Patient perceptions of and experiences with stigma using telehealth for opioid use disorder treatment: a qualitative analysis.

Background: Patients with opioid use disorder (OUD) experience various forms of stigma at the individual, public, and structural levels that can affect how they access and engage with healthcare, particularly with medications for OUD treatment. Telehealth is a relatively new form of care delivery for OUD treatment. As reducing stigma surrounding OUD treatment is critical to address ongoing gaps in care, the aim of this study was to explore how telehealth impacts patient experiences of stigma.

A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS.

Objective: Dual leucine zipper kinase (DLK), which regulates the c-Jun N-terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first-in-human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC-0134, a small-molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC-0134-treated ALS patients and DLK conditional knockout (cKO) mice.

Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease.

Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone.

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology.

We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (V), interstitial volumes (V), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements.

Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates.

Background And Purpose: The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. I.c.

Regulatory Forum Opinion Piece: Use and Utility of Animal Models of Disease for Nonclinical Safety Assessment: A Pharmaceutical Industry Survey.

An Innovation and Quality (IQ) Consortium focus group conducted a cross-company survey to evaluate current practices and perceptions around the use of animal models of disease (AMDs) in nonclinical safety assessment of molecules in clinical development. The IQ Consortium group is an organization of pharmaceutical and biotechnology companies with the mission of advancing science and technology. The survey queried the utilization of AMDs during drug discovery in which drug candidates are evaluated in efficacy models and limited short-duration non-Good Laboratory Practices (GLP) toxicology testing and during drug development in which drug candidates are evaluated in GLP toxicology studies.

Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice.

The antibody Fc region regulates antibody cytotoxic activities and serum half-life. In a therapeutic context, however, the cytotoxic effector function of an antibody is often not desirable and can create safety liabilities by activating native host immune defenses against cells expressing the receptor antigens. Several amino acid changes in the Fc region have been reported to silence or reduce the effector function of antibodies.

Balancing Blood Sample Volume with 3Rs: Implementation and Best Practices for Small Molecule Toxicokinetic Assessments in Rats.

Improved small molecule bioanalytical sensitivity and concomitant decreased sample volume requirements provide an opportunity to reconsider how toxicokinetic (TK) data are collected in rat toxicity studies. Often, satellite groups of rats are designated to separate procedural effects of TK blood collection from the primary toxicity evaluation. Blood microsampling (i.

Preexisting Antibodies to an F(ab')2 Antibody Therapeutic and Novel Method for Immunogenicity Assessment.

Anti-therapeutic antibodies (ATAs) may impact drug exposure and activity and induce immune complex mediated toxicity; therefore the accurate measurement of ATA is important for the analysis of drug safety and efficacy. Preexisting ATAs to the hinge region of anti-Delta like ligand 4 (anti-DLL4) F(ab')2, a potential antitumor therapeutic, were detected in cynomolgus monkey serum, which presented a challenge in developing assays for detecting treatment induced ATA. A total ATA assay was developed using a bridging ELISA that detected both anti-CDR and anti-framework ATA including anti-hinge reactivity.

Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain.

Treatment of diseases of the central nervous system by monoclonal antibodies may be limited by the restricted uptake of antibodies across the blood-brain barrier (BBB). An antibody targeting transferrin receptor (TfR) has been shown to take advantage of the receptor-mediated transcytosis properties of TfR in order to cross the BBB in mice, with the uptake in the brain being dependent on the affinity to TfR. In the bispecific format with arms targeting both TfR and β-secretase 1 (BACE1), altering the affinity to TfR has been shown to impact systemic exposure and safety profiles.

Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation.

Purpose: Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody.

Experimental Design: The F(ab')2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab')2) was generated and assessed in efficacy and toxicity studies.

Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates.

Using therapeutic antibodies that need to cross the blood-brain barrier (BBB) to treat neurological disease is a difficult challenge. We have shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1) can cross the BBB and reduce brain amyloid-β (Aβ) in mice. Can TfR enhance antibody uptake in the primate brain? We describe two humanized TfR/BACE1 bispecific antibody variants.

Recommendations from a global cross-company data sharing initiative on the incorporation of recovery phase animals in safety assessment studies to support first-in-human clinical trials.

An international expert group which includes 30 organisations (pharmaceutical companies, contract research organisations, academic institutions and regulatory bodies) has shared data on the use of recovery animals in the assessment of pharmaceutical safety for early development. These data have been used as an evidence-base to make recommendations on the inclusion of recovery animals in toxicology studies to achieve scientific objectives, while reducing animal use. Recovery animals are used in pharmaceutical development to provide information on the potential for a toxic effect to translate into long-term human risk.

Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier.

Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies.

Pharmaceutical toxicology: designing studies to reduce animal use, while maximizing human translation.

Evaluation of the safety of new chemicals and pharmaceuticals requires the combination of information from various sources (e.g. in vitro, in silico and in vivo) to provide an assessment of risk to human health and the environment.

The design of chronic toxicology studies of monoclonal antibodies: implications for the reduction in use of non-human primates.

The changing environment of monoclonal antibody (mAb) development is impacting on the cost of drug development and the use of experimental animals, particularly non-human primates (NHPs). The drive to reduce these costs is huge and involves rethinking and improving nonclinical studies to make them more efficient and more predictive of man. While NHP use might be unavoidable in many cases because of the exquisite specificity and consequent species selectivity of mAbs, our increasing knowledge base can be used to improve drug development and maximise the output of experimental data.

Alternative strategies for toxicity testing of species-specific biopharmaceuticals.

Although toxicology studies should always be conducted in pharmacologically relevant species, the specificity of many biopharmaceuticals can present challenges in identification of a relevant species. In certain cases, that is, when the clinical product is active only in humans or chimpanzees, or if the clinical candidate is active in other species but immunogenicity limits the ability to conduct a thorough safety assessment, alternative approaches to evaluating the safety of a biopharmaceutical must be considered. Alternative approaches, including animal models of disease, genetically modified mice, or use of surrogate molecules, may improve the predictive value of preclinical safety assessments of species-specific biopharmaceuticals, although many caveats associated with these models must be considered.

Early childhood obesity is associated with compromised cerebellar development.

As part of a study investigating commonalities between Prader-Willi syndrome (PWS-a genetic imprinting disorder) and early-onset obesity of unknown etiology (EMO) we measured total cerebral and cerebellar volume on volumetric magnetic resonance imaging (MRI) images. Individuals with PWS (N = 16) and EMO (N = 12) had smaller cerebellar volumes than a control group of 15 siblings (p = .02 control vs.

Sylvian fissure morphology in Prader-Willi syndrome and early-onset morbid obesity.

Purpose: Prader-Willi syndrome is a well-defined genetic cause of childhood-onset obesity that can serve as a model for investigating early-onset childhood obesity. Individuals with Prader-Willi syndrome have speech and language impairments, suggesting possible involvement of the perisylvian region of the brain. Clinical observations suggest that many individuals with early-onset morbid obesity have similar speech/language deficits, indicating possible perisylvian involvement in these children as well.

Pituitary abnormalities in Prader-Willi syndrome and early onset morbid obesity.

Prader-Willi syndrome (PWS) is a well-defined syndrome of childhood-obesity which can serve as a model for investigating early onset childhood obesity. Many of the clinical features of PWS (e.g.

Enhanced activation of reward mediating prefrontal regions in response to food stimuli in Prader-Willi syndrome.

Background: Individuals with Prader-Willi syndrome (PWS) exhibit severe disturbances in appetite regulation, including delayed meal termination, early return of hunger after a meal, seeking and hoarding food and eating of non-food substances. Brain pathways involved in the control of appetite in humans are thought to include the hypothalamus, frontal cortex (including the orbitofrontal, ventromedial prefrontal, dorsolateral prefrontal and anterior cingulate areas), insula, and limbic and paralimbic areas. We hypothesised that the abnormal appetite in PWS results from aberrant reward processing of food stimuli in these neural pathways.

Intracranial abnormalities detected by three-dimensional magnetic resonance imaging in Prader-Willi syndrome.

The neuropathologic abnormalities associated with Prader-Willi syndrome (PWS) are largely unknown. PWS is due to the loss of several paternally expressed genes in chromosome 15q11-q13 region. Several of the imprinted genes in the 15q11-q13 region are normally expressed in the brain and thought to be necessary for neuronal growth and development.

robo2 and robo3 interact with eagle to regulate serotonergic neuron differentiation.

The function of the central nervous system (CNS) depends crucially upon the correct differentiation of neurons and formation of axonal connections. Some aspects of neuronal differentiation are known to occur as axonal connections are forming. Although serotonin is a highly conserved neurotransmitter that is important for many CNS functions, little is known about the process of serotonergic neuron differentiation.

Axon guidance: Comm hither, Robo.

In the developing CNS, commissural axons are initially attracted to the midline, but after crossing they acquire sensitivity to midline repellent cues which prevent re-crossing. Recent studies have shed new light on the mechanism by which commissural axons change their sensitivity to guidance cues after crossing the midline.