Efficacy and safety of tirbanibulin 1% ointment in actinic keratoses: Data from two phase-III trials and the real-life clinical practice presented at the European Academy of Dermatology and Venereology Congress 2022.

BACKGROUND: The 31st European Academy of Dermatology and Venereology (EADV) Congress took place between 7th and 10th of September 2022 in Milan, Italy. OBJECTIVES: We report presented clinical data on the efficacy/effectiveness, safety and tolerability of tirbanibulin 1% ointment that has recently been licensed for actinic keratosis (AK) of the face or scalp in adults. METHODS: Summary of presentations given at the EADV Congress. RESULTS: Prof. Pellacani presented two post hoc analyses from two phase-III trials with AK patients (NCT03285477 [N = 351] and NCT03285490 [N = 351]): A descriptive analysis of medical history, concomitant medications, and safety results confirming a favourable profile for tirbanibulin showing that number of baseline AK lesions was not correlated to severity of local skin reactions. The latter analysis showed that cases of tirbanibulin application site pain or pruritus were few, and most were found to be mild. Prof. Kunstfeld reported six real-life clinical cases in Austria showing good tirbanibulin effectiveness, safety and tolerability for the treatment of new or recurring AK lesions. Results demonstrated that after 2- to 4-month follow-up, tirbanibulin was well tolerated and effective in AK patients. Presentations by Dr. Patel confirmed good outcomes and tolerability of tirbanibulin in Olsen grade 1-2 AK (N = 12) and porokeratosis patients (N = 4) treated once daily for 5 consecutive days in the United Kingdom. Furthermore, real-world experience in solid organ transplant recipients (N = 2) demonstrated effectiveness of tirbanibulin in skin field cancerization treatment. A symposium sponsored by Almirall was conducted during the congress in which Dr. Hadshiew and Dr. Lear brought together their clinical experience in Germany and the United Kingdom respectively. Interesting clinical cases of 5 consecutive days of tirbanibulin treatment compared to other treatments were discussed with attendees, as well as current treatment needs of AK patients. CONCLUSIONS: This article provides an overview of presentations and symposium discussions, summarizing key phase-III results and real-life clinical experience with tirbanibulin shared by dermatologists across Europe.

Tildrakizumab efficacy and safety in patients with psoriasis and concomitant metabolic syndrome: post hoc analysis of 5-year data from reSURFACE 1 and reSURFACE 2.

BACKGROUND: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity. OBJECTIVES: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS. METHODS: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs). RESULTS: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS. CONCLUSIONS: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status.

Psoriasis and metabolic syndrome: implications for the management and treatment of psoriasis.

Psoriasis is a chronic systemic inflammatory disorder associated with several comorbidities in addition to the characteristic skin lesions. Metabolic syndrome (MetS) is the most frequent comorbidity in psoriasis and a risk factor for cardiovascular disease, a major cause of death among patients with psoriasis. Although the exact causal relationship between these two disorders is not fully established, the underlying pathophysiology linking psoriasis and MetS seems to involve overlapping genetic predispositions and inflammatory pathways. Dysregulation of the IL-23/Th-17 immune signalling pathway is central to both pathologies and may be key to promoting susceptibility to metabolic and cardiovascular diseases in individuals with and without psoriasis. Thus, biological treatments for psoriasis that interrupt these signals could both reduce the psoriatic inflammatory burden and also lessen the risk of developing atherosclerosis and cardiometabolic diseases. In support of this hypothesis, improvement of skin lesions was associated with improvement in vascular inflammation in recent imaging studies, demonstrating that the beneficial effect of biological agents goes beyond the skin and could help to prevent cardiovascular disease. This review will summarize current knowledge on underlying inflammatory mechanisms shared between psoriasis and MetS and discuss the most recent clinical evidence for the potential for psoriasis treatment to reduce cardiovascular risk.

Long-term safety of risankizumab from 17 clinical trials in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Risankizumab has demonstrated efficacy and safety in patients with moderate-to-severe plaque psoriasis in randomized clinical trials. OBJECTIVES: To evaluate safety data from risankizumab psoriasis phase I-III clinical trials. METHODS: Short-term safety (through week 16) was analysed using integrated data from five phase II and III clinical trials. Long-term safety was evaluated using integrated data from 17 phase I-III completed and ongoing trials. RESULTS: Short-term safety analyses included 1306 patients receiving risankizumab 150 mg and 300 patients receiving placebo [402·2 and 92·0 patient-years (PY) of exposure, respectively]. Long-term analyses included 3072 risankizumab-treated patients (exposure: 7927 PY). The median (excluding four outliers) treatment duration was 2·9 years (range 2 days to 5·9 years). Exposure-adjusted adverse event rates did not increase with long-term treatment (318 vs. 171 events per 100 PY for short- and long-term analyses). With long-term risankizumab treatment, rates of serious adverse events were 7·8 per 100 PY, serious infections 1·2 per 100 PY, nonmelanoma skin cancer (NMSC) 0·7 per 100 PY, malignant tumours excluding NMSC 0·5 per 100 PY, and adjudicated major adverse cardiovascular events 0·3 per 100 PY, with no important identified risks. Limitations include that the study inclusion and exclusion criteria varied and that three studies enrolled ≤ 50 patients. CONCLUSIONS: Risankizumab demonstrated a favourable safety profile over short- and long-term treatment in patients with moderate-to-severe psoriasis.

Effect of baseline disease severity on achievement of treatment target with apremilast: results from a pooled analysis.

BACKGROUND: Treating to absolute treatment targets rather than relative measures such as Psoriasis Area and Severity Index (PASI)-75 is emerging as an important clinical concept included in psoriasis guidelines and clinical practice. Achieving treatment targets is associated with achievement of long-term outcomes. OBJECTIVE: To evaluate the relationship between psoriasis severity, disease characteristics and achievement of PASI ≤2 with apremilast in a pooled analysis of the phase 3 ESTEEM 1 and 2 (NCT01194219 and NCT01232283), phase 3b LIBERATE (NCT01690299) and phase 4 UNVEIL (NCT02425826) clinical trials. METHODS: Pooled data from patients with moderate-to-severe plaque psoriasis randomized to apremilast 30 mg BID were analysed by baseline PASI quartiles (Q1: 2.4-13.1; Q2: 13.2-15.9; Q3: 16.0-20.0; Q4: 20.1-57.8). Assessments included PASI, Dermatology Life Quality Index (DLQI), Scalp Physician's Global Assessment (ScPGA; ScPGA ≥1) and target (worst) Nail Psoriasis Severity Index (NAPSI; NAPSI ≥1). RESULTS: Of 1062 patients, 963 had ScPGA ≥1 and 643 had NAPSI ≥1; 771 patients with baseline and Week 32 PASI assessments were included in analyses of Week 32 PASI target achievement. Rates of PASI ≤2 at Week 32 were greater in lower PASI quartiles (Q1: 43.5%; Q2: 31.2%; Q3: 26.8%; Q4: 18.4%). Most patients achieving PASI ≤2 target (83.6%) achieved DLQI ≤5 at Week 32; 59.3% of patients who did not achieve PASI ≤2 target achieved DLQI ≤5. At Week 32, mean improvements in ScPGA and NAPSI were similar with more moderate vs. more severe disease (ScPGA, range: 1.1-1.4; NAPSI, range: 1.6-2.5). In a subgroup analysis, achievement of PASI ≤2 target was higher in the lowest PASI quartile and with disease duration <5 years. CONCLUSIONS: Greater achievement of PASI ≤2 was observed in patients with more moderate vs. more severe skin disease. Apremilast may be particularly beneficial in more moderate disease early in the treatment paradigm.

Long-term efficacy and safety of risankizumab for the treatment of moderate-to-severe plaque psoriasis: interim analysis of the LIMMitless open-label extension trial beyond 3 years of follow-up.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease requiring prolonged treatment. New biologic therapies require long-term evaluation to assess the durability of their efficacy and safety profiles over time. OBJECTIVES: To evaluate the long-term efficacy and safety of risankizumab (RZB) for the treatment of psoriasis. METHODS: LIMMitless is an ongoing, phase III, open-label extension study evaluating the long-term efficacy and safety of RZB in adults with moderate-to-severe plaque psoriasis following multiple phase II/III studies. This analysis assessed efficacy through 172 weeks of continuous RZB treatment by examining the proportion of patients achieving ≥ 90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90 and PASI 100), static Physician's Global Assessment of clear or almost clear (sPGA 0/1) and Dermatology Life Quality Index of no effect on quality of life (DLQI 0/1). Safety was assessed by recording adverse events (AEs) through the data cutoff date. The study is registered at ClinicalTrials.gov (identifier: NCT03047395). RESULTS: Of 955 patients randomized to RZB 150 mg in the base studies, 897 patients continued into LIMMitless; 799 patients were still receiving treatment in LIMMitless at the time of data cutoff for this analysis. After 172 weeks of continuous RZB treatment, 85·5% of patients achieved PASI 90, 54·4% achieved PASI 100, 85·2% achieved sPGA 0/1, and 78·4% achieved DLQI 0/1 using modified nonresponder imputation. Rates of AEs leading to discontinuation and AEs of safety interest were low with long-term treatment and comparable with those identified in the base studies. CONCLUSIONS: Overall, long-term continuous RZB was well tolerated and showed high and durable efficacy over 172 weeks.

Three-year efficacy and safety of certolizumab pegol for the treatment of plaque psoriasis: results from the randomized phase 3 CIMPACT trial.

BACKGROUND: Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-tumor necrosis factor biologic. OBJECTIVES: To report 3-year outcomes from the CIMPACT (NCT02346240) phase 3, CZP in moderate to severe plaque psoriasis, randomized controlled trial. METHODS: Adults were randomized 3:3:3:1 to CZP 200 mg every other week (Q2W), CZP 400 mg Q2W, etanercept biweekly or placebo. At Week 16, CZP- and etanercept-treated PASI 75 responders were re-randomized to CZP 200 mg Q2W, CZP 400 mg Q4W, CZP 400 mg Q2W or placebo for maintenance treatment; PASI 75 non-responders entered an open-label escape CZP 400 mg Q2W arm. Patients entering the open-label extension (OLE; Weeks 48-144) from blinded treatment received CZP 200 mg Q2W. RESULTS: Double-blinded results have been reported previously. 261 patients received 200 mg Q2W upon OLE entry. PASI 75 response was maintained in patients continuing 200 mg Q2W treatment through Weeks 16-144 (Week 144: 96.2%). In patients dosed down at Week 48 (double-blinded 400 mg to 200 mg Q2W), PASI 75 decreased (Week 48: 98.7%; Week 144: 85.9%). In patients who received placebo through Weeks 16-48, PASI 75 response decreased (Week 48: 60.4%), then increased following Week 48 switch to 200 mg Q2W (Week 144: 95.1%). 48 and 36 patients initially randomized to 200 and 400 mg Q2W, respectively, were Week 16 PASI 75 non-responders and entered the escape arm; at Week 144, 71.8% and 78.2% achieved PASI 75. No new safety signals were identified. CONCLUSIONS: Response to CZP was durable over three years; no new safety signals were identified.

The risk of malignancy in patients with secukinumab-treated psoriasis, psoriatic arthritis and ankylosing spondylitis: analysis of clinical trial and postmarketing surveillance data with up to five years of follow-up.

BACKGROUND: Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. OBJECTIVES: To assess the malignancy risk in patients with secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). METHODS: This integrated safety analysis from both the secukinumab clinical trial programme and postmarketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of 5 years of follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates [EAIR; incidence rates per 100 patient treatment-years (PTY)]. Standardized incidence ratios (SIRs) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. Crude incidence of malignancy was also reported using postmarketing surveillance data. RESULTS: Safety data from 49 clinical trials with secukinumab-treated patients were included: 10 685 patients with psoriasis, 2523 with PsA and 1311 with AS. Across indications over a 5-year period, the EAIR of malignancy was 0·85 per 100 PTY [95% confidence interval (CI) 0·74-0·98] in secukinumab-treated patients, corresponding to 204 patients per 23 908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by an SIR of 0·99 (95% CI 0·82-1·19) across indications. The estimated crude cumulative incidence reporting rate per 100 PTY for malignancy was 0·27 in the postmarketing surveillance data across indications with a cumulative exposure of 285 811 PTY. CONCLUSIONS: In this large safety analysis, the risk of malignancy was low for up to 5 years of secukinumab treatment. These data support the long-term use of secukinumab in these indications.

Addressing challenges associated with long-term topical treatment and benefits of proactive management in patients with psoriasis.

The majority of patients with psoriasis vulgaris (chronic plaque psoriasis) can be treated successfully with short-term topical therapies. However, long-term management of psoriasis with topicals is challenging and tends to take a reactive approach to disease relapse, rather than a proactive approach aimed at maintaining disease remission. Patients are often dissatisfied with the delay in treatment response and inconvenience of applying topical treatments, and therefore frequently discontinue treatment leading to poor outcomes. Relapse is common, particularly with reactive management, as underlying residual disease can remain following initial skin clearance; some patients find that their disease at relapse may be worse than their initial symptoms. This can have a detrimental effect on patient quality of life (QoL) and increase the risk of psoriasis-associated depression. A long-term proactive management approach, with maintenance treatment following initial treatment success, could help sustain disease remission and improve clinical and QoL outcomes for patients. Treatment with fixed-dose calcipotriol 50 µg/g betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) is effective in the short term, providing a fast onset of action and improvements in disease at 4 weeks. Results from the Phase III PSO-LONG study demonstrated that long-term proactive management was superior to reactive management in prolonging time to first relapse, reducing number of relapses and increasing days in remission in adults with psoriasis vulgaris. Furthermore, Cal/BD foam was well tolerated in PSO-LONG. No new safety concerns were identified over 52 weeks; the safety profile was consistent with that described previously. Given this, Cal/BD foam should be considered when prescribing topicals for the long-term proactive management for patients with psoriasis.

Long-term safety and efficacy of a fixed-combination halobetasol propionate 0.01%/tazarotene 0.045% lotion in moderate-to-severe plaque psoriasis: phase 3 open-label study.

BACKGROUND: The topical corticosteroid halobetasol propionate (HP) and the retinoid tazarotene (TAZ) are effective in psoriasis treatment. To mitigate adverse cutaneous reactions observed with monotherapy, a fixed- combination HP 0.01%/TAZ 0.045% lotion has been developed for the treatment of plaque psoriasis in adults. OBJECTIVES: To investigate the long-term safety, efficacy and maintenance of response with HP/TAZ lotion. METHODS: This was a 1-year, multicentre, open-label study in 555 adults with psoriasis [Investigator's Global Assessment (IGA) score of 3 ('moderate') or 4 ('severe') and body surface area (BSA) of 3-12% at baseline]. HP/TAZ was administered once daily for 8 weeks and then intermittently as needed in 4-week intervals for up to 1 year based on achievement of treatment success [IGA score of 0 ('clear') or 1 ('almost clear')]. Maximum continuous exposure was 24 weeks. RESULTS: Of 550 participants with postbaseline safety data, 318 (57.8%) achieved treatment success during the study. Of those, 54.4% achieved treatment success within the first 8 weeks; retreatment was not required for >4 weeks in over half (55.3%), and 6.6% did not require any retreatment. Among participants enrolled for the full 52 weeks, 77.5% maintained BSA ≤5% on treatment. There were marked improvements in severity of itching, dryness and burning/stinging over the study course. The most common treatment-related adverse events were application site reactions of dermatitis, pruritus, pain and irritation. CONCLUSIONS: Fixed-combination HP/TAZ lotion provided maintained efficacy with a favourable tolerability and safety profile, supporting its use for the long-term treatment and management of moderate-to-severe plaque psoriasis.

Long-term safety of certolizumab pegol in plaque psoriasis: pooled analysis over 3 years from three phase III, randomized, placebo-controlled studies.

BACKGROUND: Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-tumour necrosis factor biologic. OBJECTIVES: To report 3-year safety data from three phase III trials of CZP in adults with plaque psoriasis. METHODS: Data were pooled from CIMPASI-1 (NCT02326298), CIMPASI-2 (NCT02326272) and CIMPACT (NCT02346240). Included patients had moderate-to-severe plaque psoriasis of ≥ 6 months' duration; had been randomized to CZP 200 mg every 2 weeks (Q2W) (400 mg at weeks 0, 2 and 4) or CZP 400 mg Q2W; and had received at least one dose of CZP with up to 144 weeks of exposure. Treatment-emergent adverse events (TEAEs) were classified using MedDRA v18·1. Reported incidence rates (IRs) are incidence of new cases per 100 patient-years (PY). RESULTS: Over 144 weeks, 995 patients received at least one dose of CZP (exposure: 2231·3 PY); 731 and 728 received at least one dose of CZP 200 mg Q2W (1211·4 PY) and/or 400 mg Q2W (1019·9 PY), respectively. The IR [95% confidence interval (CI)] of TEAEs was 144·9 (135·3-155·0) for all patients, 134·1 (123·2-145·7) for CZP 200 mg Q2W and 158·3 (145·5-171·9) for CZP 400 mg Q2W. The IR (95% CI) of serious TEAEs for all patients was 7·5 (6·4-8·8); the IRs were 6·7 (5·2-8·3) and 8·7 (6·9-10·8) for CZP 200 mg and 400 mg Q2W, respectively. Overall, 3·2% of patients reported serious infections (2·2% within each of the CZP 200 and 400 mg Q2W groups). Overall, there was one case of active tuberculosis, 16 malignancies in 14 patients and seven deaths (two considered treatment-related). The cumulative IR of TEAEs did not increase over time. CONCLUSIONS: No new safety signals were identified compared with previously reported data. Risk did not increase with longer or higher CZP exposure.

Secukinumab maintains superiority over ustekinumab in clearing skin and improving quality of life in patients with moderate to severe plaque psoriasis: 52-week results from a double-blind phase 3b trial (CLARITY).

BACKGROUND: Secukinumab demonstrated superior efficacy over ustekinumab in the treatment of moderate to severe plaque psoriasis over 16 weeks in the CLARITY study and over 52 weeks in the CLEAR study. OBJECTIVE: To compare the efficacy and safety of secukinumab vs. ustekinumab over 52 weeks in CLARITY. METHODS: Analysis of 52-week data from CLARITY (NCT02826603), a phase 3b study in which patients were randomized to receive secukinumab 300 mg (n = 550) or ustekinumab 45/90 mg (n = 552) per label. RESULTS: At week 52, secukinumab was superior to ustekinumab in the proportion of patients who achieved ≥ 90% improvement in Psoriasis Area and Severity Index (73.2% vs. 59.8%; odds ratio [OR], 1.84 [95% CI, 1.41-2.41]; P < 0.0001), Investigator's Global Assessment modified 2011 responses of clear (0) or almost clear (1) skin (76.0% vs. 60.2%; OR, 2.12 [95% CI, 1.61-2.79]; P < 0.0001) and Dermatology Life Quality Index response of no effect (0/1) (69.9% vs. 61.2%; P = 0.0028). Proportions of patients with any adverse events were comparable between treatment arms. CONCLUSIONS: This second head-to-head study confirmed the superior efficacy of secukinumab over ustekinumab in skin clearance and quality of life through 52 weeks, with safety comparable to that reported in previous trials. Clinicaltrials.gov identifier: NCT02826603.

Time to relapse after tildrakizumab withdrawal in patients with moderate-to-severe psoriasis who were responders at week 28: post hoc analysis through 64 weeks from reSURFACE 1 trial.

BACKGROUND: As treatment interruptions occur during psoriasis management in clinical practice, it is important to know the duration of clinical response after treatment withdrawal. OBJECTIVES: To report time to and predictors of relapse in patients who were tildrakizumab 100 and 200 mg responders (≥75% improvement in Psoriasis Area and Severity Index, PASI 75) at week 28 re-randomized to placebo from reSURFACE 1 trial. METHODS: Post hoc analysis of adult patients with moderate-to-severe plaque psoriasis from a 64-week phase 3 trial. Relapse was primarily defined as loss of PASI 75 response. Both relapses defined as loss of PASI 90 and loss of absolute PASI < 2 response were included as sensitivity analyses. PASI 75, PASI 90 and PASI < 2 responders re-randomized to placebo at week 28 and followed up until week 64 were included. The Kaplan-Meier (KM) estimates of the 64-week relapse rate were calculated. The log-rank test to compare KM curves from responders to tildrakizumab 100 and 200 mg was used. Independent predictors of relapse were explored. RESULTS: Median time to loss of PASI 75/PASI 90/PASI < 2 response from week 28 was 142/111/112 days with tildrakizumab 100 mg and 172/140/113 days with tildrakizumab 200 mg, respectively (all not significant). Around 20% of patients did not relapse (either maintained a PASI 75 response or were lost to follow-up) during the 36-week period. Increase in body mass index (BMI) (hazard ratio, HR [95% confidence interval, CI] for loss of PASI 75 response: 1.0345 [1.0112-1.0582]) and increase in disease duration (HR [95% CI]: 1.0151 [1.0028-1.0275] for loss of PASI 75 response) were associated with an increased risk of relapse, regardless of the relapse definition. CONCLUSIONS: When treatment is interrupted, tildrakizumab provides durable maintenance of efficacy with a median time to loss of PASI 75 response of 5-6 months, irrespective of the dose. Interventions on modifiable risk factors for relapse, such as BMI, may improve personalized long-term psoriasis management.

Safety in moderate-to-severe plaque psoriasis patients with latent tuberculosis treated with guselkumab and anti-tuberculosis treatments concomitantly: results from pooled phase 3 VOYAGE 1 & VOYAGE 2 trials.

BACKGROUND: Patients treated with tumour necrosis factor (TNF) inhibitors are at risk of new-onset tuberculosis (TB) or reactivation of latent tuberculosis infection (LTBI). Association between TB/LTBI and interleukin (IL)-23 inhibitors for psoriasis is unclear. Patients with LTBI typically initiate LTBI therapy before receiving biologics. OBJECTIVES: Safety in moderate-to-severe psoriasis patients with LTBI treated with guselkumab (IL-23 inhibitor) and LTBI treatment was evaluated. METHODS: In the VOYAGE 1 & VOYAGE 2 studies, patients screened for LTBI were randomized to guselkumab, placebo, or adalimumab (TNF inhibitor) at baseline. Placebo â†’ guselkumab crossover occurred at week 16 and adalimumab â†’ guselkumab at week 52 (VOYAGE 1), or at week 28 or later (VOYAGE 2). Incidence of active TB, adverse events (AEs), serious AEs (SAEs), and markedly abnormal liver function tests [alanine aminotransferase test (ALT); aspartate aminotransferase test (AST)] were evaluated using pooled data through week 100 in guselkumab-treated patients receiving and not receiving LTBI treatment. RESULTS: At baseline, 130 randomized patients (guselkumab: n = 69; adalimumab: n = 36; placebo: n = 25) tested positive for LTBI and received concomitant LTBI treatments (LTBI+). No active TB was reported among guselkumab-treated patients without LTBI (LTBI-) through week 100. Two cases of active TB occurred in LTBI- patients treated with adalimumab. Through week 16, across all treatment groups, greater proportions of LTBI+ patients reported ALT and AST elevations compared with LTBI- patients. Through week 100, proportions of patients experiencing AEs and SAEs were comparable between LTBI+ and LTBI- patients. CONCLUSIONS: No cases of active TB, including reactivation of LTBI, were reported in patients with or without LTBI treated with guselkumab through up to 2 years. LTBI treatment was effective across all treatment groups in preventing reactivation of LTBI. Long-term treatment with guselkumab was generally well-tolerated through up to 2 years in patients receiving LTBI medications.

Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks.

BACKGROUND: Tildrakizumab is a specific anti-interleukin-23p19 monoclonal antibody approved for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy and safety of tildrakizumab treatment for patients with moderate-to-severe psoriasis for up to 148 weeks. METHODS: Pooled analysis from two double-blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50-75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4-week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all-patients-as-treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). RESULTS: At week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100-mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200-mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 1·7 per 100 patient-years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs] and exposure-adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low. CONCLUSIONS: Tildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab. What's already known about this topic? Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short-term use in the treatment of patients with moderate-to-severe plaque psoriasis. What does this study add? High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab. There is a favourable long-term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years.

Continued treatment with secukinumab is associated with high retention or regain of response.

BACKGROUND: Conventional analyses present aggregate data, masking late responders and efficacy reductions. Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows sustained efficacy in moderate-to-severe psoriasis. OBJECTIVES: To determine stability of response to secukinumab, changes in efficacy were assessed in individual patients. METHODS: This is a post hoc analysis of two phase III randomized controlled trials, FIXTURE (trial registration: NCT01358578) and CLEAR (trial registration: NCT02074982). Patients received secukinumab 300 mg (FIXTURE and CLEAR), etanercept 50 mg (FIXTURE) or ustekinumab 45 or 90 mg (CLEAR) over 52 weeks. Mutually exclusive response categories were defined: ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI 90) ('excellent'), ≥ 75% improvement in PASI (PASI 75) and < PASI 90 ('good') and < PASI 75 ('insufficient'). Reductions in efficacy were defined as shifts from higher to lower response categories between two consecutive visits maintained for a third consecutive visit. Loss of efficacy was defined as a reduction of efficacy resulting in 'insufficient' response. All comparisons are descriptive. RESULTS: At 52 weeks, in CLEAR, 90·2% (303/336) of patients on secukinumab achieved stable efficacy without loss and 77·7% (261/336) showed stable efficacy without any reduction of response [74·3% (252/339) and 59·9% (203/339) of patients for ustekinumab]. In FIXTURE, 83·5% (273/327) and 66·4% (217/327) of patients on secukinumab had stable efficacy without loss or reduction of response [58·3% (190/326) and 42·6% (139/326) for etanercept]. Response was regained by continuing secukinumab treatment in 50% (8/16) of patients in CLEAR and 26% (9/34) in FIXTURE. Similar patterns were observed for other response definitions. CONCLUSIONS: Efficacy with secukinumab was stable over 52 weeks of treatment in most patients. Continued treatment with secukinumab resulted in regain of efficacy in some patients. Persistent loss of response was uncommon. What's already known about this topic? Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, shows significant and sustained efficacy in the treatment of moderate-to-severe psoriasis. Secondary loss of response may be experienced by a minority of patients treated with secukinumab, as with other biologics, but the extent of this and the potential for regain of efficacy with continued treatment is not well understood. What does this study add? To determine stability of response to secukinumab and inform clinical practice, changes in efficacy were assessed at individual patient level using response categories. Efficacy with secukinumab was stable over 52 weeks of treatment in most patients, and continued treatment with secukinumab resulted in efficacy regain after loss in some patients. Persistent loss of response was uncommon. Patient factors such as body weight may affect the likelihood of loss of efficacy.

Comparable efficacy and safety of brodalumab in obese and nonobese patients with psoriasis: analysis of two randomized controlled trials.

BACKGROUND: Obesity is associated with psoriasis and negatively affects response to therapy. OBJECTIVES: To evaluate the efficacy and safety of brodalumab in nonobese vs. obese patients with psoriasis. METHODS: This is a post hoc analysis of the prospective, phase III, multicentre, randomized, placebo- and active-comparator-controlled AMAGINE-2 and AMAGINE-3 trials, in which patients were randomized to treatment with brodalumab 210 mg every 2 weeks, ustekinumab or placebo for a 12-week induction phase. At week 12, patients who received brodalumab 210 mg every 2 weeks continued brodalumab, those treated with ustekinumab continued ustekinumab, and those who received placebo switched to brodalumab 210 mg every 2 weeks. Patients were categorized by body mass index (BMI) category (< 30 or ≥ 30 kg m-2 ) and efficacy was evaluated using the physician-rated Psoriasis Area and Severity Index and static Physician's Global Assessment instruments. RESULTS: In total, 281 of 687 patients (40·9%) were obese. Skin clearance was comparable across BMI subgroups in brodalumab-treated patients. Psoriasis Area and Severity Index 100% improvement rates in nonobese and obese patients at week 12 were 54·1% and 49·5%, respectively, and at week 52 they were 72·6% and 64·8%, respectively. Week 12 ustekinumab responses were lower than brodalumab responses and were 6-17% lower in obese than in nonobese patients. No appreciable differences in overall safety were observed between nonobese and obese patients. CONCLUSIONS: The efficacy and safety of brodalumab did not differ between patients with moderate-to-severe psoriasis who had a BMI < 30 kg m-2 or a BMI ≥ 30 kg m-2 .