Drug Development Phases Quiz

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.