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Objectives Glucocorticoid sparing is a key priority for SLE management. We evaluated the effects of sustained glucocorticoid tapering in patients with SLE. Material and methods This was a post hoc analysis of the randomized, placebo-controlled, 52-week phase 3 Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of anifrolumab (300 mg i.v. once every 4 weeks for 48  weeks) plus standard therapy in patients with moderate to severe SLE. In a cohort of patients receiving glucocorticoids (prednisone or equivalent) 10 mg or more per day at baseline, we assessed changes in glucocorticoid dosage, patient-reported outcomes (PROs) and safety. Outcome measures were compared between sustained glucocorticoid taper responders (7.5 mg or less per day by week 40 sustained through week 52) and non-responders, regardless of treatment group, and between patients receiving anifrolumab or placebo. Results Among the 726 patients in the TULIP trials, 375 patients received glucocorticoids 10 mg or more per day at baseline, and of these, 155 (41%) patients were sustained glucocorticoid taper responders. Compared with non-responders (n  = 220), sustained glucocorticoid taper responders reduced their mean cumulative glucocorticoid dose by 32%, improved PRO scores, reduced blood pressure and experienced fewer serious adverse events. Sustained glucocorticoid tapering was achieved by 51% (96/190) of patients receiving anifrolumab vs 32% (59/185) receiving placebo. Compared with placebo, more anifrolumab-treated patients achieved both sustained glucocorticoid taper and reduced overall disease activity [38% (72/190) vs 23% (43/185)]. Conclusions Sustained glucocorticoid tapering is associated with clinical benefits. Anifrolumab treatment has potential to reduce disease activity and glucocorticoid exposure, a key goal of SLE management. Study Registration ClinicalTrials.gov identifier: NCT02446912 and NCT02446899. [ABSTRACT FROM AUTHOR]

Objective: To explore long‐term safety and tolerability of anifrolumab 300 mg compared with placebo in patients with systemic lupus erythematosus (SLE) who completed a Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trial and enrolled in the placebo‐controlled 3‐year long‐term extension (LTE) study (ClinicalTrials.gov identifier: NCT02794285). Methods: In the blinded LTE study, patients continued anifrolumab 300 mg, switched from anifrolumab 150 mg to 300 mg, or were re‐randomized from placebo to receive either anifrolumab 300 mg or to continue placebo, administered every 4 weeks. Primary comparisons in the LTE study were between patients who received anifrolumab 300 mg or placebo throughout the TULIP and LTE studies. For rare safety events, comparisons included patients who received any anifrolumab dose during TULIP or LTE. When exposure differed, exposure‐adjusted incidence rates (EAIRs) per 100 patient‐years were calculated. Results: In the LTE study, EAIRs of serious adverse events (SAEs) were 8.5 with anifrolumab compared with 11.2 with placebo; likewise, EAIRs of AEs leading to treatment discontinuation were 2.5 versus 3.2, respectively. EAIRs of non‐opportunistic serious infections were comparable between groups (3.7 with anifrolumab versus 3.6 with placebo). Exposure‐adjusted event rates of COVID‐related AEs, including asymptomatic infections, were 15.5 with anifrolumab compared with 9.8 with placebo. No COVID‐related AEs occurred in fully vaccinated individuals. EAIRs of malignancy and major acute cardiovascular events were low and comparable between groups. Anifrolumab was associated with lower cumulative glucocorticoid use and greater mean improvement in the SLE Disease Activity Index 2000, compared with placebo. Conclusion: This LTE study represents the longest placebo‐controlled clinical trial performed in SLE to date. No new safety findings were identified in the LTE study, supporting the favorable benefit–risk profile of anifrolumab for patients with moderate‐to‐severe SLE receiving standard therapy. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the pharmacokinetic/pharmacodynamic and pharmacodynamic/efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate to severe systemic lupus erythematosus. Data were pooled from the randomized, 52‐week, placebo‐controlled TULIP‐1 and TULIP‐2 trials of intravenous anifrolumab (150 mg/300 mg, every 4 weeks for 48 weeks). Pharmacodynamic neutralization was measured with a 21‐gene type I interferon gene signature (21‐IFNGS) in patients with high IFNGS. The pharmacokinetic/pharmacodynamic relationship was analyzed graphically and modeled with a nonlinear mixed‐effects model. British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response rates were compared across 21‐IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 were IFNGS high. Over 52 weeks, higher average anifrolumab serum concentrations were associated with increased median 21‐IFNGS neutralization, which was rapid and sustained with anifrolumab 300 mg (>80%, weeks 12‐52), lower and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. The proportion of patients with week 24 anifrolumab trough concentration exceeding the IC80 (3.88 μg/mL) was greater with anifrolumab 300 mg vs anifrolumab 150 mg (≈83% vs ≈27%), owing to the higher estimated median trough concentration (15.6 vs 0.2 μg/mL). BICLA response rates increased with 21‐IFNGS neutralization; more patients had a BICLA response in the highest vs lowest neutralization quartiles at week 52 (58.1% vs 37.6%). In conclusion, anifrolumab 300 mg every 4 weeks rapidly, substantially, and sustainably neutralized the 21‐IFNGS and was associated with clinical efficacy, supporting this dosing regimen in patients with systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

We characterized the population pharmacokinetics of anifrolumab, a type I interferon receptor–blocking antibody. Pharmacokinetic data were analyzed from the anifrolumab (intravenous [IV], every 4 weeks) arms from 5 clinical trials in patients with systemic lupus erythematosus (SLE) (n = 664) and healthy volunteers (n = 6). Population pharmacokinetic modeling was performed using a 2‐compartment model with parallel linear and nonlinear elimination pathways. The impact of covariates (demographics, interferon gene signature [IFNGS, high/low], disease characteristics, renal/hepatic function, SLE medications, and antidrug antibodies) on pharmacokinetics was evaluated. Time‐varying clearance (CL) was characterized using an empirical sigmoidal time‐dependent function. Anifrolumab exposure increased more than dose‐proportionally from 100 to 1000 mg IV every 4 weeks. Based on population pharmacokinetics modeling, the baseline median linear CL was 0.193 L/day in IFNGS‐high patients and 0.153 L/day in IFNGS‐low/healthy volunteers. After a year, median anifrolumab linear CL decreased by 8.4% from baseline. Body weight and IFNGS were significant pharmacokinetic covariates, whereas age, sex, race, disease activity, SLE medications, and presence of antidrug antibodies had no significant effect on anifrolumab pharmacokinetics. Anifrolumab at a concentration of 300 mg IV every 4 weeks was predicted to be below the lower limit of quantitation in 95% of patients ≈10 weeks after a single dose and ≈16 weeks after stopping dosing at steady state. To conclude, anifrolumab exhibited nonlinear pharmacokinetics and time‐varying linear CL; doses ≥300 mg IV every 4 weeks provided sustained anifrolumab concentrations. This study provides further evidence to support the use of anifrolumab 300 mg IV every 4 weeks in patients with moderate to severe SLE. [ABSTRACT FROM AUTHOR]

Objectives To characterize the relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with moderate to severe SLE despite standard therapy, using pooled data from two phase 3 trials. Methods TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks). For the exposure–response analysis, BILAG-based Composite Lupus Assessment (BICLA) or SLE Responder Index [SRI(4)] response rates at week 52 in each quartile/tertile of average anifrolumab serum concentration (Cave) were compared for anifrolumab and placebo in all-comers, patients who completed treatment, and IFN gene signature (IFNGS)-high patients who completed treatment, using average marginal effect logistic regression. Relationships between exposure and key safety events were assessed graphically. Results Of patients in TULIP-1/TULIP-2 who received anifrolumab (150 mg, n  = 91; 300 mg, n = 356) or placebo (n = 366), 574 completed treatment, of whom 470 were IFNGS high. In the exposure–efficacy analyses, BICLA and SRI(4) treatment differences favouring anifrolumab 300 mg vs placebo were observed across Cave subgroups and all analysis populations. Logistic regression identified Cave as a significant covariate for predicted BICLA response, as higher anifrolumab Cave predicted greater efficacy. There was no evidence of exposure-driven incidence of key safety events through week 52 in patients receiving anifrolumab 150 or 300 mg. Conclusion While higher Cave predicted greater efficacy, consistent positive benefit favouring anifrolumab 300 mg vs placebo was observed in BICLA and SRI(4) responses across Cave subgroups in the TULIP trials. There was no evidence of exposure-driven safety events. ClinicalTrial.gov numbers NCT02446912, NCT02446899 [ABSTRACT FROM AUTHOR]

Objectives The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I IFN receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure–response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. Methods The exposure–response relationship, pharmacokinetics (PK) and SLE Responder Index (SRI(4)) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. Results The population PK model found that type I IFNGS–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I IFN alpha receptor-mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. Conclusions Based on PK, efficacy and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE. [ABSTRACT FROM AUTHOR]

Objective: To investigate long‐term safety and tolerability of anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate‐to‐severe systemic lupus erythematosus (SLE). Methods: This 3‐year, multinational, open‐label extension study included adult patients who completed treatment (48 weeks of anifrolumab or placebo; 12‐week follow‐up) in the MUSE phase IIb randomized controlled trial (RCT). Patients initially received 1,000 mg of anifrolumab intravenously every 4 weeks, which was reduced to 300 mg every 4 weeks based on the benefit/risk profile established in the MUSE trial. Adverse events (AEs) were assessed monthly. Exploratory end points included the SLE Disease Activity Index 2000 (SLEDAI‐2K), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), pharmacodynamics, and health‐related quality of life (HRQoL). Results: Of the 246 patients who completed the RCT, 218 (88.6%) enrolled in the open‐label extension study, of which 139 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of open‐label extension treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment due to AEs. No new safety signals were identified. Improvement in the SLEDAI‐2K was sustained over 3 years. SDI and Short Form 36 health survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN‐high population, and C3, C4, and anti–double‐stranded DNA showed trends toward sustained improvement. Conclusion: Long‐term anifrolumab treatment demonstrates an acceptable safety profile with sustained improvement in SLE disease activity, HRQoL, and serologic measures. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To summarize results from pain and opioid use assessments with naloxegol in adults with opioid‐induced constipation (OIC) and chronic noncancer pain. Methods: Two phase 3 randomized, double‐blind, 12‐week studies evaluated the efficacy and safety of oral naloxegol (12.5 or 25 mg daily) in adults (18 to < 85 years) with confirmed OIC and chronic noncancer pain: KODIAC‐04 (NCT01309841) and KODIAC‐05 (NCT01323790). Pain level was assessed daily (11‐point numeric rating scale [NRS]; 0 = no pain, 10 = worst imaginable pain). Changes from baseline in mean weekly pain scores and opioid dose (weeks 1 through 12) were analyzed using mixed‐model repeated measures. Results: At baseline, mean daily NRS average pain scores ranged from 4.5 to 4.8 for all groups in KODIAC‐04 (N = 652) and were 4.6 for each group in KODIAC‐05 (N = 700). Respective mean ± SD changes from baseline average pain for placebo, naloxegol 12.5 mg, and naloxegol 25 mg were −0.2 ± 1.07, −0.3 ± 1.05 (P = 0.773 vs. placebo), and 0.2 ± 0.95 (P = 0.837 vs. placebo; KODIAC‐04) and −0.1 ± 0.94, −0.1 ± 0.87 (P = 0.744), and 0.0 ± 1.18 (P = 0.572; KODIAC‐05). At baseline, mean daily opioid doses ranged from 135.6 to 143.2 morphine equivalent units (MEUs)/day in KODIAC‐04, and from 119.9 to 151.7 MEUs/day in KODIAC‐05. Respective mean ± SD changes from baseline dose were −1.8 ± 30.19, −2.3 ± 20.52 (P = 0.724 vs. placebo), and 0.4 ± 13.01 (P = 0.188 vs. placebo; KODIAC‐04) and −0.3 ± 17.14, −1.3 ± 17.11 (P = 0.669 vs. placebo), and 0.1 ± 8.54 (P = 0.863 vs. placebo; KODIAC‐05). Changes in maintenance opioid dose were few; reasons for such changes were similar across treatment groups. Conclusion: Centrally mediated opioid analgesia was maintained during treatment with naloxegol in patients with noncancer pain and OIC. [ABSTRACT FROM AUTHOR]

TC-5214 (dexmecamylamine) is a nicotinic channel modulator that has previously been evaluated for treatment of major depression disorder (MDD) and is currently being evaluated by Targacept as a treatment for overactive bladder. A comprehensive population pharmacokinetic (POP PK) model of TC-5214 was developed using nonlinear mixed-effects modeling of pooled plasma concentration data from 6 early phase I studies in 179 healthy participants or patients with non-MDD and 1 phase II study in 68 MDD patients. Concentration-time profiles of TC-5214 after either single or multiple oral doses of TC-5214 was described by a one-compartment model with first-order absorption with lag time and first-order elimination. Covariate analysis revealed that creatinine clearance was a significant covariate on clearance and that body weight significantly influenced the central volume of distribution. The final model (with identified covariates) was used to simulate steady-state exposure for patients with impaired renal function. Results from forest plots reveal that patients with moderate to severe renal impairment or end stage renal disease are associated with significantly higher Cssmax and AUC compared to patients with normal renal function. The proposed final POP PK model could be employed in defining a TC-5214 dosage regimen in patients with impaired renal function. [ABSTRACT FROM AUTHOR]