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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), AbbVie will develop this assay format for tau andsynuclein.... |
12.0 Budget (Amounts shown are in '000s) |
CAPSID Program Research Plan (Tau and Alpha Syn) |
Year 1 Year 2 Year 3 GRAND TOTAL |
% of Team Time by Function Research Total 6% 17% 7% Technology 33% 33% 14% Process Development 20% 20% 20% All Other (Excluding Manufacturing) 6% 7% 3% |
FTE Costs by Function Research 249 888 397 1,533 Technology 904 972 416 2,293 Process Development 689 854 947 2,489 All Other (Excluding Manufacturing) 394 490 229 1,113 TOTAL FTE COST 2,236 3,204 1,989 7,428 |
Supplies Cost by Function Research 106 391 165 662 Technology 1,144 1,217 513 2,875 Process Development 1,147 1,255 1,255 3,656 TOTAL SUPPLIES COST 2,397 2,863 1,933 7,193 |
Outside Spend NHP Experiments Shared Cost Abbvie Ratio 33% 33% 33% Shared NHP Experiments 119 7 - 126 Abbvie Only NHP Characterizations 289 1,010 136 1,435 TOTAL NHP COSTS 408 1,017 136 1,561 |
Overhead Allocations Travel % 13% 13% 8% Consulting % 23% 23% 13% Rent % 23% 23% 13% IT Expense % 33% 33% 19% All Other % 7% 7% 4% |
Travel $ 13 28 18 59 Consulting $ 408 314 178 899 Rent $ 715 985 567 2,267 IT $ 319 361 232 912 All Other $ (Legal, Finance, Other) 125 120 73 318 Total Overhead 1,580 1,807 1,069 4,456 |
GRAND TOTAL 6,621 8,891 5,126 20,638 10% of Grand Total 2,064 |
Memo: Per Program 3,310 4,445 2,563 10,319 10% Per Program 1,032 |
Appendix A |
** solid (blue) color represents key data available at various stages of the Capsid Generation, Screening & Optimization process (Section 3.2.1) |
TCP Criteria - Data deliverables 1. Initial Library Screening 2. Variant Optimization 3. Pooled Screening 4. Preliminary Individual Capsid Characterization 5. Final Capsid Optimization 6. Pooled Screening 7. Final Individual Capsid - Cargo Characterization 1st Round 2nd Round 1st Round 2nd Round 1st Round 2nd Round |
Targeted Cell Type Gross neuronal transduction Quantified neuronal transduction (all targets) Quantified oligodendrocyte transduction (A-syn only) Quantified motor neuron transduction (TDP43only) |
Targeted Tissue NGS DNA level Benchmarked vector genome residence DNA MOI |
Route of Administration IV delivery |
Expression Level Bulk RNA level Bulk protein level Durability |
Tissue De-targeting (including liver and DRG) Benchmarked vector genome residence DNA MOI Bulk RNA level Bulk protein level |
Projected Human Dose Immunogenicity of capsid Immunogenicity of cargo Toxicity Histopathology Estimated Therapeutic Window (single dose) Estimated Therapeutic Window (multi dose) |
Manufacturing Packaging efficiency |
Immunogenicity Immunogenicity of capsid Immunogenicity of cargo Neutralization by human patient serum |
IP Patentability/FTO assessment |
APPENDIX B |
Table 2: TRANSFERRED Materials to be shared from Capsida to Abbvie OR AbbVie to Capsida |
Below is a list of items that each Party may transfer to the other Party for use in the Research Program. These items may be transferred as physical samples, nucleotide/amino acid sequences or both. This is not a comprehensive list and may be modified based on needs for executing the Research Plan activities towards ac... |
Table 2: TRANSFERRED Materials to be shared from |
Item Description Comments |
CAPSIDA TO ABBVIE Rodent tool capsids (Existing capsids) (i) AAV.CAP-B10 (ii) AAV.CAP-B22 Sequences, materials |
Packaged with sequence optimized tool anti-tau cargo and tool anti-a-syn cargo |
Reserved Capsids _____ _____ _____ _____ Packaged with sequence optimized tool cargo, anti-tau cargo and /or anti-a-syn cargo |
ABBVIE TO CAPSIDA |
Table 3. CARGO Materials to be Transferred from AbbVie to Capsida |
Table 3: CARGO Materials to be Transferred from AbbVie to Capsida |
Item Description Comments |
Cargo β tau (i) Sequence for tool-anti-tau cargo (ii) Sequence for final anti-tau cargo Tool cargo at start of collab |
Final cargo est 4Q2021-1Q2022 |
Cargo β -synuclein (i) Sequence for tool-anti--syn cargo (ii) Sequence for final anti--syn cargo Tool cargo est 4Q2021 |
Final cargo est 4Q2022 |
Expression elements (i) expected regulatory elements As available |
Others |
Table 4. CAPSIDS AND RESEARCH PRODUCT MATERIALS - TAU PROGRAM |
Table 4: CAPSIDS AND RESEARCH PRODUCT MATERIALS - TAU PROGRAM |
Item Description Comments |
Reserved Capsids _____ _____ _____ _____ ______ as available |
Selected Capsids (Primary and Backup Capsids) _____ _____ _____ as available |
Research Product candidates (with tool or AbbVie cargo, including rodent versions) _____ _____ _____ _____ as available |
Research Product _____ as available |
Table 5. CAPSIDS AND RESEARCH PRODUCT MATERIALS: -SYNUCLEIN PROGRAM |
Table 5: CAPSIDS AND RESEARCH PRODUCT MATERIALS: -SYNUCLEIN PROGRAM |
Item Description Comments |
Reserved Capsids _____ _____ _____ _____ ______ as available |
Selected Capsids (Primary Capsid and Backup Capsids) _____ _____ _____ as available |
Research Product candidates (with tool or AbbVie cargo, including rodent versions) _____ _____ _____ _____ as available |
Research Product as available |
Exhibit B |
Collaboration Program Research 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 Research Plan Scope and Framework |
AbbVie and Capsida have agreed to a Research Plan for the development of Capsid ("capsid") β cargo combinations for three targets: tau, Ξ±-synuclein and TDP43. This Research Plan (Collaboration Program Research Plan) outlines activities and estimated timelines to be conducted by Capsida or AbbVie, as specified below, fo... |
The Collaboration Program Research Plan will be focused on the generation of a fully characterized capsid β cargo combination for the TDP43 target. Capsida will be responsible for all activities within such plan as described in this document and in the Collaboration Program Research Plan Overview (Figure 2) below, with... |
Figure 2: Collaboration Program Research Plan Overview |
Figure 2: Collaboration Program Research Plan Overview |
3.0 Collaboration Program |
3.1 Initial Target Capsid Profile for TDP43 |
The overarching goal of the collaboration is to achieve a capsid profile with characteristics as outlined in Table 6 below aimed at delivering TDP43 cargo to relevant cell types in the CNS and spinal cord. The activities focus on the engineering of capsids directed towards a Target Capsid Profile for TDP43, which may b... |
Table 6. Initial Target Capsid Profile (TCP) for TDP43 Target |
Table 6: Initial Target Capsid Profile (TCP) for TDP43 Target |
TDP43 Capsid |
Targeted Cell Type* >80% transduction of motor neurons (upper motor neurons in the brain and lower motor neurons in the spinal cord) in the targeted tissue |
Targeted Tissue Cortex, Spinal cord |
Route of Administration IV route is required (with volume and titer feasible for IV dosing and consistent with FDA guidelines) |
Expression Level Equivalent or improved expression of RNA and / or protein as compared to efficacious expression levels observed in preclinical models using intraparenchymal or IV administration of reference capsids (e.g., AAV9, AAV.CAP-B10, AAV.CAP-B22) |
Tissue De-targeting >10-fold improved de-targeting of DRGs and liver (as compared to AAV9) |
Projected Human Dose Capsid-cargo combination safe in non-clinical safety studies in adult cynomolgus monkeys, providing an acceptable therapeutic window |
Manufacturing Improved packaging efficiency over AAV9 |
Immunogenicity Neutralizing antibody profile similar or better than AAV9 using industry standards |
IP Novel capsid β cargo combination for which IP can be filed |
*The desired percentage of transduction will be determined by the rodent efficacy studies. A lower transduction rate may be acceptable if supported by data from such studies; in such case, TCP may be amended as set forth in the Agreement. |
3.2 ALS Preclinical |
These activities will be led by Capsida, except for TDP43 cargo development which is AbbVie's responsibility (out of scope for this document). In addition, AbbVie will provide experimental support and scientific consultation to support execution of these studies. |
3.2.1 In vitro and In vivo models |
In vitro: Establish relevant biochemical and cellular assays to evaluate TDP43 biology. Characterization in neuronal / iPSC assays will be conducted unless otherwise determined by the Working Group. Expectation is to mimic rodent models by making the nuclear localization sequence defective in patient iPSC-derived neuro... |
In vivo: Establish relevant in vivo models to evaluate TDP43 pharmacology. In vivo studies will aim at relating dose- transduction efficiency β cargo expression β target engagement β TDP43 pathology. Preferred model is currently rNLS8 model expressing hTDP43 with defective nuclear localization signal, but other in vivo... |
3.2.2 Translational Biomarker Activities |
Develop a Translational / Biomarker data sets to advance TDP-43 program for ALS. (e.g., CSF, plasma biomarkers (expression, target engagement, pharmacodynamics etc.)) |
3.3 Capsid Engineering, Screening and Optimization |
Drug substance activities assume 3 parallel efforts: capsid engineering, vector optimization (e.g., promoter/ Gene Regulatory Elements (GRE)), and cargo development (out of scope for this document). |
All capsid engineering will be conducted by Capsida. There will be frequent and ad hoc communication and scientific dialogue between the Working Group while engineering is ongoing, gated by availability of relevant data. Per the governance framework, on a quarterly basis, the JGC will discuss and review available data ... |
3.3.1 Selection Process of New Capsids β TDP43 |
4.0 Initial Library Screening (6-months): |
Initial library screening efforts (i.e., de novo) begin with peptide substitutions and / or insertions and capsid variants are screened directly in 2-3 juvenile NHPs following an IV administration. Current and planned engineering efforts utilize 7-mer insertions after AA588 in AAV9, though Capsida will use all reasonab... |
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