A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia.

Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1ß (IL-1ß). We hypothesized that IL-1ß blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multicenter phase 2a study, patients aged 8 to 20 years with SCA (HbSS or HbSß0-thalassemia), history of acute pain episodes, and elevated high-sensitivity C-reactive protein >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg subcutaneous canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20, and 24 included electronic patient-reported outcomes, hospitalization rate, and adverse events (AEs) and serious AEs (SAEs). All but 1 of the 49 enrolled patients were receiving stable background hydroxyurea therapy. Although the primary objective (prespecified reduction of pain) was not met, compared with patients in the placebo arm, patients treated with canakinumab had reductions in markers of inflammation, occurrence of SCA-related AEs and SAEs, and number and duration of hospitalizations as well as trends for improvement in pain intensity, fatigue, and absences from school or work. Post hoc analysis revealed treatment effects on weight, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signal. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1ß blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as #NCT02961218.

DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function.

BACKGROUND: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. METHODS: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. FINDINGS: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. INTERPRETATION: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04382053.

Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study.

OBJECTIVES: To evaluate the effect of subcutaneous (s.c.) secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic progression in patients with psoriatic arthritis (PsA). METHODS: Adults (n=996) with active PsA were randomised 2:2:2:3 to s.c. secukinumab 300 mg or 150 mg with loading dose (LD), 150 mg without LD or placebo. All groups received secukinumab or placebo at baseline, weeks 1, 2 and 3 and then every 4 weeks from week 4. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 16. RESULTS: Significantly more patients achieved an ACR20 response at week 16 with secukinumab 300 mg with LD (62.6%), 150 mg with LD (55.5%) or 150 mg without LD (59.5%) than placebo (27.4%) (p<0.0001 for all; non-responder imputation). Radiographic progression, as measured by van der Heijde-modified total Sharp score, was significantly inhibited at week 24 in all secukinumab arms versus placebo (p<0.01 for 300 mg with LD and 150 mg without LD and p<0.05 for 150 mg with LD; linear extrapolation). Adverse event rates at week 24 were similar across treatment arms: 63.1% (300 mg with LD), 62.7% (150 mg with LD), 61.1% (150 mg without LD) and 62.0% (placebo). No deaths or new safety signals were reported. CONCLUSION: S.c. secukinumab 300 mg and 150 mg with and without LD significantly improved clinical signs and symptoms and inhibited radiographic structural progression versus placebo at week 24 in patients with PsA. TRIAL REGISTRATION NUMBER: NCT02404350; Results.

Comparing QT interval variability of semiautomated and high-precision ECG methodologies in seven thorough QT studies-implications for the power of studies intended for definitive evaluation of a drug's QT effect.

BACKGROUND: In studies of drug effects on electrocardiographic parameters, the level of precision in measuring QTc interval changes will influence a study's ability to detect small effects. METHODS: Variability data from investigational, placebo and moxifloxacin treatments from seven thorough QT studies performed by the same sponsor were analyzed with the objective to compare the performance of two commonly used approaches for ECG interval measurements: semiautomated (SA) and the high-precision QT (HPQT) analysis. Five studies were crossover and two parallel. Harmonized procedures were implemented to ensure similar experimental conditions across studies. ECG replicates were extracted serially from continuous 12-lead recordings at predefined time points from subjects supinely resting. The variability estimates were based on the time-point analysis of change-from-baseline QTcF as the dependent variable for the standard primary analysis of previous thorough QT studies. The residual variances were extracted for each study and ECG technique. RESULTS: High-precision QT resulted in a substantial reduction in ∆QTc variability as compared to SA. A reduction in residual variability or approximately 50% was achieved in both crossover and parallel studies, both for the active comparison (drug vs. placebo) and for assay sensitivity (moxifloxacin vs. placebo) data. CONCLUSIONS: High-precision QT technique significantly reduces QT interval variability and thereby the number of subjects needed to exclude small effects in QT studies. Based on this assessment, the sample size required to exclude a QTc effect >10 ms with 90% power is reduced from 35 with SA to 18 with HPQT, if a 3 ms underlying drug effect is assumed.

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses.

BACKGROUND: Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. OBJECTIVE: This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. METHODS: Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose. RESULTS: QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15) that was maximal and approximately 3-fold greater than that of omalizumab (P = .10) and 16-fold greater than that of placebo (P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. CONCLUSION: QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma.

Pharmacokinetics of fingolimod and metabolites in subjects with severe renal impairment: An open-label, single-dose, parallel-group study.

OBJECTIVE: This study assessed the pharmacokinetics and tolerability of fingolimod and its metabolites in severe renal impairment and healthy subjects. METHODS: In this single-dose, open-label study, 9 severe renal impairment subjects and 9 demographically matched healthy subjects were included. Each subject received a single oral dose of fingolimod 1.25 mg, and their blood and urine samples were assessed. The pharmacokinetics of fingolimod and its metabolites, fingolimod-phosphate (active metabolite, fingolimod-P), M2, and M3, were compared in both groups. Safety and tolerability were also assessed. RESULTS: In severe renal impairment subjects, mean±standard deviation values of Cmax (ng/mL) of fingolimod and fingolimod-P were 0.878±0.256 and 1.13±0.293 vs. 0.653±0.138 and 0.904±0.229 in healthy subjects, respectively. The overall drug exposures (AUCinf (ngxh/mL)) for fingolimod and fingolimod-P were 131±90.7 and 75.5±33.6 in severe renal impairment subjects vs. 82.3±36.9 and 65.9±30.6 in healthy subjects, respectively. t1/2 (hours) for fingolimod and fingolimod-P was comparable in severe renal impairment subjects (94±53 and 95±50) and healthy subjects (85±25 and 101±46). All adverse events were as expected for fingolimod 1.25 mg. CONCLUSIONS: The exposure to fingolimod and fingolimod-P was moderately increased (90% CI, 0.94-2.18) in severe renal impairment subjects, while half-lives and protein binding were similar to those in healthy subjects. Given that these changes are not clinically meaningful, fingolimod dose adjustment is considered unnecessary in patients with mild, moderate, or severe renal impairment.

Effect of fingolimod (FTY720) on cerebral blood flow, platelet function and macular thickness in healthy volunteers.

AIM: Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral disease modifying therapy approved for the treatment of relapsing multiple sclerosis. The aim of this double-blind, placebo-controlled study was to evaluate the effect of fingolimod on cerebral blood flow, platelet function and macular thickness in healthy volunteers. METHODS: The study included 88 healthy volunteers who received fingolimod 0.5 mg or 1.25 mg or matched placebo over a period of 4 weeks. Transcranial colour coded sonography was performed to measure mean blood flow velocities, the platelet function was measured by the PFA-100® assay using a collagen/epinephrine cartridge and macular thickness was measured using optical coherence tomography. An assessment of non-inferiority of fingolimod vs. placebo was performed against a reference value (20% of the overall baseline value). RESULTS: All 88 randomized participants completed the study. At day 28 compared with baseline value, for 0.5 mg, 1.25 mg and placebo treatments, the mean middle cerebral artery blood flow velocity decreased by 4, 1 and 3.7 cm s(-1), respectively. The platelet function analyzer closure time increase was not significant (7.8, 7.5 and 10.4 s, respectively). The mean percentage change in the central foveal thickness from baseline for both eyes was below 3% for all groups. The safety profile of fingolimod in this study was found consistent with the previous reports. CONCLUSIONS: In healthy volunteers, the changes seen with both fingolimod doses were found to be within normal variability, non-inferior and comparable with those observed with placebo for all the pharmacodynamic parameters assessed.

Pharmacokinetics of single and multiple oral doses of valsartan/amlodipine (80/5 mg) in healthy Chinese subjects.

OBJECTIVE: The efficacy and safety of valsartan/amlodipine combination have been demonstrated for the treatment of hypertension. In China, where the prevalence of hypertension is increasing the pharmacokinetic study of valsartan, amlodipine assumes significance. The aim of this study was to characterize the pharmacokinetics (PK) of valsartan and amlodipine following single- and multiple-dose oral administrations of valsartan/ amlodipine 80/5 mg fixed-dose combination in healthy Chinese subjects. MATERIALS AND METHODS: This was an open-label, two-period (single-dose treatment followed by a multiple-dose (once-daily for 9 days), with a 7-day intertreatment washout period) study conducted in 18 subjects. Serial blood samples were collected at pre-defined time points, and the plasma concentrations of valsartan and amlodipine were measured using LC-MS/MS. Safety was evaluated after single- and multiple-dose drug administration. RESULTS: Following the single-dose oral administration of valsartan/amlodipine 80/5 mg, valsartan and amlodipine plasma concentrations reached peak levels at median tmax of 3 and 6 h, respectively. These concentrations declined thereafter, with mean elimination half-lives of 7.7 h (single dose) and 8.6 h (multiple dose) for valsartan, and 47 h (single dose) and 45 h (multiple dose) for amlodipine. After a 9-day multiple-dose treatment (at steady state), accumulation of valsartan and amlodipine was consistent with their half-lives. The single- and multiple-dose administration of valsartan/amlodipine 80/5 mg was associated with asymptomatic hypotension, consistent with the pharmacological activity of the combination of these two blood pressure-lowering drugs when co-administered in healthy subjects. CONCLUSION: The PK of valsartan and amlodipine are linear following oral administration of valsartan/amlodipine fixed-dose combination.

Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results.

BACKGROUND: Fingolimod has a novel mechanism of action in multiple sclerosis, being a first-in-class sphingosine 1-phosphate receptor modulator. Because of a potential risk of fetal toxicity based on animal studies, women of childbearing potential are advised to take effective contraceptive measures during and for 2 months after stopping fingolimod therapy. To assess whether the efficacy of a combined oral contraceptive (OC) could be compromised during fingolimod therapy, a steady-state, drug-drug interaction study of fingolimod with ethinylestradiol/levonorgestrel was performed in healthy female volunteers. OBJECTIVE: To assess the interaction between fingolimod 0.5 mg once daily and ethinylestradiol 30 µg/ levonorgestrel 150 µg once daily at a steady state. METHODS: 31 healthy women received the combined OC only on Days 1 - 14, followed by OC plus fingolimod on Days 15 - 28. RESULTS: In the presence of fingolimod, ethinylestradiol pharmacokinetics were unchanged, and levonorgestrel maximum plasma concentration at steady state and area under the concentration-time curve during a dosing interval increased by factors of 1.10 (90% CI 1.05 - 1.16) and 1.22 (90% CI 1.18 - 1.27), respectively. CONCLUSIONS: Fingolimod therapy does not alter the pharmacokinetics of the combined OC ethinylestradiol/ levonorgestrel to a clinically significant degree. Ethinylestradiol/levonorgestrel does not alter the pharmacokinetics of fingolimod. Women receiving fingolimod therapy are able to use a combined OC as a means of effective birth control.

Sotrastaurin single-dose pharmacokinetics in de novo liver transplant recipients.

Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1-3 and once between days 5-8 post-transplant. Sotrastaurin absorption based on the area under the concentration-time curve (AUC) of total drug in blood (3544 ± 1434 ng·h/ml) was similar to that of healthy subjects in a previous study (4531 ± 1650 ng·h/ml). However, the sotrastaurin binding protein, α1-acid glycoprotein, was nominally higher in patients (1.07 ± 0.28 vs. 0.87 ± 0.16 g/l, P = 0.13) yielding a 60% lower AUC based on free drug versus that in healthy subjects (27 ± 13 vs. 62 ± 15 ng·h/ml, P < 0.0001). There was minor excretion of sotrastaurin in drained bile (1% of dose) consistent with the fact that sotrastaurin is extensively metabolized leaving little unchanged drug to excrete. In the first week after liver transplantation, sotrastaurin is bioavailable after oral administration. However, patients with elevated α1-acid glycoprotein levels may have lower free drug concentrations. Whether a higher dose of sotrastaurin is needed to compensate for this in the short-term after surgery will be addressed in future clinical trials.

Tolerability and Pulmonary Pharmacodynamic Effects During Treatment Initiation of Once-Daily Oral Fingolimod in Subjects With Moderate Asthma.

Fingolimod, a first-in-class sphingosine 1-phosphate receptor modulator, is the first approved oral therapy for relapsing multiple sclerosis (MS). While treatment initiation of clinical dose of fingolimod (0.5 mg) does not affect pulmonary function, supra-therapeutic doses (≥5.0 mg) increased airway resistance. The aim of this double-blind, placebo-controlled, parallel group, 10-day study was to measure the effect of fingolimod on pulmonary function in otherwise healthy patients with moderate asthma. Subjects (n = 36) were randomized into four cohorts that received either fingolimod 0.5, 1.25, 2.5 mg, or placebo once daily for 10 days. Subjects in placebo and fingolimod 0.5 mg groups did not differ in FEV1 AUEC0-6 h , FEF25-75% AUEC0-6 h , or in short-acting beta (ß) 2 agonists (SABA, rescue bronchodilator) use. Subjects on higher doses of fingolimod showed a mild reduction in FEV1 AUEC0-6 h and FEF25-75% AUEC0-6 h and a significant sixfold increase in SABA use versus placebo. One subject had moderately severe, acute exacerbation of asthma after receiving the first dose of fingolimod 1.25 mg that quickly responded to inhaled SABA. The observed safety profile was consistent with previous reports. These results provide reassurance that moderately asthmatic MS individuals can start on fingolimod 0.5 mg therapy with minimal effects on pulmonary function and SABA use.

Pharmacodynamic effects of steady-state fingolimod on antibody response in healthy volunteers: a 4-week, randomized, placebo-controlled, parallel-group, multiple-dose study.

Fingolimod, a first-in-class oral sphingosine 1-phosphate receptor (S1PR) modulator, is approved in many countries for relapsing-remitting multiple sclerosis, at a once-daily 0.5-mg dose. A reduction in peripheral lymphocyte count is an expected consequence of the fingolimod mechanism of S1PR modulation. The authors investigated if this pharmacodynamic effect impacts humoral and cellular immunogenicity. In this double-blind, parallel-group, 4-week study, 72 healthy volunteers were randomized to steady state, fingolimod 0.5 mg, 1.25 mg, or to placebo. The authors compared T-cell dependent and independent responses to the neoantigens, keyhole limpet hemocyanin (KLH), and pneumococcal polysaccharides vaccine (PPV-23), respectively, and additionally recall antigen response (tetanus toxoid [TT]) and delayed-type hypersensitivity (DTH) to KLH, TT, and Candida albicans. Fingolimod caused mild to moderate decreases in anti-KLH and anti-PPV-23 IgG and IgM levels versus placebo. Responder rates were identical between placebo and 0.5-mg groups for anti-KLH IgG (both > 90%) and comparable for anti-PPV-23 IgG (55% and 41%, respectively). Fingolimod did not affect anti-TT immunogenicity, and DTH response did not differ between placebo and fingolimod 0.5-mg groups. Expectedly, lymphocyte count reduced substantially in the fingolimod groups versus placebo but reversed by study end. Fingolimod was well tolerated, and the observed safety profile was consistent with previous reports.