subpopulation: ≥2 systemic therapy mechanisms-IR
| Placebo
(N=35)
| Golimumab
(N=65)
| Guselkumab
(N=55)
| JNJ-4804 high
(N=63)
|
Clinical remissiona,b,c
n participants (%)
95% CId
Comparator,
Adjusted treatment differencee (95% CIe)
PBO
GOL
GUS
|
4 (11.4%)
(0.9, 22.0)
-
-
-
|
15 (23.1%)
(12.8, 33.3)
-
-
-
|
15 (27.3%)
(15.5, 39.0)
-
-
-
|
31 (49.2%)
(36.9, 61.6)
39.4 (21.6, 57.3)
27.3 (10.9, 43.6)
21.2 (4.1, 38.3)
|
Endoscopic responsea,b,c
n participants (%)
95% CId
Comparator,
Adjusted treatment differencee (95% CIe)
PBO
GOL
GUS
|
1 (2.9%)
(0.0, 8.4)
-
-
-
|
8 (12.3%)
(4.3, 20.3)
-
-
-
|
11 (20.0%)
(9.4, 30.6)
-
-
-
|
21 (33.3%)
(21.7, 45.0)
35.0 (20.2, 49.7)
21.2 (7.4, 35.0)
11.7 (-4.3, 27.6)
|
Corticosteroid-free clinical remissiona,b,c
n participants (%)
95% CId
Comparator,
Adjusted treatment differencee (95% CIe)
PBO
GOL
GUS
|
4 (11.4%)
(0.9, 22.0)
-
-
-
|
14 (21.5%)
(11.5, 31.5)
-
-
-
|
15 (27.3%)
(15.5, 39.0)
-
-
-
|
29 (46.0%)
(33.7, 58.3)
37.2 (18.5, 55.8)
24.8 (8.8, 40.8)
20.1 (3.2, 37.1)
|
Endoscopic remissiona,b,c
n participants (%)
95% CId
Comparator,
Adjusted treatment differencee (95% CIe)
PBO
GOL
GUS
|
1 (2.9%)
(0.0, 8.4)
-
-
-
|
5 (7.7%)
(1.2, 14.2)
-
-
-
|
4 (7.3%)
(0.4, 14.1)
-
-
-
|
15 (23.8%)
(13.3, 34.3)
21.2 (8.0, 34.3)
19.3 (6.7, 31.9)
15.4 (3.0, 27.7)
|
Deep remissiona,b,c
n participants (%)
95% CId
Comparator,
Adjusted treatment differencee (95% CIe)
PBO
GOL
GUS
|
0
(0.0, 10.0)
-
-
-
|
4 (6.2%)
(1.7, 15.0)
-
-
-
|
3 (5.5%)
(1.1, 15.1)
-
-
-
|
13 (20.6%)
(11.5, 32.7)
20.1 (8.8, 31.4)
17.7 (6.3, 29.1)
13.8 (2.3, 25.3)
|
Change from baseline at Week 48 in fecal calprotectin (mg/kg) (log-transformed, as observed)f
n participants
Mean (SD)
|
4
0.53 (0.917)
|
18
-0.22 (1.153)
|
15
-0.84 (1.641)
|
25
-1.58 (1.425)
|
Conclusion
In the treatment-refractory subpopulation of pts with inadequate response to ≥2 ST mechanisms, JNJ-4804, the first co‑antibody therapy in development for IBD, delivered substantial and clinically meaningful efficacy, with benefits that exceeded those of GOL and GUS. The JNJ-4804 safety profile in this subpopulation was similar to the monotherapies. These results support advancement to Phase 3 in the rapidly growing population of patients with disease refractory to STs.
Disclosure
Vipul Jairath reports consulting fees from AbbVie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, Bristol Myers Squibb, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Johnson & Johnson, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma.
Geert D'Haens reports consultancy activities for AbbVie, Abivax, Agomab, Alimentiv, AnaptysBio, AstraZeneca, Biora, Bristol Meyers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Johnson & Johnson, Merck, Mirador, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, Protagonist Therapeutics, Sanofi, Sorriso, Spyre Therapeutics, and Takeda; speakers bureaus for AbbVie, Bristol Myers Squibb, Eli Lilly, Pfizer, and Takeda; and data monitoring board activities for AbbVie, AstraZeneca, Galapagos, and Seres Health.
Iris Dotan has received grants from Altman Research, Pfizer, and BMS; and received consulting fees and honoraria from and served as a speaker for AbbVie, Athos, Arena, Astra-Zeneca, Cambridge Healthcare, Celltrion, Celgene/BMS, Eli Lilly, Ferring, Falk Pharma, Gilead, Galapagos, Harp Diagnostics, Iterative Scopes, Integra Holdings, Johnson & Johnson, Mapi-Pharma, Pfizer, Roche/Genentech, Sangamo, Sublimity, Sandoz, and Takeda.
Nat A. Terry, Monica Walker, Vanessa Bundy, Hayley Perry, Dylan Richards, and Marion L. Vetter are employees of and may own stock in Johnson & Johnson.
Taku Kobayashi reports receiving advisory/consultancy fees from AbbVie, Alfresa, Alimentiv, Bristol Myers Squibb, Eli Lilly, EA, Ferring, Galapagos, Gilead, Johnson & Johnson, Kyorin, Mochida, Nippon Kayaku, Pfizer, Takeda, Thermo, research grants from AbbVie, Alfresa, EA, Google, Kyorin, Mitsubishi-Tanabe, Pfizer, Takeda, Zeria, lecture fees from AbbVie, Alfresa, Celltrion EA, Eli Lilly, Ferring, Gilead, Johnson & Johnson, JIMRO, Kyorin, Mochida, Mitsubishi-Tanabe, Nippon Kayaku, Pfizer, Sekisui, Takeda, and Zeria.
Stefan Schreiber reports personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Gilead, Hikma, Johnson & Johnson, MSD, Pfizer, Sandoz, and Takeda.
Bruce E. Sands reports honoraria for consulting from Aclaris Therapeutics, Adaxion Therapeutics, Adiso Therapeutics, Agomab Therapeutics, Alfasigma, Alimentiv, Amgen, AnaptysBio, AstraZeneca, Attovia Therapeutics, Biolojic Design, BiomeBank, Biora Therapeutics, Boehringer-Ingelheim, Caldera Therapeutics, Cellarity, Cytoki Pharma, Disc Medicine, Eil Lilly & Company, Ensho Therapeutics, Enthera, Enveda Biosciences, Equilium, Evommune, Ferring, Fzata, Galapagos, Genentech (Roche), Genesis Therapeutics, Gilead Sciences, GlaxoSmithKline, Globalport, Ignite Biomedical, Imedex, Imhotex, Immunitas Therapeutics, Immunyx Pharma, Kallyope, Kyowa Kirin, LifeMine Therapeutics, Merck & Co., Merck Sharp & Dohme, Microba, Microbiotica, Mirador Therapeutics, Mitsubishi Tanabe Pharma, Mobius Care, Morphic Therapeutic, MRM Health, Nexus Therapeutics, Nimbus Discovery, Novartis, Numab Therapeutics, Odyssey Therapeutics, ONO Pharmaceutical, OSE Immunotherapeutics, Palisade Bio, Pioneering Medicines Explorations, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Quotient Therapeutics, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sanofi, Slate Bio, Sorriso Pharmaceuticals, Spyre Therapeutics, Synlogic, Target RWE, Televant, Teva, Thetis Pharmaceuticals, SRT Therapeutics, TR1X, Trex Bio, Union Therapeutics, VectivBio, Vedanta Biosciences, Vividion Therapeutics, and Xencor; honoraria for consulting and speaking and other support from AbbVie, Abivax, Bristol Myers Squibb, Celltrion, Eli Lilly & Company, Genentech (Roche), Johnson & Johnson, Merck & Company, Pfizer, Takeda, and Teva; honoraria for consulting and stock options from Caldera Therapeutics, Mirador Therapeutics and SRT Therapeutics; and stock from Doximity.
