Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis.

The pharmacologic effect(s) of biotherapeutics directed against soluble targets are driven by the magnitude and duration of free target suppression at the tissue site(s) of action. Interleukin (IL)-17A is an inflammatory cytokine that plays a key role in the pathogenesis of psoriasis. In this work, clinical trial data from two monoclonal antibodies (mAbs) targeting IL-17A for treatment of psoriasis (secukinumab and ixekizumab) were analyzed simultaneously to quantitatively predict their target engagement (TE) profiles in psoriatic skin. First, a model-based meta-analysis (MBMA) for clinical responses was conducted separately for each drug based on dose. Next, a minimal physiologically-based pharmacokinetic (mPBPK) model was built to assess skin site IL-17A target engagement for ixekizumab and secukinumab simultaneously. The mPBPK model captured the observed drug PK, serum total IL-17A, and skin drug concentration-time profiles reasonably well across the different dosage regimens investigated. The developed mPBPK model was then used to predict the average TE (i.e., free IL-17A suppression) in skin achieved over a 12-weeks treatment period for each drug following their respective regimens and subsequently assess the TE-efficacy response relationship. It was predicted that secukinumab achieved 98.6% average TE in the skin at 300 mg q4w SC while ixekizumab achieved 99.9% average TE under 160 mg (loading) followed by 80 mg q2w SC. While direct quantification of free IL-17A levels at the site of action is technically challenging, integrated mPBPK-MBMA approaches offer quantitative predictions of free IL-17A levels at the site of action to facilitate future drug development via IL-17A suppression in psoriasis.

Preparation of CeO2/UiO-66-NH2 Heterojunction and Study on a Photocatalytic Degradation Mechanism.

CeO2/UiO-66-NH2 (marked as Ce/UN) composites were in-situ synthesized by a hydrothermal method. The properties, photocatalytic aspects, and degradation mechanism of Ce/UN were studied carefully. SEM results show that Ce/UN have a 3D flower-like structure, where octahedral UiO-66-NH2 nanoparticles are embedded in the two-dimensional sheet of CeO2. TEM results demonstrate that CeO2 and UiO-66-NH2 are bonded interfacially to constitute a hetero-junction construction. Data obtained by electrochemical impedance spectroscopy and fluorescence spectroscopy established that Ce/UN has less charge shift resistance and luminescence intensity than these of two pure substances. When the ratio of Ce/UN is 1:1, and the calcination temperature 400 °C is used, the degradation efficiency of RhB in photocatalysis by obtained Ce/UN is about 96%, which is much higher than in the case of CeO2 (4.5%) and UiO-66-NH2 (54%). The improved photocatalytic properties of Ce/UN may be due to the formation of hetero-junction, which is conducive for most photo-carriers and thus the interfacial charge shift efficiency is enhanced. By the free radical capture test, it can be inferred that the major active substances involved in the degradation related to photocatalysis is H+ and · O2−.

The Formation Process and Strengthening Mechanism of SiC Nanowires in a Carbon-Coated Porous BN/Si3N4 Ceramic Joint.

Porous BN/Si3N4 ceramics carbon-coated by carbon coating were joined with SiCo38 (wt. %) filler. The formation process and strengthening mechanism of silicon carbide nanowires to the joint were analyzed in detail. The outcome manifests that there is no distinct phase change in the porous BN/Si3N4 ceramic without carbon-coated joint. The highest joint strength was obtained at 1320 °C (~38 MPa). However, a larger number of silicon carbide nanowires were generated in the carbon-coated joints. The highest joint strength of the carbon-coated joint was ~89 MPa at 1340 °C. Specifically, silicon carbide nanowires were formed by the reaction of the carbon coated on the porous BN/Si3N4 ceramic with the SiCo38 filler via the Vapor-Liquid-Solid (VLS) method and established a bridge in the joint. It grows on the ß-SiC (111) crystal plane and the interplanar spacing is 0.254 nm. It has a bamboo-like shape with a resemblance to alloy balls on the ends, and its surface is coated with SiO2. The improved carbon-coated porous BN/Si3N4 joint strength is possibly ascribed to the bridging of nanowires in the joint.

Population pharmacokinetics and exposure-response modeling analyses of guselkumab in patients with psoriatic arthritis.

Guselkumab is an anti-interleukin-23 human monoclonal antibody effective in treating psoriatic arthritis (PsA). To characterize the pharmacokinetics (PKs) and exposure-response relationship of guselkumab in PsA, population PKs, and exposure-response modeling, analyses were conducted using data from pivotal phase III studies of subcutaneous guselkumab in patients with PsA. The observed serum concentration-time data of guselkumab were adequately described by a one-compartment linear PK model with first-order absorption and elimination. Covariates identified as contributing to the observed guselkumab PK variability were body weight and diabetes comorbidity; however, the magnitude of the effects of these covariates was not considered clinically relevant, and dose adjustment was not warranted for the patient population investigated. Positive exposure-response relationships were demonstrated with landmark and longitudinal exposure-response analyses between guselkumab exposure and clinical efficacy end points (American College of Rheumatology [ACR] 20%, 50%, and 70% improvement criteria and Investigator's Global Assessment [IGA] of psoriasis) at weeks 20 and/or 24, with no clinically relevant differences observed in improvement of PsA signs and symptoms between the two guselkumab treatment regimens evaluated (100 mg every 4 weeks or 100 mg at weeks 0 and 4, then every 8 weeks). Baseline Disease Activity Score in 28 joints (DAS28), Psoriasis Area and Severity Index (PASI) score, and/or C-reactive protein level were identified as influencing covariates on guselkumab exposure-response model parameters. These results provide a comprehensive evaluation of subcutaneous guselkumab PKs and exposure-response relationship that supports the dose regimen of 100 mg at weeks 0 and 4, then every 8 weeks in patients with PsA.

Pooled Safety Results Through 1 Year of 2 Phase III Trials of Guselkumab in Patients With Psoriatic Arthritis.

OBJECTIVE: Evaluate the safety of guselkumab (monoclonal antibody targeting interleukin [IL]-23p19) in patients with psoriatic arthritis (PsA) through 1 year (1Y) of the phase III DISCOVER-1 and DISCOVER-2 trials. METHODS: Patients with active PsA (n = 1120; biologic-naïve except 118 patients treated with tumor necrosis factor inhibitors in DISCOVER-1) were randomized to subcutaneous guselkumab 100 mg every 4 weeks (Q4W) or at Week 0, Week 4, then every 8 weeks (Q8W); or placebo. At Week 24, patients in the placebo group switched to guselkumab 100 mg Q4W. Treatment continued through 1Y and 2 years for DISCOVER-1 and DISCOVER-2, respectively. In this pooled analysis, patients with ≥ 1 adverse event (AE) through 1Y were standardized for 100 patient-years [100 PYs] of follow-up. RESULTS: Through Week 24, adverse events (AEs) were consistent between patients treated with placebo and guselkumab (Q4W + Q8W). AEs were 142.8/100 PYs and 150.6/100 PYs, serious AEs were 7.1/100 PYs and 4.4/100 PYs, and AEs leading to study agent discontinuation were 4.1/100 PYs and 3.8/100 PYs, respectively. Through 1Y in patients treated with guselkumab, no uveitis, active tuberculosis, opportunistic infections, or inflammatory bowel disease were observed, and low rates of malignancy and major adverse cardiovascular (CV) events were observed. Injection-site reactions occurred in 1.7%, and antibodies to guselkumab in 4.5% of patients treated with guselkumab through 1Y; the vast majority of antibodies to guselkumab were nonneutralizing. Serum hepatic transaminase elevations (more common with Q4W than Q8W dosing) and decreased neutrophil counts were generally mild, transient, and did not require treatment discontinuation, with minimal change from Week 24 to 1Y. CONCLUSION: Guselkumab 100 mg Q4W and Q8W were well tolerated in patients with PsA, with no new safety concerns through 1Y of the phase III DISCOVER trials. Guselkumab safety through 1Y in patients with PsA is consistent with that established in patients with psoriasis who were treated with guselkumab. [ClinicalTrials.gov: NCT03162796 and NCT03158285].

Guselkumab, an inhibitor of the IL-23p19 subunit, provides sustained improvement in signs and symptoms of active psoriatic arthritis: 1 year results of a phase III randomised study of patients who were biologic-naïve or TNFα inhibitor-experienced.

OBJECTIVE: Evaluation of the efficacy and safety of guselkumab, a human monoclonal antibody targeting the interleukin-23p19 subunit, in patients with psoriatic arthritis (PsA) through 1 year. METHODS: Adults who met ClASsification criteria for Psoriatic ARthritis, with active disease (≥3 swollen and ≥3 tender joints; C reactive protein ≥0.3 mg/dL) despite standard treatment (31% previously received ≤2 tumour necrosis factor inhibitors (TNFi)), were randomised (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week0, Week4, then Q8W; or placebo with cross-over to guselkumab 100 mg Q4W at Week24 (PBO→Q4W) through Week48. Clinical efficacy through Week52 (employing non-responder imputation) and adverse events (AEs) through Week60 were evaluated. RESULTS: Of 381 treated patients, 90% completed the study. Numerical increases in the proportions of patients achieving ≥20% improvement in ACR criteria (ACR20) were observed post-Week24, reaching 73% (94/128) and 60% (76/127) for Q4W-randomised and Q8W-randomised patients, respectively, by Week52. Proportions of patients achieving ACR50/ACR70/skin responses and minimal/very low disease activity were maintained, as were improvements in physical function and health-related quality of life, through Week52 in guselkumab-randomised patients. Response to guselkumab was maintained in both TNFi-naïve and TNFi-experienced patients. Serious AEs and serious infections occurred in similar proportions of guselkumab Q4W-randomised (3% and 0%) and Q8W-randomised (6% and 2%) patients through Week60, with no new safety concerns versus observations through Week24. No guselkumab-treated patient and two patients receiving placebo died; no study participant developed opportunistic infection or inflammatory bowel disease. CONCLUSION: Guselkumab provided sustained improvement across multiple clinical manifestations of PsA, maintaining a favourable benefit-risk profile, through 1 year regardless of prior TNFi exposure.

Are the shoreline and eutrophication of desert lakes related to desert development?

Desert lakes are unique ecosystems found in oases within desert landscapes. Despite the numerous studies on oases, there are no reports regarding the spatiotemporal distribution and causes of eutrophication in the desert lakes that are located at the edge of the Linze Oasis in northwestern China. In this study, the seasonal shoreline and eutrophication of a desert lake were monitored using an unmanned aerial vehicle (UAV) and water sampling during three crop growth stages. The spatial extents of the shoreline and algal blooms and the chromophoric dissolved organic matter (CDOM) absorption coefficient were derived through UAV images. The desert lake shoreline declined during the crop growing stage, which exhibited the largest water demand and began to expand after this stage. The estimated CDOM absorption coefficient measurements and classified algal bloom area showed seasonal variations that increased from spring to late summer and then decreased in autumn. The first two crop growth stages accounted for most of the water and fertilizer requirements of the entire growth period, which may have contributed to large amounts of groundwater consumption and pollution and resulted in peak eutrophication of the lake in the second growth stage. However, the CDOM absorption coefficient of the third stage was not well correlated with that of the first two stages, suggesting that the lake may be affected by the dual effects of groundwater and precipitation recharge in the third stage. These results indicate that the water quality of desert lakes may be affected by agricultural cultivation. The agricultural demands for water and fertilizer may change the spatiotemporal changes in water quality in the lake, especially in the middle and early stages of crop growth.

Efficacy and Safety of Guselkumab, an Interleukin-23p19-Specific Monoclonal Antibody, Through One Year in Biologic-Naive Patients With Psoriatic Arthritis.

OBJECTIVE: Guselkumab, a human monoclonal antibody specific to interleukin-23p19, demonstrated efficacy and safety versus placebo through week 24 of the phase III DISCOVER-2 trial in biologic-naive patients with psoriatic arthritis (PsA). Here we report 1-year DISCOVER-2 findings. METHODS: Adults with active PsA (≥5 swollen and ≥5 tender joints; C-reactive protein level ≥0.6 mg/dl) despite standard nonbiologic treatment were randomized to receive subcutaneous injections of guselkumab 100 mg every 4 weeks, guselkumab 100 mg at week 0, week 4 and every 8 weeks thereafter, or placebo with crossover to guselkumab 100 mg every 4 weeks at week 24. We primarily evaluated clinical efficacy through week 52 by imputing missing data (nonresponse for categorical end points; no change/using multiple imputation for continuous end points). Observed radiographic scores and adverse events (AEs) were summarized. RESULTS: Of 739 randomized, treated patients, 93% completed week 52. The proportions of patients in whom a ≥20% improvement from baseline in American College of Rheumatology criteria (ACR20) was achieved were maintained after week 24, reaching 71% (173 of 245) and 75% (185 of 248) for patients randomized to receive treatment every 4 weeks or every 8 weeks, respectively, by week 52. The proportions of patients in whom ACR50/ACR70 and skin responses, minimal or very low disease activity, and dactylitis or enthesitis resolution were achieved at week 24 were also maintained through week 52. Further, low levels of radiographic progression, along with improvements in physical function and health-related quality of life, were sustained through week 52 with continued guselkumab treatment. Few patients experienced serious infections through week 52, with no evidence of a dosing regimen response or increase from weeks 0-24 (4 of 493 [0.8%]) to weeks 24-52 (3 of 493 [0.6%]) among guselkumab-randomized patients. No patient developed an opportunistic infection or died. CONCLUSION: In biologic-naive PsA patients, guselkumab provided sustained improvements across diverse manifestations and maintained a favorable risk-benefit profile through week 52.

Comparability Considerations and Challenges for Expedited Development Programs for Biological Products.

Expedited development programs for biological products to be used in the treatment of serious conditions bring about challenges because of the compressed clinical development timeframes. As expedited development does not lessen the quality expectations, one challenge is providing adequate chemistry, manufacturing, and control (CMC) information required to support approval of a biological product. In particular, the analytical comparability and, in some cases, pharmacokinetic comparability studies needed to bridge the clinical material to the commercial material could delay submission of applications for life-saving medicines. While there is the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Topic Q5E guidance on assessing comparability of biological products before and after manufacturing changes, specific guidance on the emerging issue of conducting comparability exercises in the face of expedited drug development is lacking. In July 2019, clinical pharmacologists and product quality chemists from the US FDA and industry representatives convened an FDA workshop for a scientific exchange about considerations and challenges around conducting comparability exercises for expedited programs for biological products. This article highlights discussions from the workshop.

Evaluating Potential Disease-Mediated Protein-Drug Interactions in Patients With Moderate-to-Severe Plaque Psoriasis Receiving Subcutaneous Guselkumab.

This open-label, multicenter, phase I therapeutic protein-drug interaction study was designed to evaluate the potential effect of guselkumab, a fully human anti-interleukin-23 immunoglobulin G1 lambda monoclonal antibody, on the pharmacokinetics of a cocktail of representative cytochrome P450 (CYP) probe substrates (midazolam (CYP3A4), S-warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and caffeine (CYP1A2)). Fourteen participants with psoriasis received a single subcutaneous dose of guselkumab 200 mg on day 8 and an oral probe cocktail on days 1, 15, and 36. Blood samples were collected for measuring plasma concentrations of these probe substrates on days 1, 15, and 36. No consistent trends in observed maximum plasma concentration and area under the curve from time 0 to infinity values of each probe CYP-substrate before (day 1) and after guselkumab treatment (days 15 and 36) could be identified in each individual patient, suggesting that the use of guselkumab in patients with psoriasis is unlikely to influence the systemic exposure of drugs metabolized by CYP isozymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2). The probe cocktail was generally well-tolerated when administered in combination with guselkumab in patients with psoriasis. Clinicaltrials.gov Identifiers: NCT02397382.

Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: The interleukin-23 (IL-23)/T-helper 17 cell pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, an IL-23 inhibitor that specifically binds the IL-23 p19 subunit, significantly and safely improved psoriatic arthritis in a phase 2 study. DISCOVER-2 was a phase 3 trial to assess guselkumab in biologic-naive patients with psoriatic arthritis. METHODS: This phase 3, double-blind, placebo-controlled study was done at 118 sites in 13 countries across Asia, Europe, and North America. We enrolled biologic-naive patients with active psoriatic arthritis (at least five swollen joints, at least five tender joints, and C-reactive protein ≥0·6 mg/dL) despite standard therapies. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive protein concentration) to subcutaneous injections of guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) response at week 24 in all patients per assigned treatment group. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03158285 (active, not recruiting). FINDINGS: From July 13, 2017, to Aug 3, 2018, 1153 patients were screened, of whom 741 were randomly assigned to receive guselkumab every 4 weeks (n=246), every 8 weeks (n=248), or placebo (n=247). One patient in the every 4 weeks group and one in the placebo group did not start treatment, and the remaining 739 patients started treatment; 716 patients continued treatment up to week 24. Significantly greater proportions of patients in the guselkumab every 4 weeks group (156 [64%] of 245 [95% CI 57-70]) and every 8 weeks group (159 [64%] of 248 [58-70]) than in the placebo group (81 [33%] of 246 [27-39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22-39] for the every 4 weeks group and 31% [23-40] for the every 8 weeks group; both p<0·0001). Up to week 24, serious adverse events occurred in eight (3%) of 245 patients receiving guselkumab every 4 weeks (three serious infections), three (1%) of 248 receiving guselkumab every 8 weeks (one serious infection), and seven (3%) of 246 receiving placebo (one serious infection). No deaths occurred. INTERPRETATION: Guselkumab, a human monoclonal antibody that specifically inhibits IL-23 by binding the cytokine's p19 subunit, was efficacious and demonstrated an acceptable benefit-risk profile in patients with active psoriatic arthritis who were naive to treatment with biologics. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis. FUNDING: Janssen Research and Development.

Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial. METHODS: This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting). FINDINGS: From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50-68]) and every 8 weeks group (66 [52%] of 127 [43-61]) than in the placebo group (28 [22%] of 126 [15-30]), with percentage differences versus placebo of 37% (95% CI 26-48) for the every 4 weeks group and 30% (19-41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections. INTERPRETATION: Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis. FUNDING: Janssen Research and Development.

The hidden costs of desert development.

Economic benefits and ecological restoration are the leading drivers of desert development through man-made oasis expansion. However, the sustainability of oasis expansion in combating desertification while promoting economic growth remains unclear, though such knowledge is critical for future desert development across the globe. To address this knowledge gap, a comprehensive assessment integrating meteorological, groundwater and remote-sensing data as well as groundwater simulation datasets was conducted to evaluate the spatial-temporal changes in the desert-oasis ecotone of northwest China over the past six decades. Desert development causes a rapid decline in the surrounding groundwater table, increases pollution in soil and groundwater and is associated with an increased frequency of strong sandstorms. Desert development seems to have improved the environment and promoted the economy, but there is a huge cost for the overexploitation of water resources and the transfer of pollution from surface to underground, which could cause deserts to degrade further.

Risk-Based Comparability Assessment for Monoclonal Antibodies During Drug Development: A Clinical Pharmacology Perspective.

Due to complexities in the structure, function, and manufacturing process of antibody-based therapeutic proteins, comparability assessment for supporting manufacturing changes can sometimes be a challenging task. Regulatory guidance recommends a hierarchical risk-based approach, starting with Chemistry, Manufacturing, and Controls (CMC) analytical characterizations, followed by non-clinical and/or clinical studies to ensure that any potential changes in quality attributes have no adverse impact on efficacy and safety of the product. This review focuses on the changes in quality attributes which may potentially affect the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of a monoclonal antibody (mAb) product, and provides general guidelines in designing non-clinical and clinical PK/PD studies to help support comparability assessments. A decision tree for comparability assessment is proposed depending on the nature of the changes in quality attributes, the potential impact of such changes, and the timing of the manufacturing change relative to the development process. Ideally, the optimization of manufacturing process should take place in the early stage of drug development (i.e., preclinical to phase 2a) as more stringent comparability criteria would have to be met if manufacturing changes occur in the late stage of drug development (i.e., phase 2b and after), and consequently, major changes in manufacturing process should be avoided during confirmatory phase 3 studies and post-approval of drug products.

Joint longitudinal model development: application to exposure-response modeling of ACR and DAS scores in rheumatoid arthritis patients treated with sirukumab.

Exposure-response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure-response modeling of sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus blocking IL-6 signaling, which plays a major role in the pathophysiology of rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients with active RA despite methotrexate therapy, who received subcutaneous (SC) administration of either placebo or sirukumab of 25, 50 or 100 mg every 4 weeks (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria, and the 28-joint disease activity score using C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical and DAS28 as continuous. The results showed that, compared with the common approach of separately modeling the endpoints, the joint model could describe the observed data better with fewer parameters through the sharing of random effects, and thus more precisely characterize the dose-response relationship. The implications on future dose and dosing regimen optimization are discussed in contrast with those from landmark analysis.

Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759. FINDINGS: Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3-54·1]; p<0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred. INTERPRETATION: Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis. FUNDING: Janssen Research & Development.

Exposure-Response Modeling Analyses for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin 6, in Patients With Moderately to Severely Active Rheumatoid Arthritis.

To characterize the dose-exposure-response relationship of sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the sirukumab E-R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. Despite body weight and comorbid diabetes having significant effect on sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of sirukumab E-R to support dose recommendations in patients with RA.

Confirmatory Population Pharmacokinetic Analysis for Sirukumab, a Human Monoclonal Antibody Targeting Interleukin-6, in Patients With Moderately to Severely Active Rheumatoid Arthritis.

The population pharmacokinetics of sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin-6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND-D, -T, -H, and -M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner. The base model, that is, a 1-compartment linear model with first-order absorption and first-order elimination, was prespecified based on prior information from a phase 2 study along with information about phase 3 study design. The covariate model was also prespecified based on pharmacological/physiological relevance and sample size. After the primary covariate analysis, a simplified model was produced by removing covariates with effect sizes <10%. The estimated apparent clearance (CL/F) and volume of distribution were 0.641 L/day and 16.1 L, respectively, at standard body weights of 70 kg. The terminal elimination half-life was approximately 17.4 days. Sirukumab CL/F and volume of distribution increased with body weight, and CL/F was higher in patients with diabetic comorbidity. Simulations suggest that the effects of diabetic comorbidity and weight on sirukumab exposure were additive. To fully understand the clinical relevance including potential dose adjustment, current covariate findings need to be evaluated concurrently with the efficacy and safety data.

Efficacy and safety of monotherapy with sirukumab compared with adalimumab monotherapy in biologic-naïve patients with active rheumatoid arthritis (SIRROUND-H): a randomised, double-blind, parallel-group, multinational, 52-week, phase 3 study.

OBJECTIVE: This randomised, double-blind, parallel-group, phase 3 study compared monotherapy with sirukumab, an anti-interleukin-6 cytokine monoclonal antibody, with adalimumab monotherapy in patients with rheumatoid arthritis (RA). METHODS: Biologic-naïve patients with active RA who were inadequate responders or were intolerant to, or inappropriate for, methotrexate were randomised to subcutaneous sirukumab 100 mg every 2 weeks (n=187), sirukumab 50 mg every 4 weeks (n=186) or adalimumab 40 mg every 2 weeks (n=186). Primary endpoints at week 24 were change from baseline in Disease Activity Score in 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) and proportion of patients achieving an American College of Rheumatology (ACR) 50 response; these endpoints were tested in sequential order. This study is registered at EudraCT (number: 2013-001417-32) and ClinicalTrials.gov (number: NCT02019472). RESULTS: Significantly greater improvements from baseline in mean (SD) DAS28 (ESR) were observed at week 24 with sirukumab 100 mg every 2 weeks (-2.96 (1.580)) versus adalimumab 40 mg every 2 weeks (-2.19 (1.437); P<0.001). Sirukumab 50 mg every 4 weeks also showed significantly greater improvement from baseline at week 24 in DAS28 (ESR) (-2.58 (1.524)) compared with adalimumab (P=0.013). The ACR50 response rates with the 100 mg (35.3%) and 50 mg (26.9%) doses of sirukumab were comparable to that with adalimumab (31.7%) at week 24. The safety profile of sirukumab was consistent with that observed with anti-interleukin-6 receptor antibodies. A dose-related effect on the incidence of injection-site reactions was observed with sirukumab. CONCLUSION: Sirukumab monotherapy showed greater improvements in DAS28 (ESR), but similar ACR50 response rates, versus adalimumab monotherapy.

A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate.

OBJECTIVE: Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of rheumatoid arthritis (RA). The safety and efficacy of ustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and guselkumab, a human monoclonal anti-IL-23 antibody, were evaluated in adults with active RA despite methotrexate (MTX) therapy. METHODS: Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab 50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 and every 8 weeks (n=54) through week 28; all patients continued a stable dose of MTX (10-25 mg/week). The primary end point was the proportion of patients with at least a 20% improvement in the American College of Rheumatology criteria (ACR 20) at week 28. Safety was monitored through week 48. RESULTS: At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with placebo (40.0%) (p=0.101 and p=0.877, respectively). Through week 48, the proportions of patients with at least one adverse event (AE) were comparable among the treatment groups. Infections were the most common type of AE. CONCLUSIONS: Treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA. No new safety findings were observed with either treatment. TRIAL REGISTRATION NUMBER: NCT01645280.