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Rodent PK |
In vitro Safety Pharmacology |
hERG |
In Vivo Efficacy |
Acute Rodent PK/PD relationship (refer to Appendix G: In Vivo Acute Efficacy section) |
Appendix C – Stage 3 - Lead Optimization Criteria |
Activity / Assay |
All of the requirements of Stage 2 In vitro/in vivo |
Acute and chronic model in vivo efficacy (refer to Appendix G: In Vivo Acute Efficacy and In Vivo chronic Efficacy section |
Translational Biomarkers |
Proof of Pharmacology |
Proof of Biology |
PK and Pharmaceutics |
Physicochemical Properties |
Intellectual Property |
r/mu/hu microsomal stability |
Plasma protein binding (r/mu/hu) |
CYP Inhibition Panel |
Cellular Permeability |
Rodent PK |
Escalating dose rodent PK |
Non-rodent PK |
CYP phenotyping and induction and possible need to detect non-CYP metabolism and/or active transport |
Human PK predictions |
Solubility, LogD |
Safety Pharmacology and Toxicology |
hERG |
Rat CV |
Receptor selectivity panel (eg CEREP) |
Mini AMES |
Micronucleus |
Rodent 7- day toxicity (dose range finding) |
Bulk Drug Synthesis and Formulation |
Appendix D: Stage 4 - Candidate Selection & GLP Toxicology Criteria |
Activity / Assay Criteria Comments |
Stage 4a Prior to Candidate Selection :‐ All of the requirements of Stage 3 plus: |
Dog CV and Secondary pharmacodynamics >30X window between projected human efficacious unbound Cmax and any hemodynamic effect in dog (perform one study to GLP standards) Data interpretable and support progression |
In vitro ADME study in microsomes and hepatocytes Determine in vitro biotransformation primary pathway of metabolism to inform IVIVE of clearance and inform choice of tox species; use radiolabel if available Data interpretable and support progression |
De‐risk circulating metabolites identified for either pharmacological activity and/or bioactivation Where circulating metabolite(s) suspected from PK, PKPD and/or Tox studies, conduct follow‐up studies for relevance to human regarding potential pharmacological activity or bioactivation potential. Use in vitro systems w... |
Rodent and non‐rodent 14 day dose range finding toxicity study) NOAEL of at least 30x exposures multiple between predicted human efficacious AUC and the exposure at the NOAEL dosage. Endpoints will include clinical observations, body weight, food consumption, gross necropsy observations, organ weights, hematology, seru... |
PK and metabolism Conduct in vitro and in vivo metabolism studies using radiolabel compound. Identify metabolites Complete analysis of PK parameter (half‐life, %F, clearance, volume of distribution, Cmax, AUC) across species (eg rodents, dog, monkeys) iv and oral administration Based on a compilation of the above data ... |
Stage 4b Post Candidate Selection :‐ All of the requirements of Stage 3 and 4a plus: |
GLP bioanalytical assay Development and validation of GLP bioanalytical method for detection of parent compound in plasma as default for both rodent and non‐rodent tox species; need for parent compound detection in other matrix and/or detection of circulating metabolite to be ratified by joint JSC Provision of analytic... |
GLP toxicology studies Criteria for success would include successful generation of a NOAEL exposure (compared to the predicted human efficacious exposure) at least a) 30x for 4‐week toxicology study or b)15x for 13‐week toxicology study. NOAEL optimally based on a toxicity finding that can be detected with a readily av... |
Bulk Drug Synthesis and Formulation See CMC appendix E |
Appendix E: CMC Workplan (at time of initiation of collaboration) |
Sosei Heptares/AbbVie CMC Workplan (Pre-IND Activities/Deliverables) |
Deliverable Responsible Party Pre-OPT-IN Activity Description (Heptares or AbbVie) |
Stage 3 Support |
Drug substance solid form selection/characterization, including assessment of salts, solubility, crystallinity, polymorphism) and make an initial recommendation on preferred API form, Heptares |
Assess thermal and oxidative stability in solid and solution state Heptares |
Assessment from AbbVie process chemistry group on tractability of medicinal chemistry route AbbVie |
AbbVie will collaborate to complete advanced pharmaceutics characterization preclinical candidate – salt form selection, stability (chemical, light, solution etc), excipient compatibility, solid state characteristics, formulation, impurity profile, formulation for DRF and GLP tox AbbVie |
Manufacture of drug substance for PK Heptares |
Stage 4a support |
AbbVie will collaborate to complete salt form selection AbbVie |
Develop enabling chemistry and synthetic process Heptares |
Manufacture of drug substance for DRF Tox studies and formulation development Heptares |
Drug substance analytical release testing Heptares |
Stage 4b support |
AbbVie will collaborate to complete, stability (chemical, light, solution etc) excipient compatibility, solid state characteristics, formulation, impurity profile, formulation plans for FTIH studies Abbvie |
Manufacture of drug substance for GLP Tox, Heptares |
Drug substance analytical release testing Heptares |
Synthesis of metabolite standards as needed for de‐risking circulating metabolites Heptares |
Synthesis of 14C and/or 3H radiolabel as needed for ADME‐Tox investigation Heptares |
Produce and characterize stable label internal standard (SLIS) Heptares |
Select and manage drug substance CDMOs (SM, DS, Analytical) Heptares/AbbVie (JGC) |
Develop/Validate drug substance analytical methods (SM, INT, IPC, final API) Heptares |
Mutagenic assessment of the DS synthesis and appropriate control strategy Heptares |
Produce and characterize a suitable reference standard Heptares |
Manufacture of GMP drug substance for Phase 1 clinical supplies Heptares |
Quality release of drug substance against established specifications Heptares |
Drug substance stability program under typical ICH storage conditions Heptares |
Select and manage drug product CDMOs (DP, Pkg, Analytical) Heptares/AbbVie (JGC) |
Develop Phase 1 clinical formulation Heptares |
Drug product excipient compatibility/stress degradation assessment Heptares |
Develop pilot‐scale drug product manufacturing process Heptares |
Develop/Validate drug product analytical methods for Phase1 formulation Heptares |
Manufacture/Packaging of GMP Phase 1 clinical supplies Heptares |
Quality release of drug product against established specifications Heptares |
Drug product stability program under typical ICH storage conditions Heptares |
Deliverable Responsible Party OPT-IN Activity Description (Heptares or AbbVie) |
Documentation of drug substance and drug product development in respective development reports [identification, structural confirmation, process development, analytical development, control strategy, reference standard, stability] Heptares |
Transfer DS/DP analytical methods by: Providing written methods for all analytical release and stability assays for non‐USP methods which support regulatory filings Formal transfer methods of product specific methods are required Provide consultation to answer questions regarding analytic methods Heptares |
Setup contracts with DS/DP CDMOs conducting stability studies to transfer control of studies to AbbVie AbbVie |
Continue to provide storage of DS/DP GMP stability samples and regulatory retains or coordinate transfer to site determined by AbbVie Heptares |
Provide DS/DP release and stability testing of new GMP/clinical lots until transfer of stability studies is complete Heptares |
Assume control and costs for DS/DP stability studies and storage of materials AbbVie |
Heptares DS/DP materials to be shipped to site TBD by AbbVie at the completion of tech transfer, except for materials needed to complete tech transfer, such as reference standards: List materials DS/DP inventory (SM, INT, DS, DP) Reference standards Samples in support of tech transfer or manufacturing Note: Inventory m... |
Provide DS/DP reports which support technology transfer including: developmental history reports technical development reports Executed batch records CoA's and supporting analytical data Reports that support CMC section of the IND/CTD GMP CDMO audit reports and quality agreements Heptares |
Provide documentation/communications with Regulatory Agencies Heptares |
DS/DP Tech transfer Process Coordinate 3‐way CDAs with mfg. vendors Setup F2F meetings at mfg. sites Provide tech transfer support to manufacturing sites of AbbVie's choosing Heptares |
Appendix F: GPR132 reference ligands |
Target Target Example Ligands/Ligan series Comments (physchem properties/ pharmacology) References |
GPR132 agonist 9‐hydroxyoctadecadienoic acid Brown (2019) PRP https://doi.org/10.1002/prp2.542 |
GPR132 agonist CP‐55 940 Brown (2019) PRP https://doi.org/10.1002/prp2.542 |
GPR132 agonist N‐palmitoylglycine Brown (2019) PRP https://doi.org/10.1002/prp2.542 |
GPR132 antagonist CP‐55 940 Brown (2019) PRP https://doi.org/10.1002/prp2.542 |
GPR132 agonist SKF‐95667 Brown (2019) PRP https://doi.org/10.1002/prp2.542 |
GPR132 agonist SB‐583831 Brown (2019) PRP https://doi.org/10.1002/prp2.542 |
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