Donanemab (LY3002813) Phase 1b Study in Alzheimer's Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging.

BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an N­terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814).

Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aß) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aß production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aß species and soluble amyloid precursor proteins (sAPPß) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aß1-40 and Aß1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

Endobronchial cuff pressures.

In 20 adult patients (18 male) who presented for thoracotomy, the trachea was intubated using Mallinckrodt disposable double-lumen tubes (18 large and two medium). The endobronchial cuff was inflated by a trained operating department assistant using an air-filled syringe. The volume of air and the initial endobronchial cuff pressure were measured. The minimum cuff pressure required to prevent respiratory gas leakage from the isolated lung was measured also and maintained using the Cardiff Cuff Controller. Mean initial cuff pressure was 69.3 (SEM 6.0) mm Hg, whereas the mean minimum cuff pressure was 29.5 (4.0) mm Hg (P < 0.0001). The results suggest that the method described of inflating the endobronchial cuff may lead to overinflation and subsequent excessive pressure on the endobronchial wall.

The Riyadh Intensive Care Program applied to a mortality analysis of a teaching hospital intensive care unit.

A computerised system of prediction of death using the Riyadh Intensive Care Program was applied retrospectively over a 17-month period to data collected prospectively on 1155 patients admitted to our intensive care unit. Variables which enable organ failure scores to be generated were recorded daily to make these predictions. Consultant medical opinion predicted that outcome was hopeless in 55% (115/209) of the patients who died. The predictive power of the computer demonstrated a sensitivity of 14.8% and a specificity of 99.8%. It is possible that the occurrence of three false predictions of death in the latter part of the series may have been related to a change in our antibiotic policy. We would be unhappy to recommend the general use of a computerised program for prediction of death without careful explanation of its significance and dangers.

Resuscitation in late pregnancy.

This paper considers cardiopulmonary resuscitation in obstetric patients at term and the influence of aortocaval compression on the outcome. The maximum chest compression force produced by eight physicians was measured as a function of angle of inclination using an inclined plane. The compression force at an angle of 27 degrees is 80% of that in the supine position and the Cardiff resuscitation wedge, designed to prevent aortocaval compression, is described with this inclination. Midwives' expertise in basic life support 6 months after instruction was assessed using a manikin simulator. The majority had acquired errors in external chest compression and mouth to mouth ventilation. These were corrected by additional tuition. Resuscitation of the manikin on the Cardiff wedge was found to be as efficient as in the supine position.

Tracheal tube cuff pressure. Clinical use of the Cardiff Cuff Controller.

Seventy-one adult patients (31 male, 40 female) who presented for surgery underwent orotracheal intubation with Portex Blue Line standard cuff disposable tubes (9-mm for males, 8-mm for females). The tracheal tube cuff was inflated by a trained assistant using a syringe and the initial cuff pressure measured; the minimum cuff pressure required to prevent respiratory gas leakage was also measured and the cuff pressure maintained above this pressure throughout the operation by means of the Cardiff Cuff Controller. Initial cuff pressure values averaged 11.9 kPa for males and 13.5 kPa for females compared with minimum cuff pressure values of 5.2 and 1.2 kPa, respectively. The differences between initial and minimum pressures were statistically highly significant (p much less than 0.001). It is concluded that the present method of inflation may lead to gross overinflation of tracheal tube cuffs and that cuff pressure monitoring may be performed simply by means of an electropneumatic controller. The difference in minimum cuff pressure between males and females suggests that the difference in tracheal size between the sexes is greater than the 9-mm to 8-mm difference in tracheal tube size.

Blood-gas tension measurement in anaesthesia by bubble equilibration and mass spectrometry.

If a small bubble gas is equilibrated with a volume of blood the partial pressures of the components of the bubble after equilibration approximate to the original tensions in the blood. A method is described in which the bubble is analysed by a respiratory mass spectrometer connected to a mini-computer. The normal respiratory monitoring function of the mass spectrometer need be interrupted for only 20 s for each sample and the complete equilibration and analysis procedure takes only 3 min. Theoretical studies, experimental tests and records of experimental usage show that, in a subject anaesthetized with halothane in nitrous and oxygen, tension can be measured with an overall SD of 5% for carbon dioxide and halothane and, certain reservations, an SD of about 3% for nitrous oxide.

Entonox analgesia in labour. A pilot study to reduce the delay between demand and supply.

In a pilot study in six mothers using 50% nitrous oxide and 50% oxygen (Entonox) as an intermittent self-administered analgesic during labour, a significant reduction in the mean times to attain specified end-tidal nitrous oxide concentrations was obtained by a continuous nasal supplement of Entonox. The method proved acceptable in this small number of patients and there were no demonstrable effects upon fetal heart rate.

The reduction of pollution. A simple approach to the reduction of pollution in the dental operating theatre.

This paper describes the construction and evaluation of a simple anti-pollution device for use with the McKesson nasal mask for dental anaesthesia. The device is attached to the expiratory valve of the mask and spilled halothane vapour is adsorbed onto activated charcoal. In theatre use, comparing similar dental anaesthesia sessions, it resulted in a reduction of approximately 78% in the mean halothane concentration (vol./vol.) at a point equidistant from the expiratory valve as the faces of surgeon and anaesthetist. This percentage reduction was consistent with the weight gained by the activated charcoal container (Cardiff 'Aldasorber') compared with the weight of halothane vapourised.

Interaction of extrinsic fluorescent probes with E. coli glutamine synthetase.

Binding of 2-p-toluidinylnaphthalene-6-sulfonate (TNS) to adenylylated (E--11) glutamine synthetase is cooperative and time-dependent, with 3 dye sites per subunit. In fluorescence polarization experiments TNS and pyrene butyrate give normalized Perrin plots that indicate a symmetrical arrangement of dye excited state dipoles, relative to the rotational axis of the oblate ellipsoid of the dodecameric native enzyme.

Entonox analgesia--a method of reducing the delay between demand and supply.

Mothers in labour using a self-administered 50% N2O and 50% O2 (Entonox) demand system, experience a time lag between making a demand at the onset of a contraction and pain relief. A practical method is described of reducing this time lag by supplementing the intermittent supply from the demand valve system with a continuous nasal flow of N2O and O2. Consequently a basal arterial N2O tension is maintained and when a demand is made, a higher level of N2O is attained in any time interval compared with that using the demand system alone. In six trained volunteers under laboratory conditions, the N2O levels measured at the mouth on a breath-by-breath basis using a mass spectrometer, showed a substantial and statistically significant reduction in the time taken to attain end-tidal N2O concentrations in the range 10-25%. This method seems worthy of a clinical trial.

The Cardiff Aldavac anaesthetic-scavenging system.

The Cardiff Aldavac system consists of a reservoir, adsorption canister, flow restrictor and the necessary pipe connections. It enables theatre pollution control without structural alteration or special installation. It utilizes the hospital piped medical vacuum system but protects the system from excessive flows or contamination by volatile anaesthetics and still allows the vacuum to be used for other purposes.

Adiposity and the pharmacokinetics of halothane. The effect of adiposity on the maintenance of and recovery from halothane anaesthesia.

Thirty fit patients (15-70 years, 46-98 kg) undergoing body-surface operations were selected to include a wide range of adiposity (12-45% of total body weight estimated from measurements of skinfold thickness). They were anaesthetized with halothane and 70% N2O in O2. From measurements of total ventilation (ml min-1 kg-1) and of halothane concentrations in inspired (F1) end-tidal (FE') and 'mixed-spill' (FS) gases, the following parameters were calculated for 5-min intervals from 20 to 40 min after induction; the rate of uptake of halothane per percent inspired concentration (Vha1 ml min-1%-1) and the degree of equilibrium achieved with the inspired concentration, calculated as FE'/F1 expressed as a percentage. Multiple-regression analysis of the results for 19 patients, taking account of the effects of body fat, ventilation, age, and the blood-gas partition coefficient lambda of halothane for the individual patient, showed that Vha1 increased with adiposity (b=0-375, P=0-0019), and with ventilation (b=0-054, P=0-09) but decreased with increasing age (b=-0-258, P=0-006). The time intervals between the end of the anaesthetic and the achievement of four defined levels of recovery (response to painful stimulus obedience to a simple command, response to a question, orientation in time and space), were recorded. Multiple-regression analysis showed that recovery time increased with addiposity, duration of administration and end-tidal concentration at the end of the administration, and decreased with increasing age. All four effects were statistically non-significant at the first levels of recovery but all increased at the later levels and all eventually became significant.

Halothane solubility in human blood.

In a study of the influence of nutritional state on halothane anaesthesia, results were obtained which showed how the blood/gas partition coefficient for halothane varied with blood chemistry in 20 patients undergoing elective surgery. For each patient the partition coefficient lambda was measured by equilibration at 37 degrees C of a blood sample with a 1% halothane in 5% carbon dioxide in air mixture, followed by chemical extraction and estimation of the halothane content by gas chromatography. The haematocrit and haemoglobin, serum albumin, total protein, triglyceride and cholesterol concentrations were measured by routine laboratory methods. Regressions were sought of lambda on each of these, and on the globulin concentration and the ratios of albumin: globulin and albumin: total protein, deduced from these determinations. The only statistically significant regression (P = 0.0004) was that of lambda on the serum triglyceride concentration (T) (mmol/litre): lambda = 1.83 + 0.424T. The dependence of lambda on haemoglobin concentration was not statistically significant, but the slope of the regression was consistent with those of previous investigators. The regressions of lambda, corrected to the mean triglyceride concentration, on the ratios of albumin: globulin and albumin: total protein were not statistically significant but were not significantly different from an earlier reported result.

Rebreathing in a T-piece: volunteer and theoretical studies of the Jackson-Rees modification of Ayre's T-piece during spontaneous respiration.

The Jackson-Rees modification of Ayre's T-piece was examined experimentally and theoretically to see what effects the theoretical restrictions of Onchi, Hayashi and Ueyama (1957) (1:1 I:E ratio, zero deadspace volume) and the square-wave approximation of Mapleson (1958) may have had on the calculated critical fresh-gas flow rate necessary to prevent rebreathing of exhaled alveolar gases. In the experimental examination six conscious alert volunteers breathed through the system as the fresh-gas flow rate was varied in steps, and their ventilation was recorded at each value. Assuming that under rebreathing conditions a normal arterial PCO2 is maintained by hyperventilation, this experimental situation is identical with one of the two considered theoretically by assuming sine-wave inspiratory and expiratory waveforms, zero longitudinal mixing in deadspace volumes and perfect mixing in the alveoli. Agreement between experimental and theoretical results justifies the assumptions made in the theoretical analysis and the results indicate that a fresh-gas flow rate of about twice the normal ventilation is necessary to eliminate rebreathing completely from the Jackson-Rees modification of Ayre's T-piece. The exact requirement depends on the deadspace/tidal volume (VD/VT) and I:E ratios. The onset of hyperventilation at lower fresh-gas flow rates is gradual and, in spontaneous breathing with VD/VT approximately equal to 40% and I:E ratio = 1:1.2, is only 10-20% at a fresh-gas flow rate of 1.5 times the normal ventilation.