A Phase IIIb, Multicentre, Interventional, Randomised, Placebo-Controlled Clinical Trial Investigating the Efficacy and Safety of Guselkumab for the Treatment of Nonpustular Palmoplantar Psoriasis (G-PLUS)

of efective biologic therapies for psoriasis, there is no gold-standard treatment for nonpustular palmoplantar psoriasis (ppPsO). Methods . G-PLUS, a phase IIIb, double-blind, placebo-controlled, multicentre clinical trial, randomised adults with moderate-to-severe nonpustular ppPsO and limited plaque psoriasis (Psoriasis Area and Severity Index (PASI) ≥ 3 but < 10) to guselkumab (an interleukin-23p19 blocker) or placebo. Placebo participants were crossed over to receive guselkumab at week (Wk) 16. Te primary efcacy endpoint was the proportion of participants achieving palmoplantar PASI (ppPASI) 75 response at Wk16; clinical, biomarker, and quality-of-life endpoints were assessed through Wk48 and safety through Wk56. Results . At Wk16, ppPASI75 response was achieved by 35.9% of the guselkumab participants compared with 28.2% in the placebo group, resulting in a 7.7% diference in response rates (95% confdence interval: − 11.5 and 24.7), which was not statistically signifcant ( p � 0 . 533). More pronounced numerical improvements favouring guselkumab were observed for more stringent efcacy endpoints, such as Wk16 palmoplantar Investigator’s Global Assessment (ppIGA) 0/1 response (guselkumab 34.6% vs. placebo 15.4%). Trough Wk48, further improvements were observed in ppPASI75 response (55.1% and 64.1%) and ppIGA 0/1 response (42.3% and 48.7%) for the guselkumab and placebo-crossover groups, respectively. Dermatology Life Quality Index responses showed comparable trends at both timepoints. Safety and pharmacodynamic fndings were consistent with the established profle for guselkumab. Serum biomarker levels were signifcantly reduced with guselkumab and

Introduction.Despite the availability of efective biologic therapies for psoriasis, there is no gold-standard treatment for nonpustular palmoplantar psoriasis (ppPsO).Methods.G-PLUS, a phase IIIb, double-blind, placebo-controlled, multicentre clinical trial, randomised adults with moderate-to-severe nonpustular ppPsO and limited plaque psoriasis (Psoriasis Area and Severity Index (PASI) ≥3 but <10) to guselkumab (an interleukin-23p19 blocker) or placebo.Placebo participants were crossed over to receive guselkumab at week (Wk) 16.Te primary efcacy endpoint was the proportion of participants achieving palmoplantar PASI (ppPASI) 75 response at Wk16; clinical, biomarker, and quality-of-life endpoints were assessed through Wk48 and safety through Wk56.Results.At Wk16, ppPASI75 response was achieved by 35.9% of the guselkumab participants compared with 28.2% in the placebo group, resulting in a 7.7% diference in response rates (95% confdence interval: −11.5 and 24.7), which was not statistically signifcant (p � 0.533).More pronounced numerical improvements favouring guselkumab were observed for more stringent efcacy endpoints, such as Wk16 palmoplantar Investigator's Global Assessment (ppIGA) 0/1 response (guselkumab 34.6% vs. placebo 15.4%).Trough Wk48, further improvements were observed in ppPASI75 response (55.1% and 64.1%) and ppIGA 0/1 response (42.3% and 48.7%) for the guselkumab and placebo-crossover groups, respectively.Dermatology Life Quality Index responses showed comparable trends at both timepoints.Safety and pharmacodynamic fndings were consistent with the established profle for guselkumab.Serum biomarker levels were signifcantly reduced with guselkumab and
Furthermore, ppPsO may be underdiagnosed, undertreated, and challenging to manage [3].ppPsO and chronic hand eczema can be exacerbated by seasonal changes, activities of daily living, and environmental exposures, leading to misdiagnosis [1,4].Physical insults can exacerbate ppPsO (Koebnerisation), making it particularly difcult to treat [5,6].Given the limitations in patient-reported measures of disease severity, the impact of ppPsO remains underestimated [7,8]; however, the presence of ppPsO skin lesions and associated symptoms has been reported to considerably diminish patients' quality of life and work productivity [7,8].
Despite the availability of broad and efective biologic treatment options for the management of moderate-to-severe plaque psoriasis, no gold-standard therapy is currently recognised for ppPsO.First-line treatment consists of topical therapy such as potent or very potent corticosteroids and photo (chemo) therapy; because of the thickness of stratum corneum on the palms and soles, responses are often unsatisfactory, and the majority of patients eventually require systemic therapy [2,9,10].Tere is a lack of randomised controlled trials evaluating conventional and biologic systemic therapies for ppPsO [9,10].In particular, few clinical studies focussing on patients with nonpustular ppPsO have been conducted, and among these, outcomes have generally been disappointing [11].Trials have been challenging because of the phenotypic and underlying pathophysiological heterogeneity of pustular and nonpustular forms of ppPsO and because many patients with ppPsO do not meet typical clinical trial inclusion criteria, owing to low overall body surface area (BSA) involvement of psoriasis (e.g., BSA often <10%) [9].
Guselkumab, a fully human immunoglobulin G1 lambda monoclonal antibody that binds the p19 subunit of human interleukin (IL)-23, is approved for the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis [12,13].Te VOYAGE 1 and 2 studies demonstrated high levels of clinical response coupled with a highly favourable safety profle for guselkumab in patients with moderate-to-severe plaque psoriasis [14,15].Te efcacy profle observed in the guselkumab clinical trial programme has been further supported by subsequent real-world studies; recent retrospective studies have shown that guselkumab is efective in patients with moderate-to-severe plaque psoriasis, including in those who previously failed anti-IL-17 therapy [16] and over time through up to 3 years [17].Hand and foot Physician's Global Assessment (hf-PGA) outcomes were assessed in the phase III VOYAGE 1 and 2 clinical trials in patients with moderate-tosevere plaque psoriasis.At week (Wk) 16, 75.5% of the patients receiving guselkumab with hand/foot involvement achieved a hf-PGA 0/1 score (clear or almost clear) compared with 14.2% of the patients receiving placebo, and at Wk24, 80.4% of the patients receiving guselkumab achieved a hf-PGA 0/1 score compared with 60.3% of the patients receiving adalimumab [18].
However, patients with hand and foot involvement as a part of the phenotypic spectrum of their moderate-tosevere plaque psoriasis may not refect patients with ppPsO.To help address this gap, we conducted a phase IIIb clinical trial, G-PLUS, to investigate the efcacy and safety of guselkumab in participants with moderate-to-severe nonpustular ppPsO but limited overall plaque psoriasis burden (Psoriasis Area and Severity Index (PASI) ≥3 but <10 at the baseline).

Trial Design. G-PLUS (NCT03998683
) was a phase IIIb, 56-week, randomised, double-blind, placebo-controlled clinical trial evaluating the efcacy and safety of guselkumab for the treatment of nonpustular ppPsO.Te trial was conducted at 24 sites across fve Western European countries between 3 September 2019 and 30 November 2021.
An interactive web response system based on randomly permutated blocks was used for central randomisation (2 : 1, guselkumab : placebo).An overview of the trial design is presented in Figure 1.Guidance for virtual study visits and home administration of study medication was added in June 2020 in light of the COVID-19 pandemic.

Participants.
Participants (≥18 years of age) had moderate-to-severe nonpustular ppPsO (palmoplantar Investigator's Global Assessment (ppIGA) score ≥3) and limited overall skin involvement (PASI score ≥3 but <10) with at least one plaque at a body site other than the palms or soles present for ≥6 months.Participants must have been eligible to receive biological treatments; only participants who were naïve to biological treatments were included.Other inclusion criteria included reproductive status, tuberculosis (TB) status (no history of latent or active TB, no signs or symptoms of active TB, and no recent close contacts), laboratory screening parameters, and willingness to refrain from complementary therapies, including UV tanning, during the study.Participants were permitted to use topical emollients for psoriasis.Guidance on the study conducted during the COVID-19 pandemic was added to the Other efcacy endpoints included the proportions of participants achieving, over time, ppPASI90 and ppPASI100 responses, ppIGA response of 0 or 1 (0/1; defned as a ppIGA score of clear or minimal and a reduction of ≥2 points from the baseline), PASI75, PASI90, and PASI100 responses, and DLQI 0/1 score (among participants with the baseline DLQI score >1).Treatment-emergent adverse events (TEAEs) were assessed through Wk56.

Biomarker Analyses.
Serum samples were collected at Wks 0, 16, 24, and 48.Serum IL-17A, IL-17F, and IL-22 levels were measured using MilliporeSigma's single molecule counting (SMC) technology performed by PBL Assay Science (Piscataway, New Jersey).Healthy control (HC) samples were matched for age, sex, and race/ethnicity.Comparisons of baseline cytokine levels were performed using Welch's t-test.Associations between baseline cytokine levels and disease severity (based on ppPASI and PASI scores) were evaluated using the Pearson correlation coefcient.Pharmacodynamic parameters over time were assessed using mixed efect linear regression models, with baseline cytokine levels and body mass index (BMI) as covariates.Serum protein levels were considered elevated if >1.5-fold above those for HCs (with p < 0.05).

Statistical Analyses.
Te sample size calculation assumed a guselkumab ppPASI75 response rate ≥45% vs. ≤12.5% for the placebo group.Tese assumptions were based on a secondary analysis of palm and/or sole data in patients treated with guselkumab in two phase III trials and on results from three phase III trials in participants with palmoplantar involvement in patients with plaque psoriasis treated with ixekizumab [19].Based on these calculations, 64 guselkumab and 32 placebo participants were required to achieve ≥90% power based on Fisher's exact test at a two-sided signifcance level of 5% and a 2 :1 randomisation ratio.In a June 2020 protocol amendment, the planned sample size was increased from 105 to 114 participants to allow for 15% of the participants being nonevaluable and, therefore, compensate for protocol deviations related to the COVID-19 pandemic that could impact the primary endpoint.Tis corresponded to planned randomisation of approximately 76 participants to the guselkumab ), an open-label active treatment phase (weeks 16-48), with participants initially receiving placebo crossing over to receive guselkumab starting at week 16 and through week 48 (last dose of trial intervention was administered at week 44) and an additional 12-week safety follow-up period from week 48 through week 56.An interactive web response system based on randomly permutated blocks was used for central randomisation (2 : 1 guselkumab : placebo).Participants received guselkumab 100 mg at weeks 0, 4, and 12, and q8w thereafter through week 44 or placebo at weeks 0, 4, and 12, followed by guselkumab at weeks 16 and 20, and q8w thereafter through week 44 (referred to as the placebo-crossover group).To maintain blinding, matching placebo was used.PE, primary endpoint; q8w, every 8 weeks; R, randomisation; SE, secondary endpoint.
Dermatologic Terapy group and 38 participants to the placebo group.Ultimately, 78 participants were randomised to the guselkumab group and 39 to the placebo group.Database locks (DBLs) occurred at Wk16 and the end of the trial (Wk56).Blinding was maintained until after the Wk56 DBL.Te full analysis set included all randomised participants who received at least one dose of trial intervention, and data were analysed by the randomised treatment group.Te primary efcacy endpoint and eight major secondary efcacy endpoints were analysed using a composite estimand strategy.Handling of participants meeting any treatment failure criteria is described in Appendix A, Table S2.
Statistical comparisons between the guselkumab and placebo groups were performed through Wk16, with no adjustment for multiplicity for major secondary efcacy endpoints.Treatment comparisons were performed using Fisher's exact test with 95% confdence intervals (CIs).For continuous endpoints, a mixed model for repeated measures was used, as appropriate.All Wk24 and Wk48 efcacy endpoints were descriptively summarised by the treatment group without formal treatment comparisons.Binary response and continuous endpoints were analysed using multiple imputation for missing data and nonresponse imputation in cases of premature discontinuation from trial intervention.Safety assessments were based on the safety analysis set, according to trial intervention actually received.

Post Hoc Analyses.
Post hoc analyses were performed after the fnal DBL and included assessment of demographic and baseline disease characteristics for participants who met the primary efcacy endpoint (ppPASI75 responders at Wk16).In addition, selected efcacy endpoints (ppPASI75, ppIGA, and PASI75 responses) were evaluated by the baseline obesity status (obese vs. non-obese), and ppPASI scores were analysed separately for palms and soles to explore the differential impact of the components that contribute to the total score.Tese analyses were based on observed data, without imputation rules for missing data.

Participant Disposition.
Of 146 participants screened, 117 were randomised to receive either guselkumab (n = 78) or placebo (n = 39).All patients received at least one dose and were included in the full analysis set; 15.4% (n = 12) in the guselkumab group and 20.5% (n = 8) in the placebocrossover group discontinued study intervention prior to Wk56 (Figure 2 and Appendix B, Table S1).Demographic and baseline disease characteristics were relatively wellbalanced between treatment groups (Table 1); however, compared with the placebo group, the median age of guselkumab participants was higher (guselkumab vs. placebo: 55.0 vs. 52.0years) and a higher proportion of guselkumab participants was female (53.8% vs. 38.5%).Characteristics associated with difcult-to-treat disease were more common among participants in the guselkumab group vs. the placebo group, with a higher rate of obesity (41.6% vs. 33.3%)and longer duration of palm and sole involvement (median 5.0 vs. 4.0 years for both components) in the former.

Efcacy.
Outcomes for efcacy endpoints are shown in Table 2 (primary and major secondary efcacy endpoints at Wk16) and Table 3 (primary and other clinical and qualityof-life endpoints by visit through Wk48).For the primary endpoint, ppPASI75 response at Wk16 was achieved by 35.9% of the guselkumab participants compared with 28.2% in the placebo group, resulting in a 7.7% diference in response rates (95% CI: −11.5 and 24.7), which was not statistically significant (p � 0.533); therefore, the primary endpoint was not met (Table 2 and Figure 3).
More pronounced numerical improvements favouring guselkumab were seen for more stringent efcacy endpoints such as ppIGA 0/1 response at Wk16 (guselkumab 34.6% and placebo 15.4%; Figure 4) and ppPASI90 response at Wk16 (guselkumab 24.4% and placebo 15.4%; Table 3).Regarding broader skin outcomes, 14.1% vs. 5.1% of the participants in the guselkumab group vs. the placebo group, respectively, achieved a PASI90 response at Wk16 (Table 3 and Appendix C, Figure S1).Regarding the quality of life, a numerically greater proportion of participants in the guselkumab group reported a DLQI 0/1 score at Wk16 compared with the placebo group (19.2% vs. 7.7%, respectively; Table 3).

Post Hoc
Analyses.Demographic and baseline characteristics of ppPASI75 responders at Wk16 were analysed to further characterise their potential impact on treatment.A higher proportion of guselkumab responders than placebo responders were obese (32.1% vs. 9.1%), and guselkumab responders had longer duration of plaque psoriasis (median 10.0 vs. 7.0 years) and palmoplantar involvement (palms: median 8.0 vs. 4.0 years; soles: median 7.5 vs. 2.0 years) and higher baseline ppQLI scores (median 45.5 vs. 42.0)(Appendix D, Table S1).
Te improvements with guselkumab treatment appeared more pronounced in subgroup analyses limited to obese participants.At Wk16, 31.0%and 7.7% of the obese (BMI ≥30) participants randomised to guselkumab and placebo, respectively, achieved a ppPASI75 response.Similar observations were noted for ppIGA 0/1 and PASI90 responses (Appendix E, Figure S1).ppPASI palm and sole scores over time were evaluated independently to determine whether they contributed any diferential impact on the total score.Baseline median ppPASI scores were higher for the guselkumab group compared with the placebo group.Greater numerical improvements were observed for the guselkumab group compared with the placebo group at Wk16; similar scores were observed for the guselkumab and placebo-crossover groups at Wk48 (Appendix F, Table S1).Median S1).Serum IL-17F levels were not signifcantly elevated at the baseline for ppPsO participants compared with those for HCs (1.1-fold, p � 0.4) but were correlated with the baseline PASI score (r = 0.36; p < 1 × 10 −4 ).However, levels for none of the analytes correlated with the baseline ppPASI score (Appendix G, Figure S2).Baseline serum biomarker levels were comparable between ppPASI75 responders and nonresponders (Appendix G, Figure S3).Further analyses showed that serum IL-17A, IL-17F, and IL-22 levels were signifcantly decreased at Wk16 from the baseline in the guselkumab group but not in the placebo group (Figure 5).Te degree of reduction in IL-17F levels at Wk16 was signifcantly greater for the guselkumab group compared with that for the placebo group; however, reductions of serum IL-17A and IL-22 at Wk16 in the guselkumab group were larger than but not statistically diferent from the placebo group.From Wk16 through Wk48, IL-17A, IL-17F, and IL-22 levels in the guselkumab and placebo-crossover groups were signifcantly reduced compared with the baseline.

Discussion
G-PLUS is the frst clinical trial to evaluate biologic treatment in a cohort of participants with moderate-to-severe nonpustular ppPsO but limited psoriasis involving other body regions (PASI ≥3 and <10).Previous trials have either included pustular and nonpustular forms of ppPsO and/or patients with more extensive BSA involvement [20][21][22].Te strength of G-PLUS is that it focussed on individuals whose predominant disease feature was palm/sole involvement because such patients are typically under-represented in clinical trials, leading to limited available data [14,15,[20][21][22][23][24][25].Clearance of skin lesions is a goal for patients with psoriasis irrespective of disease location or severity [8].G-PLUS was, therefore, designed to study the impact of guselkumab treatment in this patient population with high unmet need and difcult-to-treat disease.
Guselkumab improved signs and symptoms of nonpustular ppPsO based on ppPASI75 response at Wk16.Although a numerically higher ppPASI75 response at Wk16 was observed for the guselkumab group compared with the placebo group, the diference in response rates was not statistically signifcant; therefore, the primary efcacy endpoint was not met.However, when assessing more stringent clinical endpoints, such as ppIGA 0/1, ppPASI90, and ppPASI100 responses at Wk16, greater numerical improvements were observed with guselkumab vs. placebo treatment.Improvements for the guselkumab group vs. the placebo group appeared further accentuated in post hoc subgroup analyses limited to participants who were obese at the baseline, a characteristic typically associated with more difcult-to-treat disease.

Double-blind phase (week 16) Placebo
Guselkumab 100 mg q8w EQ-5D-5L change from the baseline † ‡ § LS mean (95% CI) 0.128 (0.052, 0.203) 0.111 (0.057, 0.164) LS mean diference (95% CI) −0.017 (−0.109, 0.076) p value 0.718 † Te change from the baseline using observed data or 0 (no improvement) if a participant met treatment failure criteria prior to week 16.Participants with missing week 16 score are included with a score of "no improvement."‡ LS means and p values are based on a mixed model for repeated measures under the missing at random assumption for missing data except for missing week 16 data.§ 95% CIs were based on the Chan-Zhang method for binary response efcacy endpoints.Note.Under the composite estimand strategy, treatment efects are assessed not only based on the variable measurements but also on intercurrent events defned in treatment failure criteria.Te participant is assigned a score of no improvement for continuous variables if the participant meets any treatment failure criteria.ppPASI75 response is defned as ≥75% improvement in the ppPASI score from the baseline.In the calculation of ppPASI, the pustules score is considered 0 and the index has a maximum score of 48.aPASI, absolute Psoriasis Area and Severity Index; BSA, body surface area; CI, confdence interval; DLQI, Dermatology Life Quality Index; EQ-5D-5L, European Quality of Life, 5-Dimension, 5-Level; f-PGA, fngernail Physician's Global Assessment; LS, least squares; ppIGA, palmoplantar Investigator's Global Assessment; ppPASI, palmoplantar Psoriasis Area and Severity Index; ppQLI, palmoplantar Quality-of-Life Instrument; q8w, every 8 weeks.
Dermatologic Terapy an endpoint not reported in G-PLUS) vs. placebo at Wk16 and vs. adalimumab at Wk24 [18].Moreover, guselkumab has demonstrated efcacy for the treatment of palmoplantar pustulosis, leading to regulatory approval for this indication in several countries [30].Consequently, not meeting the primary endpoint in G-PLUS was unexpected.
A limitation of G-PLUS is that the trial was conducted during the COVID-19 pandemic.Most (≥80%) of the primary Figure 3: Proportion of participants achieving ppPASI75 response by visit through week 48 (full analysis set).Data missing due to discontinuation of treatment are imputed with nonresponse (0).Data missing due to reasons other than discontinuation of treatment are imputed using multiple imputation.Te ppPASI evaluates erythema, pustules, and desquamation on a 5-point scale (where 0 � absent and 4 � very severe) along with the extent to which the palms and/or soles are afected on a 6-point scale (where 0 � absent and 6 � 90-100%).In line with the inclusion criteria, the score for pustules was set at 0; thus, the index had a maximum score of 48.ppPASI75 response is defned as ≥75% improvement in the ppPASI score from the baseline.ppPASI, palmoplantar Psoriasis Area and Severity Index.Dermatologic Terapy endpoint assessments were conducted between April 2020 and March 2021, and the results may have been impacted by national lockdowns that took place in France, Germany, Italy, Spain, and the United Kingdom during this time [31][32][33][34][35]. Restricted movement outside the home and reduced capacity to work may have limited exposure to triggering factors and physical insults that often lead to Koebnerisation and exacerbation of palmoplantar disease [36].In addition, the use of topical emollients was permitted throughout the trial.Tese factors may have contributed [37] to the second key limitation, the higher-than-expected placebo response across all clinical endpoints, which was more than double the placebo response rates from earlier trials used for purposes of sample size calculation in G-PLUS.In the GESTURE trial for secukinumab in ppPsO, the Wk16 ppIGA 0/1 response rate for placebo was <5% [21], while in the VOYAGE 1 phase III trial for guselkumab in plaque psoriasis, the hf-PGA 0/1 placebo response rate at Wk16 was 14.2% [18].In contrast, in G-PLUS, the ppPASI75 placebo response rate at Wk16 was almost 30%.Tere was no equivalent variation in study biologic treatment response rates; for example, ppIGA 0/1 response was achieved by 33.3% of the participants receiving secukinumab in and 34.6% of the participants receiving guselkumab in G-PLUS.
It is also important to note that trials of other biologic agents for the treatment of ppPsO difer from G-PLUS in important ways.As mentioned above, other trials recruited a broader range of patients, including those with pustular or nonpustular palmoplantar disease and more generalised involvement of plaque psoriasis elsewhere on the body.In addition, diferent primary efcacy endpoints were used in other trials.Te primary efcacy endpoint of the GESTURE trial was the proportion of patients achieving ppIGA 0/1 response at Wk16, while in an open-label trial of adalimumab, change in the Physician's Global Assessment score from the baseline to Wk12 was used [20,21].In contrast, the primary efcacy endpoint in the G-PLUS trial was the proportion of ppPASI75 responders at Wk16.Although PASI-based outcomes generally provide robust assessments of response to treatment, they can be insensitive to changes in the context of relatively limited extent of disease, as is the case with palmoplantar disease [38].
Disease-and patient-specifc factors may have also limited the separation of response rates for the guselkumab and placebo groups.In the context of ppPsO, which is widely considered to be a difcult-to-treat variant of psoriatic disease, a Wk16 endpoint may be too short to fully assess treatment response [4].Consistent with this, continued improvements were observed beyond Wk16 in the guselkumab group, with a potential response plateau not being reached until Wk28.Furthermore, in patients with ppPsO who have limited psoriasis elsewhere on the body, palmoplantar disease represents a disproportionately high proportion of overall BSA involvement that may be particularly recalcitrant to treatment [2].Tese factors likely account for why overall PASI skin responses in G-PLUS were substantially lower than those observed in previous guselkumab trials in moderate-tosevere plaque psoriasis and were lower than the rate assumed in our sample size calculations.Tese factors should be taken into consideration in the design of future trials in this patient population.
In addition, participants in the guselkumab group had more features at the baseline associated with challenging-totreat disease compared with those randomised to placebo.In particular, the guselkumab group had a higher proportion of obese participants, and participants randomised to guselkumab had longer disease duration and more severe palm and/or sole involvement.Despite this, numerically greater reductions of median ppPASI palm and sole scores were observed in the guselkumab group compared with the placebo group at Wk16;   Dermatologic Terapy moreover, comparable levels of improvement were seen for the guselkumab and placebo-crossover groups at Wk48.Taken together, these observations suggest an overall positive impact of guselkumab treatment on nonpustular ppPsO.Reductions in serum biomarker levels also trended with improvements in nonpustular ppPsO.Serum IL-17A and IL-22 levels were found to be elevated in participants with ppPsO compared with HCs, and consistent with fndings from the VOYAGE 1 trial in patients with moderate-tosevere plaque psoriasis, treatment with guselkumab led to reductions in serum IL-17A, IL-17F, and IL-22 levels at Wk16 and Wk48 compared with the baseline [39].Placebocrossover participants also had signifcantly decreased levels of these cytokines at Wk48 compared with the baseline, consistent with the on-target pharmacodynamic efects of guselkumab.In addition to the intriguing and unexpected fnding that baseline biomarker levels did not correlate with ppPsO severity based on ppPASI scores, it is notable that the magnitude of cytokine reductions was lower than in moderate-to-severe plaque psoriasis in VOYAGE 1 [39].Tis may potentially refect the overall lower burden of generalised plaque psoriasis in the G-PLUS trial population or the more recalcitrant nature of palmoplantar disease.Te biomarker results of G-PLUS add to the fndings of a recent study that identifed distinct patterns of infammatory activation in participants with pustular and nonpustular ppPsO [40]; in particular, in nonpustular ppPsO, IL-17A signalling may be less relevant and interferon-c may be relatively more important, a profle that could have contributed to the lower-than-anticipated treatment beneft with guselkumab.

Conclusion
G-PLUS is the frst clinical trial to evaluate biologic treatment of nonpustular ppPsO in individuals with limited involvement of plaque psoriasis elsewhere on the body.Although the primary efcacy endpoint was not met, given the unanticipated high placebo response, more stringent clinical endpoints showed greater numerical improvements favouring guselkumab at Wk16.Similar observations were noted for participants with characteristics associated with more challenging-to-treat disease, such as obesity.Further studies are warranted to better understand the impact of guselkumab treatment in patients with ppPsO.

Figure 1 :
Figure1: G-PLUS trial design.Te trial comprised a placebo-controlled, double-blind period (weeks 0-16), an open-label active treatment phase (weeks 16-48), with participants initially receiving placebo crossing over to receive guselkumab starting at week 16 and through week 48 (last dose of trial intervention was administered at week 44) and an additional 12-week safety follow-up period from week 48 through week 56.An interactive web response system based on randomly permutated blocks was used for central randomisation (2 : 1 guselkumab : placebo).Participants received guselkumab 100 mg at weeks 0, 4, and 12, and q8w thereafter through week 44 or placebo at weeks 0, 4, and 12, followed by guselkumab at weeks 16 and 20, and q8w thereafter through week 44 (referred to as the placebo-crossover group).To maintain blinding, matching placebo was used.PE, primary endpoint; q8w, every 8 weeks; R, randomisation; SE, secondary endpoint.

Figure 2 :
Figure 2: G-PLUS participant disposition.† Participants randomised to placebo at the baseline received placebo at weeks 0-16 and then crossed over to guselkumab from week 16 to trial end.All discontinuations occurred after the week 16 visit.

Figure 4 :
Figure 4: Proportion of participants achieving a ppIGA response by visit through week 48 (full analysis set).Data missing due to discontinuation of treatment are imputed with nonresponse (0).Data missing due to reasons other than discontinuation of treatment are imputed using multiple imputation.Te ppIGA scale score is based on the version of the IGA modifed in 2011.ppIGA response is defned as a ppIGA score of 0 (clear) or 1 (almost clear/minimal) and a ≥2-point reduction from the baseline in the ppIGA score.IGA, Investigator's Global Assessment; ppIGA, palmoplantar Investigator's Global Assessment.
Subjects were counted once only for any given event, regardless of the number of times they experienced the event.AEs are coded using Medical Dictionary for Regulatory Activities Version 21.1 for AEs through week 16 and 24.1 for AEs through week 56.† For placebo-randomised subjects, only those AEs with start date at or after crossover guselkumab (i.e., week 16) are included in this column.AE, adverse event; q8w, every 8 weeks; SAE, serious adverse event.

Table 1 :
Demographic and baseline disease characteristics (full analysis set).

Table 2 :
Primary efcacy endpoint and major secondary efcacy endpoints during double-blind phase (week 16) based on the composite estimand strategy (full analysis set).

Table 4 .
. Safety fndings were consistent with other guselkumab psoriasis trials, with no new safety signals or adverse events of special interest identifed.An overall summary of TEAEs through Wk16 and Wk56 is presented in Trough Wk56, TEAEs were reported by 87.2% (n = 68) of the guselkumab participants and 56.4% (n = 22) of the placebo-crossover participants.Tere were no deaths or cases of anaphylactic reaction/serum sickness, malignancy, infammatory bowel disease, or active TB.

Table 4 :
Treatment-emergent adverse events through week 16 and week 56.