Efficacy and Safety of Oral Icotrokinra in Moderate‐to‐Severe Plaque Psoriasis: A Systematic Review, Meta‐Analysis, and Trial Sequential Analysis

Alhasan Altayf; Munder Lateiresh; Lutfiyah Marwan; Mohamed Yaseen Alfeetouri; Yassine Zouaoui; Muhammed Elhadi

doi:10.1111/ijd.70380

. 2026 Mar 17;65(6):1144–1154. doi: 10.1111/ijd.70380

Efficacy and Safety of Oral Icotrokinra in Moderate‐to‐Severe Plaque Psoriasis: A Systematic Review, Meta‐Analysis, and Trial Sequential Analysis

Alhasan Altayf ¹, Munder Lateiresh ², Lutfiyah Marwan ³, Mohamed Yaseen Alfeetouri ⁴, Yassine Zouaoui ⁵, Muhammed Elhadi ^6,^✉

PMCID: PMC13161523 PMID: 41846234

ABSTRACT

Oral therapies for moderate‐to‐severe plaque psoriasis are limited by modest efficacy or safety concerns. Icotrokinra is a novel oral interleukin‐23 receptor antagonist peptide that has shown promising efficacy in randomized trials. This study aimed to systematically evaluate the efficacy and safety of icotrokinra in patients with moderate‐to‐severe plaque psoriasis. A systematic review and meta‐analysis of randomized controlled trials (RCTs) comparing icotrokinra 200 mg once daily with placebo was conducted in accordance with PRISMA 2020 guidelines. The primary outcome was achievement of a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) at Week 16. Random‐effects models were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), and trial sequential analysis was performed. Five RCTs, including 1951 participants, were analyzed. Icotrokinra 200 mg once daily significantly increased PASI 75 response rates compared with placebo at Week 4 (15% vs. 2%; OR = 6.57, 95% CI 3.66–11.81; p < 0.0001) and Week 16 (73% vs. 11%; OR = 22.03, 95% CI 16.13–30.10; p < 0.0001). Higher clearance thresholds also favored icotrokinra, including PASI 90 (54% vs. 4%; OR = 28.24) and PASI 100 (30% vs. 1%; OR = 45.86). The incidence of adverse events, serious adverse events, and infections did not differ significantly between groups. Icotrokinra is an effective and well‐tolerated oral treatment for moderate‐to‐severe plaque psoriasis, offering rapid and sustained clinical benefit with a safety profile comparable to placebo. It represents a promising oral option bridging the gap between existing oral therapies and biologics.

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Keywords: icotrokinra, interleukin‐23 receptor antagonist, meta‐analysis, oral therapy, plaque psoriasis

Meta‐analysis of randomized controlled trials demonstrates that oral icotrokinra significantly improves PASI responses in patients with moderate‐to‐severe plaque psoriasis, with early clinical benefit and a placebo‐comparable safety profile, supported by trial sequential analysis confirming robust and sufficient evidence.

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1. Introduction

Plaque psoriasis is a chronic inflammatory skin disorder and is characterized by well‐defined, erythematous plaques with silvery scale. Although it can affect any part of the body, it most commonly involves the scalp, trunk, gluteal folds, and extensor surfaces, particularly the elbows and knees [1, 2, 3]. Beyond the skin, psoriasis is associated with systemic comorbidities, including cardiometabolic diseases, psoriatic arthritis, and mental health disorders [4], and it imposes a considerable economic burden on both patients and society [5]. The disease is also linked to malignancies [6], hypertension [7], and metabolic syndrome [8, 9].

Interleukin‐23 (IL‐23) plays a central role in driving pathogenic T‐cell activation and sustaining inflammation in psoriasis [10]. Biologic therapies, largely based on monoclonal antibodies targeting inflammatory mediators, have led to major advances in the treatment of psoriasis [11]. However, biologic therapies require intravenous or subcutaneous administration [12], which can be inconvenient for some patients. Many patients diagnosed with psoriasis prefer oral drugs over injectable therapies [13, 14], and injectable therapies may be particularly challenging for children with needle fear [15].

Oral systemic agents such as apremilast, a phosphodiesterase‐4 inhibitor, and deucravacitinib, a selective tyrosine kinase 2 inhibitor, offer alternatives but have limitations in both efficacy and safety [16, 17]. Biologic therapies, while achieving higher Psoriasis Area and Severity Index (PASI) responses, are also associated with an increased risk of infections and injection‐related reactions compared with oral treatments [11].

Icotrokinra (JNJ‐77242113) is a novel oral peptide that selectively targets the interleukin‐23 receptor, inhibiting IL‐23 binding and downstream signaling. This approach mechanistically distinguishes icotrokinra from existing monoclonal antibody therapies, which typically neutralize circulating IL‐23 cytokines rather than targeting the receptor itself (Figure 1). Early‐phase randomized trials show superior efficacy versus placebo and deucravacitinib, with high skin clearance rates and a safety profile comparable to placebo [18]. Recent randomized controlled trials show that icotrokinra improves PASI 75, 90, and 100 responses, as well as Physician Global Assessment (PGA) and Dermatology Life Quality Index scores (DLQI). Notably, icotrokinra achieves levels of skin clearance traditionally observed with biologic therapies [10, 18, 19, 20]. However, heterogeneity in trial design and safety reporting limits firm conclusions about its clinical benefit.

Mechanistic comparison of IL‐23 pathway inhibition by oral Icotrokinra and injectable monoclonal antibodies.

To date, no systematic review and meta‐analysis have evaluated Icotrokinra in moderate‐to‐severe psoriasis. This study therefore assesses its efficacy and safety, focusing on PASI outcomes, quality of life, and safety to clarify its therapeutic value and potential to bridge the oral–biologic efficacy gap and provide clinicians with evidence‐based guidance on this promising oral therapy.

2. Methods

2.1. Protocol and Registration

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) 2020 guidelines (Tables S1 and S2) [21]. Methodological quality was evaluated using the A Measurement Tool to Assess Systematic Reviews (AMSTAR‐2), with results presented in Table S3 [22]. The study protocol was registered in PROSPERO under the registration number CRD420261279962.

2.2. Search Strategy and Information Sources

On 30 December 2025, a comprehensive literature search was conducted across four databases—PubMed, Scopus, Embase, and the Cochrane Library—as well as the ClinicalTrials.gov registry. No restrictions were imposed on language, publication year, or study design. To capture additional relevant studies, the reference lists of eligible articles and citation tracking were manually examined. The search strategy employed specific terms related to the intervention (“Icotrokinra” and “JNJ‐77242113”) and the condition (“psoriasis”), with individual terms within each concept combined using the Boolean operator OR, and concepts across groups combined using the AND operator. The full list of search terms and strategy is provided in Table S4.

2.3. Eligibility Criteria

This meta‐analysis included all randomized clinical trials that met our PICO criteria: The population included adults and adolescents (≥ 12 years) diagnosed with moderate‐to‐severe psoriasis, without restrictions on sex, ethnicity, or geographic region. The intervention of interest was oral icotrokinra 200 mg once daily, while the comparator was placebo.

The primary efficacy outcome was the proportion of patients achieving a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 4 and 16 weeks. Secondary efficacy outcomes assessed after 16 weeks included PASI 90, PASI 100, Investigator's Global Assessment (IGA) score of 0/1, Dermatology Life Quality Index (DLQI) score of 0–1, Psoriasis Symptoms and Signs Diary (PSSD) score of 0, and clinically meaningful improvement in PSSD itch, defined as a ≥ 4‐point reduction from baseline on the PSSD itch scale.

Safety outcomes were assessed at Week 16 and included the incidence of adverse events (AEs), serious adverse events (SAEs), infections, serious infections, headache, nasopharyngitis, upper respiratory tract infections, gastrointestinal adverse events, and cancer. Detailed definitions of outcomes across studies are provided in Table S5.

Studies were excluded if they did not meet the predefined inclusion criteria, reported incomplete, inaccessible, or duplicated data, or were non‐randomized or non–peer–reviewed publications, including observational studies, editorials, letters, protocols, reviews, conference abstracts, or animal studies.

2.4. Study Selection and Data Extraction

Study selection was conducted in two sequential stages in accordance with the predefined inclusion and exclusion criteria, using the Covidence platform. Titles and abstracts were independently screened by two reviewers (L.M. and M.Y.A.), followed by independent full‐text assessment by the same reviewers. Any disagreements were resolved through consultation with a third reviewer (A.A.) [23].

Data extraction was independently performed by two reviewers (Y.Z. and L.M.) using a standardized Excel extraction form. When numerical values were not provided, the reviewers extracted data from graphs using a graph digitization tool; average values were used for analysis. Any discrepancies were resolved through discussion with a third reviewer (A.A.). The data extraction form comprised three domains: study characteristics (including first author, year of publication, sample size, and intervention details); baseline participant characteristics (age, sex, and clinical setting); and efficacy and safety outcomes.

2.5. Risk of Bias and Certainty of Evidence

The risk of bias in all included studies was independently assessed by two reviewers (M.L. and M.Y.A.) using the revised Cochrane Risk of Bias tool for randomized controlled trials (RoB 2) [24]. The evaluation covered five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias resulting from missing outcome data, bias in the measurement of outcomes, and bias in the selection of the reported result. Each domain and the overall study quality were classified as low risk, some concerns, or high risk of bias, and any disagreements between reviewers were settled through discussion with a third reviewer (A.A.). The results were synthesized and visually presented using the Robvis tool [25].

The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework across five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Based on these assessments, the overall certainty of evidence was categorized as high, moderate, low, or very low [26]. A summary of findings table was produced using the GRADEpro GDT tool [27].

2.6. Data Synthesis

Statistical analyses were performed using R software with the “meta” and “metapower” packages [28]. The Meta‐analyses were conducted using a random‐effects model (DerSimonian and Laird method, DL). For dichotomous outcomes, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A continuity correction was applied to studies with zero events in one arm and double‐zero studies (zero events in both arms) to avoid exclusion bias. Heterogeneity was assessed using Cochran's Q test and I ² statistic, with I ² > 50% considered substantial.

A trial sequential analysis (TSA) was conducted for the primary endpoint, achievement of PASI 75 at Week 16, to estimate the required information size (RIS) and control the type I error from repeated significance testing. A two‐sided type I error (α) of 5% and type II error (β) of 20% (80% power) were prespecified. The RIS for dichotomous outcomes was based on the relative risk reduction (RRR) from low‐risk‐of‐bias trials. O'Brien–Fleming monitoring boundaries were applied for benefit, harm, and futility, and evidence was considered robust when the cumulative Z‐curve crossed both the conventional and TSA boundaries after reaching the RIS. Power analysis was conducted to determine whether the cumulative sample size provided sufficient power (> 80%) to detect the observed effect. TSA was performed by TSA software version 0.9.5.10 Beta (Copenhagen Trial Unit, Copenhagen, Denmark).

Leave‐one‐out sensitivity analyses were performed by sequential omission of individual studies to evaluate the robustness of the findings. Publication bias was assessed using funnel plots and Egger's regression test [29].

3. Results

3.1. Study Selection and Characteristics

Database searches and registries identified 1125 records. After removal of 355 duplicates in Covidence, 770 records underwent title and abstract screening, of which 725 were excluded. Of 45 full‐text articles assessed, 41 were excluded for the following reasons: protocol reports (n = 6), absence of the intervention or comparator of interest (n = 2), duplicate publications (n = 13), ongoing studies without available results (n = 6), ineligible study design (n = 4), lack of relevant outcomes (n = 1), and abstract‐only reports (n = 9). Four studies were ultimately included, yielding five RCTs [10, 18, 19, 20]. One study reported two independent RCTs [18], all of which met eligibility criteria for the meta‐analysis. The study selection process is shown in Figure 2.

PRISMA flow diagram of the study selection process.

The five included randomized controlled trials, including one phase 2 trial (FRONTIER 1) [10] and four phase 3 trials from the ICONIC program (ICONIC‐LEAD, ICONIC‐TOTAL, and ICONIC‐ADVANCE 1 and 2) [18, 19, 20], enrolled a total of 1951 participants, of whom 1303 (66.8%) were male. All studies included adults (≥ 18 years) as well as adolescents aged 12 to < 18 years. The weighted mean age of participants was 44.9 years (SD 14.8). Follow‐up duration varied across trials. Detailed baseline demographic and clinical characteristics are summarized in Table 1.

TABLE 1.

Baseline characteristics of included randomized clinical trials.

Study ID	Design	Population	Groups	N	Age, years	Male, n (%)	BMI	Duration of psoriasis, years	PASI total score	Percentage BSA	DLQI score	IGA score, n (%)		Mean duration of follow‐up, weeks ^a
Study ID	Design	Population	Groups	N	Age, years	Male, n (%)	BMI	Duration of psoriasis, years	PASI total score	Percentage BSA	DLQI score	3	4	Mean duration of follow‐up, weeks ^a
CONIC‐LEAD	Phase 3, multicenter, randomized, double‐blind, placebo‐controlled.	Adults and adolescents (≥ 12 years) with moderate‐to‐severe plaque psoriasis.	Icotrokinra 200 mg QD ^b	456	42.4 (16.3)	291 (64%)	29.2 (6.9)	17.3 (13.9)	19.4 (7.1)	24.6 (14.3)	11.4 (6.7)	341 (75%)	115 (25%)	15.9
CONIC‐LEAD			Placebo	228	43.2 (16.6)	156 (68%)	29.3 (7.0)	16.6 (12.7)	20.8 (8.1)	27.1 (16.2)	11.0 (6.4)	173 (76%)	55 (24%)	15.8
ICONIC‐TOTAL	Phase 3, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, interventional trial	Adults (≥ 18 years of age) and adolescents (≥ 12 to < 18 years of age) with plaque psoriasis	Icotrokinra 200 mg QD	208	45.3 (14.6)	137 (65.9%)	29.0 (6.6)	16.8 (13.3)	—	16.6 (13.5)	—	153 (73.6%)	46 (22.1%)	16 (1.8)
ICONIC‐TOTAL			Placebo	103	43.5 (13.8)	63 (61.2%)	29.4 (8.1)	15.2 (10.5)	—	14.8 (11.7)	—	73 (70.9%)	22 (21.4%)	15.7 (1.9)
ICONIC‐ADVANCE 1	Phase 3, randomized, double‐blind, placebo‐controlled, and active‐comparator‐controlled ICONIC‐ADVANCE 1 and ICONIC‐ADVANCE 2 trials	Adults (aged ≥ 18 years) with moderate‐to‐severe plaque psoriasis	Icotrokinra 200 mg QD	311	47.1 (13.19)	223 (72%)	29.2 (6.31)	17.52 (11.10)	18.73 (5.36)	22.67 (11.92)	—	251 (81%)	60 (19%)	15.9 (1.88)
ICONIC‐ADVANCE 1			Placebo	156	46.9 (12.78)	105 (67%)	29.6 (8.08)	17.88 (12.75)	17.68 (5.42)	21.58 (12.53)	—	123 (79%)	33 (21%)	15.5 (2.69)
ICONIC‐ADVANCE 2			Icotrokinra 200 mg QD	322	45.9 (13.78)	218 (68%)	29.9 (6.36)	17.43 (13.38)	18.43 (5.29)	22.67 (12.66)	—	252 (78%)	70 (22%)	16
ICONIC‐ADVANCE 2			Placebo	82	48.4 (13.90)	55 (67%)	29.5 (5.78)	21.21 (15.17)	18.3 (7.02)	23.33 (13.58)	—	67 (82%)	15 (18%)	15.5
FRONTIER 1	Phase 2, dose‐finding, double‐blind, randomized, placebo‐controlled trial	Adults (≥ 18 years of age) had moderate‐to‐severe plaque psoriasis	JNJ‐77242113 100 mg 2QD ^c	42	42 (11.34)	30 (71%)	30.0 (5.40)	16.7 (13.78)	20.33 (6.51)	24.2 (12.55)	—	30 (71%)	12 (29%)	15.8
FRONTIER 1			Placebo	43	43.9 (14.70)	25 (58%)	31.2 (7.61)	17.9 (14.37)	18.99 (5.34)	26.1 (15.72)	—	38 (88%)	5 (12%)	15

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^{^a}

For safety outcomes.

^{^b}

Once daily.

^{^c}

Twice daily.

FRONTIER 1 was a dose‐finding RCT. For the purpose of this meta‐analysis, only the 100 mg twice daily regimen was included to ensure consistency with subsequent trials. Other dose arms, which were less effective and not used in later trials, were excluded to maintain comparability and avoid introducing heterogeneity.

3.2. Quality Assessment

All five included RCTs [10, 18, 19, 20] were assessed as having low risk of bias across all domains (Figures S1 and S2).

3.3. Primary Efficacy Outcome (PASI 75), With TSA & Statistical Power Analysis

The primary efficacy outcome showed that icotrokinra induced a rapid, clinically meaningful therapeutic response. A significant treatment effect was evident as early as Week 4, with icotrokinra achieving a substantially higher PASI 75 response compared with placebo (OR = 6.57, 95% CI 3.66–11.81; p < 0.0001; I ² = 0%). This benefit intensified over time, reaching a very large magnitude by Week 16, when patients receiving icotrokinra exhibited markedly greater odds of achieving PASI 75 than those receiving placebo (OR = 22.03, 95% CI 16.13–30.10; p < 0.0001; I ² = 0%) (Figure 3). In the TSA, the cumulative z‐curve (z = 19.43) exceeded the traditional significance boundary, but the sequential monitoring boundary could not be applied because the first information fraction exceeded 100%, indicating that the first study already had sufficient statistical power for a meta‐analysis (Figure 4). Post hoc power analysis showed complete statistical power (100%) to detect the observed treatment effect (Figure S52).

Forest plot of PASI 75 at 4 and 16 weeks.

Trial sequential analysis of PASI 75 at 16 weeks.

3.4. Secondary Efficacy Outcomes

The meta‐analysis found that Icotrokinra was associated with improvements across all prespecified secondary efficacy outcomes at Week 16 compared with placebo. Icotrokinra was associated with higher odds of achieving PASI 90 (OR = 28.24, 95% CI 17.29–46.12, p < 0.0001; I ² = 0%) (Figure 5) and complete skin clearance (PASI 100) (OR = 45.86, 95% CI 17.92–117.40, p < 0.0001; I ² = 0%) (Figure 6). Similarly, Investigator‐assessed global outcomes favored icotrokinra, including achievement of IGA 0 (OR = 36.49, 95% CI 18.34–72.61, p < 0.0001; I ² = 0%) (Figure S3). IGA 0/1 (OR = 19.64, 95% CI 14.47–26.64, p < 0.0001; I ² = 0%) compared with placebo (Figure S4).

Patient‐reported outcomes assessed using the Psoriasis Symptoms and Signs Diary also improved, including achievement of an overall PSSD symptom score of zero (OR = 12.07, 95% CI 6.31–23.12, p < 0.0001; I ² = 0%) (Figure S5) and a clinically meaningful improvement in pruritus (OR = 8.83, 95% CI 6.54–11.92, p < 0.0001; I ² = 0%) (Figure S6). Health‐related quality of life, measured by the Dermatology Life Quality Index, was similarly improved with icotrokinra compared with placebo (OR = 10.98, 95% CI 4.23–28.52, p < 0.0001; I ² = 28%) with minimal heterogeneity (Figure S7).

3.5. Safety Outcomes

Across the included RCTs, icotrokinra was not associated with statistically significant differences compared with placebo in the incidence of adverse events, including treatment discontinuation, overall adverse events, cancer‐related outcomes, gastrointestinal events, headache, infections, serious infections, nasopharyngitis, upper respiratory tract infections, or serious adverse events (Figures S8–S17).

3.6. Sensitivity Analysis

The leave‐one‐out sensitivity analysis showed that the effect sizes for the PSSD symptom score of zero were primarily influenced by the exclusion of ICONIC‐LEAD and ICONIC‐TOTAL (Figure S22), while all other secondary outcomes remained stable across iterations (Figures S18–S21, S23, and S24). For safety outcomes, the pooled effects were generally consistent, except for gastrointestinal adverse events after exclusion of FRONTIER 1 (Figure S28), adverse events leading to treatment discontinuation after omission of ICONIC‐LEAD and ICONIC‐ADVANCE 1, and the outcome of at least one adverse event after exclusion of ICONIC‐ADVANCE 1, each of which was associated with a reduction in heterogeneity (Figures S25 and S26). All remaining safety outcomes demonstrated stability in the sensitivity analyses (Figures S27 and S29–S34).

3.7. Publication Bias and Certainty of Evidence

Egger's test identified potential publication bias for adverse events leading to treatment discontinuation (p < 0.05) (Figure S42). In contrast, funnel plot analysis for all other outcomes showed symmetric distributions, and Egger's test results were not statistically significant (p > 0.05) (Figures S35–S41 and S43–S51).

The GRADE framework was applied to evaluate the certainty of evidence across all outcomes (Table S6). High‐certainty evidence was observed for PASI75, PASI90, PASI100, IGA 0/1, IGA 0, sPGA‐G 0/1, PSSD Symptom Score 0, PSSD itch CMI (≥ 4‐point reduction), and DLQI 0/1. Regarding safety, moderate‐certainty evidence was assigned to serious adverse events (SAEs), nasopharyngitis, upper respiratory tract infection, cancer, overall infection, serious infection, gastrointestinal adverse events, and headache. In contrast, low‐certainty evidence was assigned to the overall incidence of adverse events and adverse events leading to treatment discontinuation.

4. Discussion

This systematic review and meta‐analysis demonstrate that icotrokinra, a novel oral IL‐23 receptor peptide antagonist, is both effective and well‐tolerated in patients with moderate‐to‐severe plaque psoriasis. Clinically meaningful improvements were evident as early as Week 4, and by Week 16, patients receiving icotrokinra were more than 22‐fold more likely to achieve PASI 75 than those receiving placebo. Therapeutic benefits were consistent across key secondary endpoints, including complete skin clearance (PASI 100) and significant improvements in quality of life (DLQI) and symptom burden (PSSD). Importantly, the safety profile of icotrokinra was comparable to placebo, with no increase in overall adverse events, serious adverse events, treatment discontinuation, or infections.

Importantly, the efficacy observed in this meta‐analysis reflects a coherent progression from early phase development to confirmatory phase 3 evidence. The phase 2 FRONTIER 1 trial primarily served as a dose‐finding study, establishing biological activity and informing selection of the 200 mg once‐daily regimen. Subsequent phase 3 ICONIC trials were designed to confirm efficacy at this therapeutically optimized dose within larger, more diverse patient populations under rigorous regulatory standards. The consistency of response across phases strengthens confidence in the reproducibility of the short‐term treatment effect.

The robust efficacy of icotrokinra represents a significant advance in the therapeutic landscape of psoriasis. By Week 16, PASI 90 and PASI 100 responses were achieved in approximately 53% and 30% of patients, respectively, substantially narrowing the longstanding efficacy gap between oral systemic agents and injectable biologics. Notably, icotrokinra is the first oral therapy to demonstrate efficacy approaching that of IL‐23–targeting biologics, for which PASI 90 response rates of approximately 57% with guselkumab and 75% with risankizumab have been reported at Week 16 [30, 31]. Although even higher clearance rates are observed with IL‐17 inhibitors such as bimekizumab (PASI 90 ~85%) [32], icotrokinra's performance places it in a distinct category among oral treatments. In contrast to apremilast, which confers modest clinical benefit (~18%) [16], and deucravacitinib, which achieves PASI 90 responses in approximately 27% of patients at Week 16 [33, 34], icotrokinra combines high efficacy with the convenience of oral administration. Collectively, these findings position icotrokinra as a compelling option for patients who prefer oral therapy yet require substantial skin clearance, marking an important milestone in psoriasis management by offering biologic‐like efficacy without the need for injectable treatment.

However, the depth of response achievable with icotrokinra may be inherently constrained by its highly selective mechanism of action, as complete skin clearance (PASI 100) was attained in only approximately 30% of patients at Week 16. While IL‐23 receptor inhibition effectively attenuates Th17‐driven inflammation, it may not fully suppress all downstream or parallel inflammatory pathways implicated in psoriasis pathogenesis. Persistent activity of effector cytokines such as IL‐17F, IL‐22, and TNF‐α, along with contributions from innate immune signaling, may sustain residual keratinocyte activation and thereby limit complete lesion resolution in a subset of patients [1].

The safety profile of icotrokinra appears highly favorable and comparable to placebo. Across randomized controlled trials, our findings showed no statistically significant differences in overall adverse events, serious adverse events, or infections between icotrokinra and placebo. Common events, including nasopharyngitis, upper respiratory tract infections, and headache, occurred at similar frequencies in both groups, and no new safety signals were identified. This reassuring tolerability profile is particularly noteworthy for an oral therapy intended for long‐term management of psoriasis.

Compared with other oral agents, icotrokinra demonstrates a differentiated safety and tolerability profile. Apremilast is frequently associated with gastrointestinal adverse events, such as diarrhea and nausea, which can limit treatment adherence; in contrast, our findings indicate that icotrokinra was not associated with a significant increase in gastrointestinal adverse events relative to placebo [17]. Deucravacitinib, although more efficacious than apremilast, has been linked to higher rates of cutaneous adverse events, including acne and folliculitis, as well as laboratory abnormalities such as creatine phosphokinase elevation [34, 35]. In comparison, icotrokinra does not share these cutaneous or laboratory‐related safety concerns in the included RCTs, further supporting its favorable safety profile among available oral therapies.

Comparing icotrokinra to injectable biologic therapies also highlights its unique position. Biologics, including IL‐23 inhibitors (e.g., guselkumab, risankizumab) and IL‐17 inhibitors (e.g., ixekizumab, secukinumab), generally have favorable safety profiles but are associated with specific considerations. Injection site reactions (ISRs) are common with injectable biologics, although typically mild [36]. Icotrokinra, being an oral peptide, completely circumvents the need for injections and thus eliminates ISRs, which can be a significant factor for patients with needle aversion. While IL‐23 inhibitors have a low risk of serious infections, IL‐17 inhibitors carry a known risk of mucocutaneous candidiasis and, rarely, exacerbation of inflammatory bowel disease [37, 38]. Our safety analysis for icotrokinra, particularly its lack of increased infection rates compared to placebo, aligns well with the generally safe profile of IL‐23 pathway inhibition, without the specific risks associated with IL‐17 blockade or the inconvenience of injections.

The emergence of icotrokinra carries profound clinical implications. It introduces a new, highly effective oral treatment option that aligns with many patients' preferences for non‐injectable therapies [13, 14]. Its rapid onset of action and high clearance rates suggest it could become a valuable systemic therapy for patients with moderate‐to‐severe psoriasis, potentially challenging the current dominance of both newer oral agents and some injectable biologics. For dermatologists, icotrokinra offers a valuable tool for personalized treatment, providing biologic‐level efficacy in a convenient oral formulation. This could streamline treatment initiation and enhance adherence for a significant number of patients. The favorable safety profile, particularly the absence of significant gastrointestinal issues or infections, further augments its clinical utility.

This meta‐analysis possesses several strengths, including being the first to systematically evaluate the efficacy and safety of icotrokinra, thereby providing a comprehensive and up‐to‐date evidence synthesis. The inclusion of only high‐quality, low‐risk‐of‐bias RCTs and the application of trial sequential analysis bolster the validity of our findings. Assessing a broad spectrum of efficacy and safety outcomes provides a holistic perspective on the treatment's clinical value. Nevertheless, certain limitations must be acknowledged. The primary limitation is the short‐term follow‐up (up to 16 weeks) in the included trials, which precludes definitive conclusions regarding long‐term efficacy, safety, and durability of response. The analysis relied on pooled data, which may obscure subtle differences among individual patient populations. Finally, as with all new therapies, real‐world effectiveness and the identification of rare adverse events will necessitate longer‐term observational studies and post‐marketing surveillance.

5. Conclusion

Oral icotrokinra is a highly effective and well‐tolerated treatment for moderate‐to‐severe plaque psoriasis, demonstrating rapid and sustained therapeutic benefits. The significant improvements in PASI scores and quality‐of‐life outcomes, coupled with a safety profile comparable to placebo, highlight its potential as a valuable oral treatment option. Future studies should focus on longer‐term safety assessments and direct comparisons with other systemic treatments to fully establish its place in the management of plaque psoriasis.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

TABLE S1: Abstract PRISMA 2020 checklist.

TABLE S2: Main‐text PRISMA 2020 checklist.

TABLE S3: AMSTAR 2 checklist.

TABLE S4: Search strategy table.

TABLE S5: Outcomes definitions table.

TABLE S6: Summary findings table with GRADE assessment.

FIGURE S1: Traffic light plot.

FIGURE S2: Summary plot.

FIGURE S3: Investigator‐assessed global (IGA 0).

FIGURE S4: Investigator‐assessed global (IGA 0/1).

FIGURE S5: PSSD symptom score of zero.

FIGURE S6: PSSD CLM ≥ 4.

FIGURE S7: Dermatology Life Quality Index.

FIGURE S8: Adverse events leading to treatment.

FIGURE S9: At least 1 adverse event.

FIGURE S10: Cancer.

FIGURE S11: Gastrointestinal adverse events.

FIGURE S12: Headache.

FIGURE S13: Infection.

FIGURE S14: Nasopharyngitis.

FIGURE S15: Serious adverse events.

FIGURE S16: Serious infection.

FIGURE S17: Upper respiratory tract infection.

FIGURE S18: Leave‐one‐out sensitivity analysis for PASI 75.

FIGURE S18: Leave‐one‐out sensitivity analysis for PASI 90.

FIGURE S19: Leave‐one‐out sensitivity analysis for PASI 100.

FIGURE S20: Leave‐one‐out sensitivity analysis for IGA 0.

FIGURE S21: Leave‐one‐out sensitivity analysis for IGA 0/1.

FIGURE S22: Leave‐one‐out sensitivity analysis for PSSD of zero.

FIGURE S23: Leave‐one‐out sensitivity analysis for PSSD of itch.

FIGURE S24: Leave‐one‐out sensitivity analysis for DLQI.

FIGURE S25: Leave‐one‐out sensitivity analysis for adverse events leading to treatment discontinuation time.

FIGURE S26: Leave‐one‐out sensitivity analysis for at least one adverse event.

FIGURE S27: Leave‐one‐out sensitivity analysis for cancer.

FIGURE S28: Leave‐one‐out sensitivity analysis for gastrointestinal adverse events.

FIGURE S29: Leave‐one‐out sensitivity analysis for headache.

FIGURE S30: Leave‐one‐out sensitivity analysis for infection.

FIGURE S31: Leave‐one‐out sensitivity analysis for nasopharyngitis.

FIGURE S32: Leave‐one‐out sensitivity analysis for SAEs.

FIGURE S33: Leave‐one‐out sensitivity analysis for serious infection.

FIGURE S34: Leave‐one‐out sensitivity analysis for URTIs.

FIGURE S35: Contour‐enhanced funnel plot for PASI 75.

FIGURE S36: Contour‐enhanced funnel plot for PASI 90.

FIGURE S37: Contour‐enhanced funnel plot for PASI100.

FIGURE S38: Contour‐enhanced funnel plot for IGA 0.

FIGURE S39: Contour‐enhanced funnel plot for IGA 0/1.

FIGURE S40: Contour‐enhanced funnel plot for PSSD zero.

FIGURE S41: Contour‐enhanced funnel plot for PSSD itch.

FIGURE S42: Contour‐enhanced funnel plot for adverse events leading to treatment discontinuation.

FIGURE S43: Contour‐enhanced funnel plot for incidence of adverse events.

FIGURE S44: Contour‐enhanced funnel plot for cancer.

FIGURE S45: Contour‐enhanced funnel plot for gastrointestinal adverse events.

FIGURE S46: Contour‐enhanced funnel plot for headache.

FIGURE S47: Contour‐enhanced funnel plot for infection.

FIGURE S48: Contour‐enhanced funnel plot for nasopharyngitis.

FIGURE S49: Contour‐enhanced funnel plot for serious adverse events.

FIGURE S50: Contour‐enhanced funnel plot for serious infection.

FIGURE S51: Contour‐enhanced funnel plot for upper respiratory tract infections.

FIGURE S52: Power analysis for summary effect size.

IJD-65-1144-s001.docx^{(30.4MB, docx)}

Acknowledgments

The authors have nothing to report.

Declaration of generative AI and AI‐assisted technologies in the writing process: Figure 1 was generated with the assistance of an artificial intelligence–based image generation tool (Nano Banana). The authors subsequently reviewed, edited, and refined the figure to ensure scientific accuracy, an appropriate representation of biological mechanisms, and consistency with the manuscript. The final version of the figure reflects the authors' expert interpretation and responsibility. Also, during the preparation of this manuscript, the authors used ChatGPT solely to assist with sentence paraphrasing and language refinement. ChatGPT was not used for study design, data extraction, data analysis, interpretation of results, or generation of scientific content. All sections of the manuscript, including the Methods and Results, were written, reviewed, and verified by the authors, who take full responsibility for the accuracy, integrity, and originality of the work.

Data Availability Statement

All relevant data are contained within the manuscript and its Supporting Information files. The datasets used and analyzed in this study are available from the corresponding author upon reasonable request.

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