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Dose ranging studies in TDP43 disease models will be conducted by Capsida, or contracted to CRO (e.g., Psychogenics), for the purpose of establishing a relationship between dose – cargo expression – efficacy (i.e., clearance of TDP43 pathology). Disease proof-of-concept can be established using already developed and ef... |
Some of the parameters to be decided by the Working Group includes: |
Expected study duration = To be determined (TBD) based on dose-efficacy relationship in mice studies and choice of disease model (e.g., for rNLS8 model = 16 weeks, with dox removed at 5 weeks of age and timing of AAV administration TBD by previous studies). |
Biodistribution of capsid and TDP43-cargo transgene evaluated in all relevant tissues. |
TDP43 pathology and neuroinflammation assessed across target CNS regions as relevant in chosen disease model. |
Survival time, body weight, and disease behavior phenotypes assessed as relevant in chosen disease model. |
Compound muscle action potentials assessed as relevant in chosen disease model. |
Assessment of target engagement biomarker. |
10.2.3 Additional NHP Studies for Target Engagement |
Capsida will work to translate the biomarker discovery from the rodent efficacy model to NHP to incorporate metrics for target engagement efficacy, should NHP model exist and as determined by the Working Group. Based on the dose response results in mice and following the Final Individual Capsid – Cargo Characterization... |
10.2.4 TDP43 Cargo – Capsid characterization: Selection of Research Product |
Vector optimization will be finalized as described in Section 3.4.1 TDP43 Cargo Development, with data relating various vector compositions to efficacy in mouse models arriving at a similar time as finalized TDP43 cargo (4Q2022). To avoid repeating studies, these elements will be incorporated into the screening and bio... |
10.2.5 TDP43 Capsid – Cargo Program (Research Product) Data Package: Reports and Deliverables |
Upon completion of the TDP43 capsid – cargo studies, data sets outlined in Appendix 6 and the corresponding reports for the top performing capsids (i.e., Reserved Capsids, Primary Capsid and Back-Up Capsids) will be provided to AbbVie. These include: |
• In-vitro validation of TDP43 cargo in human iPSC-derived neurons with TDP43 pathology |
• Rodent TDP43 model proof-of-concept data confirming efficacy |
• Mouse/NHP data supporting validation of target-engagement biomarker for TDP43 cargo |
• Cell-type distribution in NHPs and rodents after peak expression established (e.g., IHC, RNA scope or preferred method) |
• DNA MOI data in tissues (CNS cells and selected peripheral tissues) in NHPs and / or rodents |
• Bulk RNA and / or protein data in targeted tissues and in selected peripheral tissues in NHPs and / or rodents |
• Acceptable immunogenicity profile in NHP and low prevalence of preexisting antibodies (<50%) in the target patient population (sufficient sample size to estimate nADA in ALS serum samples, but not to exceed 50 samples) |
• Toxicity profiles in adult cynomolgus monkeys, including clinical pathology and histopathology at peak expression and later (e.g., later timepoints for recovery) |
• Sequence of the Research Product, Primary and Back-up capsids including patentability and FTO assessment |
The Target Product Profile for the Research Product for the TDP43 program has the following attributes: |
Meets TCP criteria as agreed by JGC |
In vivo activity established with evidence of on-target effect (e.g., ALS correlation) in a preclinical model (preferably TDP43 model) |
Projected human efficacious dose with appropriate preclinical safety profile (acceptable therapeutic window) and feasible dosing regimen for IV administration in human |
Data supportive of translational biomarkers to enable dose selection, target engagement and mode of action in clinical studies |
Packaging efficiency and scalability supportive of generating a suitable dosing regimen for human use via the intended route of administration (i.v.) |
Acceptable neutralizing antibody data and plan for widespread use in the intended patient population supportive of advancement to IND enabling studies |
Manufacturing executable plan in place including process, scalability, analytical methods etc. |
11.0 Process and Analytical Development, Scale up, and Supply |
Capsida will provide non-GLP supply (research grade material) for discovery and preclinical research. Upon opt-in, Capsida will initiate process development activities shown below in preparation for GLP-tox material generation and clinical supply. |
The FDA guidelines on potency testing for cellular and gene therapy products recommends multiple CMC-related activities to characterize product quality and manufacturing controls, to assure identity, purity, strength (potency), sterility and stability of products to certify lot release and establish product dating and ... |
The cargo sequence will be transferred to the process development team and synthesized in a plasmid backbone suitable for manufacturing. Positive control material will be generated using the selected capsid and cargo to serve as a reference control for analytical development activities and evaluate process fit in each ... |
Some analytical methods, specifically the in vitro potency assay, are known to be complicated for AAV gene therapy products. Regarding the potency assay (used to quantify the transducibility and efficacy of the protein produced from a specific lot of product), Capsida will take primary responsibility for developing the... |
18 |
12.0 Collaboration Program Research Plan Budget (note: numbers below in '000s) |
Collaboration Program Research Plan (TDP43 only) |
Year 1 Year 2 Year 3 GRAND TOTAL |
% of Team Time by Function Research Total 12% 17% 7% Technology 17% 17% 7% Process Development 10% 10% 10% All Other (Excluding Manufacturing) 3% 3% 2% |
FTE Costs by Function Research 474 888 397 1,758 Technology 452 486 208 1,146 Process Development 344 427 473 1,245 All Other (Excluding Manufacturing) 197 245 115 557 TOTAL FTE COST 1,468 2,046 1,193 4,706 |
Supplies Cost by Function Research 235 391 165 791 Technology 572 609 257 1,437 Process Development 573 627 627 1,828 TOTAL SUPPLIES COST 1,381 1,627 1,049 4,057 |
Outside Spend NHP Experiments Shared Cost Abbvie Ratio Shared NHP Experiments 60 4 - 63 Abbvie Only NHP Characterizations 145 505 68 718 NHP Target Engagement - - 263 263 TOTAL NHP COSTS 204 509 331 1,043 |
Mouse Dose Efficacy Relationship 111 333 56 500 Biomarker Studies 111 333 56 500 |
Overhead Allocations Travel % 7% 7% 4% Consulting % 12% 12% 7% Rent % 12% 12% 7% IT Expense % 17% 17% 9% All Other % 3% 3% 2% |
Travel $ 7 14 9 30 Consulting $ 204 157 89 450 Rent $ 358 492 284 1,134 IT $ 159 181 116 456 All Other $ (Legal, Finance, Other) 62 60 37 159 Total Overhead 790 904 535 2,228 |
GRAND TOTAL 4,065 5,751 3,218 13,034 10% of Grand Total 1,303 |
19 |
13.0 Appendix |
** solid (blue) color represents key data available at various stages of the Capsid Generation, Screening & Optimization process Section 3.3.1). |
[Table showing TCP Criteria - Data deliverables across different stages including Initial Library Screening, Variant Optimization, Pooled Screening, Preliminary Individual Capsid Characterization, Final Capsid Optimization, Pooled Screening, and Final Individual Capsid - Cargo Characterization] |
20 |
Table 7. TDP43 CARGO Materials to be Transferred from AbbVie to Capsida |
Table 7: TDP43 CARGO Materials to be Transferred from AbbVie to Capsida |
Item Description Comments Cargo – TDP43 (i) Sequence for tool-anti-TDP-43 cargo (ii) Sequence for final anti-TDP-43 cargo Tool cargo est 4Q2021 Final cargo est 4Q2022 |
Table 8. CAPSIDS AND RESEARCH PRODUCT MATERIALS: TDP43 PROGRAM |
Table 8: CAPSIDS AND RESEARCH PRODUCT MATERIALS: TDP43 PROGRAM |
Item Description Comments Reserved Capsids _____ _____ _____ _____ as available |
Selected Capsids (Primary Capsids and Backup Capsids) _____ _____ _____ as available |
Research Product candidates (with cargo, including rodent versions) _____ _____ _____ _____ as available |
Research Product as available |
1 |
Exhibit C |
POC Plan |
1.0 Background |
AbbVie and Capsida are collaborating on research activities aimed at identifying and optimizing capsids using the Capsida platform to deliver the AbbVie Cargo ("cargo") to cells in the central nervous system and / or spinal cord. |
Capsida will harness its biologically driven, high-throughput non-human primate (NHP) screening platform and adeno-associated virus (AAV) engineering know-how to develop and validate novel AAVs with increased cargo expression and specificity for CNS cells (e.g., cortical neurons, dopaminergic neurons, oligodendrocytes)... |
2.0 POC Plan Scope and Framework |
The POC Plan will be focused on the IND-enabling work and First in Human / Proof-of-Concept (FIH / POC) clinical study for the TDP43 target (Figure 3). Capsida will be responsible for all activities within such plan as described in this document. |
Figure 3: POC Plan (TDP43 Licensed Product) |
Figure 3: POC Plan (TDP43 Licensed Product) |
2 |
3.0 Preclincal / IND Enabling Studies |
3.1 Additional Preclincal Pharmacology & Biomarker Studies with TDP43 |
Any additional preclinical efficacy/biomarker studies beyond what was conducted during the Collaboration Program Research Plan would be conducted at this stage. Although it will be the subject of a future FDA INTERACT meeting, below is a preliminary study design of a potential pharmacology study in rodents. |
Group Dose Level Number of Animals WT + High Dose TBD 15 male 15 female WT + vehicle 0 15 male 15 female Disease + vehicle 0 15 male 15 female Disease + Low Dose TBD 15 male 15 female Disease + Med Dose TBD 15 male 15 female Disease + High Dose TBD 15 male 15 female |
• Doses will be chosen based of previous mouse PK/PD work and expected target engagement. • Based on the data from the Collaboration Program Research Plan efforts (see Exhibit B), the Working Group would decide what additional pharmacological studies, if any, may be required and appropriate for further characterization... |
• Expected study duration = To be determined (TBD) based on dose-efficacy relationship in mice studies and choice of disease model (e.g., for rNLS8 model = 16 weeks, with dox removed at 5 weeks of age and timing of AAV administration TBD by previous studies). • Biodistribution of capsid and TDP43-cargo transgene evalua... |
3.2 IND Enabling GLP Toxicology Studies (Licensed Product) |
Although it will be the subject of a future FDA pre-IND meeting, below is a preliminary study design of the planned GLP toxicology study in NHPs. |
Group Assignment and Dose Level |
Group Dose Level Dose Concentration No. of Animals (VG/kg) (VG/mL) 3-Months (Main) 6-Months (Recovery/Persistence) 1 (Control) + IS 0 0 6 (3/sex) 6 (3/sex) 2 (low) + IS TBD TBD 6 (3/sex) 6 (3/sex) 3 (mid) + IS TBD TBD 6 (3/sex) 6 (3/sex) 4 (high) + IS TBD TBD 6 (3/sex) 6 (3/sex) |
Key study design elements and endpoints |
• 3 males and 3 females per group per timepoint will be given a single dose of TDP43 cargo - capsid via 15-minute IV infusion • Biodistribution of Capsid and TDP43cargo transgene will be evaluated in tissues (including DRGs) and blood • IFN-y ELISPOT or equivalent against TDP43 cargo and Capsid peptide pool • TDP43 car... |
3.3 IND Data Package |
The IND data package for the TDP43 program will be designed in accordance with 21 CFR Part 312, Investigational New Drug Application. The package will also consider FDA and international guidance on development of gene therapy products, as well as advice provided at planned FDA Interact and pre-IND meetings. In additio... |
4.0 ALS POC |
4.1 Clinical Development Plan |
4.1.1 Study Design and Assumptions (high-level) |
• Population: >18 years of age; weakness attributed to ALS; forced vital capacity (FVC) ≥ 50% of predicted value; consider El Escorial criteria • Single dose, randomized, double-blinded, placebo-controlled study • 2 dose levels: cohort 1 (n=10; 6 active); cohort 2 (n=16; 10 active) • 6-month biomarker interim analysis;... |
4.1.2 TDP43 Human POC Study Data Package: Reports & Deliverables |
Clinical Study Report: This section highlights details of data and results to be included in the Clinical Study Report(s) after completion of the ALS POC plan. |
Clinical data sets to include: o Safety and tolerability data sets o PK data sets o Rating Scale results o Pharmacodynamic measures including target engagement / biomarker expression levels in CSF / plasma (e.g., pNFH etc.) |
Clinical Data Reporting: Reporting will include the following (to the extent applicable) |
Data sets to include the following: o Development Safety Update Reports o Annual blinded / unblinded efficacy o Clinical Study Report (CSR) for completed studies |
Specifically, table(s) of key clinical data to be provided, to the extent applicable, (in a MS Word or pdf format of SAS outputs) that includes summary table and patient level data (data listings) for: |
• Patient demographics, baseline characteristics and patient dispositions • Endpoints / efficacy parameters measured • Safety data including SAEs, AEs, fatal adverse events & discontinuations due to AEs • Laboratory analysis and vital signs • PK, PD and /or distribution measures • Biomarkers and imaging, where applicab... |
4.1.3 Quality Assurance Considerations |
Documentations from Capsida (and chosen CROs as applicable) to demonstrate that all studies are conducted in compliance with protocol, Good Clinical Practice and all other applicable regulatory requirements including the archiving of essential documents. This will include required maintenance of quality-control systems... |
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