Explore the vast range of titles available.

In this phase 1 study involving persons with hypertension, zilebesiran (an RNA interference therapeutic agent) was associated with decreases in angiotensin levels and systolic and diastolic blood pressure.

Givosiran, an RNA interference‐based therapeutic, is a recent addition to the limited treatment armamentarium for acute hepatic porphyria (AHP). As a small interfering RNA that is selectively taken up in the liver, both the mechanism and targeted delivery create a complex relationship between givosiran pharmacokinetics (PK) and the pharmacodynamic (PD) response. Using pooled data from phase I–III clinical trials of givosiran, we developed a semimechanistic PK/PD model to describe the relationship between predicted liver and RNA‐induced silencing complex concentrations of givosiran and the associated reduction in synthesis of δ‐aminolevulinic acid (ALA), a toxic heme intermediate that accumulates in patients with AHP, contributing to disease pathogenesis. Model development included quantification of variability and evaluation of covariate effects. The final model was used to assess the adequacy of the recommended givosiran dosing regimen across demographic and clinical subgroups. The population PK/PD model adequately described the time course of urinary ALA reduction with various dosing regimens of givosiran, the interindividual variability across a wide range of givosiran doses (0.035–5 mg/kg), and the influence of patient characteristics. None of the covariates tested had a clinically relevant effect on PD response that would necessitate dose adjustment. For patients with AHP, including adults, adolescents, and patients with mild to moderate renal impairment or mild hepatic impairment, the 2.5‐mg/kg once monthly dosing regimen of givosiran results in clinically meaningful ALA lowering, reducing the risk for AHP attacks.

Background Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics. Methods Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both. Results In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV 1 post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation. Conclusions In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma. Trial registration ClinicalTrials (NCT): NCT00507130 and ClinicalTrials (NCT): NCT00590720

Background Cemdisiran, an N -acetylgalactosamine (GalNAc) conjugated RNA interference (RNAi) therapeutic, is currently under development for the treatment of complement-mediated diseases by suppressing liver production of complement 5 (C5) protein. This study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cemdisiran in healthy subjects and in patients with paroxysmal nocturnal hemoglobinuria (PNH) in order to support dose selection for late-stage clinical trials. Methods Healthy volunteers (HVs; n  = 32, including 12 Japanese subjects) were randomized (3:1) to receive single doses of subcutaneous cemdisiran (50–900 mg) or placebo, or repeat doses of subcutaneous cemdisiran (100–600 mg) or placebo weekly, biweekly, weekly/biweekly, or weekly/monthly for 5, 8, or 13 weeks ( n  = 24). Cemdisiran 200 or 400 mg was administered weekly in an open-label manner, for varying durations, as monotherapy in three eculizumab-naïve PNH patients or in combination with eculizumab in three PNH patients who were receiving stable label doses of eculizumab (900 or 1200 mg biweekly) before the start of the study. After the last dose of cemdisiran, patients were followed for safety and ongoing pharmacologic effects with the eculizumab regimen (600 or 900 mg every month). Results In HVs, cemdisiran was rapidly converted to a major active metabolite, AS(N-2)3′-cemdisiran, both declining below the lower limit of quantification (LLOQ) in plasma within 48 h, and showing minimal renal excretion. AS(N-2)3′-cemdisiran exhibited more than dose-proportional PK. The C5 protein reductions were dose-dependent, with > 90% reduction of C5 protein beginning on days 21–28 and maintained for 10–13 months following single and biweekly doses of 600 mg. The dose–response relationship, described by an inhibitory sigmoid maximum effect ( E max ) model, estimated half-maximal effective dose (ED 50 ) of 14.0 mg and maximum C5 reduction of 99% at 600 mg. The PK and PD were similar between Japanese and non-Japanese subjects, and PNH patients and HVs. One of 48 subjects tested transiently positive for antidrug antibody with low titer, with no impact on PK or PD. In PNH patients, C5 suppression by cemdisiran enabled effective inhibition of residual C5 levels with lower dose and/or dosing frequency of eculizumab, which was maintained for 6–10 months after the last dose of cemdisiran. Conclusions Consistent with the PK/PD properties of liver targeting GalNac conjugates, cemdisiran and AS(N-2)3′-cemdisiran plasma concentrations declined rapidly while showing rapid and robust C5 suppression maintained up to 13 months following single and multiple doses, which indicates long residence times of cemdisiran within hepatocytes. The long PD duration of action in liver, low immunogenicity and acceptable safety profiles enables low, infrequent SC dosing and support further evaluation of cemdisiran in complement-mediated diseases as monotherapy or in combination with a C5 inhibitor antibody. Clinical Trial Registration No NCT02352493.

Background and Objective Givosiran, approved for the treatment of acute hepatic porphyria (AHP), is the first subcutaneously administered RNAi therapeutic. This analysis was undertaken to describe the plasma pharmacokinetics (PK) of givosiran and its active metabolite, AS(N-1)3′ givosiran, and to identify factors that contribute to intersubject PK variability. Methods A population PK model was developed using data from givosiran clinical trials that enrolled patients with AHP or who were asymptomatic chronic high excreters (CHEs) of toxic heme intermediates. Givosiran and AS(N-1)3′ givosiran PK were modeled simultaneously using non-linear mixed-effects modeling. Results Plasma PK of givosiran was best described by a two-compartment model. Givosiran absorption after subcutaneous administration and conversion of givosiran to AS(N-1)3′ givosiran were incorporated as first-order processes. Hepatic clearance was the major route of elimination from the central compartment, with renal clearance accounting for < 20% of the total clearance. Body weight, East Asian ethnicity, and renal impairment were significant covariates in the model; however, none of the covariates evaluated resulted in clinically meaningful differences in plasma exposures of givosiran and AS(N-1)3′ givosiran. The model adequately described observed concentrations and variability across a wide range of dose levels. Model-derived simulations showed similar exposures for givosiran and its active metabolite in adults and adolescents. Conclusions The PK of givosiran and its active metabolite were not significantly affected by demographic or clinical parameters that would require adjustment from the approved body weight-based dose of givosiran 2.5 mg/kg once monthly.

Background and Objective Variants of the transthyretin ( TTR ) gene cause hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis (v for variant), which results from deposition of misfolded TTR protein as amyloid in organs and tissues. Patisiran is an RNA interference (RNAi) therapeutic that suppresses the hepatic production of TTR protein. Patisiran improves multiple clinical manifestations of hATTR amyloidosis in patients without liver transplantation (LT). Because the liver is the predominant source of circulating TTR, LT has been prescribed to eliminate the production of the variant TTR. However, the continued production of wild-type TTR can contribute to disease progression after LT. Patisiran could potentially address an unmet need in these affected patients. This clinical trial was conducted to evaluate the safety, efficacy, and pharmacokinetics (PK) and pharmacodynamics (PD) of patisiran in patients with hATTR amyloidosis with polyneuropathy progression after LT. In this paper, we describe the PK/PD of patisiran in post-LT patients and compare it with prior patisiran studies in healthy subjects and patients without LT. Methods In an open-label study, patients ( N = 23) with hATTR amyloidosis with polyneuropathy progression after LT received 0.3 mg/kg patisiran intravenously every 3 weeks (q3w) for 12 months. As a post hoc analysis, the PK and PD results from the current study were compared with prior patisiran studies in healthy volunteers from a Phase 1 study and in patients with hATTR amyloidosis without LT from Phase 2 and 3 studies. Results The PK profile of patisiran siRNA (ALN-18328) and its 2 lipid excipients, DLin-MC3-DMA and PEG2000-C-DMG, in hATTR amyloidosis patients after LT was consistent with prior patisiran studies in non-LT subjects. Plasma PK profiles of ALN-18328 and DLin-MC3-DMA exhibited 2 phases, the first characterized by a short distribution half-life and the second by a minor peak and relatively long elimination half-life. The plasma concentrations of PEG 2000 -C-DMG reached C max at the end of infusion and declined in a multiphasic manner. There was no appreciable accumulation at steady state. Consistent with prior studies in non-LT subjects, the post-LT patients showed a robust, and sustained TTR reduction; with median TTR reduction from baseline of 91% (average of Month 6 and Month 12). No anti-drug antibodies were observed in any patient. Conclusions The consistency of patisiran PK and PD between patients with and without LT suggests that neither LT nor concomitantly administered immunosuppressants influence hepatic uptake or RNAi activity of patisiran. The patisiran dosing regimen of 0.3 mg/kg q3w is appropriate for hATTR amyloidosis patients with or without LT. Clinical Trial Registration No NCT03862807.

Background and Objective VIR-2218 is an investigational N -acetylgalactosamine–conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology. This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers. Methods Preclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50–900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods. Results In rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3’VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration ( t max ) of 4–7 h, and had a short median plasma half-life of 2–5 h. Plasma exposures for area under the plasma concentration–time curve up to 12 h (AUC 0–12 ) and mean maximum concentrations ( C max ) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for C max . A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3’VIR-2218, with a median t max of 6–10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3’VIR-2218 was similar to that of VIR-2218, with plasma AUC 0–12 and C max values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3’VIR-2218 were detectable in urine through the last measured time point, with approximately 17–48% of the administered dose recovered in urine as unchanged VIR-2218 over 0–24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data). Conclusions VIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection. Clinical Trial Registration No NCT03672188, September 14, 2018.

Background and Objectives Sifalimumab is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes a majority of the subtypes of human interferon-α. Sifalimumab is being evaluated as a treatment for systemic lupus erythematosus (SLE). The primary objectives of this analysis were (a) to develop a population pharmacokinetic model for sifalimumab in SLE; (b) to identify and quantitate the impact of patient/disease characteristics on pharmacokinetic variability; and (c) to evaluate fixed versus body weight (WT)-based dosing regimens. Methods Sifalimumab serum concentration-time data were collected from a phase Ib study (MI-CP152) designed to evaluate the safety and tolerability of sifalimumab in adult patients with SLE. Sifalimumab was administered every 14 days as a 30- to 60-minute intravenous infusion with escalating doses of 0.3, 1.0, 3.0, and 10 mg/kg and serum concentrations were collected over 350 days. A total of 120 patients provided evaluable pharmacokinetic data with a total of 2,370 serum concentrations. Sifalimumab serum concentrations were determined using a validated colorimetric enzyme-linked immunosorbent assay (ELISA) with a lower limit of quantitation of 1.25 μg/mL. Population pharmacokinetic modeling of sifalimumab was performed using a non-linear mixed effects modeling approach with NONMEM VII software. Impact of patient demographics, clinical indices, and biomarkers on pharmacokinetic parameters were explored using a stepwise forward selection and backward elimination approach. The appropriateness of the final model was tested using visual predictive check (VPC). The impact of body WT-based and fixed dosing of sifalimumab was evaluated using a simulation approach. The final population model was utilized for phase IIb dosing projections. Results Sifalimumab pharmacokinetics were best described using a two-compartment linear model with first order elimination. Following intravenous dosing, the typical clearance (CL) and central volume of distribution ( V 1 ) were estimated to be 176 mL/day and 2.9 L, respectively. The estimates (coefficient of variation) of between-subject variability for CL and V 1 were 28 and 31 %, respectively. Patient baseline body WT, interferon gene signature from 21 genes, steroid use, and sifalimumab dose were identified as significant covariates for CL, whereas only baseline body WT was a significant covariate for V 1 and peripheral volume of distribution ( V 2 ). Although the above-mentioned covariates were statistically significant, they did not explain variability in pharmacokinetic parameters to any relevant extent (<7 %). Thus, no dosing adjustments are necessary. VPC confirmed good predictability of the final population pharmacokinetic model. Simulation results demonstrate that both fixed and body WT-based dosing regimens yield similar median steady state concentrations and overall variability. Fixed sifalimumab doses of 200, 600, and 1,200 mg monthly (with a loading dose at Day 14) were selected for a phase IIb clinical trial. Conclusion A two-compartment population pharmacokinetic model adequately described sifalimumab pharmacokinetics. The estimated typical pharmacokinetic parameters were similar to other monoclonal antibodies without target mediated elimination. Although the population pharmacokinetic analysis identified some statistically significant covariates, they explained <7 % between-subject variability in pharmacokinetic parameters indicating that these covariates are not clinically relevant. The population pharmacokinetic analysis also demonstrated the feasibility of switching to fixed doses in phase IIb clinical trials of sifalimumab.

Acute hepatic porphyria (AHP) is a family of rare, serious, and potentially life‐threatening metabolic disorders caused by mutations in genes encoding enzymes involved in hepatic heme biosynthesis. AHP is characterized by accumulation of neurotoxic heme intermediates, δ‐aminolevulinic acid (ALA), and porphobilinogen (PBG), which are thought to be causal for the disease manifestations. Novel therapeutic treatments such as givosiran, an RNA interference therapeutic that was recently approved for treatment of adults with AHP, are focused on reducing the levels of ALA and PBG in patients toward levels observed in a healthy population. While there are two published reports on the distribution of urinary ALA and PBG levels in healthy subjects, these lacked the required details to enable the calculation of reference limits for ALA and PBG. Therefore, urinary ALA and PBG levels were quantified in 150 healthy subjects using a validated liquid chromatography tandem mass spectrometry (LC‐MS/MS) method that is highly sensitive, specific, accurate, and reproducible. These data were used to establish the upper limit of normal (ULN) values for ALA and PBG as 1.47 and 0.137 mmol/mol Cr, respectively. Relative to these ULN values, baseline urinary ALA and PBG levels in AHP patients were found to be 9.3‐ to 12‐fold, and 238‐ to 336‐fold higher, respectively. Results from this study can serve as a guide to assess the effectiveness of therapeutic interventions in lowering ALA and PBG.