Drug discovery Flashcards
Define Indications and drugs - Trends in drug discovery and development in neuroscience
(Industry and Society)
What kind of conditions are meant when we talk about CNS disorders?
What is a drug?
What are the major trends in terms of costs for treating CNS disorders?
Outsourcing
What is the reason for drug development failure? – and what can we do to make it better?
What kind of conditions are meant when we talk about CNS disorders?
Neurological (neurodegenerative) – Epilepsy, Alzheimer’s disease (AD) (and other dementias); Parkinson’s disease (PD); Multiple sclerosis (MS); Stroke (ischemic brain diseases); Migraine; minor indications
Psychiatric condition – Unipolar depressive disorder(s)/Major depression (MDD) – bipolar affective disorders (BD); schizophrenia (SCZ); anxiety - posttraumatic stress disorder; panic disorders; obsessive-compulsive disorder (OCD); insomnia
Substance abuse conditions – Alcohol use disorders; drug-use disorders, other
What is a drug?
a substance (chemical agent) that affects a biological system in a potentially useful way.
Drugs are used in the prevention, diagnosis, treatment or cure of disease in man or other animals.
What are the major trends in terms of costs for treating CNS disorders?
Prices increase or decrease depending on new/old drugs. We have direct cost for treatments and indirect, which is for care and disability adjusted life years (especially high for mood disorders, substance use disorder, schizophrenia). There is an overall increase in cost, as people get older and dementia therefore increases. Addiction is more expensive in the US than in EU, where affective disorders are larger.
a) Increasing healthcare expenditures: The costs associated with the diagnosis, treatment, and management of CNS disorders have been rising steadily, partly due to the growing prevalence of these disorders and advancements in medical technologies.
b) High drug development costs: Developing new drugs for CNS disorders involves extensive research, preclinical studies, and clinical trials, which are expensive and time-consuming. The costs associated with developing and bringing a new drug to market contribute to the overall expenses in treating CNS disorders.
c) Long-term healthcare and support services: Many CNS disorders, such as Alzheimer’s disease and Parkinson’s disease, require long-term healthcare services, including specialized care facilities, home healthcare, and supportive therapies. These ongoing expenses contribute to the overall costs of treating CNS disorders.
Outsourcing
Outsourcing in the context of drug discovery and development refers to the practice of delegating certain research, development, or manufacturing activities to external partners or contract research organizations (CROs). It is a strategy often employed by pharmaceutical companies to access specialized expertise, increase efficiency, reduce costs, and accelerate drug development timelines. Outsourcing can involve various aspects of drug discovery and development, such as preclinical studies, clinical trials, data analysis, and manufacturing processes.
What is the reason for drug development failure? – and what can we do to make it better?
We know that CNS drugs are the ones that are the most likely to fail. Many drugs fail because they don’t do what we think they’re doing. Very few drugs come on the market in psychiatry because we don’t understand the diseases properly (biologically). Pathophysiology and etiology might be unknown with overlapping triggers and symptoms. For schizophrenia, drugs were developed in 1942 and not much has changed since. Patients have differing underlying pathophysiology but might have the same disorder on paper.
The suggested way forward is to recognize that….
* Mental disorders are brain diseases; commonly
developmental disorders
* Illness defined by pathology of neural circuits
* Strong push by institutions, such as NIMH while under Thomas Insel, to develop circuitry framework for mental diseases
* Develop precision psychiatry treatments based on brain
circuit based interventions
* To modulate Default mode network (DMN), Negative affect, Positive affect or Cognitive control circuit
* Synaptic plasticity as therapeutic targets to modulate circuits
GPT:
Reasons for CNS drug development failure in particular include:
a) Lack of efficacy: Developing drugs for CNS disorders is challenging due to the complex nature of the brain and the limited understanding of disease mechanisms. The inability of a drug to demonstrate meaningful therapeutic effects in clinical trials can lead to development failure.
b) Safety concerns: The blood-brain barrier and potential off-target effects in the CNS can pose safety challenges for CNS drugs. Adverse events or toxicities specific to the brain can arise, leading to the discontinuation or withdrawal of the drug candidate.
c) Poor pharmacokinetics in the CNS: CNS drugs may face challenges related to crossing the blood-brain barrier, achieving optimal brain distribution, or being efficiently metabolized within the CNS.
To improve the success rate of CNS drug development, several strategies can be implemented:
a) Enhanced target validation: Thorough understanding of the specific targets and pathways implicated in CNS disorders can help identify more effective drug candidates.
b) Innovative preclinical models: Utilizing advanced in vitro and in vivo models that better mimic CNS physiology and pathology can aid in predicting drug efficacy and safety in humans.
c) Biomarker-driven approaches: Incorporating biomarkers as measurable indicators of disease progression or drug response can help guide the selection and evaluation of CNS drug candidates, enabling more accurate and efficient clinical trials.
d) Personalized medicine approaches: Recognizing the heterogeneity of CNS disorders and considering individual patient characteristics, such as genetic profiles or biomarker patterns, can help identify subgroups of patients who may respond better to specific treatments.
e) Collaboration and data sharing: Promoting collaboration among researchers, pharmaceutical companies, and regulatory agencies facilitates the sharing of knowledge, data, and resources, ultimately accelerating CNS drug development.
f) Adaptive trial designs: Implementing adaptive clinical trial designs in CNS drug development allows for flexibility in trial parameters and can help optimize study design and decision-making based on emerging data.
Define a drug target
Mention current drug targets in CNS for various indications.
Describe for each of these drug targets their mechanisms, and how they may (or may not) link to a given disease or condition
Define a drug target
Drug targets are a kind of biological macromolecule in the body that have a pharmacodynamics function by interacting with drugs, such as certain proteins and nucleic acids. Drugs achieve disease treatment by binding specific targets and changing gene function of their targets.
Historically, the main classes of drug targets have beenreceptors, enzymes, ion channels and transporters. But it could also be proteins/peptides (e.g. amyloid) or metabolites or transcription factors (not a lot of examples, but in theory). They can really be anything.
Targets can be found inside the cell or outside. They need to be the cells we should manipulate (so same mechanisms as neurons), but we don’t screen on neurons, because they have to be as similar as possible (difficult with neurons, as they’re not always similar without IPSCs which is hard to get enough numbers). We use HEK cells, which are tumor derived and grow like crazy.
Mention current drug targets in CNS for various indications.
Describe for each of these drug targets their mechanisms, and how they may (or may not) link to a given disease or condition
- Acetylcholinesterase (AChE) inhibitors:
* * Mechanism: Inhibit the enzyme acetylcholinesterase, which breaks down the neurotransmitter acetylcholine, thereby increasing acetylcholine levels.
* * Indication: Alzheimer’s disease, to alleviate cognitive symptoms.
* * Link to disease: Alzheimer’s disease is characterized by a deficiency of acetylcholine due to the degeneration of cholinergic neurons, and AChE inhibitors can help compensate for this deficiency.
- Acetylcholinesterase (AChE) inhibitors:
- Dopamine D2 receptor antagonists:
- Mechanism: Block dopamine D2 receptors, reducing dopamine activity.
- Indication: Schizophrenia, to reduce positive symptoms like hallucinations and delusions.
- Link to disease: Schizophrenia is associated with dysregulated dopamine signaling, and D2 receptor antagonists help normalize dopamine activity.
- Selective serotonin reuptake inhibitors (SSRIs):
- Mechanism: Inhibit the reuptake of serotonin, increasing serotonin levels in the synaptic cleft.
- Indication: Major depressive disorder, to alleviate depressive symptoms.
- Link to disease: Depression is associated with low serotonin levels, and SSRIs increase serotonin availability to enhance mood.
Define unmet medical needs
In terms of unmet needs, what criteria are important before IND and NDA/MAA?
Discuss costs for different diseases
Discuss direct and indirect expenses
Discuss differences of unmet needs and their costs for different countries
Criteria before the IND application:
- Preclinical Data: Demonstrating the drug candidate’s pharmacology, toxicology, and potential efficacy through in vitro and in vivo studies.
- Pharmacokinetics (PK) and Pharmacodynamics (PD): Assessing the drug’s absorption, distribution, metabolism, and elimination in the body, as well as its relationship between drug concentration and pharmacological effect.
- Safety Assessments: Conducting comprehensive safety evaluations, including acute and chronic toxicity, genotoxicity, carcinogenicity, reproductive toxicity, and addressing any other safety concerns.
- Manufacturing and Quality Control: Establishing a well-controlled drug manufacturing process that ensures consistent quality, purity, and stability of the drug product according to Good Manufacturing Practices (GMP) guidelines.
Criteria before the MAA/NDA submission:
- Clinical Trial Design: Developing a scientifically rigorous clinical trial protocol, determining appropriate patient populations, defining primary and secondary endpoints, selecting controls or comparators, and establishing a statistically robust sample size.
- Clinical Trial Ethics and Patient Safety: Ensuring ethical considerations and patient safety are addressed by obtaining approval from Institutional Review Boards (IRBs) or Ethics Committees.
- Efficacy and Safety Data from Clinical Trials: Conducting Phase 1, 2, and 3 clinical trials to evaluate the drug’s efficacy and safety in human subjects.
- Benefit-Risk Assessment: Conducting a comprehensive analysis to assess the overall therapeutic value of the drug and determining whether the potential benefits outweigh the potential risks.
Discuss costs for different diseases
Alzheimer’s will have a large cost in care, where depression, substance use disorder, schizophrenia and bipolar costs a lot in years lost due to disability. Some disorders like MS can be large in direct cost.
Dementia is one of the costliest disorders overall and I becoming more prevalent (so is ADHD). Mood disorders are expensive because there are so many patients.
Discuss direct and indirect expenses
Direct expenses are related to the medication and the treatment in the hospital. The indirect costs are associated with the care of the patient (daycare) but also the difference in the profit they could generate for the society if they were healthy. Lost years are related to any value the person would have contributed to society, but now is unable to.
Discuss differences of unmet needs and their costs for different countries
When looking at cost, alcohol dependence, substance use, MDD and bipolar are the top costs, but in Europe it’s affective disorders, addiction and dementia, suggesting we have less addiction but more depression.
Describe criteria for identifying novel drug targets
What kind of data would you like to see when picking a novel target for CNS disorders?
What is meant by a “screenable” target?
What kind of data would you like to see when picking a novel target for CNS disorders?
GPT:
Biological Relevance: Data indicating the target’s biological relevance to the CNS disorder of interest is crucial. This can include information on the target’s expression in relevant brain regions or cell types, its involvement in disease pathways or mechanisms, and evidence of its role in disease progression or symptomatology.
Genetic and Genomic Data: Genetic and genomic data can provide insights into the association between the target and CNS disorders. This can include data from genome-wide association studies (GWAS), gene expression profiling, or genetic mutations specifically linked to the disease. Such data can help establish a genetic basis for targeting the molecule of interest.
Preclinical Models: Preclinical data obtained from animal models or in vitro studies can be valuable in assessing the target’s potential. This may involve demonstrating the target’s modulation in disease models, the impact of target manipulation on disease phenotypes, or the effect of target-specific interventions on relevant endpoints.
Validation Studies: Validation studies provide evidence that the target’s modulation leads to the desired therapeutic effect. This can include studies using pharmacological tools, such as small molecules or antibodies, that selectively interact with the target and demonstrate efficacy in relevant disease models.
Safety Considerations: Safety data, particularly in the context of the CNS, are crucial. This includes assessing whether modulation of the target affects normal brain functions or leads to undesirable side effects. Safety assessments can involve evaluating the target’s expression or function in non-disease states, studying potential off-target effects, and considering any known safety concerns associated with similar targets.
Druggability: Assessing the target’s druggability is important to determine its potential as a therapeutic target. This involves evaluating whether the target can be effectively modulated by small molecules, biologics, or other therapeutic modalities. Factors such as the presence of suitable binding sites, the target’s structural characteristics, and the availability of tools or approaches to modulate its activity are considered.
What is meant by a “screenable” target?
You can screen drug molecules/compounds on the target – all GPCRs and ion channels are in principle druggable, but a structural protein or kinase is more difficult to screen. You should be able to screen molecules on the target. How you do it is a different question.
A druggable target are targets where we can do a screen. Typically, these can be GPCR. A druggable target might be an enzyme and DNA as well.
GPT:
When a target is considered “screenable,” it means that it is amenable to screening large compound libraries or test compounds to identify potential drug candidates that interact with the target. High-throughput screening (HTS) involves the rapid testing of thousands or even millions of compounds against the target in a relatively short period.
A screenable target possesses certain characteristics that make it suitable for screening, such as:
Assay Compatibility: The target must have an assay or screening method that allows for the detection of interactions or changes in its activity. This can include biochemical assays, cell-based assays, or functional assays depending on the nature of the target and the disease being targeted.
Accessibility: The target should be accessible and available for testing. This means that the target can be obtained or produced in a purified form, or it can be expressed in appropriate cell systems or model organisms for screening purposes.
Robustness: The target should demonstrate a stable and reproducible response to the screening process. This ensures that the screening results are reliable and can be replicated across multiple experiments.
Disease Relevance: The target should have a known or strongly suspected role in the disease being targeted. It should be biologically linked to the disease pathology, providing a rationale for targeting it for therapeutic intervention.
Describe the phases in preclinical drug discovery
What phases are usually necessary to complete before IND?
Describe for each phase or activity the purpose and acceptable outcome
What phases are usually necessary to complete before IND?
The drug discovery and preclinical development. The IND is a license to give the drug to patients.
Describe for each phase or activity the purpose and acceptable outcome
In preclinical drug discovery, several phases and activities are conducted to evaluate the safety, efficacy, and pharmacokinetics of a potential drug candidate before moving to human clinical trials. Here are the typical phases in preclinical drug discovery, along with their purposes and acceptable outcomes:
- Target Validation:
- Purpose: Confirm the biological target’s relevance to the disease and its potential as a therapeutic intervention.
- Acceptable Outcome: Demonstration of the target’s involvement in disease pathology through various techniques, such as genetic studies, in vitro experiments, or animal models.
- Hit Identification and Lead Generation:
- Purpose: Identify initial compounds that interact with the target of interest and show potential for further development.
- Acceptable Outcome: Identification of hit compounds with reasonable potency and selectivity against the target, often identified through high-throughput screening or virtual screening approaches.
- Lead Optimization:
- Purpose: Improve the properties of lead compounds, including potency, selectivity, pharmacokinetics, and safety.
- Acceptable Outcome: Identification of lead compounds that exhibit enhanced properties, such as improved potency, selectivity, metabolic stability, and reduced toxicity. These compounds should have suitable drug-like characteristics and demonstrate efficacy in relevant preclinical models.
- In vitro and In vivo Pharmacology:
- Purpose: Evaluate the compound’s pharmacological effects, mechanism of action, and therapeutic potential.
- Acceptable Outcome: Demonstration of the compound’s desired pharmacological effects in relevant in vitro assays and animal models, supporting its therapeutic potential. This includes assessing target engagement, activity against disease-related endpoints, and understanding the compound’s mechanism of action.
- Pharmacokinetics and Toxicology:
- Purpose: Assess the compound’s absorption, distribution, metabolism, and excretion (ADME) characteristics, as well as its potential toxic effects.
- Acceptable Outcome: Generation of pharmacokinetic data, including bioavailability, half-life, clearance, and tissue distribution. Additionally, assessment of toxicology parameters, such as acute toxicity, genotoxicity, and organ-specific toxicity, to establish an acceptable safety profile.
- Formulation Development:
- Purpose: Develop suitable formulations to ensure optimal delivery and stability of the drug candidate.
- Acceptable Outcome: Development of formulations that provide adequate solubility, stability, and bioavailability for the drug candidate, ensuring its appropriate delivery and dosing in subsequent studies.
- IND-Enabling Studies:
- Purpose: Generate comprehensive data to support the safety and rationale for initiating human clinical trials.
- Acceptable Outcome: Successful completion of studies, including additional pharmacology, toxicology, and safety assessments, to establish the safety profile of the drug candidate and support the planned clinical trial design.
The successful completion of these preclinical phases and activities, with acceptable outcomes in terms of target validation, lead optimization, pharmacology, pharmacokinetics, toxicology, and formulation development, provides the necessary foundation for submitting an Investigational New Drug (IND) application to regulatory authorities.
Describe the phases in drug development – Phase I-III
What kind of studies (and results) are needed to bring a novel drug to the market? - Describe the goal of each phase, and use examples of read outs
What is an FDA guideline? Discuss also overall, what criteria that could be met to make a drug successful
What kind of studies (and results) are needed to bring a novel drug to the market? - Describe the goal of each phase, and use examples of read outs
Phase I
* Microdosing
* Dose escalation
* Safety
Phase II
* Clinical protocol
* Patients included
* Efficacy
Phase III
* Comparator
* Efficacy
* Dose response
Phase I of Drug Development:
* * Goal: Assess the safety, tolerability, and pharmacokinetics of the investigational drug in a small number of healthy volunteers or patients.
* * Studies: Conducted in a small group (typically tens of participants) to determine the drug’s dosage, route of administration, absorption, distribution, metabolism, and elimination.
* * Results: The primary readouts include data on safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic parameters, and initial assessment of efficacy in some cases.
Phase II of Drug Development:
* * Goal: Evaluate the drug’s efficacy and further assess its safety and optimal dosing in a larger population of patients.
* * Studies: Involve hundreds of patients with the targeted disease or condition to assess the drug’s effectiveness and optimal dosage range. Often divided into Phase IIa (exploratory) and Phase IIb (confirmatory) studies.
* * Results: The main readouts include efficacy data, such as improvements in disease-specific biomarkers, clinical endpoints, or symptom relief, along with continued evaluation of safety and tolerability.
Phase III of Drug Development:
* * Goal: Confirm the drug’s efficacy, monitor its side effects, and compare it to existing treatments in a larger and more diverse patient population.
* * Studies: Involve thousands of patients across multiple clinical trial sites. Placebo-controlled or comparative trials are conducted to gather robust data on efficacy, safety, and long-term effects.
* * Results: The primary readouts are statistically significant evidence of the drug’s efficacy and safety in a large patient population. These results are crucial for regulatory submissions, such as a New Drug Application (NDA) to the FDA.
What is an FDA guideline? Discuss also overall, what criteria that could be met to make a drug successful
FDA Guidelines:
FDA guidelines are documents provided by the U.S. Food and Drug Administration (FDA) that offer recommendations and regulatory expectations for the development, evaluation, and approval of drugs. These guidelines provide clarity on the data required to demonstrate safety and efficacy, trial design, patient population considerations, and other regulatory aspects.
Criteria for a Successful Drug:
To make a drug successful, it generally needs to meet the following criteria:
Efficacy: The drug should demonstrate statistically significant and clinically meaningful efficacy in treating the targeted disease or condition, as evidenced by robust clinical trial data.
Safety: The drug should have an acceptable safety profile, with a favorable benefit-to-risk ratio. Adverse events should be manageable and outweighed by the therapeutic benefits.
Quality and Manufacturing: The drug should meet quality standards and be consistently manufactured to ensure uniformity and reliability of its therapeutic effects.
Regulatory Compliance: The drug should fulfill the regulatory requirements set by the FDA or relevant regulatory authorities, including submission of comprehensive data, adherence to ethical standards, and compliance with regulatory guidelines.
Market Demand: There should be a significant unmet medical need for the drug, along with a viable market and potential patient population to support its commercial success.
Intellectual Property: Adequate intellectual property protection is crucial to ensure exclusivity and market exclusivity for a reasonable period, allowing the company to recoup development costs and generate profits.
Meeting these criteria enhances the likelihood of a drug’s success in gaining regulatory approval, addressing patient needs, and achieving commercial viability in the market.
Describe links between genotype and target identification
What kind of data have been used to define new targets?
How do certain genes and certain variations link to disease and drug target?
Mention methods and activities (i.e. from Didriksens slide deck) that can be used to find novel drug targets for schizophrenia (or other diseases)
What kind of data have been used to define new targets?
CNVs can be useful, as they typically lead to a lot higher odds ratios than SNPs. Note that if you’re looking at SNPs, you need to see if they fall into the same category of cells or pathway, so that we can target that with drugs. CNVs typically are linked to higher risk, but as they are rare you have a smaller patient group.
- Genetic Studies: Genome-wide association studies (GWAS) and whole-genome sequencing have identified genetic variants associated with diseases. These studies provide insights into genes that may be involved in disease development and progression.
- Gene Expression Profiling: Transcriptomic data, such as RNA sequencing or microarray analysis, can reveal genes that are differentially expressed in disease states compared to healthy conditions. This information helps identify potential targets that play a role in disease pathophysiology.
- Proteomics and Metabolomics: Proteomic and metabolomic studies provide information on the protein and metabolic profiles associated with specific diseases. This data can highlight potential targets involved in disease-related pathways or dysregulated processes.
- Literature Mining: Mining scientific literature, such as published research articles and patents, allows researchers to identify potential targets that have been previously studied or associated with specific diseases.
- Bioinformatics and Data Integration: Integrating various data sources, including genomics, proteomics, and clinical data, through computational methods can help identify potential targets and their relationships to diseases.
How do certain genes and certain variations link to disease and drug target?
Disorders like Schizophrenia has a genetic relationship. The heritability shows us that there is an interaction between the genes and environment. For some disorders it can be super hard to link, as Schizophrenia has 8300 genes linked to it, all with different functions.
Problem: some genes have different expression profile over time (maybe due to environmental changes) and might have pleiotropic effects. CNVs might be more informative than SNPs, but also rarer and explain less cases. Another problem include that some people can have the risk variants without the disorder but still with cognitive impairments (for schizophrenia)
- Disease-Associated Genes: Genes that are found to be associated with a disease through genetic studies (e.g., GWAS) are candidates for further investigation as potential targets. These genes may be involved in disease pathways, regulation of key biological processes, or modulating disease risk.
- Functional Variations: Specific genetic variations, such as single nucleotide polymorphisms (SNPs), can affect gene expression, protein function, or drug response. Variations in drug target genes may influence the effectiveness or safety of targeted therapies.
- Pathogenic Mutations: Disease-causing mutations in specific genes can directly contribute to the development of a disease. Targeting these mutated genes or their downstream effects can be a therapeutic strategy.
Mention methods and activities (i.e. from Didriksens slide deck) that can be used to find novel drug targets for schizophrenia (or other diseases)
Genetic analysis where we try to add up different SNPs affecting the same pathway so we can target it.
taking the genes and introduce the big variant –> looked at changes –> figure out a way to rescue it –> what the drug should do
Here we take the variant, model it in the mouse, see if the phenotype is the same, select a variation, use that tissue and put it in a dish to develop and screen drugs on it to see if it can fix the phenotype
- Genetic Studies: Conducting GWAS or genome sequencing studies in individuals with schizophrenia to identify genetic variations associated with the disease.
- Transcriptomic Analysis: Comparing gene expression profiles in schizophrenia patients and healthy controls to identify differentially expressed genes or dysregulated pathways.
- Proteomic and Metabolomic Studies: Investigating protein and metabolic profiles in schizophrenia patients to identify potential targets or altered pathways associated with the disease.
- Animal Models: Using animal models that exhibit schizophrenia-like symptoms to study the underlying molecular mechanisms and identify potential drug targets.
- High-Throughput Screening: Screening large compound libraries against specific targets or disease models to identify molecules that modulate the target of interest.
- Computational Approaches: Utilizing bioinformatics, network analysis, and data integration techniques to identify potential targets based on genetic, transcriptomic, proteomic, or metabolomic data.
- Literature Review: Analyzing existing literature and databases to identify genes or proteins previously implicated in schizophrenia or related pathways.
Pharmacological principles
Discuss different pharmacological effects in vitro and in
vivo?
Define efficacy and potency and make curves and figures
that explain this.
Define the therapeutic window, - on target and off target
Discuss different pharmacological effects in vitro and in
vivo?
In vitro refers to experiments conducted in controlled laboratory settings outside of a living organism, typically using isolated cells or tissues. In this context, pharmacological effects are observed at the cellular or molecular level, providing insights into the direct interaction between a drug and its target. In vitro studies allow researchers to assess parameters like binding affinity, enzymatic activity, or cellular responses to understand the drug’s mechanism of action.
In vivo refers to studies conducted in living organisms, such as animals or humans. In this setting, pharmacological effects are observed in a more complex biological system, including interactions with various organs, tissues, and physiological processes. In vivo studies provide information on drug absorption, distribution, metabolism, and excretion, as well as overall efficacy and safety profiles. These studies help evaluate the drug’s effects on the whole organism, its therapeutic potential, and any potential adverse reactions.
Define efficacy and potency and make curves and figures
that explain this.
Efficacy: Efficacy refers to the maximum therapeutic effect a drug can produce. It represents the drug’s ability to elicit a desired response or produce a specific therapeutic outcome. It is often measured as the magnitude of the response or the percentage of patients showing a predefined clinical improvement. Efficacy is an important consideration when evaluating the therapeutic value of a drug.
Potency: Potency refers to the concentration or dose of a drug required to produce a specific effect. It indicates the strength or activity of a drug. A more potent drug requires a lower concentration or dose to achieve a given level of response. Potency is determined by measuring the drug’s activity against a specific target or endpoint. It is typically represented by the EC50 (half-maximal effective concentration) value, which is the concentration of the drug required to produce 50% of the maximum response.
Curves and figures illustrating efficacy and potency:
The dose-response curve is commonly used to illustrate the relationship between drug concentration or dose and the magnitude of the response. The curve typically shows a sigmoidal shape, with increasing response as the drug concentration or dose increases.
Efficacy: The curve’s upper plateau represents the maximum response achievable, indicating the drug’s efficacy. It shows the point at which further increasing the drug concentration or dose does not result in a higher response.
Potency: The position of the curve along the concentration or dose axis represents the drug’s potency. A more potent drug will have its curve shifted to the left, indicating that it achieves the same response at lower concentrations or doses compared to a less potent drug.
Define the therapeutic window, - on target and off target
Therapeutic window: The therapeutic window is the range of drug concentrations or doses that provide a desirable therapeutic effect while minimizing the risk of adverse effects. It represents the safety margin between the effective dose and the dose that causes unacceptable toxicity. A wide therapeutic window indicates a greater safety margin, making the drug more suitable for clinical use.
On-target effects: On-target effects refer to the desirable pharmacological effects produced by a drug’s specific interaction with its intended target. These effects are usually related to the drug’s primary mechanism of action and contribute to its therapeutic benefit.
Off-target effects: Off-target effects refer to unintended pharmacological effects that occur when a drug interacts with other targets in addition to its intended target. These effects may arise from interactions with related proteins or receptors, leading to potentially unwanted side effects. Minimizing off-target effects is important for ensuring drug safety and tolerability.
Describe the role of antibodies in CNS drug discovery and development
Consider CGRP receptor antibodies as an example
Evaluate the use of antibodies as novel drug candidates for CNS indications.
What are the benefits of using antibodies? – What are the challenges?
Mention examples where antibodies are used as drug candidates (indications, targets etc)
Evaluate the use of antibodies as novel drug candidates for CNS indications.
Antibodies have emerged as promising novel drug candidates for CNS indications in neuroscience. They offer target specificity, the potential to cross the blood-brain barrier, diverse mechanisms of action, and enhanced half-life. Clinical successes, such as natalizumab for multiple sclerosis and monoclonal antibodies for migraines, highlight their efficacy. However, challenges such as manufacturing complexity, immunogenicity, limited tissue penetration, and high costs need to be addressed. Ongoing research aims to optimize antibodies and develop innovative delivery strategies. Overall, antibodies show great potential for precise intervention in complex CNS diseases, and advancements in engineering and drug delivery are expected to further enhance their therapeutic value.
What are the benefits of using antibodies? – What are the challenges?
What make antibodies a great tool for theraputics?
* * They are specific in their binding as they have high sequence diversity
* * They have good serum stability and circulate long in the body due to their long serum stability
* * Different parts can be used in different disorders
* * High engeneering potential
* * They are known to the body, so they have pretty low immunigenicity
* * They can act in different ways: antagonists, agonists and cytotoxic agents (kill the target)
Challenges:
* - The BBB is hard to pass
Mention examples where antibodies are used as drug candidates (indications, targets etc)
Diabetes & obesity
Neurodenerative diseases
Alzheimer’s: beta amyloid can be target with antibodies. Aducanumab clears the peptides and plagues by binding to them and attracting microglia. It binds the oligomers and fibrils. From the early clinical development. Problem: doesn’t have a lot of effect (high dose and not everyone responds). Doesn’t help much will the cognitive effects, but some effect.
Tau is also a target for AD. It’s heavily modified post-translation and the phosphorylation pattern of the protein correlates with the disease stage (the more phosphorylation, the more disease). It has a cross-beta strand structure and from monomers you can form different types of fibrils. The original antibodies include C10.2 and only binds to the hyper-phosphorylated forms of tau.
Antibody to increase microglia function by boosting TREM2 activity (you’re binding to TREM2). AB is called AL002. This is also used to clear plagues. Treating with anti-TREM2 will rescue some learning deficiency.
MS
Anti-DC20 is used as an example (many exists, but CD20 is most used and found on the B-cells). MS is an autoimmune disorder, where B cells express anti-self antibodies. In MS the antigens that the B cells make antibodies against is myelin. CD-20 antibodies bind to CD-20, which causes B cell apoptosis. Problem: the patient have no adaptive immune response.
Migrane
Anti-CGRP are for migraine (calcitonin gene-related peptide). It’s released from the trigeminal nerves leading to vasodilation and migraine attacks. Preventing this peptide binding to the receptors will stop the attacks. 3 types target the peptide and 1 target the receptor.
By immunizing a rabbit, we get the AB (has to be humanized first by making the rabbit sequence into human except the part that binds to the epitope - therefore the CDRs are still rabbit). The AB is made in yeast.
IgG1 can do almost everything because it has very high affinity to the FC gamma receptor. IgG4 has low activity on most of these parameters and therefore gives very little effect. IGg1 is good for cancer where you want the immune system involved, but if it’s an autoimmune disease, you want something that doesn’t further trigger the immune system.
Describe technology-driven drug target strategies
Give examples of target/technology driven drug discovery strategies
Give examples of target classes that have been successful and describe why these have been successful.
Give examples of target/technology driven drug discovery strategies
* * Structure-Based Drug Design: This strategy utilizes structural information of a target protein to design small molecules that can bind to the target with high affinity and specificity. Techniques such as X-ray crystallography, nuclear magnetic resonance (NMR), or cryo-electron microscopy (cryo-EM) are employed to determine the three-dimensional structure of the target protein.
* * High-Throughput Screening (HTS): HTS involves the screening of large compound libraries against specific target proteins to identify molecules that interact with the target of interest. This approach allows for the rapid identification of potential hits or lead compounds.
* * Fragment-Based Drug Design: Fragment-based approaches involve screening small fragments or low molecular weight compounds against a target protein, followed by optimization to design more potent and selective drug candidates. Fragment screening can be conducted using techniques such as NMR, surface plasmon resonance (SPR), or differential scanning fluorimetry (DSF).
* * Phenotypic Screening: In phenotypic screening, compounds are screened based on their ability to modulate a specific cellular phenotype or disease-related phenotype. This approach allows for the identification of drug candidates that affect the desired disease pathway or target.
Give examples of target classes that have been successful and describe why these have been successful.
* * Kinases: Kinases are enzymes involved in cell signaling pathways and regulate various cellular processes. They have been successfully targeted in diseases such as cancer and inflammatory disorders. Kinases play critical roles in disease-related signaling pathways, making them attractive targets. Small molecules or antibodies can be designed to selectively inhibit or modulate kinase activity.
* * G protein-coupled receptors (GPCRs): GPCRs are a large family of membrane receptors involved in cell signaling and are implicated in numerous diseases. Many successful drugs target GPCRs, such as beta-blockers for cardiovascular diseases and antipsychotics for mental disorders. GPCRs are well-characterized, and their structural information is available, making them amenable to structure-based drug design approaches.
* * Ion Channels: Ion channels are involved in the regulation of ion flux across cell membranes and play crucial roles in neuronal signaling and muscle contraction. Drugs targeting ion channels have been successful in treating conditions such as epilepsy and cardiac arrhythmias. Modulating ion channel activity can regulate aberrant electrical signaling, making them important therapeutic targets.
* * Enzymes: Enzymes involved in disease-related pathways are attractive targets for drug discovery. For example, inhibitors of proteases, such as HIV protease inhibitors, have been successful in treating viral infections. Inhibiting disease-associated enzymes can disrupt specific metabolic pathways or halt pathological processes.
The success of these target classes can be attributed to their key roles in disease biology, druggability (ability to be targeted by small molecules or biologics), availability of structural information, and validation through preclinical and clinical studies. Understanding the target class’s function, role in disease, and appropriate modulation is crucial for successful drug discovery efforts.
Describe indication-driven drug discovery
What kind of activities could help you in discovering new targets for a defined disease?
How would you consider a target useful for a given disease. What kind of data would be valuable in indication-driven drug discovery?
What kind of activities could help you in discovering new targets for a defined disease?
* * Disease Biology Understanding: Comprehensive understanding of the disease’s underlying biology, including molecular pathways, cellular mechanisms, and disease progression, is crucial. This can be achieved through literature review, analysis of clinical data, and collaborations with disease experts.
* * Genetic Studies: Conducting genetic studies, such as genome-wide association studies (GWAS) or sequencing studies, can identify genetic variations or mutations associated with the disease. These studies can provide insights into potential target genes or pathways involved in disease development or progression.
* * Biomarker Identification: Identifying disease-specific biomarkers, such as proteins, metabolites, or genetic markers, can guide target discovery. Biomarkers can highlight relevant pathways or cellular processes and aid in the identification of potential therapeutic targets.
* * High-Throughput Screening: Performing high-throughput screening of compound libraries or small molecule libraries against disease-specific cellular or biochemical assays can help identify molecules that modulate the disease phenotype. This approach can uncover potential targets or pathways involved in the disease.
* * Omics Data Analysis: Analyzing large-scale omics data, such as genomics, transcriptomics, proteomics, or metabolomics, can reveal disease-associated molecular signatures or dysregulated pathways. Integrating these datasets with clinical data can identify potential targets for intervention.
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How would you consider a target useful for a given disease. What kind of data would be valuable in indication-driven drug discovery?
Target Usefulness in Indication-Driven Drug Discovery and Valuable Data: A target is considered useful for a given disease in indication-driven drug discovery if it meets certain criteria:
* * Disease Association: The target should have a strong biological rationale and be directly or indirectly linked to the disease pathophysiology. It should play a crucial role in disease development, progression, or maintenance.
* * Druggability: The target should be amenable to therapeutic intervention using small molecules, biologics (e.g., antibodies), or other modalities. It should have accessible binding sites or interaction interfaces for drug molecules.
* * Preclinical and Clinical Evidence: Preclinical studies, such as animal models or in vitro assays, demonstrating the target’s modulation leads to desired therapeutic effects are valuable. Additionally, clinical evidence from biomarker studies, genetic studies, or previous drug trials that support the target’s involvement in the disease can further establish its usefulness.
* * Safety and Feasibility: Consideration should be given to the safety and feasibility of targeting the specific target. Potential side effects, target specificity, and potential off-target effects should be evaluated.
In indication-driven drug discovery, valuable data includes:
* * Clinical Data: Data on disease prevalence, patient demographics, disease progression, and treatment outcomes are essential for understanding the disease landscape and identifying unmet needs.
* * Genetic and Omics Data: Genetic data, such as GWAS or sequencing data, can provide insights into disease-associated genes or variations. Omics data, including transcriptomics, proteomics, or metabolomics, can highlight dysregulated pathways or biomarkers associated with the disease.
* * Preclinical Studies: Data from preclinical studies using animal models or in vitro assays can provide evidence of target involvement in disease biology and support its usefulness.
* * Biomarker Identification: Data on disease-specific biomarkers and their association with disease progression, treatment response, or prognosis can guide target selection and validation.
* * Pharmacological Data: Data on existing drugs or compounds that modulate the target and their effects on the disease phenotype can provide evidence for target usefulness.
Overall, indication-driven drug discovery relies on a comprehensive understanding of disease biology, integration of various data types, and evidence supporting the target’s relevance and druggability for a given disease.
Define the Translational gap
What is meant by a translational gap in drug development (CNS)?
Discuss and give examples of drug candidates that fall into the gap
Discuss cross-species issues in drug discovery and development – both at a molecular and physiological level
What is meant by a translational gap in drug development (CNS)?
The translational gap, also known as the “valley of death,” refers to the challenges and barriers that occur during the transition of promising drug candidates from preclinical stages to clinical development and ultimately to successful commercialization in the field of drug development for CNS (Central Nervous System) disorders. It represents a gap between preclinical research and clinical translation, where many potential drug candidates fail to progress.
Discuss and give examples of drug candidates that fall into the gap
* Disease-Modifying Therapies: Drug candidates aimed at modifying disease progression in neurodegenerative disorders, such as Alzheimer’s disease or Parkinson’s disease, have faced difficulties in demonstrating efficacy in clinical trials. Promising results observed in preclinical studies often fail to translate into positive outcomes in human trials, leading to a translational gap.
* Novel Mechanisms of Action: Drug candidates targeting novel mechanisms of action or novel targets in the CNS often face challenges during translation. Limited understanding of the complex biology of the CNS and the lack of suitable preclinical models that accurately reflect human pathophysiology contribute to the translational gap.
* Blood-Brain Barrier (BBB) Penetration: Many drug candidates struggle to cross the BBB and reach the target in the CNS. Despite promising preclinical data, insufficient penetration across the BBB limits their efficacy in clinical trials, creating a translational gap.
Discuss cross-species issues in drug discovery and development – both at a molecular and physiological level
3. Cross-species issues arise in drug discovery and development when findings from preclinical studies in animal models do not directly translate to human biology. These issues can occur at both the molecular and physiological levels:
* Molecular Differences: There can be species-specific differences in the expression, structure, or function of target proteins or receptors, which can affect the response to drug candidates. For example, a drug candidate that shows efficacy in an animal model may not interact with the human target in the same way, leading to a lack of translation.
* Physiological Variability: Variations in the physiology and metabolism between species can impact drug absorption, distribution, metabolism, and excretion (ADME). Differences in drug metabolism enzymes, transporters, or receptor systems can affect the pharmacokinetics and pharmacodynamics of drug candidates, resulting in variations in drug response between animals and humans.
Addressing these cross-species issues requires the development of more sophisticated preclinical models that better recapitulate human physiology, such as humanized animal models or in vitro organoid systems derived from human cells. Additionally, advancements in computational modeling and simulation techniques can aid in predicting the efficacy and safety of drug candidates in humans, bridging the gap between preclinical and clinical stages.
The use of RNA therapeutics in CNS drug discovery . Define RNA therapeutics
Describe the chemical nature of molecules that can interact with RNA
Define and describe some targets that are suitable for RNA therapeutics
Describe some mechanisms of action though which RNA therapeutics may act.
Describe the chemical nature of molecules that can interact with RNA
Small molecules drugs, ASOs (single under 14 dalton long) and double stranded (over 14 dalton) siRNAs
- Antisense Oligonucleotides (ASOs): ASOs are short, single-stranded nucleic acid sequences that are complementary to a specific target RNA sequence. They can hybridize with the target RNA through Watson-Crick base pairing. Chemical modifications, such as phosphorothioate backbone modifications or 2’-O-methoxyethyl (MOE) sugar modifications, are often incorporated into ASOs to enhance stability and optimize binding affinity.
- Small Interfering RNAs (siRNAs): siRNAs are double-stranded RNA molecules typically about 21-25 base pairs in length. They work through a process called RNA interference (RNAi), where one strand of the siRNA guides the sequence-specific degradation of the target RNA by the RNA-induced silencing complex (RISC). siRNAs are chemically synthesized and often modified with 2’-O-methyl or other chemical groups to improve stability and reduce off-target effects.
Define and describe some targets that are suitable for RNA therapeutics
Any RNAs – has been used for the SOD1 gene or intron 7 for the SMA ASO.
- mRNA Targets: RNA therapeutics can specifically target disease-related mRNA molecules. By binding to the mRNA, they can modulate gene expression, either by enhancing or inhibiting translation or by inducing RNA degradation. This approach can be used to upregulate the production of therapeutic proteins or downregulate the expression of disease-causing proteins.
- Non-coding RNA Targets: Non-coding RNAs, such as long non-coding RNAs (lncRNAs) or microRNAs (miRNAs), play important roles in gene regulation and disease pathways. RNA therapeutics can target these non-coding RNAs to modulate their function and disrupt disease-associated processes.
Describe some mechanisms of action though which RNA therapeutics may act.
Either you have a mixmer that will change the splicing and give rise to different versions of the protein. Gapmer leads to a downregulation (the gap in green can recruit enzymes to break down the RNA) and will fx decrease the level of toxic proteins.
You make a revers complement of a sequence of interest, but the sequence might be unstable and not have the preferable properties
Small molecules has a complex scheme with splicing. They can stabilize, prevent proteins binding to RNA –> up or downregulation of the RNA (only manipulating slicing - you can add a stopcodon)
Comparing it to spinraza (ASO binding to intron to include exon) and risdiplam will attract more splicosome to upregulate exon 7 transcription by binding to the 5’splice site of SMN2 around exon 7.
- mRNA Degradation: RNA therapeutics can induce targeted degradation of disease-related mRNA molecules. For example, ASOs can hybridize with the target mRNA and recruit cellular enzymes to promote its degradation, effectively reducing the expression of disease-causing proteins.
- Translation Inhibition: RNA therapeutics can prevent the translation of mRNA into protein. For instance, siRNAs can guide the RISC complex to bind to target mRNA, leading to its degradation or inhibition of translation.
- Alternative Splicing Modulation: RNA therapeutics can influence alternative splicing, a process that generates multiple mRNA isoforms from a single gene. By targeting specific splicing events, RNA therapeutics can promote or inhibit the production of specific protein isoforms, thereby altering disease-related pathways.
- Antisense-Mediated Exon Skipping: ASOs can be designed to selectively bind to specific regions of pre-mRNA and induce exon skipping during mRNA splicing. This mechanism can restore the reading frame and functional protein production in genetic disorders caused by specific mutations.
What is meant by an animal model of (CNS) disease? Consider validity in animal models
Give examples of animal models of disease, and describe their validity, strengths and weaknesses
What kind of validity would be important to include in such models?
Give examples of animal models of disease, and describe their validity, strengths and weaknesses
Problem: for Schizophrenia, we can’t model a lot of the symptoms and there are components of human behavior that we can’t mimic. As a cortical disease, there is a big difference in the cortical development, making it difficult to translate. If you have a SNP, it might also not be a disease gene (it might just be inherited with others) and you might need 1000s of these to have the effect you can’t just make one genetic mutation and they might not be super relevant.
- Transgenic Mouse Models of Alzheimer’s Disease: These models are genetically modified mice that express human genes associated with Alzheimer’s disease, such as amyloid precursor protein (APP) and presenilin. They develop amyloid plaques and neurofibrillary tangles, key pathological features of Alzheimer’s disease. These models have good face validity (resemblance to human pathology) and allow the study of disease mechanisms and testing of potential therapies. However, they may not fully recapitulate the complexity and progression of the human disease.
- Rodent Models of Parkinson’s Disease: Rodent models, such as the 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models, are commonly used to study Parkinson’s disease. These models induce selective degeneration of dopaminergic neurons and motor deficits. They offer good construct validity (relevance to disease mechanisms) and allow testing of new therapies. However, they may not fully capture the non-motor symptoms seen in human patients.
- Rodent Models of Depression: Chronic unpredictable stress models or social defeat models in rodents are used to mimic depressive-like behaviors. These models exhibit behavioral changes, altered neurochemistry, and neuroplasticity in response to stress. They provide construct validity and allow the study of neurobiological mechanisms underlying depression. However, they may not fully capture the complexity and subjective experience of human depression.
What kind of validity would be important to include in such models?
* * Face Validity: Face validity refers to the extent to which the model exhibits features resembling the human disease. It involves similarities in pathological hallmarks, symptoms, and behavioral manifestations. Models with good face validity enhance the relevance of the research findings to the human condition.
* * Construct Validity: Construct validity assesses the degree to which the model reflects the underlying biological mechanisms or etiology of the disease. Models with good construct validity provide insights into disease mechanisms and facilitate the evaluation of potential therapeutic targets and interventions.
* * Predictive Validity: Predictive validity refers to the ability of the model to accurately predict the effects of interventions or therapies in humans. Models with high predictive validity are more likely to yield translatable findings and guide clinical trial design.
ADME
What is ADME?
Discuss each of the components and describe what the body can do to the drug
What preclinical ADME criteria are important to fulfill to bring leads further in development?
What is ADME?
ADME stands for absorption, distribution, metabolism, and excretion. It represents a set of processes that describe how a drug is handled by the body after administration. These processes play a crucial role in determining the drug’s pharmacokinetics (PK), which influences its efficacy and safety.
Discuss each of the components and describe what the body can do to the drug
* * Absorption: Absorption refers to the movement of a drug from its site of administration into the bloodstream. It can occur through various routes such as oral (through the gastrointestinal tract), intravenous (directly into the bloodstream), inhalation, or topical application. The absorption process determines the rate and extent to which the drug reaches systemic circulation and becomes available to exert its effects.
* * Distribution: Distribution involves the transport of a drug throughout the body after it enters the bloodstream. It is influenced by factors such as blood flow, tissue permeability, binding to plasma proteins, and partitioning into different body compartments. Distribution determines how the drug is distributed to its target site(s) and other tissues, impacting its concentration at the site of action.
* * Metabolism: Metabolism refers to the enzymatic conversion of a drug into different chemical forms (metabolites) in the body. The primary site of drug metabolism is the liver, although other organs may also contribute. Metabolism can lead to the activation or inactivation of the drug and plays a crucial role in determining its duration of action, elimination half-life, and potential for drug-drug interactions.
* * Excretion: Excretion involves the elimination of a drug and its metabolites from the body. The primary organ responsible for drug excretion is the kidney, although other routes such as bile (via the liver) and lung exhalation may also contribute. Excretion helps remove the drug and its metabolites, regulating drug concentrations and preventing potential toxicity.
What preclinical ADME criteria are important to fulfill to bring leads further in development?
In preclinical drug development, certain ADME criteria are crucial to ensure that lead compounds have desirable properties for progression to clinical development. These include:
* * Favorable absorption: Lead compounds should exhibit adequate absorption to reach therapeutic concentrations in the systemic circulation. This is assessed through in vitro and in vivo studies that evaluate factors such as solubility, permeability, and stability.
* * Metabolic stability: Lead compounds should demonstrate metabolic stability, indicating that they are not rapidly metabolized or prone to significant metabolic transformations. This helps ensure sufficient systemic exposure and facilitates longer duration of action.
* * Minimal off-target interactions: Lead compounds should have minimal off-target interactions and be selective for the intended target. This reduces the potential for unwanted side effects and increases the likelihood of therapeutic specificity.
* * Acceptable excretion: Lead compounds should have an acceptable excretion profile, allowing for efficient elimination from the body. This is evaluated through studies assessing factors such as renal clearance and potential for accumulation.
