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Activity / Assay: 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. |
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. |
Activity / Assay: PK and Pharmaceutics |
Physicochemical Properties: MW <500, Measured logD 1.5-3.5, clogP<5, tPSA 70-120, Kinetic solubility >100 μM (Stock solution DMSO followed by dilution in PBS or water) |
Intellectual Property: No insurmountable issues with prior art searches based on Markush searches on each chemotype |
r/mu/hu microsomal stability: > 70% parent at 25 mins |
Plasma protein binding (r/mu/hu): < 95% across species |
CYP Inhibition Panel: IC50 >10 μM versus 2D6, 3A4, 2C9, 2C19, 1A2, SimCYP modelling if outside desired criteria demonstrating no DDI risk |
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) |
Rodent PK: In vivo rodent PK of selected analogs: oral bioavailability >30%; Clp < 1L/hr/kg; t1/2 > 2.5hrs; low-medium Vss |
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 |
Non-rodent PK: In vivo PK of selected analogs: oral bioavailability >30%; Clp < 1L/hr/kg; t1/2 > 2.5hrs; low-medium Vss |
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 |
Human PK predictions: QD or BID (minimally); F >30% |
Solubility, LogD: Thermodynamic aqueous solubility >50 uM; Solubility in SIF >50 uM log D 1.5 – 4.0 |
Activity / Assay: Safety Pharmacology and Toxicology |
hERG: IC50 >1000x primary pharmacology in patch clamp |
Rat CV: >30X window between projected human efficacious Cmax and any hemodynamic effect in rat |
Receptor selectivity panel (eg CEREP): No insurmountable issues |
Mini AMES: Negative (+/- S9) |
Micronucleus: Negative |
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: 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) |
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 |
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... |
Activity / Assay: 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 |
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) |
[Table with columns for Deliverable, Responsible Party (Heptares or AbbVie), and various CMC activities across different stages] |
Appendix F: FP2 reference ligands |
[Table listing various FPR2 agonist/antagonist compounds with references] |
Appendix G: Product-Specific In Vitro Cellular Assays and In Vivo Acute and Chronic Models for Advancement of FPR2 Research Target |
Lead and backup target criteria for advancement to IND-enabling studies. Outlined chronic models are suggested based on the knowledge of the target to date, AbbVie reserves the right to test compounds in more than one chronic model. |
[Table with columns for Attribute, Activity/Assay, Criteria, Comments, describing various in vitro and in vivo assays] |
Appendix H: Stage 4a&b - CMC & Toxicology Workflow |
[Workflow diagram] |
Appendix I: Nonclinical and CMC reports and documents to be included for an IND submission |
Nonclinical reports for an IND (small molecule) should cover, but not limited to, the following topics: |
Pharmacology: Primary Pharmacology: in vitro, in vivo; Secondary Pharmacology: off target binding assays for receptors, ion channels, enzymes and transporters; Safety Pharmacology: CV (hERG, in vivo), CNS, respiratory |
Pharmacokinetics: Bioanalytical method validation; Absorption: cellular permeability, pharmacokinetics in nonclinical species, dose response, formulation effects (if necessary); Distribution: protein binding across species and concentration, red blood cell distribution, tissue distribution (optional); Metabolism: in vi... |
Toxicology: Single dose toxicity (optional); Repeat dose toxicity in rodent and non-rodent; Genotoxicity package: In vitro mutagenicity, in vitro chromosomal aberration, in vivo micronucleus |
CMC reports and documents for an IND (small molecule) should cover, but not limited to, the following topics: |
CMC Drug Substance: Properties of the drug substance; Names and addresses of sites performing drug substance manufacture and testing; Drug substance batch records; Documentation for starting materials; Documentation on GLP tox batch manufacture; Confirmation of structure; PGI assessment reports and control strategies; ... |
CMC Drug Product: List of all excipients used; High level description of the manufacturing process; Names and addresses of sites performing drug product manufacture and testing; Excipient amounts for an exemplary batch; Detailed description of manufacturing process; Critical steps list; Specifications for non-compendia... |
Schedule 3.2.3 |
Approved Subcontractors |
CONFIDENTIAL |
Service Provider Function Services |
1 Piramal MedChem FTE chemistry DMPK Tdsol |
2 O2h MedChem FTE chemistry |
3 Jubilant MedChem FTE chemistry |
5 Syngene MedChem FTE chemistry |
6 Schrodinger CompChem FEP+ |
7 Discngine CompChem 3decision database |
8 ADMEScope DMPK Mechanistic in vitro DMPK studies |
9 Charles River DMPK General in vitro ADME screening Non-clinical safety General tox & safety pharm Non-clinical safety FIH enabling toxicology |
10 Cyprotex DMPK General in vitro ADME screening |
11 Puracyp DMPK AhR/PXR activation |
12 Pharmidex DMPK Bioanalysis of PKPD samples |
13 ChemPartner DMPK In vivo PK Invivo Biology In vivo animal model |
14 Gastroplus DMPK Modelling support |
15 Wuxi DMPK In vivo PK |
16 Eurofins Non-clinical safety Off-target pharmacology Hep2 cytotoxicity Mitotoxicity (glu/gal) BSEP inhibition & other transporter profiling |
17 Vivonics Non-clinical safety Rat CV study In vivo haemodynamics |
18 Covance Non-clinical safety Safety pharmacology In vivo general tox FIH enabling tox |
19 Metrion DMPK Ion Channel Screening |
20 Gentronix Non-clinical safety Genetic tox screening |
22 Imperial College Invitro/Invivo Biology PI Gary Frost (academic collaboration) In vitro/ex vivo cell work Human tissue access |
23 Fidelta MedChem FTE chemistry Invivo Biology/DMPK FTE (DMPK/Biology) In vivo animal work In vitro/ex vivo cell work Human tissue access |
24 Renasci Invivo Biology In vivo animal work |
25 Biopta/Reprocell Invitro Biology Human tissue work |
26 Johnson Matthey DMPK DMPK FTE work |
35 Enamine (https://enamine.net/ ) MedChem Chemical Compounds |
36 Chembridge (https://www.chembridge.com/ ) MedChem Chemical Compounds |
37 ChemDiv (https://www.chemdiv.com/ ) MedChem Chemical Compounds |
38 LifeChemicals (https://lifechemicals.com/ ) MedChem Chemical Compounds |
39 WuXi AppTec (https://www.wuxiapptec.com/ ) MedChem Chemical Compounds |
40 Sigma Aldrich (https://www.sigmaaldrich.com/united-kingdom.html ) MedChem Chemical Compounds |
41 Tocris (https://www.tocris.com/ ) MedChem Chemical Compounds |
42 MedChemExpress (https://www.medchemexpress.com ) MedChem Chemical Compounds |
43 Asinex (http://www.asinex.com/ ) MedChem Chemical Compounds |
44 Bionet/Keyorganics (https://www.keyorganics.net/ ) MedChem Chemical Compounds |
45 Specs (https://specs.net/ ) MedChem Chemical Compounds |
Schedule 7.6.2 |
Example Calculation |
If annual Net Sales of all Licensed Products from the GPR65 Program is $1.2 billion Dollars in a Calendar Year and the annual Net Sales of all Licensed Products from the GPR132 Program is $3.5 billion Dollars in the same Calendar Year, the amount due to Heptares for such Calendar Year would be $356 million, determined ... |
Royalties from the GPR65 Program are an amount equal to ($500 million Dollars * 0.06) + ($500 million Dollars *0.07) + ($200 million Dollars * 0.08) = $81 million Dollars, plus |
Royalties from the GPR132 Program are an amount equal to ($500 million Dollars * 0.06) + ($500 million Dollars *0.07) + ($2 billion Dollars * 0.08) + ($500 million * 0.10) = $275 million Dollars. |
Schedule 9.5 |
Form of Press Releases |
See attached. |
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