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In vitro ADME |
r/mu/hu microsomal &/or hepatocyte stability |
Plasma protein binding (r/mu/hu) |
CYP Inhibition Panel |
Thermodynamic Solubility (pH 7.4) |
Cellular Permeability |
In Vivo Pharmacokinetics |
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, Criteria, Comments |
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), Efficacy ED50 <10mg/kg in model defined in target validation / MoA section. Dose responsive with understanding of target occupancy (PK‐PD), Data to be generated and understood, and drug series co... |
Translational Biomarkers |
Proof of Pharmacology, Demonstrate a dose dependent induction of biomarkers with in vivo animal systems that tracks with PK. Demonstrate the ability to induce the biomarker in in vitro human correlate., Assays need to be clinically feasible. Examples of clinically feasible assays consist of interrogation of serum, plas... |
Proof of Biology, Demonstrate dose dependent induction of biomarkers that tracks with efficacy in animal models. Demonstrate same proof of biology biomarkers in human systems or using cyno in vivo models if appropriate., Assays need to be clinically feasible. Examples of clinically feasible assays consist of interrogat... |
PK and Pharmaceutics |
Physicochemical Properties, MW <500, Measured logD 1.5‐3.5, clogP<5, tPSA 70‐120, Kinetic solubility >100 M (Stock solution DMSO followed by dilution in PBS or water), Guidelines only Operating in property space that increases the likelihood of achieving favorable oral PK attributes in humans is preferred to avoid sign... |
Intellectual Property, No insurmountable issues with prior art searches based on Markush searches on each chemotype, Required Liaison with AbbVie IP attorneys to align on searches and conclusions |
r/mu/hu microsomal stability, > 70% parent at 25 mins, Required |
Plasma protein binding (r/mu/hu), < 95% across species, Guidelines only Data generated: PPB should not be used as a design criteria or to select between molecules |
CYP Inhibition Panel, IC50 >10 M versus 2D6, 3A4, 2C9, 2C19, 1A2 SimCYP modelling if outside desired criteria demonstrating no DDI risk, Data to be generated and understood, series considered tractable to optimisation |
Cellular Permeability, Papp >10 x 10‐6 cm/sec; no efflux issues as judged by AB/BA ratio; not a PGP inhibitor (unless designing for peripheral restriction), Data to be generated and understood, series considered tractable to optimisation |
Rodent PK, In vivo rodent PK of selected analogs: oral bioavailability >30%; Clp < 1L/hr/kg; t1/2 > 2.5hrs; low‐medium Vss, PK commensurate with required human dose prediction using allometric scaling. If rodent specific route of clearance then adequate exposure in efficacy and safety studies. Exposure should enable co... |
Escalating dose rodent PK, Understanding of Cmax, AUC dose response; exposure at higher doses to support design of rodent tox species; achieve multiples of efficacious AUC consistent with at least 30X therapeutic index, Data to be generated and understood, series considered tractable to optimisation |
Non‐rodent PK, In vivo PK of selected analogs: oral bioavailability >30%; Clp < 1L/hr/kg; t1/2 > 2.5hrs; low‐medium Vss PK commensurate with required human dose prediction using allometric scaling. If 2nd sp. specific route of clearance, then adequate exposure in efficacy and safety studies., Data to be generated and u... |
CYP phenotyping and induction and possible need to detect non‐CYP metabolism and/or active transport, Determine which CYP(s) are responsible for metabolism; assess potential for CYP induction, Data to be generated and understood, series considered tractable to optimisation |
Human PK predictions, QD or BID (minimally); F >30%, Data to be generated and understood, series considered tractable to optimisation |
Solubility, LogD, Thermodynamic aqueous solubility >50 uM; Solubility in SIF >50 uM log D 1.5 – 4.0, Data to be generated and understood, series considered tractable to optimisation |
Safety Pharmacology and Toxicology |
hERG, IC50 >1000x primary pharmacology in patch clamp, Data to be generated and understood, series considered tractable to optimisation |
Rat CV, >30X window between projected human efficacious Cmax and any hemodynamic effect in rat, Data to be generated and understood, series considered tractable to optimisation |
Receptor selectivity panel (eg CEREP), No insurmountable issues, Data to be generated and understood, series considered tractable to optimisation |
Mini AMES, Negative (+/‐ S9), Required |
Micronucleus, Negative, Required |
Rodent 7‐ day toxicity (dose range finding), NOAEL (at least) 30x exposures multiple between predicted human efficacious AUC and adverse event. Plasma exposures. Endpoints include a) clinical observations (b) body weight (c) food consumption (d) gross necropsy observations (e) organ weights (f) hematology (g) serum che... |
Bulk Drug Synthesis and Formulation See CMC appendix E |
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 ... |
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, ser... |
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 analyt... |
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 a... |
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) |
1. 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 |
2. 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: Inv... |
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 |
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