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For Scientists

Preclinical Roadmap

The goal in preclinical research is to find a new clinical therapeutic candidate. The components of translational research are integrated into the preclinical research process outlined in this roadmap. The RSZ TNC facilitates preclinical research through consultation and the services offered in the cores.​ 

Target validation

  • Demonstrate that a protein, pathway, or phenotype is associated with a disease and provide evidence that intervention can change a disease state and will result in a favorable clinical outcome.
  • Provide evidence that a small molecule (or gene therapy) can target the protein or pathway or correct the pathogenic phenotype.
  • Consider the safety profile associated with the desired intervention.
  • Create a preliminary “Target Product Profile” (e.g. oral once a day tablet, one-time ICV delivery, etc.).

Screening

6-12 months

  • Optimize assay performance and select a screening library. This work is often done in collaboration with a dedicated screening facility like the Human Neuron Core, the ICCB screening facility, or a contract research organization (CRO).
  • When appropriate, conduct a “virtual screen” to narrow the library of screened compounds.
  • Conduct the assay and identify ”hit” compounds that affect the desired validated target.

Hit to Lead

6-12 months

  • Identify a lead molecule, one that can be modified to optimize multiple parameters necessary to select a clinical candidate.
  • Use both a primary assay and a secondary assay to confirm the hit. For example, a primary assay might be conducted in a recombinant cell line, whereas the secondary assay would be conducted in patient-derived human neurons or primary animal neurons.
  • Conduct counter screens to measure selectivity for the desired target relative to a related and undesirable targets.
  • Conduct preliminary in vivo pharmacokinetics and pharmacodynamics studies, if possible.

Lead Optimization

18-24 months

  • Modify the lead molecule so that a drug candidate can be selected for clinical trials. In a typical project, 10 new compounds would be synthesized each week and tested in primary screening assays. These and other data would guide synthesis of new compounds.
  • Implement a screening funnel to select compounds for desired activities and filter out undesired activities. A total of 500-1000 novel compounds are usually synthesized and tested over the course of a project.
  • Protect intellectual property by filing one or more patent applications.
  • Estimate human dosing with a combination of in vitro and in vivo pharmacokinetics assays and studies in disease models.

Preclinical Development

(9-18 months)

  • Complete all work necessary to file an IND application with the FDA to dose a novel drug candidate in people. This includes: conducting toxicology, safety pharmacology, and pharmacokinetics studies under FDA regulated Good Laboratory Practices (GLP). It also includes preparing the Active Pharmaceutical Ingredient (API) and Drug Product under current Good Manufacturing Practices (cGMP or GMP).
  • Hold a pre-IND meeting with the FDA.
  • Prepare and file an IND application.

Early Clinical Development

(36-48 months)

Early clinical development includes Phase 1 and Phase 2 studies.

  • Phase 1 Studies include single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) dose studies in healthy volunteers to determine drug pharmacokinetics and the maximum tolerated doses. An efficacy biomarker can also be measured. Phase 1 data is used to design a Phase 2 study.
  • A Phase 2 studies is designed to demonstrate initial proof-of-concept in patients and set the dose for a pivotal Phase 3 trial that will be used in a New Drug Application (NDA). In some cases, such as rare disease, a sponsor can seek approval after a successful Phase 2 study.
  • In parallel, non-clinical safety and drug manufacturing research continues.