Translational and early clinical research plans to (Portfolio Entry — PE)
| Confidence in | Portfolio Entry (PE) |
|---|---|
| Translation | Selecting animal model for predicting human dosing |
| Safety | Target risks are identified and have mitigation plan in place (Target Safety Review) Tier 1 and 2 safety assays performed on exemplar compounds (e.g. hERG, Bluescreen, etc.) |
| Execution | Plan and timeline to IND submission is identified. Fit in to TAU strategy Patient benefit is clearly recognized |
| Asset | Tractable molecules in hand with path to IP Developability assessment plan is in place. |
[Gene therapy 20210224 Research playbook]
Portfolio Entry (PE)
Update on the evolving translation/biomarker/early clinical plan, including timeline of translatable biomarker & readiness for clinical use
Identification of any rate limiting steps, issues or capability gaps that must be resolved before an investment is made in clinical studies
Update on development of quantitative criteria for proposed EPOC
Progress on patient segmentation hypotheses
PK/PD and human efficacious dose & exposure prediction
Target-related safety issues highlighted as high risk has been addressed
There is an acceptable in vivo exposure multiple in non-GLP repeat dose toxicity studies in 2 species with at least 1 relevant non-clinical species using the planned clinical route of administration (single- and repeat-dose when applicable)
Off-target profiling and tiered safety profile are acceptable (Liver tox (e.g. InSphero), CV tox (e.g. hERG, telemetry), genotox (e.g. Bluescreen, 2-strain Ames/MN))
Doses can be established for IND enabling studies
The off-target and non-specific binding characterization has been performed and assessment is considered acceptable by project team. Any key concerns are addressed.
Description of any unusual resource/investment needs to advance to the next decision point
Confirm availability of test article for IND enabling work or time to obtain
Highlight competitive advantages of the selected Candidate, if the target is precedented
Summary of back-up program, if there is one
Developable molecule with FTO
Candidate Selection (CS)
| Portfolio Entry (PE) | Candidate Selection (CS) | |
|---|---|---|
| Definition | Strategy towards CS and IND is clarified | Clinical candidate is identified with sound confidence in mechanism, translation, safety, execution, and asset itself. Takeda is ready to start GLP studies in order to file IND, and invest for clinical studies. |
| Key Points to Consider | The concept is clear and based on solid evidence and biology. The go/no-go decision criteria are clear along with the key milestones. Anticipated issues/risks/bottlenecks towards CS are identified. There is a roadmap to collect enough information to create target product profile (TPP). | Commitments at PE are met. Candidate Profile declared at PE is achieved or not. Issues/highlighted risks/bottlenecks identified at PE are resolved or not. Commitments towards next milestone are clarified. Issues/risks/bottlenecks towards next milestone are identified. |
| Mechanism & Pharmacology | With a tool gene therapy vector, Initial proof of principle outcome and assays to measure pharmacological outcome is obtained. vector optimization proposal vector characterization assays, and drug product characterization strategy in PD | Clinical dose prediction with a dose range to be used for calculating starting clinical dose. GLP safety study strategy in place. Route of administration determined (and device strategy if such is needed). Ability to execute the IND enabling studies, clinical study and the clinical plan. |
| Translation | Translational plan that allows preclinical measurement of biomarker(s) that could be used for human dose calculation to be used in the clinic. Preclinical species translatability (e.g. there are species-specific differences in genomic sequence (eg. gene editing) or the human protein functions similarly in animal models. If so, the mitigation plan is identified.) | The translational plan and alignment that ties the preclinical work to the future clinical plan (e.g. infectivity, transducability, expression of transgene across species and disease-relevant biomarkers) |
| Safety | Identification of target risks (Target Safety Review) and mitigation plan in place including preclinical species homology for transgene product and vector and need for early regulatory engagement. | Immunogenicity assessment of optimized vector and capsid and acceptable (DMPK) Biodistribution and characterization of transgene expression of clinical candidate vector in translatable and relevant animal models Non-GLP safety of clinical candidate vector and capsid has been assessed in vivo in relevant animal model The off-target and non-specific binding characterization has been performed for the transgene product and assessment is considered acceptable by project team. Any key concerns are addressed. |
| Execution | Winning strategy in competition is identified. Strategy in manufacturing is identified. Fit into technical success requirement and good proposal developability. Associated cost towards IND is identified. Regulatory, clinical and PVS on board with the overall project proposal | Process development plan for GMP manufacturing is clear. Vector characterization assays (for Pharm Sci) and GMP mfg campaign Regulatory strategy and support for early agencies interaction Clinical team with defined unmet needs, clinical strategy and clinical plan |
| Asset | Strategy on patent filing and third-party IP management is in place. Proposal of how to differentiate from competitors is identified. | Overall FTO analysis is completed, and provisional patent application(s) filed or to be filed, and strategy with respect to the third party IP in place. |
High-level scientific definition/requirements for each sub-stage in NS DDU (6/21)
| Project Start | Lead Generation | Portfolio Entry | Candidate Nomination (for SM) | Candidate Selection | |
|---|---|---|---|---|---|
| Strategy / differentiation | Confirmed strategic fit, unmet medical needs (UMN) for the potential indications and favorable opportunity / advantage in the competitive landscape |
Developed preliminary TPP Shawn Developed strategy of differentiation and related specific work plans |
Developed a target candidate profile (TCP) based on the TPP Established a compelling vision for competitive differentiation (including administration route, frequency, etc.) |
Shown a clear value proposition for patients Shown compelling advantage over competitors with risk mitigation plan/scenarios | |
| Mechanism / Pharmacology |
Demonstrated rationale for the concept (ideally with in house data) using tool molecules if not directly targeting a disease causal gene Provided genetic and genomic evidence supporting validity of the target if available |
Demonstrated rationale for MoA with in-house pharmacological data to support progression of hit series Developed a screening scheme with a series of in vitro / vivo assays to generate lead molecules Proposed candidate PD markers |
Provided pharmacological data with lead molecules to explain scientific rationale to address the UMN Provided some patient evidence for the indication | Confirmed target engagement in target organs and defined PK/PD |
Shown convincing data to indicate disease association of the mechanism / target for the indication with appropriate models and/or assay systems Assessed genetic and genomic evidence |
| Translation | No killer on-target safety risk |
Possible path forward to demonstrate hypothesis in the clinic Developed a translational plan for feasibility assessment Provided biomarker options with defined candidates |
Proposed animal models most likely to predict human dosing Developed detailed timeline for TE & PD biomarker development |
Defined PK/PD relationship and human efficacious dose & exposure prediction Updated translation / biomarker / early clinical plan towards ePoC with patient segmentation strategy | |
| Safety | Assessed by Early Safety Review (TSR) and proposed counter measures for identified risks |
Confirmed opportunity to achieve an appropriate safety profile No killer safety risk to advance the chemotypes / modalities |
Defined relative safety profile threshold for CN/CS Developed program-specific evaluation for on/off-target safety risks |
Updated timeline for biomarker development (TE, PD, DR, PS) Acceptable ADME-Tox profile or favorable "risk benefit" profile Negative in Ames test |
Achieved an acceptable tox profile in 2 weeks - 2 species tox studies with no critical CV risk and genotox Confirmed clinical developability |
| Execution | Assessed financial feasibility to advance the program from the portfolio perspective | Highlighted potential rate limiting steps, issues or capability gaps with proposal of mitigation plan | Developed feasible timeline for IND with availability of clinical materials | ||
| Asset |
Demonstrated confidence in hit identification or generation of tractable molecules Made a plan to secure FTO in non-SM programs |
Obtained / designed at least one hit / lead series or developed a clear plan for asset generation Shown reasonable confidence in patentability |
Identified and developed tractable molecules in hand with a path to IP Developed further optimization scheme with robust in vitro / vivo assay methods | Selected molecules with efficacious plasma concentration and acceptable ADME-tox profile for preliminary tox studies |
Actual candidate profile reached a level of the desired profile defined at PE as a whole Developable molecule with FTO and competitive advantages Confirmed manufactural developability |
12 | Confidential - for internal use only
* PE and CS decisions are made by PRC and RSLT, respectively
NEUROSCIENCE
High-Level Guideline for Activities/Deliverables in Pre-Clinical Stages
| Project Start | Lead Generation | Portfolio Entry | Candidate Nomination | Candidate Selection | |
|---|---|---|---|---|---|
| Target | Likely target indication and high level description of unmet medical need |
Preliminary TPP Showed scientific rationale toward target indication Competitive status Obtained at least one |
Preliminary asset strategy and TPP Target candidate profile Key Go/NoGo criteria for IND Tractable molecules in hand with path to IP |
Updated risk mitigation plan and competitive status Go/NoGo criteria for IND Timeline Gantt Selected molecules for preliminary tox studies | Developable molecule with FTO |
Essential for stage-up
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| NS DDU 6/21 footer | `12 | Confidential - for internal use only` |
| Pre-Clinical Stages slide | Maiko Tanaka / Metabolomics / MIBG / Milestones (process) | The leftmost column-1 cells are partly cut by the navigation pane; these appear to be navigation entries rather than table rows on this slide. |
| Pre-Clinical Stages slide | last row Asset | The bottom Asset row of the Pre-Clinical Stages slide is partly cut at the bottom of the photo; remainder continues on the next photo. |