Preclinical Safety

Basel, Switzerland

Preclinical Safety

Basel, Switzerland

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Kerlin R.,Pfizer | Bolon B.,GEMpath Inc. | Burkhardt J.,Preclinical Safety | Francke S.,College Park | And 3 more authors.
Toxicologic Pathology | Year: 2016

Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as "adverse" and assigning a "no observed adverse effect level" (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating "harm" to the test animal, while nonadverse indicates lack of harm. Adverse findings in the study reports should be defined in relation to effects on the test species used and within the context of the given study. Test article-related effects should be described on their own merits, and decisions to consider them as adverse or nonadverse should be justified. Related effects may be discussed together; in particular, markers of toxicity that are not in and of themselves adverse ideally should be discussed in conjunction with the causal toxicity to determine adversity. Adverse findings should be identified in subreports (clinical data, pathology data, etc.) if sufficient information is available, and/or in the final study report as individual or grouped findings, but study NOAELs should be established at the level of the overall study report. Interpretations such as "not biologically relevant" or "not toxicologically important" should be avoided unless defined and supported by scientific rationale. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines. Where possible, use of NOAELs in data tables should be linked to explanatory text that places them in context. Ideally, in nonclinical summary documents, NOAELs from multiple studies are considered together in defining the most important adverse responses in the most sensitive species. These responses are then considered along with an understanding of their likely mechanisms, as well as other information such as variability in species sensitivity, comparative pathology, reversibility and progression, kinetics, and metabolism of the test substance to help assess human risk. © The Author(s) 2015.


Neumann U.,Novartis | Rueeger H.,Global Discover Chemistry | MacHauer R.,Global Discover Chemistry | Veenstra S.J.,Global Discover Chemistry | And 13 more authors.
Molecular Neurodegeneration | Year: 2015

Background: Alzheimer's disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans. Results: Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared. Conclusions: In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease. © 2015 Neumann et al.


PubMed | Novartis, Global Discover Chemistry, Preclinical Safety, DMPK and Metabolism and Pharmacokinetics
Type: | Journal: Molecular neurodegeneration | Year: 2015

Alzheimers disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid- (A) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target A via inhibition of -secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower A. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans.Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of A deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of A was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared.In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid- deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid- pathology can have beneficial downstream effects on the progression of Alzheimers disease.


Andrews L.,AbbVie Research Center | Ralston S.,Preclinical Safety | Blomme E.,Comparative and Molecular Toxicology | Barnhart K.,AbbVie
Human and Experimental Toxicology | Year: 2015

Since the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products. © The Author(s) 2015.


PubMed | AbbVie, AbbVie Research Center, Preclinical Safety and Comparative and Molecular Toxicology
Type: Journal Article | Journal: Human & experimental toxicology | Year: 2015

Since the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products.


Brennan F.R.,Preclinical Safety | Cauvin A.,Preclinical Safety | Tibbitts J.,Preclinical Safety | Wolfreys A.,Preclinical Safety
Drug Development Research | Year: 2014

Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I-III Regulatory, Quality, Manufacturing An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex- mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and reduced host defence against infection and cancer. Nonclinical strategies to facilitate clinical and market entry in the most efficient timeframe are presented. © 2014 Wiley Periodicals, Inc.


PubMed | Preclinical Safety
Type: Journal Article | Journal: Birth defects research. Part B, Developmental and reproductive toxicology | Year: 2013

This study was conducted as part of an ILSI-HESIconsortium effort to assess the utility of circulating inhibin B as an early biomarker of testicular toxicity in rats.Two known testicular toxicants were selected for use in this study: ethylene glycol monomethyl ether (EGME) and dibromoacetic acid (DBAA). EGME (200 mg/kg/day), DBAA (250 mg/kg/day), or vehicle control (0.2% hydroxypropyl methylcellulose [HPMC]) was administered orally to male rats for 3, 6, or 14 consecutive days. On study days 4, 7, and 15, serum was collected for evaluation of inhibin B levels from all surviving animals and a subset of animals was necropsied from each of the control, EGME, and DBAAgroups.Administration of EGMEresulted in spermatocyte degeneration in late stage tubules and spermatocyte depletion to stage III on day 4, progressing to loss of spermatocytes and round spermatids to stage VI by day 7 and continued germ cell loss and degeneration of elongating spermatids by day 15. Inhibin B levels among EGME-treated animals progressively decreased relative to their respective controls at all time points. Administration of DBAA was associated with spermatid retention at all three time points and abnormal residual bodies at days 7 and 15. Inhibin B levels among DBAA-treated animals decreased progressively relative to their respective controls on days 7 and 15.Serum inhibin B levels in rats provided a signal of testicular toxicity for each of these known testicular toxicants administered at high levels; however, histopathology provided the earliest evidence of toxic effects.


Cannon K.E.,Pfizer | Hudzik T.J.,Preclinical Safety
Suicide: Phenomenology and Neurobiology | Year: 2014

This book addresses the phenomenology, demographics, and neurobehavioral aspects of suicidal behavior and its risk factors, underscoring common neurobehavioral threads among different approaches which may underlie such extreme behavior. It additionally provides an overview of new approaches, such as imaging techniques to identify at-risk individuals or in response to drug treatment associated with suicidal behavior, neurodevelopmental approaches, genetic and epigenetic linkages to suicidal behavior, animal models of specific risk factors, as well as potential biomarkers being employed to help assess risk. © Springer International Publishing Switzerland 2014. All rights reserved.


Enright B.P.,Preclinical Safety | Tornesi B.,Preclinical Safety | Lorenz H.,AbbVie GmbH and Co. KG | Whitney K.,Preclinical Safety
Birth Defects Research Part B - Developmental and Reproductive Toxicology | Year: 2013

BACKGROUND: This study was conducted as part of an ILSI-HESIconsortium effort to assess the utility of circulating inhibin B as an early biomarker of testicular toxicity in rats. METHODS: Two known testicular toxicants were selected for use in this study: ethylene glycol monomethyl ether (EGME) and dibromoacetic acid (DBAA). EGME (200 mg/kg/day), DBAA (250 mg/kg/day), or vehicle control (0.2% hydroxypropyl methylcellulose [HPMC]) was administered orally to male rats for 3, 6, or 14 consecutive days. On study days 4, 7, and 15, serum was collected for evaluation of inhibin B levels from all surviving animals and a subset of animals was necropsied from each of the control, EGME, and DBAAgroups. RESULTS: Administration of EGMEresulted in spermatocyte degeneration in late stage tubules and spermatocyte depletion to stage III on day 4, progressing to loss of spermatocytes and round spermatids to stage VI by day 7 and continued germ cell loss and degeneration of elongating spermatids by day 15. Inhibin B levels among EGME-treated animals progressively decreased relative to their respective controls at all time points. Administration of DBAA was associated with spermatid retention at all three time points and abnormal residual bodies at days 7 and 15. Inhibin B levels among DBAA-treated animals decreased progressively relative to their respective controls on days 7 and 15. CONCLUSIONS: Serum inhibin B levels in rats provided a signal of testicular toxicity for each of these known testicular toxicants administered at high levels; however, histopathology provided the earliest evidence of toxic effects. © 2013 Wiley Periodicals, Inc.

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