text stringlengths 1 5.46k |
|---|
Second-round screening will be conducted in 2-3 NHPs. The second-round library will contain AAV9, and any other characterized capsids (e.g., CAP-D1, etc.) as comparator benchmarks. Vector genome residence will be assessed using DNA sequencing in CNS cells and off-target tissues such as the liver and DRGs. In addition, ... |
Each of the two screening rounds in this Step #1 take 3-months to conduct, leading to a total period of 6-months. Five of the top performing variant capsids from this initial screening effort can be moved by AbbVie into Reserved Capsids and / or Pooled Screening, which decision may be made by the Working Group's determ... |
5.0 Variant Optimization (6-months): |
Top performing capsids from the Initial Library Screening will be moved into re-diversification and stabilizing library screening in 2-3 NHPs, aimed at increasing efficacy and / or specificity in CNS cells. Scanning (e.g., scanning 3-mer diversification) is currently being utilized for Variant Optimization purposes, th... |
Second-round screening of Variant Optimization libraries will be conducted in 2-3 NHPs. The second-round library will contain AAV9, and any other characterized capsids (e.g., CAP-D1, etc.) as benchmarks. Enrichment data will be read out at the DNA level in target tissues and off-target tissues such as the liver and DRG... |
Each of the two screening rounds during Step#2 take 3-months to conduct (total period of 6-months). Five capsid variants within the top performing capsids can be moved by AbbVie into Reserved Capsids and / or Pooled Screening, which decision may be made by the Working Group's determination that their fold-enrichment in... |
6.0 Pooled Screening (3-months): |
The top performing capsid variants from Initial Library Screening and from the Variant Optimization screening, including the 5 Reserved Capsids selected by AbbVie in the capsid selection process, will be tested in a small pooled screening experiment with a cargo (e.g., neutral cargo, tool TDP43 cargo or final TDP43 car... |
Five capsid variants within the top performing capsids from the Pooled Screening efforts can be moved by AbbVie into Reserved Capsids, which decision may be made by the Working Group's determination that their fold-enrichment in CNS cells versus off target tissues over benchmark comparator capsids meets TCP criteria. B... |
7.0 Preliminary Individual Capsid Characterization (6-months): |
Based upon the data package from capsid selection and pooled screening, AbbVie will decide whether there are capsids that meet or are sufficiently close to the desired TCP to proceed with Preliminary Capsid Characterization. |
AbbVie will select up to 3 capsid variants, preferentially representative of different capsid families for Preliminary Capsid Characterization in 3 NHPs and in rodents when applicable. The final study design will be determined by the Working Group considering the inclusion of up to 3 capsids preferentially from differe... |
8.0 Final Capsid Optimization (6-months): |
In parallel with Preliminary Capsid Characterization, unless otherwise determined by the JGC, Capsida will perform final capsid optimization, screening (6 months) and pooled screening (3 months) prior to Final Individual Cargo - Capsid Characterization. Further capsid optimization and screening involves re-differentiat... |
9.0 Final Pooled Screening (3-months; Activities similar to Step 3): |
The top performing variants from the Final Capsid Optimization screening, including any variants previously reserved by AbbVie during the capsid selection process would be moved into Pooled Screening, These capsid variants will be tested in a small pooled screening experiment with a cargo (e.g., neutral cargo, tool TDP... |
The collective data generated during the Final Capsid Optimization (Step#5) and the subsequent Pooled Screening (Step#6), in combination with the data generated from the Preliminary Characterization (Step#4) will inform AbbVie's decision on the selection of a Primary Capsid and two Back-Up Capsids. The Primary Capsid w... |
10.0 Final Individual Capsid β Cargo Characterization (6-months): |
Based upon the data package from capsid selection, pooled screening, and upon selection of a final cargo vector design, AbbVie will select a single variant (i.e., Primary Capsid) to carry forward for Final Individual Capsid β Cargo Characterization in up to 6 NHPs and rodents with AbbVie cargo. Capsida will perform a b... |
The final data package for the Primary Capsid selected for Final Individual Capsid - Cargo Characterization will be based on the collective data package across capsid engineering, cargo development and optimization, and disease efficacy studies with an ultimate objective of defining a therapeutic window that is satisfa... |
All screening and pooled testing steps will be done in juvenile NHPs, as well as the preliminary capsid characterization. The stage at which the capsid -- cargo pairing can be characterized in adults is the final characterization stage; the Working Group will decide on the age range, depending on animal availability. |
10.1.1 Mechanics of Capsid Variant Selection Process |
In advance of the JGC meetings, Capsida will aggregate and prepare all relevant available data, based on stage of engineering, including library screening and/or pooled screening data, as summarized in Appendix 6. This summary will include rationale for sequence modifications and based on available datasets, the relati... |
In order to track the top performing capsids, Capsida will maintain an excel spreadsheet which documents and identifies the top performing capsids. This tracker will be reviewed as standard part of agenda at JGC meetings and memorialized in the meeting minutes. The tracker can be stored on a shared file server and made... |
10.2 TDP43 Capsid β Cargo Characterization |
10.2.1 TDP43 Cargo Development |
AbbVie is developing a tool TDP43 cargo and the final TDP43 cargo, which activities are outside the scope of the research plans. The tool TDP43 cargo will be verified in solubility and target-engagement assays before transferring to Capsida. Using this tool TDP43 cargo, AbbVie and Capsida jointly will design a vector o... |
10.2.2 Dose β Efficacy Relationship Studies in Mice |
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 β cargo expression β 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 β Cargo Characterization... |
10.2.4 TDP43 Cargo β 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 β Cargo Program (Research Product) Data Package: Reports and Deliverables |
Upon completion of the TDP43 capsid β 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: |
β’ In-vitro validation of TDP43 cargo in human iPSC-derived neurons with TDP43 pathology |
β’ Rodent TDP43 model proof-of-concept data confirming efficacy |
β’ Mouse/NHP data supporting validation of target-engagement biomarker for TDP43 cargo |
β’ Cell-type distribution in NHPs and rodents after peak expression established (e.g., IHC, RNA scope or preferred method) |
β’ DNA MOI data in tissues (CNS cells and selected peripheral tissues) in NHPs and / or rodents |
β’ Bulk RNA and / or protein data in targeted tissues and in selected peripheral tissues in NHPs and / or rodents |
β’ 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) |
β’ Toxicity profiles in adult cynomolgus monkeys, including clinical pathology and histopathology at peak expression and later (e.g., later timepoints for recovery) |
β’ 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 β 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) |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.