Pharmacokinetics and pharmacodynamics across infusion rates of intravenously administered nipocalimab: results of a phase 1, placebo-controlled study.

Introduction: Nipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibody-mediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo. Methods: The current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebo-controlled, sequential-dose study. Forty participants were randomized to receive nipocalimab 30 mg/kg over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min); nipocalimab 60 mg/kg over 15 min (4 mg/kg/min); or matching placebo. Results: At doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min (maximum clinically feasible rate), single doses of nipocalimab were tolerable, with 12 (40%) participants experiencing AEs across nipocalimab cohorts compared with 1 (10%) participant in the placebo cohort. AEs deemed treatment related occurred in 6 (20%) participants receiving nipocalimab and 1 (10%) participant receiving placebo. None of the AEs were severe, and no participants discontinued treatment due to AEs. Nipocalimab provided consistent, dose-dependent serum pharmacokinetics and IgG reductions, regardless of infusion rate. Discussion: This study supports the use of shortened durations of nipocalimab infusion for future studies.

Safety and Efficacy of Nipocalimab in Patients With Generalized Myasthenia Gravis: Results From the Randomized Phase 2 Vivacity-MG Study

BACKGROUND AND OBJECTIVES: To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups. RESULTS: Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend). DISCUSSION: Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG. TRIAL REGISTRATION INFORMATION: Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.

Agreement between the Swept-Source Optical Coherence Tomography and the Image-Guided System for Biometry Assessment in Cataract Surgery.

PURPOSE: To assess the agreement on biometric data obtained using the Verion image-guided surgery system and the swept-source-OCT biometer IOL Master 700. MATERIALS AND METHODS: All patients underwent biometry using the SS-OCT and the Image-Guide System. The comparison between instruments was assessed using the Intraclass correlation coefficient (ICC). Level of Agreement (LoA) employing the Bland-Altman analysis. RESULTS: The image-based system produced significantly higher keratometry values, evidencing a low LoA between the SS-OCT and the image-based system, ranging from -1.30 D to 0.65 D (1.95 D), -1.04 D to 0.72 D (1.76 D), and -1.31 D to 0.65 D (1.96 D), respectively. The LoA for the Cylinder ranged from -0.46 D to 0.74 D (1.2 D) and from 0.82 to 0.94 mm for WTW. CONCLUSIONS: In our study, the SS-OCT biometer and the Image-based System evidenced statistically significant differences in measuring the main biometric parameters except for the WTW.

Unintentional injection of a dexamethasone implant into the crystalline lens: a case report.

The intravitreal dexamethasone implant is a sustained-release anti-inflammatory drug system that releases 0.7 mg of dexamethasone into the vitreous cavity. The following case report describes a rare complication: accidental injection of the dexamethasone implant into the crystalline lens. A 73-year-old woman was diagnosed with central retina vein occlusion and cystoid macular edema. Initial tSreatment included three monthly intravitreal doses of anti-vascular endothelial growth factor treatment, which was not successful. Treatment was then modified to an intravitreal dexamethasone implant. Ten weeks later, the implant was observed in the posterior cortex of the crystalline lens. Because no improvement had occurred, the patient underwent phacoemulsification surgery, during which part of the lens migrated into the vitreous cavity. Therefore, 23-gauge pars plana complete vitrectomy was performed with trans-surgical administration of intravitreal aflibercept. Crystalline lens injury due to an intravitreal dexamethasone implant is a rare complication and typically results from the injection procedure. Immediate surgical or conservative approaches should be considered on an individual basis.

Unintentional injection of a dexamethasone implant into the crystalline lens: a case report / Injeção não intencional de implante de dexametasona no cristalino: relato de caso, acompanhamento e desfecho

ABSTRACT The intravitreal dexamethasone implant is a sustained-release anti-inflammatory drug system that releases 0.7 mg of dexamethasone into the vitreous cavity. The following case report describes a rare complication: accidental injection of the dexamethasone implant into the crystalline lens. A 73-year-old woman was diagnosed with central retina vein occlusion and cystoid macular edema. Initial tSreatment included three monthly intravitreal doses of anti-vascular endothelial growth factor treatment, which was not successful. Treatment was then modified to an intravitreal dexamethasone implant. Ten weeks later, the implant was observed in the posterior cortex of the crystalline lens. Because no improvement had occurred, the patient underwent phacoemulsification surgery, during which part of the lens migrated into the vitreous cavity. Therefore, 23-gauge pars plana complete vitrectomy was performed with trans-surgical administration of intravitreal aflibercept. Crystalline lens injury due to an intravitreal dexamethasone implant is a rare complication and typically results from the injection procedure. Immediate surgical or conservative approaches should be considered on an individual basis.

RESUMO O implante intravítreo de dexametasona é um sistema anti-inflamatório de liberação sustentada que libera 0,7 mg de dexametasona na cavidade vítrea. O relato de caso a seguir descreve uma complicação rara: injeção acidental do implante de Dexametasona no cristalino. Uma mulher de 73 anos foi diagnosticada com oclusão da veia central da retina e edema macular cistóide. O tratamento inicial incluiu três doses intravítreas mensais de tratamento com fator de crescimento endothelial anti-vascular, que não tiveram sucesso. O tratamento foi então mudado para um implante intravítreo de dexametasona. Dez semanas depois, o implante foi observado no córtex posterior do cristalino. Como não houve melhora, a paciente foi submetida à cirurgia de facoemulsificação, durante a qual parte do cristalino migrou para a cavidade vítrea. Portanto, foi realizada vitrectomia completa via pars plana 23-gauge com administração de aflibercepte intravítreo durante a cirurgia. Lesões no cristalino devido a implantes intravítreos de dexametasona são uma complicação rara e geralmente resulta do procedimento de injeção. Abordagens cirúrgicas ou conservadoras imediatas devem ser consideradas caso a caso.

M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study.

M281 is a fully human, anti-neonatal Fc receptor (FcRn) antibody that inhibits FcRn-mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double-blind, placebo-controlled, first-in-human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose-dependent serum IgG reductions, which were similar across all IgG subclasses. Multiple weekly doses of 15 or 30 mg/kg achieved mean IgG reductions of ≈85% from baseline and maintained IgG reductions ≥75% from baseline for up to 24 days. M281 was well tolerated, with no serious or severe adverse events (AEs), few moderate AEs, and a low incidence of infection-related AEs similar to placebo treatment. The tolerability and consistency of M281 pharmacokinetics and pharmacodynamics support further evaluation of M281 in diseases mediated by pathogenic IgG.

Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial.

PURPOSE: To evaluate efficacy and safety of adjunctive treatment with rufinamide 1600 mg twice daily in subjects aged > or = 16 years with refractory partial seizures. METHODS: This double-blind, placebo-controlled, randomized, parallel-group, multicenter trial included an 8-week baseline phase and a 13-week double-blind phase. Treatment was initiated with rufinamide 400 mg twice daily or placebo; rufinamide was titrated to 1600 mg twice daily. Percentage change in partial seizure frequency was the primary outcome measure. Secondary outcome measures included total partial seizure frequency and the percentage of subjects experiencing a >/=50% reduction in partial seizure frequency. RESULTS: Three hundred thirteen subjects were randomized; 156 subjects received rufinamide and 157 received placebo. Rufinamide-treated subjects experienced a 20.4% median reduction in partial seizure frequency relative to baseline, while placebo-treated subjects had an increase of 1.6% (p = 0.02). Exclusion of subjects taking carbamazepine in a post hoc analysis resulted in a reduction of 29.2% versus 0.7% in the placebo group (p = 0.05), whereas the treatment difference in subjects taking carbamazepine was not significant. Of rufinamide-treated subjects, 28.2% experienced a > or = 50% decrease in partial seizure frequency versus 18.6% of placebo-treated subjects (p = 0.04). The most common adverse events associated with rufinamide treatment were dizziness, nausea, diplopia, and ataxia; they occurred primarily during the titration phase. DISCUSSION: Adjunctive therapy with rufinamide 3200 mg/day compared with matching placebo demonstrated efficacy and was generally well tolerated in adults with partial seizures. Further study of this agent in adults with partial seizures taking a range of baseline AEDs is warranted.

Rufinamide.

Rufinamide is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs. Rufinamide was profiled for anticonvulsant activity at the National Institutes of Health and showed broad-spectrum anticonvulsant properties at nontoxic doses in animal models. The principal mechanism of action of rufinamide is considered to be the modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide provides an efficacious and well-tolerated treatment option for use as adjunctive therapy in patients with partial seizures and with Lennox-Gastaut syndrome (LGS). In LGS, rufinamide is effective in controlling multiple seizure types and in reducing the severity of the seizures. The most commonly observed (> or =10%) adverse experiences seen in association with rufinamide are headache, dizziness, fatigue, somnolence and nausea. Rufinamide is generally well tolerated, and its safety profile is well-established.

Psychiatric disorders, trauma, and MMPI profile in a Spanish sample of nonepileptic seizure patients.

The aim of this study was to examine clinical characteristics in patients with psychogenic nonepileptic seizures and to analyze the Minnesota Multiphasic Personality Inventory (MMPI) profiles and their relation to psychopathology. Thirty patients with nonepileptic seizures confirmed through video-electroencephalography were included. A structured clinical interview (Structured Clinical Interview for DSM-III-R), a measure of personality variables (MMPI), and several structured interviews designed for collecting data on clinical and personal history were administered. Descriptive and comparative statistical methods were used. Of the sample, 67.7% met criteria for two or more simultaneous Axis I diagnoses, and 60% for an Axis II personality disorder. The most frequently elevated scales of the MMPI were Schizophrenia and Depression. There were multiple scale elevations in 12 profiles, the 91.7% of which had elevated "neurotic" and "psychotic" scales. The subgroup with personality disorders showed higher scores on the MMPI Paranoia and Hypomania scales, and the subgroup with traumatic experiences showed higher scores on the MMPI Hypomania scale. Our sample comprising patients with nonepileptic seizures showed a significant degree of psychopathology and absence of a unique character substrate. According to grades of clinical severity of pseudoseizures, several subgroups and different therapeutic implications may be defined.

Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures.

PURPOSE: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add-on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs). METHODS: An international (13 countries), multicenter (45 centers), 12-week, double-blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8-week baseline (pretreatment phase) and the 12-week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent-to-treat population. RESULTS: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [-11.5 (p = 0.0007) and -31.4 (p < or = 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure-frequency reductions from baseline of -1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p < or = 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (> or =50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p < or = 0.001). PGB was well tolerated. Dose-related, treatment-emergent adverse events (> or =10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo. CONCLUSIONS: PGB, 150 mg/day and 600 mg/day, is highly effective and well-tolerated add-on therapy in patients with partial seizures.

Translating monotherapy trials into clinical practice: a look into the abyss.

To be approved for monotherapy by regulatory authorities, new antiepileptic drugs (AEDs) must first be tested in well-controlled studies in refractory patients (conversion to monotherapy trials) or in patients with newly diagnosed epilepsy. However, the applicability of the information obtained in these trials to day-to-day clinical practice is limited. Clinical trials in newly diagnosed patients, particularly those allowing dose flexibility, offer more useful information, but a close scrutiny of methodological details is required to avoid misinterpretation of the findings. In many instances, the neurologist has a drug with a label, but lacks critical information on optimal titration rates, optimal target and maintenance dosages, response rates in populations with different epilepsy syndromes, different age ranges and comorbidities, and long-term safety data. Such information becomes available only through general clinical experience, well-designed phase IV studies, and postmarketing surveillance.

Safety profile of levetiracetam.

A good balance between safety and tolerability is necessary for an antiepileptic drug (AED) to be successful in the management of patients with epilepsy. Levetiracetam is one of the new generation of AEDs licensed as an add-on therapy for the treatment of patients with partial-onset seizures. Leveti-racetam's mechanisms of action are not fully understood. Controlled clinical trials, open-label studies, and postmarketing surveillance indicate that leveti-racetam has a favorable safety profile characterized by little effect on vital signs or clinical laboratory values, reported adverse events that are mild to moderate, and no known drug-drug interactions. The tolerability of levetiracetam may extend to both pediatric and elderly patients based on analyses of small numbers of patients. Tolerability is maintained over the long term. Levetirac-etam does not appear to have a different safety profile in learning-disabled patients. Levetiracetam appears to have a good balance between tolerability and efficacy in the treatment of a wide variety of patients with partial epilepsy.

Is refractory epilepsy preventable?

About a third of the patients diagnosed with epilepsy will not be fully controlled with antiepileptic drugs (AEDs), and many of them will have frequent and disabling seizures. These patients will undergo multiple drug trials, most often without complete seizure remission. Moreover, refractory epilepsy is associated with increased morbidity (from seizures and medications), social isolation, unemployment, and overall reduced quality of life. There is evidence that refractory epilepsy can be a progressive disorder, which, if controlled early, might never develop into a full syndrome with all of its associated sequelae. The difficulty lies in identifying at an early stage patients who are likely to progress to intractability. No currently known markers enable clinicians to make this identification with confidence. Advances in pharmacogenomics and our understanding of pharmacologic responsiveness in epilepsy may change this situation. Even now, we are able to identify many patients with a poor prognosis earlier than before, particularly in the pediatric population, in which syndromic classification may provide an approach to predict intractability. The early initiation of aggressive therapy may improve outcome and overall quality of life.