Phase IIb randomized CONTROL study demonstrates a novel topical isotretinoin formulation, TMB-001, is safe and effective in participants with either recessive X-linked or autosomal recessive lamellar congenital ichthyosis.

BACKGROUND: In two severe congenital ichthyosis subtypes, autosomal recessive lamellar ichthyosis (ARCI-LI) and X-linked recessive ichthyosis (XLRI), cutaneous manifestations include widespread scaling. Approved topical treatment options are limited to emollients and keratolytics. AIM: This analysis from the randomized phase IIb CONTROL study assessed whether the efficacy and safety of TMB-001, a novel topical isotretinoin ointment formulation, differed between ARCI-LI and XLRI subtypes. METHODS: Participants ≥ 9 years with genetically confirmed XLRI or ARCI-LI and ≥ 2 (of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%/TMB-001 0.1%/vehicle, twice daily for 12 weeks. The proportion of participants with ≥ 50% reduction vs. baseline in VIIS scaling (VIIS 50; primary endpoint) and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score vs. baseline (key secondary endpoint) were evaluated. Adverse events (AEs) were monitored. RESULTS: Among enrolled participants (TMB-001 0.05%, n = 11; 0.1%, n = 10; and vehicle, n = 12), 52% had ARCI-LI and 48% XLRI subtypes. Mean age was 33.6 and 35.4 years for participants with ARCI-LI and XLRI, respectively. Overall, 33%, 50% and 17% of participants with ARCI-LI and 100%, 33% and 75% of participants with XLRI achieved VIIS 50 in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.24 for 0.05% vs. vehicle, intent-to-treat population). Improvement of ≥ 2-grade IGA score was observed in 33%, 50% and 0% of participants with ARCI-LI and 83%, 33% and 25% of participants with XLRI in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.03 for 0.05% vs. vehicle, intention-to-treat population). Most AEs were application-site reactions. CONCLUSION: Regardless of congenital ichthyosis subtype, TMB-001 demonstrated greater proportions of participants achieving VIIS 50 and ≥ 2-grade IGA improvement vs. vehicle.

Characteristics and outcomes for participants with congenital ichthyosis who responded to treatment with the topical isotretinoin formulation TMB-001: results from the Phase IIb CONTROL study.

BACKGROUND: Emollients and keratolytics are frequently used to manage symptoms of congenital ichthyosis (CI). Systemic retinoid treatment is complicated by teratogenicity and dose-limiting adverse effects. OBJECTIVES: This analysis from the randomized Phase IIb CONTROL study investigated the characteristics of participants who responded to treatment with TMB-001, a novel topical isotretinoin ointment formulation. METHODS: Participants ≥ 9 years of age with genetically confirmed CI and ≥ 2 (out of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%, TMB-001 0.1% or vehicle, twice daily for 12 weeks. Efficacy endpoints included the proportion of participants with ≥ 50% reduction in VIIS-scaling (VIIS-50) compared with baseline and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score compared with baseline. Changes in body surface area (BSA) involvement, Dermatology Life Quality Index (DLQI) scores and Itch-Numeric Rating Scale (I-NRS) scores were assessed. RESULTS: Among the 33 participants (11 randomized to TMB-001 0.05%, 10 to TMB-001 0.1% and 12 to vehicle), median age was 29 years (range 9-80), and most were male (64%) and White (79%). Baseline demographics were generally similar among participants who did or did not achieve TMB-001 treatment success. Participants who had lower mean BSA involvement and higher DLQI and I-NRS scores at baseline were more likely to achieve VIIS-50. Similarly, higher baseline DLQI and I-NRS scores were associated with IGA response; BSA involvement was similar for IGA responders vs. nonresponders. CONCLUSIONS: Higher DLQI and I-NRS scores at baseline were associated with participants achieving treatment success by VIIS-50 and IGA response. Lower BSA involvement was associated with VIIS-50 success.

Efficacy and safety of tildrakizumab in patients with active psoriatic arthritis: results of a randomised, double-blind, placebo-controlled, multiple-dose, 52-week phase IIb study.

OBJECTIVES: To evaluate efficacy and safety of the anti-interleukin-23p19 monoclonal antibody tildrakizumab in patients with psoriatic arthritis (PsA). METHODS: In this randomised, double-blind, placebo-controlled, phase IIb study, patients with active PsA were randomised 1:1:1:1:1 to tildrakizumab 200 mg every 4 weeks (Q4W); tildrakizumab 200, 100 or 20 mg Q12W; or placebo Q4W. Patients receiving tildrakizumab 20 mg or placebo switched to tildrakizumab 200 mg Q12W at W24; treatment continued to W52. The primary efficacy endpoint was proportion of patients with ACR20 response (≥20% improvement by American College of Rheumatology criteria) at W24. Secondary efficacy endpoints were assessed without adjustment for multiplicity. Safety was evaluated from treatment-emergent adverse events (TEAEs). RESULTS: 391/500 patients screened were randomised and treated. At W24, 71.4%-79.5% of tildrakizumab-treated versus 50.6% of placebo-treated patients achieved ACR20 (all p<0.01). Patients receiving tildrakizumab versus placebo generally achieved higher rates of ACR50, Disease Activity Score in 28 joints with C reactive protein <3.2, minimal disease activity and 75%/90%/100% improvement from baseline Psoriasis Area and Severity Index responses at W24 and through W52. Improvement in dactylitis and enthesitis was not observed; results were mixed for other outcomes. Responses in patients switched to tildrakizumab 200 mg at W24 were consistent with treatment from baseline. TEAEs and serious TEAEs occurred in 64.5% and 3.3%, respectively, of all patients through W52 and were comparable among treatment arms. CONCLUSIONS: Tildrakizumab treatment significantly improved joint and skin manifestations of PsA other than dactylitis and enthesitis. Treatment was generally well tolerated through W52. Clinicaltrials.gov NCT02980692.

Tildrakizumab efficacy, drug survival, and safety are comparable in patients with psoriasis with and without metabolic syndrome: Long-term results from 2 phase 3 randomized controlled studies (reSURFACE 1 and reSURFACE 2).

BACKGROUND: Data for the effect of metabolic syndrome (MetS) on the efficacy and safety of biologic agents for psoriasis treatment are limited. OBJECTIVE: To evaluate long-term tildrakizumab efficacy, drug survival, and safety in patients with psoriasis by baseline MetS status. METHODS: Post hoc analyses of up to 3 years of efficacy data and 5 years of safety data from the phase 3, double-blind, randomized controlled reSURFACE 1 and 2 trial (NCT01722331 and NCT01729754) base and extension studies were conducted for patients receiving continuous tildrakizumab 100 or 200 mg. RESULTS: Of 338 (n = 124/214 in reSURFACE 1/2) and 307 (n = 147/160 in reSURFACE 1/2) patients continuously receiving tildrakizumab 100 and 200 mg, respectively, throughout the studies, 26/44 (21%/21%) and 34/30 (23%/19%) met MetS criteria. Proportions of patients who achieved a 75% improvement in the Psoriasis Area and Severity Index (PASI) in reSURFACE 1/2 were generally comparable among those with versus without MetS at week 52 (tildrakizumab 100 mg, 85%/86% vs 86%/94%; tildrakizumab 200 mg, 76%/87% vs 76%/87%) and through week 148. Results were similar for responders with 90% and 100% improvement in the PASI. Tildrakizumab's safety profile did not vary by MetS status. LIMITATIONS: Small sample size and post hoc analysis limit interpretation. CONCLUSION: Long-term tildrakizumab efficacy and safety were comparable between patients with and without MetS.

Real-world biologic and apremilast treatment patterns in patients with psoriasis and psoriatic arthritis.

PURPOSE: Real-world treatment patterns among psoriasis patients with and without psoriatic arthritis (PsA) newly initiating treatment with a biologic or apremilast were assessed. PATIENTS AND METHODS: MarketScan claims data from adults with psoriasis and ?1 new prescription for secukinumab, adalimumab, ustekinumab, etanercept, or apremilast from January 1, 2015, to August 31, 2018, were assessed for adherence, switching, and combination therapy by index medication and PsA diagnosis. RESULTS: At treatment initiation, 22.0%-45.7% of patients had PsA. Over 24 months, discontinuation rates were high (34.4%-54.6%) overall and higher in patients with versus without PsA (all P<0.05 except secukinumab). Adherence was poor (16.8%-34.8%); switching and combination therapy were common. CONCLUSION: Treatment patterns varied, with better outcomes in PsA patients receiving anti-tumor necrosis factor versus anti-IL17/IL12/23 agents.

Real-world biologic and apremilast treatment patterns and healthcare costs in moderate-to-severe plaque psoriasis.

Plaque psoriasis is a chronic disease requiring long-term therapy. However, long-term real-world treatment patterns and costs are not well characterized. This study examined treatment patterns and healthcare costs among patients newly initiating a biologic or apremilast for moderate-to-severe plaque psoriasis. Included patients had ?1 prescription for secukinumab, ixekizumab, adalimumab, ustekinumab, etanercept, or apremilast between 01/01/2015 and 08/31/2018, no prior use of the index medication, and continuous enrolment 12 months pre-index and 24 months post-index. Treatment adherence, non-persistence, discontinuation, switching, use of combination therapy, and re-initiation were assessed at 12, 18, and 24 -months post-index. In addition, total and psoriasis-related healthcare costs were evaluated at 24 months. A total of 7,773 patients with 24-month follow-up were included. Overall, adherence was low (21.3%-33.5%) and non-persistence was high (58.4%-86.5%) over 24 months. Discontinuation (38.4%-51.3%), switching (29.7%-52.6%), combination therapy (27.6%-42.9%), and re-initiation of the index medication (19.3%-44.5%) were common. Healthcare costs were high and mostly contributed by psoriasis treatment. Therefore, maintaining disease control on long-term therapy is still challenging for many patients.

The Effect of Tildrakizumab on Cardiometabolic Risk Factors in Psoriasis by Metabolic Syndrome Status: Post Hoc Analysis of Two Phase 3 Trials (ReSURFACE 1 and ReSURFACE 2).

Background: Metabolic syndrome (MetS) is the most prevalent comorbidity in psoriasis and increases the risk of cardiovascular disease, diabetes, and mortality. Assessment of impacts of biologic therapies on cardiometabolic risk factors are relatively limited. This study evaluated the effect of tildrakizumab on cardiometabolic risk factors in patients with moderate to severe plaque psoriasis and stratified by MetS status. Methods: In this post hoc analysis of reSURFACE 1/2, tildrakizumab 100 and 200 mg were continuously administered to patients with moderate to severe plaque psoriasis at weeks 0 and 4, and every 12 weeks thereafter. Mean and mean percent changes from baseline were assessed for fasting serum glucose, low/high-density lipoprotein-cholesterol, total cholesterol, triglyceride levels, body weight, and blood pressure at week 64/52 for reSURFACE 1 and 2, respectively, in patients with and without MetS. Results: A total of 369 patients in reSURFACE 1 and 2 received continuous tildrakizumab 100 mg and 330 received tildrakizumab 200 mg; 21.4% and 20.3% in reSURFACE 1 and 2, respectively, had MetS. At week 64/52, mean changes in cardiometabolic risk factors from baseline did not significantly differ regardless of MetS status. Numerically larger mean decreases in fasting glucose, triglycerides, and systolic blood pressure following tildrakizumab 100 mg and in systolic and diastolic blood pressure following tildrakizumab 200 mg were observed in patients with MetS relative to those without MetS. Conclusions: Changes in cardiometabolic disease risk factors following tildrakizumab treatment were limited. Risk factors were not increased in patients with MetS vs without MetS. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5337.

Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial.

BACKGROUND: Many patients with psoriasis develop psoriatic arthritis, a chronic inflammatory disease that afflicts peripheral synovial, axial, and entheseal structures. The fully human monoclonal antibody ustekinumab is an efficacious treatment for moderate-to-severe plaque psoriasis. We did a randomised, placebo-controlled, phase 3 trial to assess the safety and efficacy of ustekinumab in patients with active psoriatic arthritis. METHODS: In this phase 3, multicentre, double-blind, placebo-controlled trial at 104 sites in Europe, North America, and Asia-Pacific, adults with active psoriatic arthritis (≥5 tender and ≥5 swollen joints, C-reactive protein ≥3·0 mg/L) were randomly assigned (1:1:1, by dynamic central randomisation based on an algorithm implemented by an interactive voice-web response system) to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued at week 28 and every 12 weeks thereafter. Our primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24. This trial is registered with ClinicalTrials.gov (NCT01009086) and EudraCT (2009-012264-14). FINDINGS: Between Nov 30, 2009, and March 30, 2011, 615 patients were randomly assigned-206 to placebo, 205 to 45 mg ustekinumab, and 204 to 90 mg ustekinumab. More ustekinumab-treated (87 of 205 [42·4%] in the 45 mg group and 101 of 204 [49·5%] in the 90 mg group) than placebo-treated (47 of 206 [22·8%]) patients achieved ACR20 at week 24 (p<0·0001 for both comparisons); responses were maintained at week 52. At week 16, proportions of patients with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [41·8%] vs 86 of 205 [42·0%]). INTERPRETATION: Ustekinumab significantly improved active psoriatic arthritis compared with placebo, and might offer an alternative therapeutic mechanism of action to approved biological treatments. FUNDING: Janssen Research & Development.

Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials.

OBJECTIVE: Evaluate ustekinumab, an anti-interleukin (IL)-12 and IL-23 antibody, effects on radiographic progression in psoriatic arthritis (PsA). METHODS: We conducted preplanned integrated analyses of combined radiographic data from PSUMMIT-1 and PSUMMIT-2 phase 3, randomised, controlled trials. Patients had active PsA despite prior conventional and/or biologic disease-modifying antirheumatic drugs (≥5/66 swollen, ≥5/68 tender joints, C-reactive protein ≥3.0 mg/L, documented plaque psoriasis). Patients (PSUMMIT-1, n=615; PSUMMIT-2, n=312) were randomised to ustekinumab 45 mg, 90 mg, or placebo, at weeks (wk) 0, 4 and every (q) 12 wks. At wk 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape. All other placebo patients received ustekinumab 45 mg at wk 24 and wk 28, then q 12 wks. Radiographs of hands/feet at wks 0/24/52 were assessed using PsA-modified van der Heijde-Sharp (vdH-S) scores; combined PSUMMIT-1 and PSUMMIT-2 changes in total vdH-S scores from wk 0 to wk 24 comprised the prespecified primary radiographic analysis. Treatment effects were assessed using analysis of variance on van der Waerden normal scores (factors=treatment, baseline methotrexate usage, and study). RESULTS: Integrated data analysis results indicated that ustekinumab-treated patients (regardless of dose) demonstrated significantly less radiographic progression at wk 24 than did placebo recipients (wk 0-24 total vdH-S score mean changes: 0.4-combined/individual ustekinumab dose groups, 1.0-placebo; all p<0.02). From wk 24 to wk 52, inhibition of radiographic progression was maintained for ustekinumab-treated patients, and progression was substantially reduced among initial placebo recipients who started ustekinumab at wk 16 or wk 24 (wk 24 - wk 52, total vdH-S score mean change: 0.08). CONCLUSIONS: Ustekinumab 45 and 90 mg treatments significantly inhibited radiographic progression of joint damage in patients with active PsA.

Radiographic benefit and maintenance of clinical benefit with intravenous golimumab therapy in patients with active rheumatoid arthritis despite methotrexate therapy: results up to 1 year of the phase 3, randomised, multicentre, double blind, placebo controlled GO-FURTHER trial.

OBJECTIVE: Report on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA). METHODS: Patients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15-25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape; <10% improvement in tender and swollen joints) or wk24 (crossover by design). Week 24 and wk52 radiographic (van der Heijde-Sharp (vdH-S) scores), clinical efficacy and safety data up to 1 year are reported here. RESULTS: Significant and rapid clinical improvement was observed up to wk24 of intravenous golimumab therapy. Golimumab+MTX treated patients demonstrated less radiographic progression than placebo treated patients at wk24 (vdH-S score mean change 0.03 vs 1.09; p<0.001) and wk52 (0.13 vs 1.22; p=0.001). Among patients with ≥20% improvement in the American College of Rheumatology response criteria or who achieved a 'good' or 'moderate' response according to the 28 joint Disease Activity Score employing CRP at wk24, approximately 80% maintained this response up until wk52. Through an average of 43.5 weeks of follow-up, 64.6% of patients receiving golimumab+MTX reported adverse events, most commonly non-serious infections. CONCLUSIONS: In patients with active RA despite MTX, intravenous golimumab+MTX yielded significant inhibition of structural damage at wk24 and wk52, and sustained clinical improvement in signs and symptoms with no new safety signals up to 1 year. CLINICALTRIALSGOV: NCT00973479, EudraCT 2008-006 064-11.

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial.

OBJECTIVE: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. METHODS: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. RESULTS: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change -0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change -0.13). No unexpected adverse events were observed through week 60. CONCLUSIONS: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.

Latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint.

Informative exposure-response modeling of clinical endpoints is important in drug development. There has been much recent progress in latent variable modeling of ordered categorical endpoints, including the application of indirect response (IDR) models and accounting for residual correlations between multiple categorical endpoints. This manuscript describes a framework of latent-variable-based IDR models that facilitate easy simultaneous modeling of a continuous and a categorical clinical endpoint. The model was applied to data from two phase III clinical trials of subcutaneously administered ustekinumab for the treatment of psoriatic arthritis, where Psoriasis Area and Severity Index scores and 20, 50, and 70 % improvement in the American College of Rheumatology response criteria were used as efficacy endpoints. Visual predictive check and external validation showed reasonable parameter estimation precision and model performance.

Intravenous golimumab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses as early as week 2: results of the phase 3, randomised, multicentre, double-blind, placebo-controlled GO-FURTHER trial.

OBJECTIVES: Evaluate the efficacy of intravenous golimumab 2 mg/kg+methotrexate (MTX) in patients with active rheumatoid arthritis (RA) receiving MTX. METHODS: Patients (n=592) with active disease (≥6/66 swollen, ≥6/68 tender joints, C-reactive protein ≥1.0 mg/dl, rheumatoid factor positive and/or anticyclic citrullinated protein antibody positive at screening) despite MTX (15-25 mg/week) participated in this double-blind, placebo-controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg, or placebo infusions at weeks 0 and 4 and every (q) 8 weeks; patients continued MTX. Placebo patients with <10% improvement in combined swollen/tender joint counts at week 16 could early escape to intravenous golimumab 2 mg/kg. The primary endpoint was week 14 American College of Rheumatology 20% (ACR20) response. Analyses employed non-responder imputation and last-observation-carried-forward. RESULTS: At week 14, significantly (p<0.001) larger proportions of golimumab+MTX than placebo+MTX patients achieved ACR20 response (59% vs 25%, respectively), a disease activity score of good/moderate (EULAR) response (81% vs 40%), and greater median improvement in health assessment questionnaire scores (0.500 vs 0.125). Improvements versus placebo+MTX were observed by week 2. Similar proportions of patients receiving golimumab+MTX and placebo+MTX, respectively, reported adverse events through week 16 (47% and 44%) and week 24 (53% and 49%). Serious adverse events were reported by more golimumab+MTX (4.1%) than placebo+MTX (2%) patients at week 24. CONCLUSION: The addition of intravenous golimumab rapidly and significantly improved signs and symptoms in patients with active RA despite ongoing MTX, in some patients by week 2.

Latent variable indirect response modeling of categorical endpoints representing change from baseline.

Accurate exposure-response modeling is important in drug development. Methods are still evolving in the use of mechanistic, e.g., indirect response (IDR) models to relate discrete endpoints, mostly of the ordered categorical form, to placebo/co-medication effect and drug exposure. When the discrete endpoint is derived using change-from-baseline measurements, a mechanistic exposure-response modeling approach requires adjustment to maintain appropriate interpretation. This manuscript describes a new modeling method that integrates a latent-variable representation of IDR models with standard logistic regression. The new method also extends to general link functions that cover probit regression or continuous clinical endpoint modeling. Compared to an earlier latent variable approach that constrained the baseline probability of response to be 0, placebo effect parameters in the new model formulation are more readily interpretable and can be separately estimated from placebo data, thus allowing convenient and robust model estimation. A general inherent connection of some latent variable representations with baseline-normalized standard IDR models is derived. For describing clinical response endpoints, Type I and Type III IDR models are shown to be equivalent, therefore there are only three identifiable IDR models. This approach was applied to data from two phase III clinical trials of intravenously administered golimumab for the treatment of rheumatoid arthritis, where 20, 50, and 70% improvement in the American College of Rheumatology disease severity criteria were used as efficacy endpoints. Likelihood profiling and visual predictive checks showed reasonable parameter estimation precision and model performance.

Topical Isotretinoin (TMB-001) Treatment for 12 Weeks Did Not Result in Clinically Relevant Laboratory Abnormalities in Participants with Congenital Ichthyosis in the Phase 2b CONTROL Study.

INTRODUCTION: Treatment with oral retinoids can be effective in patients with congenital ichthyosis (CI) but may be associated with clinically significant laboratory changes. In this Phase 2b CONTROL study analysis, we characterize the effects of TMB-001, a novel topical isotretinoin formulation, on laboratory values in participants with X-linked recessive (XLRI) and autosomal recessive lamellar (ARCI-LI) ichthyosis at 12 weeks. METHODS: A randomized, double-blind, vehicle-controlled, Phase 2b study was conducted with participants ≥ 9 years of age with confirmed XLRI and ARCI-LI. Participants were randomized 1:1:1 and stratified by CI subtype to receive TMB-001 0.05%:TMB-001 0.1%:vehicle twice daily for 12 weeks. Laboratory analyses were performed at screening and Week 12. RESULTS: Among 33 enrolled participants (TMB-001 0.05% n = 11, TMB-001 0.1% n = 10, and vehicle n = 12), 52% had ARCI-LI and 48% had XLRI. At 12 weeks, there were single reports of anemia, neutropenia, leukopenia, lymphocytosis, and leukocytosis after vehicle treatment; neutropenia was reported in one participant receiving TMB-001 0.1%. There were single reports of abnormal biochemistry values-liver enzymes, creatinine, urea nitrogen, hyperkalemia, and hyperproteinemia-across treatment cohorts. Non-fasting hyperglycemia was observed in three participants receiving TMB-001 0.1% and one participant receiving vehicle. Urinalysis abnormalities reported in > 1 participant included urobilinogen (TMB-001 0.1% n = 2, vehicle n = 2), protein (TMB-001 0.1% n = 3, vehicle n = 2), and leukocyte esterase (TMB-001 0.1% n = 2). Laboratory parameter changes were asymptomatic and did not require study discontinuation or drug withdrawal. CONCLUSION: There were no clinically significant laboratory changes in participants receiving TMB-001 isotretinoin ointment through 12 weeks of treatment, which differs from reported results for systemic isotretinoin. TRIAL REGISTRATION: NCT04154293.

Clinical implications and predictive values of early PASI responses to tildrakizumab in patients with moderate-to-severe plaque psoriasis.

OBJECTIVE: To evaluate whether early Psoriasis Area Severity Index (PASI) improvements can predict week 28 tildrakizumab responders and nonresponders. METHODS: Psoriasis patients pooled from two tildrakizumab phase 3 trials randomized to receive tildrakizumab 100 mg at weeks 0, 4, 16, and 28 were included. Patients were grouped by week 28 PASI responses (<50, 50-74, 75-89, and 90-100). PASI improvements from baseline at weeks 4 and 16 were analyzed for each response group. RESULTS: Of 575 patients included, 8.3%, 14.3%, 23.8%, and 53.6%, respectively, achieved PASI <50, 50-74, 75-89, and 90-100 at week 28. Of patients with PASI <50 at week 16, 85% did not achieve PASI ≥75 at week 28 (nonresponders). Rapid response, defined as PASI ≥50 at week 4 (after a single tildrakizumab dose), was observed in 41% of patients. Of these patients, 87% were week 28 responders (PASI ≥75); 67% were 'super responders' (PASI 90-100). Among week 28 responders and super responders, 45% and 50% achieved PASI ≥50 at week 4, respectively. CONCLUSIONS: Tildrakizumab week 28 nonresponders can be identified by week 16 PASI response. PASI improvements as early as week 4 can predict patients' week 28 PASI improvement status.

Cost-effectiveness of tildrakizumab for the treatment of moderate-to-severe psoriasis in the United States.

OBJECTIVE: To evaluate the relative cost-effectiveness of tildrakizumab and other biologic and targeted systemic treatments compared with a mix of topical therapies, phototherapies, and other conventional systemic therapies as first-line treatment for moderate-to-severe plaque psoriasis from a United States payer's perspective. METHODS: A Markov model consisting of health states based on Psoriasis Area Severity Index (PASI) response rate categories and death was developed. The probabilities of achieving PASI responses were derived from a network meta-analysis based on published efficacy data. Health care costs and effectiveness measured in quality-adjusted life-years (QALYs) were estimated. Incremental costs per QALY gained of each biologic/targeted first-line treatment versus a mix of conventional treatments were compared to provide relative cost-effectiveness among biologic and targeted first-line treatments. RESULTS: Over 10 years, the incremental cost per QALY gained compared with a mix of topical therapies, phototherapies, and other oral systemic therapies was lowest for brodalumab, infliximab, apremilast, and tildrakizumab, followed by secukinumab, ixekizumab, guselkumab, adalimumab, ustekinumab, and etanercept. The position of tildrakizumab relative to the other treatments remained the same across multiple scenarios. CONCLUSIONS: Tildrakizumab is among the most cost-effective first-line therapies for moderate-to-severe plaque psoriasis and is more cost-effective than secukinumab, ixekizumab, guselkumab, adalimumab, ustekinumab, and etanercept.

Real-world treatment patterns and healthcare costs of biologics and apremilast among patients with moderate-to-severe plaque psoriasis by metabolic condition status.

OBJECTIVES: To compare treatment patterns and costs among psoriasis patients with and without metabolic conditions newly initiating a biologic or apremilast. METHODS: Adult patients included had ≥1 prescription for secukinumab, adalimumab, ustekinumab, etanercept, or apremilast between 01/01/2015 and 08/31/2018 (date of first prescription was index date) and no index drug use in the 12-months pre-index, and continuous enrollment in the 12-month pre-index and 24-month post-index periods. Patients were divided into mutually exclusive treatment cohorts and stratified by their pre-index metabolic condition status. Treatment patterns (adherence, non-persistence, switching, discontinuation, use of combination therapy, and re-initiation) and healthcare costs were compared. RESULTS: Overall, 7773 patients were included; 47.5-56.7% had a metabolic condition. Except for the apremilast group, patients with metabolic conditions had higher discontinuation (secukinumab: 50.6% vs. 43.7%; adalimumab*: 53.9% vs. 48.7%; ustekinumab*: 41.9% vs. 35.1%; etanercept: 42.8% vs. 41.2%; apremilast: 43.1% vs. 46.1%) and switching (secukinumab: 48.1% vs. 41.2%; adalimumab*: 47.8% vs. 41.9%; ustekinumab*: 34.5% vs. 25.3%; etanercept*: 53.6% vs. 51.5%; apremilast: 45.8% vs. 44.6%) than patients without (*p < .05). Patients with metabolic conditions incurred significantly higher costs. CONCLUSION: Many psoriasis patients initiating biologics or apremilast had metabolic conditions. These patients had higher discontinuation and switching, and significantly higher healthcare costs.