Introduction
Psoriasis is a chronic, immune-mediated, inflammatory skin disease that affects more than 7.5 million adults in the United States [
1] and approximately 125 million individuals globally [
2]. Plaque psoriasis (PsO) is the most common type of psoriasis, affecting approximately 80–90% of patients with psoriasis [
3].
Systemic treatments used to treat moderate to severe PsO include nontargeted, nonbiologic agents (e.g., acitretin, methotrexate, and cyclosporine), targeted small molecules (apremilast and deucravacitinib), and biologic agents (e.g., tumor necrosis factor inhibitors [TNFis], interleukin [IL]-12/23 inhibitors, IL-17 inhibitors, and selective IL-23 inhibitors) [
3]. Adalimumab, a TNFi, has been widely used to treat adults with moderate to severe PsO since its approval by the US Food and Drug Administration in 2008 [
2,
4]. As new PsO therapies become available, including those administered orally, long-term efficacy and safety data as well as comparative data are needed to better understand the role of new therapies and their place in the existing PsO treatment landscape [
5].
In September 2022, the US Food and Drug Administration approved deucravacitinib as a first-in-class, oral, allosteric tyrosine kinase 2 inhibitor for treatment of adults with moderate-to-severe PsO who are candidates for systemic therapy and phototherapy [
6,
7]. The efficacy and safety of deucravacitinib in adults with moderate to severe PsO were demonstrated in the phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) registrational trials [
8,
9]. Deucravacitinib administered once daily demonstrated superior efficacy in both trials compared with placebo and with apremilast across a variety of primary and secondary prespecified endpoints [
8,
9]. After 52 weeks, patients completing the POETYK PSO-1 and PSO-2 trials could enroll in the POETYK PSO long-term extension (LTE) study to receive open-label deucravacitinib 6 mg once daily. In the POETYK PSO-LTE (NCT04036435) study, clinical efficacy was maintained for up to 2 years in patients treated with deucravacitinib, regardless of the treatment received at week 52 in the POETYK PSO-1 or PSO-2 trials [
10].
Comparable efficacy was shown for deucravacitinib and some of the most effective first-generation biologics, including adalimumab, over 52 weeks in a previous systematic literature review and network meta-analysis [
11]. However, the longer-term efficacy of deucravacitinib versus that of first-generation biologics is unknown. In lieu of results from head-to-head clinical trials comparing deucravacitinib with adalimumab in adults with moderate to severe PsO, a matching-adjusted indirect comparison (MAIC) was performed to compare long-term clinical outcomes with these agents. This paper aims to inform clinical practice by comparing long-term efficacy outcomes between a novel and an established treatment for PsO using a methodologically rigorous analytic technique.
Discussion
This MAIC compared the long-term efficacy of deucravacitinib versus that of adalimumab in adults with moderate to severe PsO using a well-established, rigorous analytic method. Results from the base case analysis showed that, following an adjustment for differences in baseline patient characteristics, adults with moderate to severe PsO treated with deucravacitinib had a significantly higher PASI 75 response rate at week 112 compared with those treated with adalimumab. In sensitivity analyses evaluating the effects of potentially relevant clinical characteristics, results generally confirmed the base case results. Prior use of topical therapy was the only baseline characteristic from the REVEAL study not included in the matching adjustment. However, prior use of topical therapy was deemed not clinically important for the MAIC because patients included in this analysis were initially treated with placebo during the registrational studies, resulting in a 16-week washout period. In addition, there were limited nontopical treatment options available to treat PsO at the time of the REVEAL study, so more than twice as many patients in the REVEAL group D versus POETYK PSO-LTE cohorts had prior use of topical therapy (71.9% vs. 30.1%), whereas more treatment options were available when the POETYK PSO-LTE study was conducted.
Results from a prior network meta-analysis demonstrated that oral deucravacitinib had comparable efficacy to adalimumab over 52 weeks [
11], consistent with the results of our study at the same time point. In addition, results from this MAIC suggest that efficacy with deucravacitinib was maintained, as response rates were consistently higher with continuous deucravacitinib than with adalimumab from weeks 52 through 112. Our study results may be similar to those observed in a previous study that showed that patients may experience a loss of efficacy with biologic therapy over time [
24]. Biologic therapies are large proteins with complex structures. There is a risk of these large, complex structures being recognized by the patient’s immune system as foreign bodies that may elicit an immune response and the production of antidrug antibodies. This host immune response may be responsible for downstream effects, which include secondary nonresponse [
25].
Although this study adjusted for the patient characteristics reported in both trials, no two trials are exactly alike; outcomes for this MAIC are subject to a higher level of uncertainty than would occur in a head-to-head randomized controlled trial comparing deucravacitinib and adalimumab. The adjustment to the published adalimumab data was based on aggregate proportions of patient characteristics but did not necessarily control for the joint distribution between characteristics associated with each individual patient. Therefore, associations between outcomes and baseline factors at the study level may be different than they would have been at the patient level. This MAIC was based on an interim data analysis for the POETYK PSO-LTE study; once the extension study has been completed, a data refresh will be warranted. The REVEAL OLE results were reported as full integers without decimal places, most likely for better clinical interpretability, so they may not represent the true values.
As an indirect comparison evaluates previously published data, differences in study design, such as when a patient enters the open-label portion of a study, could not be controlled. In the POETYK trials, patients remained blinded to treatment from weeks 16 to 52, whereas patients in the REVEAL trials received open-label treatment during the same period. However, data suggest that the absence of blinding (i.e., open-label versus blinded treatment) has little effect on perceived drug efficacy or on the outcome reporting rate [
26].
The POETYK and REVEAL trials were conducted more than a decade apart [
8,
9,
13]. During this time, the treatment landscape for PsO expanded and patients gained access to novel treatments with various mechanisms of action [
5]. Patients enrolled in the POETYK trials may have had a more diverse treatment history than those in the REVEAL trials owing to the approval and availability of new medications from 2004 to 2018. Additionally, previous treatment exposure in the REVEAL trial was limited to the 12 months prior to study initiation [
12]. Conversely, previous systemic treatment exposure in the POETYK trials was not restricted to the 12 months prior to study initiation [
8,
9]. Thus, it is not surprising that a greater proportion of patients in the POETYK PSO-LTE than in the REVEAL OLE studies previously received systemic nonbiologic or biologic PsO treatment. As few biologic therapies were approved before 2004, when the REVEAL trial was initiated (i.e., alefacept [later withdrawn], etanercept, efalizumab [later withdrawn], and infliximab), with many more recent biologic treatments available by the time the POETYK studies were initiated, we opted to keep the different capture periods for the POETYK and REVEAL trials for the base case analysis. The impact of this difference in definitions was explored in sensitivity analyses, which did not alter the main conclusions. Although patients were excluded from the REVEAL trial for prior TNFi use, we did not exclude patients with prior TNFi use (other than adalimumab) from the POETYK PSO-LTE population whose data were used to conduct this MAIC. Overall, the methodologic issue of a heterogeneous treatment history is mitigated by evidence from the POETYK trials demonstrating that prior biologic therapy is not prognostic of response to deucravacitinib [
27]. Additionally, we adjusted for the placebo response after week 16, which should be considered as an all-inclusive composite measure of patients’ likelihood to respond to future treatments.
We also examined the impact of using LOCF imputation on missing PASI 75 and PASI 90 values in the POETYK PSO-LTE study by comparing imputed values to the values obtained from patients with complete response data. We observed that the estimates obtained from patients with complete response data were higher than the estimates obtained using an LOCF approach. It is possible that the response estimates obtained using data from patients with complete response data were overestimated, as they represent patients with longer treatment durations; therefore, using the LOCF-imputed values is a more conservative approach. Moreover, the LOCF approach is consistent with the REVEAL OLE study analysis [
12].
As previously described, the trial design for both long-term efficacy analyses included patients who initiated treatment with placebo then switched to active treatment at week 16. Some cohorts in the REVEAL OLE study that were not used for this comparative analysis initiated treatment with adalimumab 80 mg, which was then tapered to 40 mg. Patients in these cohorts had higher response rates than patients from REVEAL group D, who were included as the comparator arm in this MAIC (i.e., patients who switched from placebo to adalimumab 40 mg at week 16) [
4]. Further research may be needed to compare dose-specific response rates for deucravacitinib and adalimumab.
Several limitations that apply to any indirect comparison of published data should be acknowledged. As discussed above, the results of this study are subject to a higher level of uncertainty than what would occur in a head-to-head randomized, controlled trial, and differences in study design (e.g., open-label vs. blinded treatment) could not be controlled. There also may be different associations between outcomes and baseline factors at the study level than at the patient level.