Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice.

INTRODUCTION: Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible. METHODS: Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid-related imaging abnormality-edema (ARIA-E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges. RESULTS: Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aß42 and the plasma Aß42/ Aß40 ratio-fluid biomarkers to detect central amyloid negativity-is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24-month, 48-month and 64-month interval for 10 mg/kg (mpk) lecanemab, 10 mpk aducanumab, and 20 mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA-E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA-E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA-E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period. DISCUSSION: This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.

Analysis of clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration using a quantitative systems pharmacology model.

Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of oligomeric protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and oligomeric tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of oligomeric tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6-8% in CSF, 4-6% and 1-2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies.

Computational neurosciences and quantitative systems pharmacology: a powerful combination for supporting drug development in neurodegenerative diseases.

Successful clinical development of new therapeutic interventions is notoriously difficult, especially in neurodegenerative diseases, where predictive biomarkers are scarce and functional improvement is often based on patient's perception, captured by structured interviews. As a consequence, mechanistic modeling of the processes relevant to therapeutic interventions in CNS disorders has been lagging behind other disease indications, probably because of the perceived complexity of the brain. However in this report, we develop the argument that a combination of Computational Neurosciences and Quantitative Systems Pharmacology (QSP) modeling of molecular pathways is a powerful simulation tool to enhance the probability of successful drug development for neurodegenerative diseases. Computational Neurosciences aims to predict action potential dynamics and neuronal circuit activation that are ultimately linked to behavioral changes and clinically relevant functional outcomes. These processes can not only be affected by the disease state, but also by common genotype variants on neurotransmitter-related proteins and the psycho-active medications often prescribed in these patient populations. Quantitative Systems Pharmacology (QSP) modeling of molecular pathways allows to simulate key pathological drivers of dementia, such as protein aggregation and neuroinflammatory responses. They often impact neurotransmitter homeostasis and voltage-gated ion-channels or lead to mitochondrial dysfunction, ultimately leading to changes in action potential dynamics and clinical readouts. Combining these two modeling approaches can lead to better actionable understanding of the many non-linear pharmacodynamic processes active in the human diseased brain. Practical applications include a rational selection of the optimal doses in combination therapies, identification of subjects more likely to respond to treatment, a more balanced stratification of treatment arms in terms of comedications, disease status and common genotype variants and re-analysis of small clinical trials to uncover a possible clinical signal. Ultimately this will lead to a higher success rate of bringing new therapeutics to the right patient populations.

A combined physiologically-based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease.

Antibody-mediated removal of aggregated ß-amyloid (Aß) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aß monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aß40 and Aß42 aggregation and clearance of aggregated Aß by activated microglia cells, which is enhanced by the interaction of antibody-bound Aß. The model allows for the prediction of Aß positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aß42 and plasma Aß42 /Aß40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aß42 /Aß40 ratio while slightly overestimating the change in CSF Aß42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.

A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant.

The clinical impact of therapeutic interventions in Parkinson's disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) model of the basal ganglia motor circuit, essentially a computer model of neuronal firing in the different subregions with anatomically informed connectivity, cell-specific expression of 17 different G-protein coupled receptors and corresponding coupling to voltage-gated ion channel effector proteins based on experimentally observed intracellular signaling. The calculated beta/gamma (b/g) power spectrum of the local field potentials in the subthalamic nucleus was previously calibrated on the clinically relevant Unified Parkinson's Disease Rating Scale (UPDRS). When combining this QSP model with PK modeling of different formulations of L-DOPA, we calculated the b/g fluctuations over a 16 h awake period and used a weighted distance from a specific threshold to determine the cumulative liability of OFF-Time. Prediction of OFF-time with clinical observations of different L-DOPA formulations showed a significant correlation. Simulations show that augmentation with the adenosine A2A antagonist preladenant reduces OFF-time with 6 min for carbidopa/levodopa 950 mg 5-times daily to 37 min for 100 mg L-DOPA - 3 or 5 times daily. Exploring delays between preladenant and L-DOPA intake did not improve the outcome. Hypothetical A2A antagonists with an ideal PK and pharmacology profile can achieve OFF-Time reductions ranging from 9.5 min with DuoDopa to 55 min with low dose L-DOPA formulations. Combination of the QSP model with PK modeling can predict the anticipated OFF-Time reduction of novel A2A antagonists with standard of care. With the large number of GPCR in the model, this combination can support both the design of clinical trials with new therapeutic agents and the optimization of combination therapy in clinical practice.

Hallmarks of neurodegenerative disease: A systems pharmacology perspective.

Age-related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease-modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

The future of Parkinson's disease research: A new paradigm of human-specific investigation is necessary and possible.

Parkinson's disease (PD) is a complex neurodegenerative condition with a multifactorial origin. To date, approaches to drug discovery for PD have resulted in symptomatic therapies for the motor manifestations and signs associated with neurodegeneration but have failed to identify preventive or curative therapies. This failure mainly originates from the persistence of major gaps in our understanding of the specific molecular basis of PD initiation and progression. New approach methodologies (NAMs) hold the potential to advance PD research while facilitating a move away from ani-mal-based research. We report a workshop involving NAM experts in the field of PD and neurodegenerative diseases, who discussed and identified a scientific strategy for successful, human-specific PD research. We outline some of the most important human-specific NAMs, along with their main potentials and limitations, and suggest possible ways to overcome the latter. Key recommendations to advance PD research include integrating NAMs while accounting for multiple levels of complexity, from molecular to population level; learning from recent advances in Alzheimer's disease research; increasing the sharing of data; promoting innovative pilot studies on disease pathogenesis; and accessing philanthropic funding to enable studies using novel approaches. Collaborative efforts between different stakeholders, including researchers, clinicians, and funding agencies, are urgently needed to create a scientific roadmap and support a paradigm change towards effective, human-specific research for neurodegenerative diseases without animals, as is already happening in the field of toxicology.

Computational Approaches for Supporting Combination Therapy in the Post-Aducanumab Era in Alzheimer's Disease.

With the approval of aducanumab on the "Accelerated Approval Pathway" and the recognition of amyloid load as a surrogate marker, new successful therapeutic approaches will be driven by combination therapy as was the case in oncology after the launch of immune checkpoint inhibitors. However, the sheer number of therapeutic combinations substantially complicates the search for optimal combinations. Data-driven approaches based on large databases or electronic health records can identify optimal combinations and often using artificial intelligence or machine learning to crunch through many possible combinations but are limited to the pharmacology of existing marketed drugs and are highly dependent upon the quality of the training sets. Knowledge-driven in silico modeling approaches use multi-scale biophysically realistic models of neuroanatomy, physiology, and pathology and can be personalized with individual patient comedications, disease state, and genotypes to create 'virtual twin patients'. Such models simulate effects on action potential dynamics of anatomically informed neuronal circuits driving functional clinical readouts. Informed by data-driven approaches this knowledge-driven modeling could systematically and quantitatively simulate all possible target combinations for a maximal synergistic effect on a clinically relevant functional outcome. This approach seamlessly integrates pharmacokinetic modeling of different therapeutic modalities. A crucial requirement to constrain the parameters is the access to preferably anonymized individual patient data from completed clinical trials with various selective compounds. We believe that the combination of data- and knowledge driven modeling could be a game changer to find a cure for this devastating disease that affects the most complex organ of the universe.

Toward Predicting Impact of Common Genetic Variants on Schizophrenia Clinical Responses With Antipsychotics: A Quantitative System Pharmacology Study.

CNS disorders are lagging behind other indications in implementing genotype-dependent treatment algorithms for personalized medicine. This report uses a biophysically realistic computer model of an associative and dorsal motor cortico-striatal-thalamo-cortical loop and a working memory cortical model to investigate the pharmacodynamic effects of COMTVal158Met rs4680, 5-HTTLPR rs 25531 s/L and D2DRTaq1A1 genotypes on the clinical response of 7 antipsychotics. The effect of the genotypes on dopamine and serotonin dynamics and the level of target exposure for the drugs was calibrated from PET displacement studies. The simulations suggest strong gene-gene pharmacodynamic interactions unique to each antipsychotic. For PANSS Total, the D2DRTaq1 allele has the biggest impact, followed by the 5-HTTLPR rs25531. The A2A2 genotype improved efficacy for all drugs, with a more complex outcome for the 5-HTTLPR rs25531 genotype. Maximal range in PANSS Total for all 27 individual combinations is 3 (aripiprazole) to 5 points (clozapine). The 5-HTTLPR L/L with aripiprazole and risperidone and the D2DRTaq1A2A2 allele with haloperidol, clozapine and quetiapine reduce the motor side-effects with opposite effects for the s/s genotype. The COMT genotype has a limited effect on antipsychotic effect and EPS. For cognition, the COMT MM 5-HTTLPR L/L genotype combination has the best performance for all antipsychotics, except clozapine. Maximal difference is 25% of the total dynamic range in a 2-back working memory task. Aripiprazole is the medication that is best suited for the largest number of genotype combinations (10) followed by Clozapine and risperidone (6), haloperidol and olanzapine (3) and quetiapine and paliperidone for one genotype. In principle, the platform could identify the best antipsychotic treatment balancing efficacy and side-effects for a specific individual genotype. Once the predictions of this platform are validated in a clinical setting the platform has potential to support rational personalized treatment guidance in clinical practice.

Exploring the relation between BOLD fMRI and cognitive performance using a computer-based quantitative systems pharmacology model: Applications to the COMTVAL158MET genotype and ketamine.

BOLD fMRI is increasingly used mostly in an observational way to probe the effect of genotypes or therapeutic intervention in normal and diseased subjects. We use a mechanism-based quantitative systems pharmacology computer model of a human cortical microcircuit, previously calibrated for the 2-back working memory paradigm, adding established biophysical principles, of glucose metabolism, oxygen consumption, neurovascular effects and the paramagnetic impact on blood oxygen levels to calculate a readout for the voxel-based BOLD fMRI signal. The objective was to study the effect of the Catechol-O-methyl Transferase Val158Met (COMT) genotype on performance and BOLD fMRI. While the simulation suggests that on average virtual COMTVV genotype subjects perform worse, subjects with lower GABA, lower 5-HT3 and higher 5-HT1A activation can improve cognitive performance to the level of COMTMM subjects but at the expense of higher BOLD fMRI signal. In a schizophrenia condition, increased NMDA, GABA tone and noise levels, and lower D1R activity can improve cognitive outcome with greater BOLD fMRI signal in COMT Val-carriers. We further generate hypotheses about why ketamine in healthy controls increases the BOLD fMRI signal but reduces cognitive performance. These simulations suggest a strong non-linear relationship between BOLD fMRI signal and cognitive performance. When validated, this mechanistic approach can be useful for moving beyond the descriptive nature of BOLD fMRI imaging and supporting the proper interpretation of imaging biomarkers in CNS disorders.

Quantitative systems pharmacology in neuroscience: Novel methodologies and technologies.

The development and application of quantitative systems pharmacology models in neuroscience have been modest relative to other fields, such as oncology and immunology, which may reflect the complexity of the brain. Technological and methodological advancements have enhanced the quantitative understanding of brain physiology and pathophysiology and the effects of pharmacological interventions. To maximize the knowledge gained from these novel data types, pharmacometrics modelers may need to expand their toolbox to include additional mathematical and statistical frameworks. A session was held at the 10th annual American Conference on Pharmacometrics (ACoP10) to highlight several recent advancements in quantitative and systems neuroscience. In this mini-review, we provide a brief overview of technological and methodological advancements in the neuroscience therapeutic area that were discussed during the session and how these can be leveraged with quantitative systems pharmacology modeling to enhance our understanding of neurological diseases. Microphysiological systems using human induced pluripotent stem cells (IPSCs), digital biomarkers, and large-scale imaging offer more clinically relevant experimental datasets, enhanced granularity, and a plethora of data to potentially improve the preclinical-to-clinical translation of therapeutics. Network neuroscience methodologies combined with quantitative systems models of neurodegenerative disease could help bridge the gap between cellular and molecular alterations and clinical end points through the integration of information on neural connectomics. Additional topics, such as the neuroimmune system, microbiome, single-cell transcriptomic technologies, and digital device biomarkers, are discussed in brief.

A modeling informed quantitative approach to salvage clinical trials interrupted due to COVID-19.

Many ongoing Alzheimer's disease central nervous system clinical trials are being disrupted and halted due to the COVID-19 pandemic. They are often of a long duration' are very complex; and involve many stakeholders, not only the scientists and regulators but also the patients and their family members. It is mandatory for us as a community to explore all possibilities to avoid losing all the knowledge we have gained from these ongoing trials. Some of these trials will need to completely restart, but a substantial number can restart after a hiatus with the proper protocol amendments. To salvage the information gathered so far, we need out-of-the-box thinking for addressing these missingness problems and to combine information from the completers with those subjects undergoing complex protocols deviations and amendments after restart in a rational, scientific way. Physiology-based pharmacokinetic (PBPK) modeling has been a cornerstone of model-informed drug development with regard to drug exposure at the site of action, taking into account individual patient characteristics. Quantitative systems pharmacology (QSP), based on biology-informed and mechanistic modeling of the interaction between a drug and neuronal circuits, is an emerging technology to simulate the pharmacodynamic effects of a drug in combination with patient-specific comedications, genotypes, and disease states on functional clinical scales. We propose to combine these two approaches into the concept of computer modeling-based virtual twin patients as a possible solution to harmonize the readouts from these complex clinical datasets in a biologically and therapeutically relevant way.

Simulating the Effects of Common Comedications and Genotypes on Alzheimer's Cognitive Trajectory Using a Quantitative Systems Pharmacology Approach.

BACKGROUND: Many Alzheimer's disease patients in clinical practice are on polypharmacy for treatment of comorbidities. OBJECTIVE: While pharmacokinetic interactions between drugs have been relatively well established with corresponding treatment guidelines, many medications and common genotype variants also affect central brain circuits involved in cognitive trajectory, leading to complex pharmacodynamic interactions and a large variability in clinical trials. METHODS: We applied a mechanism-based and ADAS-Cog calibrated Quantitative Systems Pharmacology biophysical model of neuronal circuits relevant for cognition in Alzheimer's disease, to standard-of-care cholinergic therapy with COMTVal158Met, 5-HTTLPR rs25531, and APOE genotypes and with benzodiazepines, antidepressants, and antipsychotics, all together 9,585 combinations. RESULTS: The model predicts a variability of up to 14 points on ADAS-Cog at baseline (COMTVV 5-HTTLPRss APOE 4/4 combination is worst) and a four-fold range for the rate of progression. The progression rate is inversely proportional to baseline ADAS-Cog. Antidepressants, benzodiazepines, first-generation more than second generation, and most antipsychotics with the exception of aripiprazole worsen the outcome when added to standard-of-care in mild cases. Low dose second-generation benzodiazepines revert the negative effects of risperidone and olanzapine, but only in mild stages. Non APOE4 carriers with a COMTMM and 5HTTLPRLL are predicted to have the best cognitive performance at baseline but deteriorate somewhat faster over time. However, this effect is significantly modulated by comedications. CONCLUSION: Once these simulations are validated, the platform can in principle provide optimal treatment guidance in clinical practice at an individual patient level, identify negative pharmacodynamic interactions with novel targets and address protocol amendments in clinical trials.

Learning from amyloid trials in Alzheimer's disease. A virtual patient analysis using a quantitative systems pharmacology approach.

BACKGROUND: Many trials of amyloid-modulating agents fail to improve cognitive outcome in Alzheimer's disease despite substantial reduction of amyloid ß levels. METHODS: We applied a mechanism-based Quantitative Systems Pharmacology model exploring the pharmacodynamic interactions of apolipoprotein E (APOE), Catechol -O -methyl Transferase (COMTVal158Met), and 5-HT transporter (5-HTTLPR) rs25531 genotypes and aducanumab. RESULTS: The model predicts large clinical variability. Anticipated placebo differences on Alzheimer's Disease Assessment Scale (ADAS)-COG in the aducanumab ENGAGE and EMERGE ranged from 0.77 worsening to 1.56 points improvement, depending on the genotype-comedication combination. 5-HTTLPR L/L subjects are found to be the most resilient. Virtual patient simulations suggest improvements over placebo between 4% and 20% at the 10 mg/kg dose, depending on the imbalance of the 5-HTTLPR genotype and exposure. In the Phase II PRIME trial, maximal anticipated placebo difference at 10 mg/kg ranges from 0.3 worsening to 5.3 points improvement. DISCUSSION: These virtual patient simulations, once validated against clinical data, could lead to better informed future clinical trial designs.

Challenges in Alzheimer's Disease Drug Discovery and Development: The Role of Modeling, Simulation, and Open Data.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. With 35 million people over 60 years of age with dementia, there is an urgent need to develop new treatments for AD. To streamline this process, it is imperative to apply insights and learnings from past failures to future drug development programs. In the present work, we focus on how modeling and simulation tools can leverage open data to address drug development challenges in AD.

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges.

The substantial progress made in the basic sciences of the brain has yet to be adequately translated to successful clinical therapeutics to treat central nervous system (CNS) diseases. Possible explanations include the lack of quantitative and validated biomarkers, the subjective nature of many clinical endpoints, and complex pharmacokinetic/pharmacodynamic relationships, but also the possibility that highly selective drugs in the CNS do not reflect the complex interactions of different brain circuits. Although computational systems pharmacology modeling designed to capture essential components of complex biological systems has been increasingly accepted in pharmaceutical research and development for oncology, inflammation, and metabolic disorders, the uptake in the CNS field has been very modest. In this article, a cross-disciplinary group with representatives from academia, pharma, regulatory, and funding agencies make the case that the identification and exploitation of CNS therapeutic targets for drug discovery and development can benefit greatly from a system and network approach that can span the gap between molecular pathways and the neuronal circuits that ultimately regulate brain activity and behavior. The National Institute of Neurological Disorders and Stroke (NINDS), in collaboration with the National Institute on Aging (NIA), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and National Center for Advancing Translational Sciences (NCATS), convened a workshop to explore and evaluate the potential of a quantitative systems pharmacology (QSP) approach to CNS drug discovery and development. The objective of the workshop was to identify the challenges and opportunities of QSP as an approach to accelerate drug discovery and development in the field of CNS disorders. In particular, the workshop examined the potential for computational neuroscience to perform QSP-based interrogation of the mechanism of action for CNS diseases, along with a more accurate and comprehensive method for evaluating drug effects and optimizing the design of clinical trials. Following up on an earlier white paper on the use of QSP in general disease mechanism of action and drug discovery, this report focuses on new applications, opportunities, and the accompanying limitations of QSP as an approach to drug development in the CNS therapeutic area based on the discussions in the workshop with various stakeholders.

Neuronal Circuit-Based Computer Modeling as a Phenotypic Strategy for CNS R&D.

With the success rate of drugs for CNS indications at an all-time low, new approaches are needed to turn the tide of failed clinical trials. This paper reviews the history of CNS drug Discovery over the last 60 years and proposes a new paradigm based on the lessons learned. The initial wave of successful therapeutics discovered using careful clinical observations was followed by an emphasis on a phenotypic target-agnostic approach, often leading to successful drugs with a rich pharmacology. The subsequent introduction of molecular biology and the focus on a target-driven strategy has largely dominated drug discovery efforts over the last 30 years, but has not increased the probability of success, because these highly selective molecules are unlikely to address the complex pathological phenotypes of most CNS disorders. In many cases, reliance on preclinical animal models has lacked robust translational power. We argue that Quantitative Systems Pharmacology (QSP), a mechanism-based computer model of biological processes informed by preclinical knowledge and enhanced by neuroimaging and clinical data could be a new powerful knowledge generator engine and paradigm for rational polypharmacy. Progress in the academic discipline of computational neurosciences, allows one to model the effect of pathology and therapeutic interventions on neuronal circuit firing activity that can relate to clinical phenotypes, driven by complex properties of specific brain region activation states. The model is validated by optimizing the correlation between relevant emergent properties of these neuronal circuits and historical clinical and imaging datasets. A rationally designed polypharmacy target profile will be discovered using reverse engineering and sensitivity analysis. Small molecules will be identified using a combination of Artificial Intelligence methods and computational modeling, tested subsequently in heterologous cellular systems with human targets. Animal models will be used to establish target engagement and for ADME-Tox, with the QSP approach complemented by in vivo preclinical models that can be further refined to increase predictive validity. The QSP platform can also mitigate the variability in clinical trials with the concept of virtual patients. Because the QSP platform integrates knowledge from a wide variety of sources in an actionable simulation, it offers the possibility of substantially improving the success rate of CNS R&D programs while, at the same time, reducing both cost and the number of animals.