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Four approaches will be undertaken: 1. Work-up and evaluation of current hits/tools reported from previous screening campaigns, utilising further compound design, synthesis and compound acquisition. |
Computational chemistry approaches coupled with SDM, will provide binding site(s) and mode hypothesis to drive SAR optimisation and support hit confirmation via further file mining (internal and external) and/or early hit to lead chemistry. The ligand may act as a positive modulator that can be used to enhance acidic p... |
2. Scaffold hopping from existing compounds, using structural information / de novo design approaches from the refined model. |
Validated GPR65 ligand binding mode models in approach 1 can serve as templates for ligand and structure-based hit ID approaches in addition to virtual screening inspired hit ID approaches (approach 3) to identify new scaffolds/ligands targeting the same binding site. Furthermore, biophysical mapping and crystallograph... |
3. Virtual screening based on the binding site(s) in an active (or inactive) state model of the receptor. |
Sosei Heptares will screen a database of commercially available compounds which are suitable starting points for drug discovery, selecting a subset of virtual hits for testing in assays. Complementary ligand-based and protein-based virtual screening approaches will be used including: - Ligand-based approaches will incl... |
GPCR structure/sequence analysis based chemogenomics approaches facilitated by Sosei Heptares' 3Decision enabled GPCR structural databases combining public and proprietary GPCR structural information and bio/chemoinformatics tools (including ss-Tea, BioGPS, and customised GPCR structural cheminformatics workflows) will... |
4. Screening of Sosei Heptares proprietary GPCR diversified libraries generated through a combination of chemoinformatic data mining and manual curation techniques |
Customised screening libraries designed to cover the GPCRome are available at Sosei Heptares to enable early hit identification and establish target tractability. These will be profiled in an in-house developed wild-type GPR65 agonist assay in vitro and/or via SPR (when a GPR65 agonist StaR protein is available) outlin... |
Single concentration hits from any of the approaches outlined above will be confirmed by re-testing in the same assay by profiling in concentration response to generate a pIC50/pKi/pEC50 result and checked with orthogonal assays if feasible. |
Additional Hit ID utilising StaR protein |
The aim of this phase will be to use GPR65 StaR protein to generate new chemical matter via enablement of the following potential approaches: |
1. GPR65 StaR protein will be characterised to confirm retainment of agonist binding to support hit identification using the thermostabilised receptor. Stabilised GPR65 will be purified in detergent to provide soluble protein and enable the potential application of DNA-encoded library screening against GPR65. GPR65 aff... |
2. Fragment screening will be employed when a suitable biophysical assay format has been established for GPR65 using a focused fragment library. Based on experience of family A targets we might expect acidic fragments (which are well represented in the Sosei Heptares fragment library) to bind different orthosteric and ... |
"Technical Failure" for GPR65 Agonist Program will mean that Heptares fails to deliver a completed GPR65 Stabilized Receptor (StaR protein) which is subsequently demonstrated to enable compound screening in e.g. SPR or DNA-encoded library platforms as described above in section 'b) Stage 1: Hit identification'. |
Stage 1 (Hit ID) Deliverable: Identification of ≥ 2 novel structurally distinct hit chemical series with calculated ECFP4 Tanimoto similarity values of less than 0.4 and on target potency <10uM in a GPR65 overexpressing cell line with cAMP readout and less than 3x standard deviation of vehicle control in parental cell ... |
c) Stage 2: Lead Generation |
Aim: To identify lead candidates from 2 distinct chemical series with the calculated ECFP4 Tanimoto similarity values of less than 0.4 and demonstrate in vitro and acute in vivo activity • To identify potent modulators of GPR65 using SAR/SBDD medicinal chemistry efforts. • To evaluate ADME/PK properties of selected hit... |
Once hits are confirmed and concentration response curves obtained, the most promising examples for further elaboration will be selected based on several factors, including molecular efficiencies, synthetic tractability, confidence in modelled binding modes, and prioritising chemotypes based on developability. |
Complementary 2D/topology based (fast GPU similarity, orthogonal molecular fingerprints) and 3D based similarity search methods (shape/pharmacophore search, protein docking-structural interaction fingerprint scoring protocols) against purchasable, synthesisable (e.g. Enamine REAL), and de novo virtual library design ap... |
Complementary medicinal chemistry ligand design strategies will be used in conjunction with above hit elaboration approaches, including structure-based bio-isosteric replacement strategies based on comparative analyses of combined public and in-house GPCR structures and models. Physiochemical property assessment in com... |
Binding poses for key molecules will be obtained from docking into models, enhanced with Biophysical Mapping data if feasible, or, if possible, from X-ray structures. Molecule design will be part guided by docking poses, and part empirically to build up SAR of the series. As more SAR is established, and confidence incr... |
As described in section b), experimentally enhanced GPR65 models accommodating different orthosteric and allosteric ligand binding sites and agonist/antagonist conformations are available based on public and proprietary insights into class A GPCR structure, biophysical (e.g. HDX), and pharmacological (mutation mapping)... |
The in vitro pharmacology of compounds will be tested in primary functional assays to determine potency/efficacy and competition binding if available for affinity measurements. Activity at orthologue receptors will also be examined to understand cross species activity in addition to other off-target GPCR selectivity as... |
Molecules with appropriate pharmacology and in vitro ADME properties will be selected for rodent PK profiling to establish IVIV Cl correlation and oral bioavailability determination. Molecules with sufficient free exposure cover over primary pharmacology will be further selected as tools for in vivo efficacy profiling ... |
Stage 2 (Lead Generation) Deliverable: To identify lead molecules from two (2) prioritised and distinct chemical series with appropriate pharmacology, ADME, PK and in vivo acute PK/PD consistent with the criteria in Appendix B. Translational biomarker strategy will be generated to outline clinically feasible biomarker ... |
d) Stage 3: Lead Optimisation |
Aim: To optimize lead candidates from two (2) distinct chemical series and demonstrate in vivo activity in a relevant chronic disease model(s) and acceptable safety profile • To demonstrate efficacy in appropriate in vivo disease model(s) |
The prioritised and elaborated two (2) lead chemical series will be subjected to further optimisation. Both binding affinity and functional activity of compounds will be monitored, with the emphasis on relevant assay(s) that correlate to PK/PD understanding. Parameters such as residence time on the receptor may also be... |
At this stage, it is anticipated that X-ray structures with compounds bound will be available to guide the design of compounds for synthesis. Well-established medicinal chemistry considerations will be used to ensure good developability properties of compounds, consistent with oral delivery. Physiochemical property con... |
The DMPK properties of promising compounds will be continually measured and optimised to support further progression toward Candidate Nomination / Selection. Properties such as solubility, lipophilicity, metabolic stability, clearance, volume of distribution and brain penetration will be measured at Sosei Heptares CROs... |
The lead molecules from each chemical series will be tested in relevant in vitro and in vivo studies to confirm target engagement (biomarker), drug distribution profile and efficacy in in vivo animal model studies. Studies and endpoints will be aligned to an agreed Target Product Profile and will form key components to... |
1. In vitro evaluation • Confirm pharmacology in relevant human cell / tissue-based assays and demonstrate evidence of in vitro target engagement and pathway modulation. • Identify target-engagement biomarkers (e.g. gene transcription / phosphorylation profiles) suitable for future clinical validation/development. It i... |
2. In vivo evaluation • The in vivo strategy will be planned/agreed jointly by ABBV and Sosei Heptares and ratified by the JGC. Abbvie will run chronic models of disease, as appropriate. • Confirm distribution of drug to the target site of action. • Confirm PD activity of lead molecule(s) in a relevant acute/subchronic... |
The best compounds will undergo additional in vitro and in vivo toxicological profiling |
1. In vitro safety assessment • The lead molecules will be evaluated in assays to assess hERG inhibition and other off-target pharmacology, HepG2 cytotoxicity and mitotoxicity (Glu/Gal), BSEP inhibition, 5-strain AMES and in vitro micronucleus (Sosei Heptares). |
2. In vivo safety • In vivo safety will be assessed in rodent and non-rodent MTD studies to understand acute tolerability and high dose TK (Sosei Heptares). The non-rodent MTD species selection will incorporate cross-species pharmacology and metabolic profiling data (Sosei Heptares). |
3. Mechanistic safety • An assessment of mechanistic safety will be undertaken (Sosei Heptares) and any proposed de-risking studies will be performed (Sosei Heptares) as agreed by JSC. |
CMC |
1. Fit-for-purpose route selection/development will be conducted at Sosei Heptares to provide a batch to support pre-clinical studies including high dose oral PK studies, additional mechanistic safety/PD studies and solid form characterisation. |
2. Initial solid form characterisation (XRPD, TGA, DSC, DVS, microscopy), biopharmaceutics screening (to include biorelevant solubility and chemical stability) as well as preclinical formulation development (for early in-vivo and toxicology studies) will be conducted on this batch (Sosei Heptares). |
Stage 3 (Lead Optimization) Deliverables: Prioritised 2-4 Leads from each of two (2) distinct chemical series (for clarity, each chemical series to produce 2-4 lead molecules) fulfilling the desired in vitro pharmacology, target engagement in relevant human cell/tissue assays, in vivo efficacy, DMPK and safety profile ... |
Preclinical Development |
a) Stage 4a: Candidate Nomination to Candidate Selection |
Aim: To further optimize and select a minimum of 2 candidates in total (at any given time) to take through to candidate nomination phase and which would be suitable for advancement into preclinical development; likely that a frontrunner from one series and a back-up from a distinct chemical series would initially be pr... |
Lead molecules (Stage 3 Deliverables) from each chemical series will be tested in relevant in vitro and in vivo studies outlined below to support candidate nomination and candidate selection (Appendix H). It is expected that these studies will continue post-candidate selection to support PKPD and human dose predictions... |
• Conduct mechanistic PK and metabolism studies as needed, as described in Appendix D, to support 1) toxicology evaluation(s) such as potential of metabolite(s) to induce toxicity, 2) to support refinement of human PK predictions including comparison of primary metabolic pathways and kinetics in animals and human in vi... |
• A salt screen (if appropriate) and polymorph screen will typically be carried out prior to manufacture of the non-GMP batch to support GLP tox studies. This non-GMP batch will also support initial ICH stability studies, and formulation development activities including Tech batch stability. Details of the CMC delivera... |
• Provision of non-GMP material for 2 species DRF will be coordinated by Sosei Heptares. Both ABBV and Sosei Heptares will contribute to the CMC strategy of DRF bulk delivery and enabling GMP manufacture, and strategy will be mutually agreed / ratified by the JGC (Appendix H). |
Final agreement for the GMP API manufacture, as well as the GMP API and DP CROs, will be mutually agreed / ratified by the JGC. It is expected that these activities will be initiated following Candidate Nomination and following provision of non-GMP material for the DRF and GLP studies. |
In parallel with detailed preclinical candidate selection studies with the most advanced current leads from each chemical series, a backup program will identify additional candidate quality molecules for each chemical series, if required. Detailed profiling of existing advanced ligands in combination with new molecule ... |
Stage 4a (Preclinical Candidate Selection) Deliverables: • Two chemically differentiated compounds (one from each chemical series) selected fulfilling criteria outlined in Appendix D including rodent and non-rodent 14d DRF and dog CV molecule with acceptable safety profiles and defined therapeutic margins to progress t... |
b) Stage 4b: Candidate Selection to IND |
1. GLP toxicology studies in rodent and non-rodent |
Following selection of a leading candidate at Candidate Selection, planning for rodent and non-rodent GLP toxicology studies will be initiated and conducted (Appendices D&H). It is anticipated that a 1-month GLP toxicology study will be the default duration of study. However, if AbbVie decides a 3-month duration is nee... |
Development and validation of GLP bioanalytical methods will be undertaken for detection of parent compound in plasma as default; need for parent compound detection in another matrix and/or detection of circulating metabolite to be ratified by joint decision via the JGC. |
2. Provision of IND-ready package |
Preparation of the IND-ready package will be the responsibility of Sosei Heptares to include: 1) transfer of data in suitable format including SEND-ready format for GLP toxicology and toxicokinetic data; 2) provision of study reports for GLP Toxicology, Toxicokinetics, Pharmacology/Safety Pharmacology, DMPK and CMC (Dr... |
3. Non-GMP and GMP material synthesis |
Following selection of a leading candidate and the duration of GLP toxicology study at Candidate Selection, manufacture of sufficient non-GMP material will be initiated along with supporting studies on stability, impurity profile, etc as described in Appendix E&H. (Sosei-Heptares) |
Suitable formulation will be developed for GLP toxicology studies. (Sosei-Heptares) |
If needed, synthesis of metabolite standards will be conducted for detection of metabolite(s) in GLP toxicology studies and, if appropriate, in clinical studies. (Sosei-Heptares) |
If needed, synthesis of radiolabelled material (14C or 3H) will be conducted to support mechanistic ADME-Tox studies pre-FTIH. The requirement for this, or otherwise, will be ratified at the JGC. (Sosei-Heptares) |
Subsequently GMP material will be manufactured to support Phase 1 studies with supporting studies as described in Appendix E&H. (Sosei-Heptares) |
To support the wide dose range typically studied in the first time in human single ascending dose study, a simple oral dosing suspension/solution or powder in capsule formulation will likely be used dependent upon emergent information about systemic absorption from the upper small intestine and safety margins from syst... |
Stage 4b Deliverables: • FTIH enabling GLP toxicology package in rodent and non-rodent species as outlined in Appendix D (Sosei Heptares). • Development and validation of GLP bioanalytical methods for detection of parent compound in plasma as default; need for parent compound detection in another matrix and/or detectio... |
c) Phase 1 Set Up |
Preparation for FTIH study will be managed by Sosei Heptares and AbbVie as outlined below: |
1. Bioanalytical Method and Pharmacodynamic Biomarkers |
Development and validation of bioanalytical methods for use in the FTIH study are the responsibility of AbbVie. Development of potential pharmacodynamic markers with relevant pre-clinical validation for use in the FTIH study are the responsibility of Sosei Heptares (see also deliverables in pre-clinical candidate selec... |
2. General Investigational Plan and FTIH study |
The Target Product Profile and General Investigational Plan to deliver on the profile are the responsibility of AbbVie. Details will be shared through the JGC. After opt-in by AbbVie, AbbVie will be responsible for design and conduct of the FTIH study. |
3. Preparation for submission of IND/CTA |
After opt-in by AbbVie, AbbVie will be responsible for submission of an IND or CTA for the FTIH study. |
Appendix A: Stage 1 - Hit Identification |
Activity / Assay |
Chemistry |
Chemical Series |
Structure Activity Relationships |
SBDD |
Physicochemical Properties |
Intellectual Property |
Pharmacology & Biophysics |
On Target GPCR: Refer to Appendix G: In Vitro section |
Off Target effects |
Biophysical demonstration of a specific interaction with GPCR StaR protein: Refer to Appendix G: In Vitro section |
Appendix B – Stage 2 - Lead Generation Criteria |
Activity / Assay |
Chemical Series and SAR |
Chemical Series |
Synthetic Tractability |
Structure Activity Relationships |
Structural Biology |
Physicochemical Properties |
Intellectual Property |
In Vitro |
Target GPCR Refer to Appendix G: In Vitro section |
Off Target GPCR |
Binding assays |
Cell based assays |
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