Laura Fabbri

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome

Objective CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy. Design Multicentre cohort study. Patients Forty infants from 27+0 to 33+6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO2) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg. Outcome measures Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO2 after dosing and need for poractant-alfa rescue. Results Rapid and sustained improvements in FiO2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viral bronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected. Conclusions Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials. Trial registration number ClinicalTrials.gov NCT01651637.

Safety, pharmacokinetics, and pharmacodynamics of CHF 3381, a novel N-methyl-D-aspartate antagonist, after single oral doses in healthy subjects.

A double‐blind, randomized, placebo‐controlled study was performed to assess the safety, tolerability, and pharmacokinetics of single oral doses of CHF 3381 in 56 young healthy male volunteers. The central nervous system effects of CHF 3381 were also evaluated, as well as the effect of food on the rate and extent of CHF 3381 absorption. Seven doses of CHF 3381 (25, 50, 100, 200, 300, 450, and 600 mg) were evaluated in an escalating order. At each dose level, 6 subjects were given CHF 3381, and 2 subjects were given placebo. Safety and tolerability evaluation included adverse events, physical examination, vital functions, electrocardiogram, laboratory tests, and 24‐hour Holter (100‐mg and 450‐mg dose panels). Plasma and urinary concentrations of CHF 3381 and its two main metabolites (CHF 3567 and 2‐aminoindane) were measured with a validated high‐performance liquid chromatography method. Central nervous system effects were evaluated with the simple reaction time (SRT); learning memory task (LMT); Bond & Lader Visual Analog Scale for alertness, contentedness, and calmness; Addiction Research Center Inventory (ARCI); and electroencephalogram. There were no serious adverse events; the most frequent adverse events were dizziness, abnormal thinking, and asthenia. The number of adverse events with moderate intensity increased sharply with the dose, with no or few events up to 450 mg and 17 events with 600 mg. Therefore, 600 mg was defined as the maximum tolerated dose. There were no significant treatment effects on cardiovascular function and electrocardiogram parameters at any CHF 3381 dose or on oral temperature or laboratory tests. There were no clinically significant changes in laboratory variables. CHF 3381 was absorbed rapidly (tmax = 0.5–2 h) and cleared from plasma with a half‐life of 3 to 4 hours. Plasma levels of CHF 3381 and its two major metabolites were found to be proportional to the dose. 2‐Aminoindane formed slowly and reached much lower concentrations compared to the parent compound and the other metabolite (CHF 3567). Within 48 hours after dosing, 2% to 6% of the administered dose was found in the urine as unchanged drug, about 50% to 55% as the acid derivative (CHF 3567), and 2% to 3% as 2‐aminoindane. Ingestion of food did not affect the extent of absorption of the drug, while the rate of absorption was considerably reduced (tmax = 4 h). No significant effects of CHF 3381 were observed on attention (SRT) or memory (LMT). Visual analog scales revealed a decreasing effect of CHF 3381 on alertness at 1 hour that reached statistical significance at 300 and 600 mg. EEG spectral analysis revealed minor decreasing effects of the 200‐mg dose on total electric power measured at 2 hours. A stimulant effect was detected by the ARCI scale 24 hours after the 300‐mg dose and might be related to the slow formation of the 2‐aminoindane metabolite. In conclusion, this study has shown that the maximum tolerated dose of CHF 3381 after single oral administration in young healthy male volunteers is 600 mg. CHF 3381 displays linear pharmacokinetics in the dose range of 25 to 600 mg. The compound is rapidly absorbed and cleared from plasma with a half‐life of 3 to 4 hours. The ingestion of food seems to not affect the extent of absorption of the drug. Minor effects on the central nervous system were detected at doses equal to or greater than 300 mg.

First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease.

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimers disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.

Chronic Pulmonary Insufficiency of Prematurity: Developing Optimal Endpoints for Drug Development

C hronic pulmonary insufficiency is the most common health morbidity of extremely preterm birth. It is associated with increased resource utilization during the initial hospitalization, as well as short-term and longer-term respiratory morbidities that drive health care costs and are associated with worse neurodevelopmental outcomes. Chronic pulmonary insufficiency of prematurity (CPIP) refers to respiratory morbidity after preterm birth during the birth hospitalization and through infancy and childhood (Figure). It is usually captured during the initial hospitalization with a diagnosis of bronchopulmonary dysplasia (BPD). Despite advances in respiratory management, the incidence of BPD in the smallest neonates continues to rise, and there have been few therapeutic advances over the last 25 years. The many reasons for these ongoing gaps in drug development include difficulties with clinical trial design, a population viewed as high risk by regulators and industry, and the need to wait months or even years to establish safety and efficacy. These problems are compounded by definitions of BPD that are applied inconsistently and are not clearly related to long-term outcomes of importance to clinicians and families. Consideration of a broader concept of CPIP is important because the diagnosis of BPD does not capture all infants with chronic pulmonary insufficiency. The concept of BPD grew out of radiologic and pathological examinations of neonates with significant lung injury, and assumes that an oxygen requirement stems from lung damage that is similar between infants, and that different lung insults produce similar effects on the lung. Although oxygen dependence is related to injury of the lung parenchyma, it also may be influenced by injury to or immaturity of the brain, airways, or pulmonary vasculature. Moreover, an early measure of gas exchange might not reflect the pathophysiology of later problems, such as reactive airway disease or susceptibility to viral infections. Optimizing and harmonizing clinical definitions of CPIP, including BPD and later respiratory outcomes, while developing strong surrogate endpoints useful for regulators, industry, clinicians, and families would greatly benefit future interventional trials and accelerate the development of new therapies for these highrisk and vulnerable patients.

Is Less Invasive Surfactant Administration Necessary or “Only” Helpful or Just a Fashion?

In the 1990s, the most relevant pillars in the treatment of neonatal respiratory distress syndrome (RDS) have been improvements in ventilation strategies, the introduction of exogenous surfactant replacement therapy, and the use of antenatal steroids. Lately, in addition to the standard INSURE (INtubation-SURfactant administration-Extubation) method to administer surfactant, a new technique has been gaining increasing popularity. It is the so-called less invasive surfactant administration (LISA) method, which has shown promising results in preventing bronchopulmonary dysplasia development and in reducing mortality in preterm neonates. The rationale behind this technique is to avoid positive pressure ventilation and the endotracheal tube, being surfactant delivered through a thin catheter while the neonate is maintained on continuous positive airway pressure. Given the paucity of large-scale randomized trials on LISA method to prove its effects on short- and long-term outcomes, some questions still remain unanswered. Then, uncertainty regarding the feasibility of this maneuver needs to be better clarified before gaining wide acceptance in routine clinical practice. In our report, we aim at hypothesizing the main mechanisms behind the efficacy of LISA, considering it as a single maneuver in a comprehensive approach for RDS management in the delivery room.

Five-country manikin study found that neonatologists preferred using the LISAcath rather than the Angiocath for less invasive surfactant administration.

Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting.

Pharmacokinetic(PK)/pharmacodynamic(PD) evaluation of CHF 2819.01 (novel cholinesterase inhibitor) in patients with probable Alzheimer's disease

To assess the plasma and CSF pharmacokinetics/pharmacodynamics of CHF 2819.01 in patients with AD.