Human Safety Studies Research Articles

Development of an in vitro compound screening system that replicate the in vivo spine phenotype of idiopathic ASD model mice.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by core symptoms including social difficulties, repetitive behaviors, and sensory abnormalities. Aberrant morphology of dendritic spines within the cortex has been documented in genetic disorders associated with ASD and ASD-like traits. We hypothesized that compounds that ameliorate abnormalities in spine dynamics might have the potential to ameliorate core symptoms of ASD. Because the morphology of the spine is influenced by signal inputs from other neurons and various molecular interactions, conventional single-molecule targeted drug discovery methods may not suffice in identifying compounds capable of ameliorating spine morphology abnormalities. In this study, we focused on spine phenotypes in the cortex using BTBR T + Itpr3 tf /J (BTBR) mice, which have been used as a model for idiopathic ASD in various studies. We established an in vitro compound screening system using primary cultured neurons from BTBR mice to faithfully represent the spine phenotype. The compound library mainly comprised substances with known target molecules and established safety profiles, including those approved or validated through human safety studies. Following screening of this specialized library containing 181 compounds, we identified 15 confirmed hit compounds. The molecular targets of these hit compounds were largely focused on the 5-hydroxytryptamine receptor (5-HTR). Furthermore, both 5-HT1AR agonist and 5-HT3R antagonist were common functional profiles in hit compounds. Vortioxetine, possessing dual attributes as a 5-HT1AR agonist and 5-HT3R antagonist, was administered to BTBR mice once daily for a period of 7days. This intervention not only ameliorated their spine phenotype but also alleviated their social behavior abnormality. These results of vortioxetine supports the usefulness of a spine phenotype-based assay system as a potent drug discovery platform targeting ASD core symptoms.

Profiling Bioactive Compounds in the Bark of Cinchona officinalis L. and Anti-arthritic Properties Thereof

The bark samples of C. officinalis were collected from The Nilgiris district of Tamil Nadu. The collected samples were processed and extracted using methanol solvent. The extracts showed high yield of secondary metabolites especially alkaloids, phenols, flavonoids, steroids, terpenoids, sterols, quinones and tannins. Alkaloid content was very high in C.officinalis followed by phenol, flavonoid, steroid and Tannin. The secondary metabolites present in C. officinalis (Bark) were isolated, purified, identified and characterized using differential Chromatographic techniques such as TLC, HPLC and GC-MS/ MS. The compounds identified using High Performance Liquid Chromatography (HPLC) technique in bark of C. officinalis in the retention times of 1.750, 2.250, 4.016 and 7.266 minutes were quinine, isoquinidine and cinchonidine. The compounds were then characterized using GC- MS/ MS technique with reference to NIST library. The compounds were eluted from the bark of C. officinalis in the retention time of 9.569, 10.488, 11.814, 13.593, 14.282, 16.542, 16.967, 23.494, 24.954, 25.151, 25.988, 26.752, 26.982, 27.906, 28.277, 31.454, 33.604, and 35.744 minutes. By correlating the retention times with (NIST) mass spectral library the eluted compounds were confirmed as Phthalic acid, Hexadecanoic acid,1,2,3,5-Cyclohexanetetrol, Cinchonab-9-one, 9,12-Octadecadienoic acid (Z,Z)-, Heptadecanoic acid, Quinine, Cinchonine, Cinchonidine, Phenol, Quinine, and gamma.-Sitosterol. The phytochemicals present in the C. officinalis (Bark) samples were evaluated for their biological properties viz., anti-inflammatory activity and anti-arthritic activity in in-vitro conditions. Anti- inflammatory properties of plant samples were tested by protein denaturation method using diclofenac (75 mg/ ml concentration) as positive control. The methanol extract of C.officinalis (Bark) showed anti- inflammatory properties of range between 17.0 and 57.3%. Anti- arthritic activity of bark extract of C. officinalis (75 mg/ ml concentration) was evaluated by albumin denaturation method using diclofenac (75 mg/ ml concentration) as positive control. The methanol extract of C.officinalis (Bark) showed anti- arthritic properties of range between 18.4 and 58.5%. From the study it is understood that the alkaloids and polyphenols present in the methanolic extract of bark of C. officinalis were responsible for their biological properties. Hence, C. officinalis can serve as an alternative to synthetic drugs available in the market to treat arthritis subject to safety (toxicity) studies in humans. Based on the In vitro results, it was confirmed that the bark of C.officinalis possesses comparatively high biological values. Thus an herbal aerosol for arthritis may be formulated using the bark extract of C.officinalis as key ingredient and the therapeutic product will be of cost effective, easy to use and pocket friendly.

Placenta-Derived Decidua Stromal Cells: A New Frontier in the Therapy of Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (GVHD) is a frequent and potentially life-threatening complication following allogeneic hematopoietic cell transplantation (HCT). Mesenchymal stromal cells (MSCs), rare precursors found in all body tissues, possess immunosuppressive properties and can inhibit alloreactivity both in vitro and in vivo. Two decades ago, we introduced bone marrow-derived (BM) MSCs as a novel therapy for acute GVHD. While some patients responded to BM-MSCs, the response was not universal. Commercially available BM-MSCs are now used for acute GVHD treatment in Canada, Japan, and New Zealand. The fetus is protected from the mother's immune system by the placenta, and our research found that placenta-derived decidua stromal cells (DSCs) offer a stronger immunosuppressive effect than other sources of stromal cells. Safety studies in rabbits, rats, mice, and humans have shown negligible or no side effects from BM-MSCs or DSCs. In a phase I/II trial for severe acute GVHD, we treated 21 patients (median age, 49 years; range 1.6-72 years) with severe biopsy-proven gastrointestinal acute GVHD. The median cell dose of DSCs was 1.2 × 106 (range 0.9-2.9) cells/kg body weight, with a median of 2 (range 1-6) infusions given 1 week apart. The cell viability of DSCs was 93% (range, 69%-100%), and the median cell passage number was 4 (range, 2-4). All patients responded, with a complete response of acute GVHD in 11 patients and partial response in 10 and 1-year survival of 81%. Randomized trials are needed to prove the superiority of DSCs compared to ruxolitinib and/or other novel immunosuppressive therapies.

Prediction of clinical trials outcomes based on target choice and clinical trial design with multi-modal artificial intelligence.

Drug discovery and development is a notoriously risky process with high failure rates at every stage including disease modeling, target discovery, hit discovery, lead optimization, preclinical development, human safety and efficacy studies. Accurate prediction of clinical trial outcomes may help significantly improve the efficiency of this process by prioritizing therapeutic programs that are more likely to succeed in clinical trials and ultimately benefit patients. Here we describe inClinico, a transformer-based artificial intelligence software platform designed to predict the outcome of Phase II clinical trials. The platform combines an ensemble of clinical trial outcome prediction (CTOP) engines that leverage generative artificial intelligence and multimodal data, including omics, text, clinical trial design, and small molecule properties. inClinico was validated in retrospective, quasi-prospective, and prospective validation studies internally and with pharmaceutical companies and financial institutions. The platform achieved 0.88 ROC AUC in predicting the Phase II to Phase III transition on a quasi-prospective validation dataset. The first prospective predictions were made and placed on date-stamped preprint servers in 2016. To validate our model in a real-world setting, we published forecasted outcomes for several Phase II clinical trials achieving 79% accuracy for the trials that have read out. We also present an investment application of inClinico using date stamped virtual trading portfolio demonstrating 35% 9-month return on investment (ROI).

Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products: A Scientific Statement From the American Heart Association.

Vaping and electronic cigarette (e-cigarette) use have grown exponentially in the past decade, particularly among youth and young adults. Cigarette smoking is a risk factor for both cardiovascular and pulmonary disease. Because of their more limited ingredients and the absence of combustion, e-cigarettes and vaping products are often touted as safer alternative and potential tobacco-cessation products. The outbreak of e-cigarette or vaping product use-associated lung injury in the United States in 2019, which led to >2800 hospitalizations, highlighted the risks of e-cigarettes and vaping products. Currently, all e-cigarettes are regulated as tobacco products and thus do not undergo the premarket animal and human safety studies required of a drug product or medical device. Because youth prevalence of e-cigarette and vaping product use was as high as 27.5% in high school students in 2019 in the United States, it is critical to assess the short-term and long-term health effects of these products, as well as the development of interventional and public health efforts to reduce youth use. The objectives of this scientific statement are (1) to describe and discuss e-cigarettes and vaping products use patterns among youth and adults; (2) to identify harmful and potentially harmful constituents in vaping aerosols; (3) to critically assess the molecular, animal, and clinical evidence on the acute and chronic cardiovascular and pulmonary risks of e-cigarette and vaping products use; (4) to describe the current evidence of e-cigarettes and vaping products as potential tobacco-cessation products; and (5) to summarize current public health and regulatory efforts of e-cigarettes and vaping products. It is timely, therefore, to review the short-term and especially the long-term implications of e-cigarettes and vaping products on cardiopulmonary health. Early molecular and clinical evidence suggests various acute physiological effects from electronic nicotine delivery systems, particularly those containing nicotine. Additional clinical and animal-exposure model research is critically needed as the use of these products continues to grow.

Preclinical safety assessment of JNJ-10450232 (NTM-006), a structural analog of acetaminophen, that does not cause hepatotoxicity at supratherapeutic doses

JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity. In the 28-day toxicity studies, all treatment-related findings were monitorable and reversible. Methemoglobinemia, which was observed in dogs and to a lesser extent in rats, is also observed with acetaminophen. This finding is considered not relevant to humans due to species differences in metabolism. Thyroid hypertrophy and hyperplasia were also observed in dogs and were shown to be a consequence of a species-specific UGT induction also demonstrated with increased thyroid hormone metabolism. Indirect bilirubin elevation was observed in rats as a result of UGT1A1 Inhibition. JNJ-10450232 (NTM-006) had no toxicologically relevant findings in safety pharmacology or genotoxicity studies. Together, these data supported progressing into safety and efficacy studies in humans.

Evaluation of Genotoxicity of SU-Eohyeol Pharmacopuncture Using an In Vitro Chromosome Aberration Test in Chinese Hamster Lung Cell

ObjectivesThis study was conducted to evaluate the safety of SU-Eohyeol pharmacopuncture (SUEP) by assessing its potential to cause chromosomal abnormalities in Chinese hamster lung cells (CHL/IC).MethodsA dose-curve was conducted to determine the highest dose of SUEP. Doses of 10, 5, 2.5, 1.25, 0.625, and 0.313% were used, and no cytotoxicity or SUEP precipitation was observed. SUEP doses of 10, 5, and 2.5%, with positive and negative controls, were used in a chromosome aberration test.ResultsIn this study, the frequency of abnormal chromosomal cells in the SUEP group did not show a statistically significant difference from that of the negative control group in short-term treatments with and without metabolic activation and the continuous treatment without metabolic activation. Compared with the negative control group, the positive control group had a significantly higher frequency of cells with structural chromosomal abnormalities. This test’s results satisfied all conditions for determining the results.ConclusionSUEP did not induce chromosomal aberrations under the conditions of this study. Other toxicity evaluations, safety studies in humans, and various clinical trials are required to evaluate the safety and efficacy of SUEP.

No Evidence of Induced Skin Cancer or Other Skin Abnormalities after Long-Term (66 week) Chronic Exposure to 222-nm Far-UVC Radiation.

Far-UVC radiation, typically defined as 200-235 nm, has similar or greater anti-microbial efficacy compared with conventional 254-nm germicidal radiation. In addition, biophysical considerations of the interaction of far-UVC with tissue, as well as multiple short-term safety studies in animal models and humans, suggest that far-UVC exposure may be safe for skin and eye tissue. Nevertheless, the potential for skin cancer after chronic long-term exposure to far-UVC has not been studied. Here, we assessed far-UVC induced carcinogenic skin changes and other pathological dermal abnormalities in 96 SKH-1 hairless mice of both sexes that were exposed to average daily dorsal skin doses of 400, 130 or 55 mJ cm-2 of 222 nm far-UVC radiation for 66 weeks, 5 days per week, 8 h per day, as well as similarly-treated unexposed controls. No evidence for increased skin cancer, abnormal skin growths or incidental skin pathology findings was observed in the far-UVC-exposed mice. In addition, there were no significant changes in morbidity or mortality. The findings from this study support the long-term safety of long-term chronic exposure to far-UVC radiation, and therefore its potential suitability as a practical anti-microbial approach to reduce airborne viral and bacterial loads in occupied indoor settings.

Stem Cell-based therapies for COVID-19-related acute respiratory distress syndrome.

As the number of confirmed cases and resulting death toll of the COVID‐19 pandemic continue to increase around the globe ‐ especially with the emergence of new mutations of the SARS‐CoV‐2 virus in addition to the known alpha, beta, gamma, delta and omicron variants ‐ tremendous efforts continue to be dedicated to the development of interventive therapeutics to mitigate infective symptoms or post‐viral sequelae in individuals for which vaccines are not accessible, viable or effective in the prevention of illness. Many of these investigations aim to target the associated acute respiratory distress syndrome, or ARDS, which induces damage to lung epithelia and other physiologic systems and is associated with progression in severe cases. Recently, stem cell‐based therapies have demonstrated preliminary efficacy against ARDS based on a number of preclinical and preliminary human safety studies, and based on promising outcomes are now being evaluated in phase II clinical trials for ARDS. A number of candidate stem cell therapies have been found to exhibit low immunogenicity, coupled with inherent tropism to injury sites. In recent studies, these have demonstrated the ability to modulate suppression of pro‐inflammatory cytokine signals such as those characterizing COVID‐19‐associated ARDS. Present translational studies are aiming to optimize the safety, efficacy and delivery to fully validate stem cell‐based strategies targeting COVID‐19 associated ARDS for viable clinical application.

506 Samelisant: Baseline Characteristics from a Phase 2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

Abstract Introduction histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile. Methods The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of < 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021. Support (if any):

Endovascular Cerebral Venous Sinus Imaging with Optical Coherence Tomography.

Imaging of the cerebral venous sinuses has evolved Substantially during the past 2 decades, and most recently intravascular sinus imaging with sonography has shed light on the pathophysiology of sinus thrombosis and intracranial hypertension. Optical coherence tomography is the highest resolution intravascular imaging technique available but has not been previously used in cerebral sinus imaging. The purpose of this study was to develop a preclinical animal model of endovascular optical coherence tomography cerebral venous sinus imaging and compare optical coherence tomography findings with histology. Four consecutive Yorkshire swine were selected. The superior sagittal sinus was first catheterized with a microwire, and the optical coherence tomography catheter was delivered via a monorail technique into the sinus. Luminal blood was cleared with a single arterial injection. After structural and Doppler optical coherence tomography imaging, a craniotomy was performed and the sinus and adjacent dura/veins were resected. Bland-Altman analysis was performed to compare optical coherence tomography and histology. Technically successful optical coherence tomography images were obtained in 3 of 4 swine. The luminal environment and visualization of dural arteries and draining cortical veins were characterized. The average maximum diameters of the sinus, dural arteries, and cortical veins were 3.14 mm, 135 µm, and 260 µm, respectively. Bland-Altman analysis demonstrated good agreement between histology and optical coherence tomography images. Endovascular optical coherence tomography imaging was feasible in this preclinical animal study. Adoption of this imaging technique in the human cerebral venous sinus could aid in the diagnosis, treatment, and understanding of the pathophysiology of various diseases of the sinus. Human safety and feasibility studies are needed.

Filociclovir Is a Potent In Vitro and In Vivo Inhibitor of Human Adenoviruses.

Human adenovirus (HAdV) infection is common in the general population and can cause a range of clinical manifestations, among which pneumonia and keratoconjunctivitis are the most common. Although HAdV infections are mostly self-limiting, infections in immunocompromised individuals can be severe. No antiviral drug has been approved for treating adenoviruses. Filociclovir (FCV) is a nucleoside analogue which has successfully completed phase I human clinical safety studies and is now being developed for treatment of human cytomegalovirus (HCMV)-related disease in immunocompromised patients. In this report, we show that FCV is a potent broad-spectrum inhibitor of HAdV types 4 to 8, with 50% effective concentrations (EC50s) ranging between 1.24 and 3.6 μM and a 50% cytotoxic concentration (CC50) of 100 to 150 μM in human foreskin fibroblasts (HFFs). We also show that the prophylactic oral administration of FCV (10 mg/kg of body weight) 1 day prior to virus challenge and then daily for 14 days to immunosuppressed Syrian hamsters infected intravenously with HAdV6 was sufficient to prevent morbidity and mortality. FCV also mitigated tissue damage and inhibited virus replication in the liver. The 10-mg/kg dose had similar effects even when the treatment was started on day 4 after virus challenge. Furthermore, FCV administered at the same dose after intranasal challenge with HAdV6 partially mitigated body weight loss but significantly reduced pathology and virus replication in the lung. These findings suggest that FCV could potentially be developed as a pan-adenoviral inhibitor.

Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety.

Cationic arginine-rich peptides represent a novel class of peptides being developed as neuroprotective agents for stroke and other acute and chronic neurological disorders. As a group, cationic arginine-rich peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds. At present, while many neuroprotective cationic arginine-rich peptides have been examined in preclinical animal neuroprotection studies, few have been assessed in human safety studies. Despite this, the safety of the prototypical cationic arginine-rich peptide, protamine, which has been in clinical use for over 70years to reverse the anticoagulant effects of heparin and as an excipient in certain insulin preparations, is well established. In addition, the poly-arginine peptide R9 (ALX40-4C) was developed as an anti-human inmmunodeficiency virus therapeutic in the mid-1990s, and more recently, the neuroprotective cationic arginine-rich peptides TAT-NR2B9c (NA-1), CN-105 and RD2 are being evaluated for the treatment of ischaemic stroke, haemorrhagic stroke and Alzheimer's disease, respectively. Based on the available clinical data, cationic arginine-rich peptides as a group appear to be safe when administered at therapeutic doses by a slow intravenous infusion. While protamine, owing to its isolation from salmon milt and homology with human sperm protamine, can trigger anaphylactic and anaphylactoid reactions in a small proportion of patients previously exposed to the peptide (e.g. diabetic patients), who are allergic to fish or have undergone a vasectomy, such reactions are unlikely to be triggered in individuals exposed to non-protamine cationic arginine-rich peptides.

Therapies from Fucoidan: New Developments.

Since our last review in 2015, the study and use of fucoidan has extended in several research areas. Clinical use of fucoidan for the treatment of renal disease has become available and human safety studies have been undertaken on radiolabeled fucoidan for the purpose of imaging thrombi. Fucoidan has been incorporated into an increasing number of commercially available supplements and topical treatments. In addition, new measuring techniques are now available to assess the biologically relevant uptake of fucoidans and to assist in production. Microbiome modulation and anti-pathogenic effects are increasingly promising applications for fucoidans, due to the need for alternative approaches to antibiotic use in the food chain. This review outlines promising new developments in fucoidan research, including potential future therapeutic use.

Polymeric Approaches to Reduce Tissue Responses Against Devices Applied for Islet-Cell Encapsulation.

Immunoisolation of pancreatic islets is a technology in which islets are encapsulated in semipermeable but immunoprotective polymeric membranes. The technology allows for successful transplantation of insulin-producing cells in the absence of immunosuppression. Different approaches of immunoisolation are currently under development. These approaches involve intravascular devices that are connected to the bloodstream and extravascular devices that can be distinguished in micro- and macrocapsules and are usually implanted in the peritoneal cavity or under the skin. The technology has been subject of intense fundamental research in the past decade. It has co-evolved with novel replenishable cell sources for cure of diseases such as Type 1 Diabetes Mellitus that need to be protected for the host immune system. Although the devices have shown significant success in animal models and even in human safety studies most technologies still suffer from undesired tissue responses in the host. Here we review the past and current approaches to modulate and reduce tissue responses against extravascular cell-containing micro- and macrocapsules with a focus on rational choices for polymer (combinations). Choices for polymers but also choices for crosslinking agents that induce more stable and biocompatible capsules are discussed. Combining beneficial properties of molecules in diblock polymers or application of these molecules or other anti-biofouling molecules have been reviewed. Emerging are also the principles of polymer brushes that prevent protein and cell-adhesion. Recently also immunomodulating biomaterials that bind to specific immune receptors have entered the field. Several natural and synthetic polymers and even combinations of these polymers have demonstrated significant improvement in outcomes of encapsulated grafts. Adequate polymeric surface properties have been shown to be essential but how the surface should be composed to avoid host responses remains to be identified. Current insight is that optimal biocompatible devices can be created which raises optimism that immunoisolating devices can be created that allows for long term survival of encapsulated replenishable insulin-producing cell sources for treatment of Type 1 Diabetes Mellitus.

Human health safety studies of a new insecticide: Dissipation kinetics and dietary risk assessment of afidopyropen and one of its metabolites in cucumber and nectarine

To preliminarily study the law of natural dissipation and the relation to human health of a new insecticide (afidopyropen), the QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method and a UHPLC-MS/MS system were used to extract and detect the afidopyropen and its metabolite (M440I007) from cucumber and nectarine. The limits of quantitation (LOQs) of both target compounds in two matrixes were reduced to 0.0001 mg/kg. Dissipative dynamics experiments indicated that afidopyropen residue dissipation is more consistent with a two-compartment kinetic model than a first-order kinetic model whether in cucumber or nectarine. The half-lives were less than 1.1 and 2.0 days in the distribution phase and up to 9.9 and 27.7 days in the elimination phase in cucumber and nectarine, respectively. The correlation coefficients were 0.9620, 0.9391, and 0.9923 for cucumber and 0.9676 and 0.9985 for nectarine from different locations. M440I007 initially increased rapidly, reached a maximum at 2 days, and then decreased gradually over time. Finally, dietary risk assessment indicated that the mixed residues of afidopyropen and M440I007 at the recommended dosage would not cause health concerns in population.

NGP 555, a γ-secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

IntroductionCurrently, there is no cure for Alzheimer's disease (AD), and it is widely accepted that AD is a complex disease with multiple approaches necessary to prevent and treat the disease. MethodsUsing amyloid biomarkers in human cerebrospinal fluid, pharmacokinetic, safety, and metabolism studies, we investigate the properties of NGP 555, γ-secretase modulator, for the first time in human clinical trials. ResultsOur preclinical and clinical studies combined show beneficial effects with NGP 555 on synaptic response and amyloid cerebrospinal fluid biomarkers while avoiding negative side effects. Importantly, pharmacokinetic and pharmacodynamic parameters combined with safety outcomes indicate that NGP 555 penetrates the blood-brain barrier and increases the ratio of amyloid-β peptide Aβ37 and Aβ38 compared with that of Aβ42, establishing a proof of target engagement in humans in a 14 day, once-daily oral dosing trial. DiscussionIn humans, NGP 555 has demonstrated a beneficial shift in the production of Aβ37 and Aβ38 versus Aβ42 biomarker levels in the cerebrospinal fluid while maintaining an adequate safety profile. The overall clinical goal is to achieve an optimal balance of efficacy for altering amyloid-β peptide (Aβ) biomarkers while maintaining a safe profile so that NGP 555 can be given early in AD to prevent production of Aβ42 and accumulation of amyloid plaques, in an effort to prevent aggregation of tau and destruction of neurons and synapses resulting in cognitive decline.

CNS Drug Development, Lessons Learned, Part 5: How Preclinical and Human Safety Studies Inform the Approval and Subsequent Use of a New Drug-Suvorexant as an Example.

This column is the fifth in a series examining the advances being made in central nervous system drug development because of advances in molecular pharmacology and an improved understanding of the neurobiology underlying disturbances in brain function including psychiatric illnesses. This column covers the special animal and human studies conducted as part of the development of suvorexant, which is the first in the class of dual orexin 1 and 2 receptor antagonists to be approved; it has an indication for the treatment of disturbances in sleep onset and maintenance. The animal studies included determination of the therapeutic index of the drug (ie, lethal dose 50 which is the dose at which 50% of animals die following administration of the drug), adverse effects on fertility, teratogenicity, carcinogenicity, and ability to cause narcolepsy. The human studies included investigation of the effects of the drug on balance, memory, driving performance, and propensity to cause respiratory depression in normal volunteers and individuals with mild to moderate chronic obstructive pulmonary disorder or mild to moderate obstructive sleep apnea. This column illustrates how targeting the drug to one mechanism out of hundreds yields increased safety and highlights the importance of the package insert which summarizes the results of all of the studies from the drug's development program.

793Validation of cardiac optogenetics against patch clamp electrophysiology in human cardiomyocyte drug efficacy and safety studies

793Validation of cardiac optogenetics against patch clamp electrophysiology in human cardiomyocyte drug efficacy and safety studies

Biosimilars for psoriasis: clinical studies to determine similarity.

Biosimilars are drugs that are similar, but not identical, to originator biologics. Preclinical analytical studies are required to show similarity on a molecular and structural level, but efficacy and safety studies in humans are essential to determining biosimilarity. In this review, written by members of the International Psoriasis Council, we discuss how biosimilars are evaluated in a clinical setting, with emphasis on extrapolation of indication, interchangeability and optimal clinical trial design.