Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Treating moderate-to-severe menopausal vasomotor symptoms with fezolinetant: analysis of responders using pooled data from two phase 3 studies (SKYLIGHT 1 and 2).

OBJECTIVES: The aims of the study were to further characterize the efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms (VMS) due to menopause using responder analysis and to investigate whether efficacy, not adjusted for placebo, resulted in clinically meaningful within-patient change. METHODS: This prespecified analysis used pooled data from two phase 3, randomized, double-blind, placebo-controlled studies (SKYLIGHT 1 and 2). Responders were those experiencing ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. Responder analysis was performed for patient-reported outcome (PRO) measures to evaluate participants achieving a clinically meaningful within-patient change (not placebo adjusted) at week 4 and 12 versus baseline. Single responders were based on outcomes of VMS frequency, Patient-Reported Outcomes Measurement Information System Sleep Disturbance-Short Form 8b Total Score, Menopause-Specific Quality of Life (MENQoL) Total Score, and MENQoL VMS Domain Score. Double and triple responder analyses combined VMS frequency plus one or more of the PRO. Patient Global Impression of Change VMS was deemed a suitable anchor measure for meaningful within-patient change in VMS frequency. RESULTS: A greater proportion of fezolinetant-treated versus placebo-treated participants had ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. A greater proportion of responders were observed in the fezolinetant groups versus placebo at week 12 in all four single responder analyses. In the double and triple responder analyses, odds ratios were supportive of a beneficial effect for both doses of fezolinetant versus placebo. CONCLUSIONS: Fezolinetant was associated with significantly higher within-patient clinically meaningful improvement in important PRO, including VMS frequency, PROMIS SD SF 8b Total Score, MENQoL Total Score, and MENQoL VMS Domain Score.

Cariprazine in Pediatric Patients with Autism Spectrum Disorder: Results of a Pharmacokinetic, Safety and Tolerability Study.

Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies.

Treatment of pediatric behavioral health patients with intravenous and intramuscular chemical restraints: Results from a nationwide sample of emergency departments.

BACKGROUND: Behavioral health crises in pediatric emergency department (ED) patients are increasingly common. Chemical restraints can be utilized for patients who present imminent danger to self or others. We sought to describe the use of intravenous (IV)/intramuscular (IM) chemical restraints for pediatric behavioral health ED patients across a nationwide sample of hospitals and describe factors associated with restraint use. METHODS: This was a retrospective study of patients ages 8-17 treated at 822 EDs contributing data to the Premier Healthcare Database between January 1, 2018, and December 31, 2020, with a behavioral health discharge diagnosis. The primary outcome was the use of IV/IM chemical restraint medication. We developed a hierarchical model to examine patient and hospital-level factors associated with treatment with IV/IM chemical restraint medications. RESULTS: Of 630,384 cases, 4.8% received IV/IM chemical restraint. Patient factors associated with higher odds of chemical restraint were older age (ages 13-17 years [adjusted odds ratio {AOR} 1.53, 95% confidence interval {CI} 1.48-1.58]), anxiety disorders (AOR 1.69, 95% CI 1.64-1.74), disruptive disorders (AOR 1.61, 95% CI 1.53-1.69), suicide/self-injury (AOR 1.3, 95% CI 1.26-1.34), substance use (AOR 1.24, 95% CI 1.20-1.28), and bipolar disorder (AOR 1.23, 95% CI 1.17-1.30). Participants with complex comorbidities were more likely to receive chemical restraint (AOR 1.32, 95% CI 1.26-1.39). After patient and hospital factors were adjusted for, the median OR indicating the influence of the individual hospital on the odds of chemical restraint was 1.43 (95% CI 1.40-1.47). CONCLUSIONS: We found that age and certain behavioral health diagnoses were associated with receipt of IV/IM chemical restraint during pediatric behavioral health ED visits. Additionally, whether a patient was treated with chemical restraints was strongly influenced by the hospital to which they presented for treatment.

The verification of wildland-urban interface fire evacuation models.

This paper introduces a protocol for the verification of multi-physics wildfire evacuation models, including a set of tests used to ensure that the conceptual modelling representation of each modelling layer is accurately implemented, as well as the interactions between different modelling layers and sub-models (wildfire spread, pedestrian movement, traffic evacuation, and trigger buffers). This work presents a total of 24 verification tests, including (1) 4 tests related to pedestrians, (2) 15 tests for traffic evacuation, (3) 5 tests concerning the interaction between different modelling layers, along with 5 tests for wildfire spread and trigger buffers. The evacuation tests are organized in accordance with different core components related to evacuation modelling, namely Population, Pre-evacuation, Movement, Route/destination selection, Flow constraints, Events, Wildfire spread and Trigger buffers. A reporting template has also been developed to facilitate the application of the verification testing protocol. An example application of the testing protocol has been performed using an open wildfire evacuation modelling platform called WUI-NITY and its associated trigger buffer model k-PERIL. The verification testing protocol is deemed to improve the credibility of wildfire evacuation model results and stimulate future modelling efforts in this domain. Supplementary Information: The online version contains supplementary material available at 10.1007/s11069-023-05913-2.

Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT.

CONTEXT: Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause. OBJECTIVE: We aimed to assess efficacy/safety of fezolinetant for treatment of moderate to severe VMS associated with menopause. METHODS: In this double-blind, placebo-controlled, 12-week phase 3 trial with a 40-week active treatment extension (NCT04003142; SKYLIGHT 2), women aged 40 to 65 years with minimum average 7 moderate to severe VMS/day were randomized to 12 weeks of once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Completers were rerandomized to fezolinetant 30/45 mg for 40 additional weeks. Coprimary efficacy endpoints were mean daily change from baseline to week 4 (W4) and W12 in VMS frequency and severity. Safety was also assessed. RESULTS: Both fezolinetant doses statistically significantly reduced VMS frequency/severity at W4 and W12 vs placebo. For VMS frequency, W4 least squares mean (SE) reduction vs placebo: fezolinetant 30 mg, -1.82 (0.46; P < .001); 45 mg, -2.55 (0.46; P < .001); W12: 30 mg, -1.86 (0.55; P < .001); 45 mg, -2.53 (0.55; P < .001). For VMS severity, W4: 30 mg, -0.15 (0.06; P < .05); 45 mg, -0.29 (0.06; P < .001); W12: 30 mg, -0.16 (0.08; P < .05); 45 mg, -0.29 (0.08; P < .001). Improvement in VMS frequency and severity was observed by W1 and maintained through W52. Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively. CONCLUSION: Daily fezolinetant 30 and 45 mg were efficacious and well tolerated for treating moderate to severe VMS associated with menopause.

Origin of anomalously stabilizing ice layers on methane gas hydrates near rock surface.

Gas hydrates (GHs) in water close to freezing temperatures can be stabilised via the formation of ice layers. In a recent work [Boström et al., Astron. Astrophys., A54, 650, 2021], it was found that a surface region with partial gas dilution could be essential for obtaining nano- to micron-sized anomalously stabilizing ice layers. In this paper, it is demonstrated that the Casimir-Lifshitz free energy in multi-layer systems could induce thinner, but more stable, ice layers in cavities than those found for gas hydrates in a large reservoir of cold water. The thickness and stability of such ice layers in a pore filled with cold water could influence the leakage of gas molecules. Additional contributions, e.g. from salt-induced stresses, can also be of importance, and are briefly discussed.

Evaluation of mRNA-1273 Vaccine in Children 6 Months to 5 Years of Age.

BACKGROUND: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-µg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo. RESULTS: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-µg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-µg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-µg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant. CONCLUSIONS: Two 25-µg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Unmet clinical needs and burden of disease in hidradenitis suppurativa: real-world experience from EU5 and US.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating skin disease characterized by painful deep lesions and associated with substantial disease burden. OBJECTIVES: The objective of this study was to describe physician- and patient-reported clinical unmet needs from a real-world perspective. METHODS: This study used data from the Adelphi HS Disease Specific Programme, a point-in-time survey of dermatologists and their patients with HS in Europe and the United States. Dermatologists completed patient record forms (PRFs) for 5-7 consecutively consulting patients with HS; patients or carers of patients also optionally completed a patient/carer self-completion questionnaire (PSC/CSC). Data collection included demographics, symptomatology and impact on quality of life (QoL). RESULTS: Dermatologists (N = 312) completed PRFs for 1787 patients with HS; patient- and carer-reported questionnaires (PSC/CSC) were completed for 33.1% (591/1787) of patients. The mean age was 34.4 ± 12.2 years and 57.6% of patients were female (1029/1787). Physician-judged disease severity at sampling was categorized as mild in 66.0% (1179/1787), moderate in 29.3% (523/1787) and severe in 4.7% (85/1787) of patients. Deterioration or unstable condition over the previous 12 months was described by 17.1% [235/1372] and 12.6% [41/325] of physician- and patient/carer-reported cases, respectively. Despite receiving treatment, high proportions of patients still experienced symptoms at sampling (general pain/discomfort [49.5%, 885/1787]; inflammation/redness of lesions/abscesses [46.1%, 823/1787] and itching [29.9%, 535/1787]); these symptoms were more frequent in patients with moderate or severe disease. Patients reported a mean Dermatology Life Quality Index score of 5.9 ± 5.4 (555/591; mild, 4.1 ± 4.3; moderate, 9.4 ± 5.4; severe, 13.3 ± 5.5) and a mean Hidradenitis Suppurativa Quality of Life score of 11.0 ± 10.6 (518/591; mild, 7.6 ± 8.3; moderate, 17.7 ± 10.0; severe, 31.0 ± 15.4) indicating a substantial impact on QoL. CONCLUSIONS: Patients with HS experienced a high disease burden despite being actively treated by a dermatologist. This study demonstrates that the burden of HS disease is generally poorly managed with a considerable impact observed on patients' QoL.

Pregnancy outcomes in patients with psoriasis, psoriatic arthritis, or axial spondyloarthritis receiving ixekizumab.

BACKGROUND: Psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are chronic inflammatory diseases that often affect women of childbearing age. Detailed information about pregnancy and related outcomes across these indications in patients exposed to ixekizumab is lacking. OBJECTIVES: To evaluate pregnancy outcomes after maternal or paternal exposure to ixekizumab in patients with psoriasis, PsA, or axSpA. METHODS: Pregnancy cases from clinical trials and post-marketing reports, associated with either maternal or paternal exposure to ixekizumab cumulatively through 22 March 2019, were identified in the Eli Lilly Global Safety Database and described separately. RESULTS: One hundred and ninety-three ixekizumab-exposed pregnancies were identified. Maternal exposure occurred in 51.3% of pregnancies (clinical trials: n = 58; post-marketing: n = 41). The majority of paternal exposure pregnancies occurred in clinical trials (91 of 94). Live births were reported for 53.8 and 61.1% of known outcomes in maternal exposure pregnancies during clinical trials and post-marketing surveillance, respectively. No congenital malformations resulting from maternal exposure were reported in clinical trials: one case, not causally related to ixekizumab therapy, was recorded in the post-marketing setting. CONCLUSIONS: This integrated safety analysis provides relevant information for clinicians treating patients with psoriasis, PsA, or axSpA with ixekizumab. No new safety signals were identified in patients receiving ixekizumab.

Effect of Prior Embolization on Outcomes After Stereotactic Radiosurgery for Pediatric Brain Arteriovenous Malformations: An International Multicenter Study.

BACKGROUND: Pediatric brain arteriovenous malformations (AVMs) are a significant cause of morbidity but the role of multimodal therapy in the treatment of these lesions is not well understood. OBJECTIVE: To compare the outcomes of stereotactic radiosurgery (SRS) with and without prior embolization for pediatric AVMs. METHODS: We retrospectively evaluated the International Radiosurgery Research Foundation pediatric AVM database. AVMs were categorized, based on use of pre-embolization (E + SRS) or lack thereof (SRS-only). Outcomes were compared in unadjusted and inverse probability weight (IPW)-adjusted models. Favorable outcome was defined as obliteration without post-SRS hemorrhage or permanent radiation-induced changes (RIC). RESULTS: The E + SRS and SRS-only cohorts comprised 91 and 448 patients, respectively. In unadjusted models, the SRS-only cohort had higher rates of obliteration (68.5% vs 43.3%,  < .001) and favorable outcome (61.2% vs 36.3%, P < .001) but a lower rate of symptomatic RIC (9.0% vs 16.7%, P = .031). The IPW-adjusted rates of every outcome were similar between the 2 cohorts. However, cumulative obliteration rates at 3, 5, 8, and 10 yr remained higher in the absence of prior embolization (46.3%, 64.6%, 72.6%, and 77.4% for SRS-only vs 24.4%, 37.2%, 44.1%, and 48.7% for E + SRS cohorts, respectively; SHR = 0.449 [0.238-0.846], P = .013). CONCLUSION: Embolization appears to decrease cumulative obliteration rates after SRS for pediatric AVMs without affecting the risk of post-treatment hemorrhage or adverse radiation effects arguing against the routine use of pre-SRS embolization. While endovascular therapy can be considered for occlusion of high-risk angioarchitectural features prior to SRS, future studies are necessary to clarify its role.

Negativity of the Casimir Self-Entropy in Spherical Geometries.

It has been recognized for some time that, even for perfect conductors, the interaction Casimir entropy, due to quantum/thermal fluctuations, can be negative. This result was not considered problematic because it was thought that the self-entropies of the bodies would cancel this negative interaction entropy, yielding a total entropy that was positive. In fact, this cancellation seems not to occur. The positive self-entropy of a perfectly conducting sphere does indeed just cancel the negative interaction entropy of a system consisting of a perfectly conducting sphere and plate, but a model with weaker coupling in general possesses a regime where negative self-entropy appears. The physical meaning of this surprising result remains obscure. In this paper, we re-examine these issues, using improved physical and mathematical techniques, partly based on the Abel-Plana formula, and present numerical results for arbitrary temperatures and couplings, which exhibit the same remarkable features.

Psoriasis severity: commonly used clinical thresholds may not adequately convey patient impact.

BACKGROUND: Psoriasis severity is usually evaluated using quantitative and qualitative measures, including per cent body surface area (BSA) involvement, the Psoriasis Area and Severity Index (PASI) and the Dermatology Life Quality Index (DLQI), a patient-reported questionnaire. However, standardized definitions for psoriasis severity categories have not been well established. A PASI of 10 or 12 has remained the minimal severity threshold defining eligibility for psoriasis treatments. In the present study, the validity of this cut-off was re-evaluated in the context of quality of life. OBJECTIVE: To determine whether the thresholds commonly used to define moderate psoriasis (PASI of 10-12 and BSA of 10) are supported by patient-reported DLQI data. METHODS: A systematic review of randomized controlled trials that enrolled mild or moderate patients published between January 2000 and June 2017 was used to assess correlations between provider and patient-generated severity at baseline. RESULTS: For subject groups with high impact on quality of life (DLQI > 10), the mean weighted BSA was 7.6 (Range: 7.1-8.4) and the mean weighted DLQI was 11 (Range: 10.2-12.2). Similarly, the mean weighted PASI for patients with DLQI > 10 was 8.7 (Range: 7.1-10.1) and the mean weighted DLQI was 10.9 (Range: 10.1-12.2). CONCLUSION: Patients with PASI or BSA scores less than 10 can have major quality of life impairment. In general, the objective measures of BSA and PASI alone, when excluding DLQI, may not fully capture the impact of disease severity.

Publication trends in hidradenitis suppurativa from 2008 to 2018.

BACKGROUND: Increased interest in hidradenitis suppurativa (HS) research is encouraging. A critical analysis of the state of HS literature may demonstrate the strength of existing knowledge and highlight current gaps. OBJECTIVES: To analyse changes in HS literature from 2008 to 2018 with focus on quantity and quality of annual publications. METHODS: Review of all indexed publications reporting on HS on PubMed. Publications were categorized based on study design, study topic and treatment type where applicable. Publications were dichotomized into high level of evidence and low level of evidence groups. Linear regression analyses were performed to investigate the change in publication number over time. Annual average growth rate and distribution of high versus low level of evidence publications were calculated. RESULTS: Publication number increased over time overall (R2  = 0.64, P = 0.003) and for all publication types except randomized clinical trials. Case reports and case series represented the majority of HS publications (n = 479, 40.3%). Treatment was the main focus of publications (n = 445, 37.6%) with increasing interest in medical management evident in recent years. Distribution of low level of evidence studies (n = 974) compared with high level of evidence studies over time (n = 209) was significant (x2 : 11.45, P = 0.0007). High level of evidence studies had a higher average annual growth rate (49.9%) compared with low level of evidence studies (23.7%). Few randomized clinical trials were performed (n = 16), focusing equally on medical or procedural treatments. CONCLUSIONS: Hidradenitis suppurativa research is undergoing a tremendous shift, suggesting rapid maturation of the field. Current HS literature, however, remains primarily based on limited clinical observation data, with a particular lack of randomized clinical trials. Despite this, the increase in high level of evidence studies is encouraging and may herald a shift towards improved disease understanding and treatment paradigms.

Assessment of the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab.

BACKGROUND: We evaluated antidrug antibody (ADA) development in patients with chronic plaque psoriasis from three clinical trials of tildrakizumab, a humanized anti-interleukin-23p19 monoclonal antibody (P05495, reSURFACE 1 and reSURFACE 2). OBJECTIVES: To determine the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab. METHODS: In 1400 (weeks 12-16) and 780 (weeks 52-64) evaluable patients randomized to tildrakizumab 100 or 200 mg, treatment-emergent ADA-positive (TE-POS) patients were identified and characterized for neutralizing antibodies (NAbs). Pharmacokinetics, safety and efficacy were evaluated by ADA status. RESULTS: In patients treated with tildrakizumab 100 or 200 mg continuously, < 7% were inconclusive at 52-64 weeks. In long-term data through 52-64 weeks, the incidence of TE-POS was 6·5% (100 mg) and 8·2% (200 mg) and the incidence of TE-POS NAb-POS was 2·5% (100 mg) and 3·2% (200 mg). TE-POS NAb-POS patients had modestly increased median tildrakizumab clearance (36·5%) compared with ADA-NEG patients. Percentage Psoriasis Area and Severity Index improvements in TE-POS NAb-POS vs. ADA-NEG patients on continuous treatment through week 52 were 76% (n = 10) vs. 91% (n = 342) for 100 mg and 77% (n = 12) vs. 87% (n = 299) for 200 mg. The incidence of potential immunogenicity-related adverse events did not indicate a clear trend in any positive ADA patient category compared with ADA-NEG patients through weeks 52-64. The effects of ADA on pharmacokinetics, efficacy and safety at 12-16 weeks were also summarized. CONCLUSIONS: ADA development with tildrakizumab treatment for 52-64 weeks was low; around 3% of patients developed TE-POS NAb-POS ADAs and showed lower serum concentrations and corresponding reduced efficacy. No relationship between ADAs and safety was observed. What's already known about this topic? Unwanted immune responses - for example immunogenicity and antidrug antibodies (ADAs) - have been observed with therapeutic monoclonal antibodies and can affect efficacy and safety. Tildrakizumab is a humanized monoclonal antibody targeting interleukin-23 and is currently approved for patients with plaque psoriasis. What does this study add? ADA development in tildrakizumab-treated patients with psoriasis over 52 weeks was low. The small proportion of patients who had treatment-emergent ADAs and had neutralizing antibodies experienced lower serum tildrakizumab concentrations and reduced efficacy. No relationship between ADAs and safety events was observed.