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Analysis from a multicenter, randomized, double-blind, parallel group study comparing the drugs as induction and maintenance therapies in biologic-naïve patients.
Despite the rapid expansion of therapeutic modalities available for both induction and maintenance therapy in inflammatory bowel disease (IBD), data from active-comparator trials between available treatment options remains severely limited.
This requires clinicians to indirectly juxtapose efficacy and safety data from heterogeneous studies, differing in patient populations, study designs and outcomes measured, to guide therapy.
Although the VARSITY trial began to fill this void in the management of Ulcerative Colitis, no such data existed for first line therapy in Crohn’s disease (CD) until the SEAVUE trial was published last year.
Sands et al. conducted a randomized, double-blind, parallel-group phase 3b superiority trial comparing the efficacy and safety of ustekinumab vs. adalimumab as first-line biologic therapy in moderately to severely active Crohn’s disease.
This study enrolled 386 biologic-naïve adult patients across 121 institutions who had failed conventional therapy or were steroid-dependent. Patients were required to have evidence of active CD for 3 months preceding enrollment, defined endoscopically (≥1 ulcer) and clinically (CDAI score >250). Notably, patients who had recent surgery, hospitalization, or bowel obstruction, as well as those with significant history of infection and malignancy, were excluded.
Randomization was stratified by baseline corticosteroid use, CDAI score and presence of large ulcers (defined as >5 mm). Patients received US Food and Drug Administration (FDA)-approved dosing regimens for both drugs, without possibility of dose escalation.
The principal study outcome was clinical remission at the end of the study period (1 year), defined as a CDAI score <150. Secondary outcomes included corticosteroid free remission, clinical response (CDAI score decrease by >100 from baseline), clinical remission at 16 weeks and endoscopic remission at the end of the study period.
Overall, there was no significant difference in the occurrence of the primary outcome between the 2 groups, with 65% one-year clinical remission rates in the ustekinumab group versus 61% in the adalimumab group. There was similar parity with respect to secondary outcomes including steroid free remission (61% vs 57%, respectively), 1-year clinical response (72% vs 66%), clinical remission at 16 weeks (57% vs 60%), and endoscopic remission.
Notably, however, there was a higher rate of early discontinuation of adalimumab (24%) compared to ustekinumab (15%). Although both adverse events (80% vs 78%, respectively) and serious adverse events (16% vs 13%) were of similar frequency in both groups, nearly twice as many patients had an adverse event requiring drug discontinuation among those on adalimumab compared to ustekinumab (11% vs 6%). Although adalimumab was far more immunogenic than ustekinumab, with a 74% rate of antibody formation compared to just 2%, antibody titers were generally low and did not correlate with lower rates of clinical remission.
Overall, this study demonstrates similarly high clinical efficacy between ustekinumab and adalimumab in biologically-naïve patients with moderately to severely active CD with high rates of mild adverse reactions but overall favorable safety profiles.
This reasonably suggests that either agent could be appropriately positioned as first-line therapy in this population. However, this study raised suggestion of better tolerability of ustekinumab, evidenced by higher rates of drug discontinuation in the adalimumab arm. This potential benefit, however, should be weighed against practical considerations such as costs (generally higher for ustekinumab), dosing frequency (every 2 weeks for adalimumab compared to 8 weeks for ustekinumab) and patient preference.
However, as the authors appropriately note, the long-term implications of the higher rate of antibody formation with adalimumab compared to ustekinumab remains an unanswered question. Although no such implications were noted during a 1-year study window, it is plausible this would lead to higher loss of response or adverse events rates over time.
Long-term follow-up, as well as studies better clarifying the role of concurrent immunomodulator therapy with each agent—particularly in relation to the immunogenicity of adalimumab—will be invaluable in further guiding therapy.
Additionally, studies exploring the role of each agent in management of patients with longer disease histories, including those with prior biologic exposures, as well as the role of dose escalation upon agent failure, will be critical in expanding these study results to a wider populations of patients with Crohn’s disease.
Sands BE, Irving PM, Hoops T, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn's disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet. 2022;399(10342):2200-2211. doi:10.1016/S0140-6736(22)00688-2