Podcast
Questions and Answers
What is the primary focus during the Preclinical phase of drug development?
What is the primary focus during the Preclinical phase of drug development?
Which clinical trial phase is primarily concerned with testing a drug's safety and tolerability in a small group of volunteers?
Which clinical trial phase is primarily concerned with testing a drug's safety and tolerability in a small group of volunteers?
During which phase is the largest number of volunteers typically involved in clinical trials?
During which phase is the largest number of volunteers typically involved in clinical trials?
What is the primary goal of the FDA Review phase in drug development?
What is the primary goal of the FDA Review phase in drug development?
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Which phase involves performing Phase IV studies for long-term effectiveness?
Which phase involves performing Phase IV studies for long-term effectiveness?
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What is the primary focus of the drug discovery phase?
What is the primary focus of the drug discovery phase?
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Which phase follows after initial lead identification in drug discovery?
Which phase follows after initial lead identification in drug discovery?
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What is the typical duration for the preclinical phase in drug development?
What is the typical duration for the preclinical phase in drug development?
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What is one of the major goals during the preclinical phase?
What is one of the major goals during the preclinical phase?
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What role do Contract Development & Manufacturing Organizations (CDMOs) play in drug development?
What role do Contract Development & Manufacturing Organizations (CDMOs) play in drug development?
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What significant change occurred in the profits of contract organizations between 1995 and 2005?
What significant change occurred in the profits of contract organizations between 1995 and 2005?
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Which model supports drug discovery through significant grants with potential ROI?
Which model supports drug discovery through significant grants with potential ROI?
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What major shift was noted in biotech funding between 2019 and 2021?
What major shift was noted in biotech funding between 2019 and 2021?
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What is the typical duration of the Preclinical phase in drug development?
What is the typical duration of the Preclinical phase in drug development?
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Which phase involves testing the drug on the largest number of volunteers?
Which phase involves testing the drug on the largest number of volunteers?
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What type of study is performed during the Post-Approval phase?
What type of study is performed during the Post-Approval phase?
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What is the primary purpose of the FDA Review phase?
What is the primary purpose of the FDA Review phase?
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In which phase are PK/PD and MTD studies primarily conducted?
In which phase are PK/PD and MTD studies primarily conducted?
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Which stage of drug development typically lasts the longest?
Which stage of drug development typically lasts the longest?
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What is the role of larger established companies in drug development compared to universities?
What is the role of larger established companies in drug development compared to universities?
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What trend is noted regarding large pharmaceutical companies in drug discovery?
What trend is noted regarding large pharmaceutical companies in drug discovery?
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Study Notes
RNA Therapeutics Development and Application
- RNA therapeutics are a rapidly developing field with significant potential.
- Drug development is costly and risky, with an average pre-tax cost of $2 billion per new drug approval.
- For every 10,000 molecules tested in biopharma, only one becomes a drug.
- This costly and lengthy process involves various stages.
Drug Development Process
- The drug development process is complex and involves several key steps.
- Target identification and validation is essential for selecting appropriate targets.
- Target validation involves assessing the target's role in the disease and possible beneficial effects from modulation.
- Druggability is a vital factor in drug development – the ease of modulating the target via a therapeutic.
- Safety profile assessment considers possible side effects and redundancy/compensatory mechanisms.
- Target sequence screening and lead optimization are crucial steps.
- Preclinical studies, including in vitro and in vivo experiments, are performed to evaluate safety, efficacy, and mechanism of action.
- Necessary chemical modifications of the compound are performed to achieve desired characteristics (nuclease resistance, toxicity)
- Delivery methods optimize the distribution of compounds for effectiveness within the target tissue & system
- Clinical trials are critical for confirming safety and efficacy.
- Post-approval marketing analysis and safety monitoring are essential for long-term follow-up.
- Target selection involves scientific, strategic, and practical considerations, along with potential market opportunity & unmet needs.
- The feasibility of drug discovery and clinical development strategy, regulatory pathways, biomarker availability, and proof-of-concept studies need to be considered during this stage.
Target Selection Criteria and Considerations
- Target validation is critical to confirm targeting the correct therapeutic effect.
- Genetic and preclinical evidence showing efficacy of target modulation is essential.
- Druggability examines the target's amenability to modulation via a therapeutic (e.g., suitable binding pockets).
- Safety Profile evaluation involves assessing potential safety issues related to target modulation (e.g., target expression patterns, side effects).
- Companies consider factors like novelty vs. established targets, commercial potential, patent landscape, and organizational fit.
- Feasibility of drug discovery is assessed through screening assays, animal models, and target coverage.
- Clinical development strategy and regulatory pathways are important considerations.
Practical Considerations
- The likelihood of successful drug development needs assessment.
- Availability of screening assays and animal models needs to be ascertained.
- Challenges in optimizing drug-like properties need addressing.
- Regulatory pathway feasibility and possibilities for accelerated approval pathways need assessment.
- The design and development of proof-of-concept studies need consideration.
Lead Identification and Optimization
- Target identification and RNA design are crucial steps, identifying optimal target, design of RNA construct, including codon optimization, backbone, and sugar modifications for efficacy and stability.
- Chemical modifications (e.g., backbone modifications, sugar modifications, base modifications) are important, ensuring resistance to nucleases, preventing degradation, reducing immunogenicity.
- The delivery method is critical for effective delivery, including formulations and optimizing delivery vehicle/ROA for specific RNA types and targets.
Preclinical Candidate Development
- Rigorous preclinical studies are conducted to evaluate efficacy and mechanism of action, pharmacokinetics, biodistribution and safety of the compound.
- Manufacturing feasibility needs to be ascertained, ensuring consistent quality during large-scale production.
- Preparation for IND (Investigational New Drug) application includes planning and execution of all enabling studies.
- GLP (Good Laboratory Practice) toxicology studies and proof-of-concept in non-human primates are performed.
Clinical Trial Approval Process
- Clinical trials (phases 1, 2, and 3) are conducted.
- FDA/EMA review evaluates safety and efficacy.
- Post-approval marketing and safety monitoring occur, including phase 4 analyses.
Target of Interest Informs Platform Modifications
- The target of interest shapes platform development, including modifications for localization, specific cell types, mode of action(MOA), etc.
- Different delivery mechanisms and strategies are used.
Preclinical Research Activities
- In vitro studies evaluate efficacy and mechanism of action, focusing on pharmacokinetics, biodistribution, and safety.
- Animal studies confirm results obtained from cell-based experiments.
- Toxicology studies evaluate potential side effects.
- Manufacturing feasibility and scale-up are tested to ensure product consistency and quality across different scales.
- IND application preparation and implementation of GLP toxicology studies for verification in non-human primates, along with proof-of-concept studies in different species are included.
Lead Identification and Optimization and Preclinical Development
- Optimal siRNA target identification, design, and optimization are crucial steps.
- Critical chemical modifications of the compound are necessary for effective therapy, along with appropriate delivery systems.
- Rigorous preclinical and clinical studies are required to confirm the safety and efficacy of candidate compounds.
Target Sequence Selection
- mRNA variant selection is needed.
- NCBI (National Center for Biotechnology Information) and Ensembl resources are used.
- Alignment files are created and redundant variants/discrepancies are eliminated.
- Exon composition, mutational variants, and disease-associated SNPs are considered.
Screening Workflow
- Primary screening and hit identification are used to filter targets for lead candidate selection.
- Secondary screening and lead candidate selection determine potency, species cross-reactivity, and potentially off-target effects.
- Lead optimization involves in vivo testing of lead candidates to refine characteristics, such as acute tolerability, PK/PD, potency, and duration of action.
Core Oligo Therapeutic Development
- Safety, potency, selectivity, durability, and distribution analyses are critical in oligo therapeutic development.
Compound Development and Selection
- The optimal oligo type for the target is determined and algorithms are used to select potential sequences.
- Sequence selection considers and evaluates conjugation efficiency to identify the best candidate.
- Toxicity and off-target effects are evaluated through in vitro tests.
- In vivo screening for lead identification and final candidate selection.
Additional Information (including process)
- In vitro and in vivo analyses and analyses of potency, tolerability, duration, and activity.
- Pharmacological characteristics (e.g., efficacy, PK/PD, tolerability).
###Clinical Candidate ASO Examples
- Examples of clinical candidate ASOs are provided such as IONIS/Roche's tominersen and BIIB080.
- The presented examples exemplify the importance of specific modifications for appropriate delivery and therapeutic outcomes.
- LNA-modified ASOs are a strategy for specific and effective drug delivery.
Clinical Development Plan
- Phase I/IIa studies involve first-in-human testing.
- Phase I/lla studies include early patient selection, focused on safety, tolerability, and pharmacodynamics (PD) (including PK) characteristics for candidate compounds.
- Phases I and IIa are followed by open-label extension studies and natural history studies.
- Pivotal Phase III studies assess efficacy and safety in a larger patient population and guide commercialization decisions.
Statistical Analysis
- Treatment differences in mutant HTT concentrations are evaluated using specific statistical techniques.
- Correlations between parameters are explored to identify relationships.
- Adjustments for multiple testing are done due to the trial's exploratory nature.
Patient Selection
- Patient selection and drug characteristics detail the age range in patients that participated in this study.
- All patients underwent baseline and follow-up assessments, including drug administration with corresponding blood and cerebrospinal fluid (CSF) sampling procedures.
Pharmacokinetic Analysis
- Pharmacokinetic (PK) analysis is planned for all patients
- CSF and plasma samples are quantitatively assessed.
Additional Information
- A list of exploratory biomarker panels (CSF and serum) are included, detailing all the specific tests involved,
- Sampling schedules for all periods (pre-treatment, post-treatment, and visits for early termination) are provided.
- Methods and results concerning preclinical studies are described,
- in vivo experiments in animals (mice, monkeys), followed by human studies.
- The full investigative plan includes detailed descriptions and methodologies for study set-up, analysis methodologies, and experimental parameters.
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Description
Test your knowledge on the various phases of drug development, from preclinical to FDA review. This quiz covers important aspects, including safety testing, volunteer involvement, and the role of contract organizations. Challenge yourself and learn more about the drug development process!
