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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 is envisaged that biomarker development and validation work will progress beyond the end of candidate selection. Biomarkers may be anticipated to be reproducible, dose dep... |
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 in vivo efficacy model(s). |
• Demonstrate in vivo target engagement / modulation of pathway specific biomarkers. |
• Determine a PKPD relationship between unbound drug concentrations at the target and relevant acute/sub-acute/chronic efficacy endpoints to support human dose predictions. |
• Develop a PBPK model to support human PK prediction. |
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... |
• To generate PK and PKPD data and interpretation supporting optimum therapeutic profile. |
• To evaluate cardiovascular safety and secondary pharmacodynamics studies in the context of predicted human efficacy and PKPD. |
• To identify and select the most promising lead candidates for GLP-toxicology studies. |
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 to pre-FTIH GLP toxicology studies (Sosei Heptares). |
• Understanding of potential on-target safety risks (Sosei Heptares). |
• Full translational biomarker packages (discovered in Stage 3: Lead Optimization) will be generated for lead candidates (Sosei Heptares). Delivery of candidate pharmacodynamic biomarkers with pre-clinical validation and evidence to support clinical proof of mechanism/pharmacology studies (expectation that these will r... |
• Non-GMP API provision for 2 species DRF studies to support further progression of candidates (Sosei Heptares). |
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 detection of circulating metabolite(s) to be ratified by joint agreement at the JGC (Sosei Heptares). |
• Manufacture of sufficient non-GMP and GMP material, as described in Appendix E (Sosei Heptares). |
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 |
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 |
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