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It is expected that the JGC will discuss, review, and approve amendments to this Research Plan on a periodic basis based on scientific data, developments in the field, or other matters that may arise, in each case as set forth in the Agreement. The JGC will also monitor workflow, resource allocation, timelines, and ove... |
The Capsid Program Research Plan (Figure 1) includes two Research Stages as shown in the diagram below. |
Figure 1: Capsid Program Research Plan Overview |
In the Research Stage One, Capsida will be responsible for the screening and optimization of capsid variants for tau and Ξ±-synuclein and for the characterization of Capsid Program Capsid in NHP distribution studies. AbbVie and Capsida will share responsibilities for the proof of principle studies of the capsid β cargo ... |
3.0 Capsid Program Research Plan |
3.1 Initial Target Capsid Profile (TCP): Tau and Ξ±-Synuclein |
The overarching goal of the collaboration is to achieve a capsid profile with characteristics as set forth in Table 1 aimed at delivering a novel cargo to relevant cell types in the CNS to mediate efficacy in preclinical disease models. The activities focus on the development and engineering of capsids directed towards... |
Table 1: Initial Target Capsid Profile (TCP) for the Tau and Ξ±-synuclein Targets |
Tau Capsid -Synuclein Capsid |
Targeted Cell Type* >80% transduction of neurons in the targeted tissue >80% transduction of dopaminergic neurons in the targeted tissue. Confirm 80% expression in oligodendrocytes (e.g., MSA) |
Targeted Tissues Cortex, Hippocampus, Entorhinal Cortex, Anterior Cingulate Midbrain SN, Striatum, Frontal Cortex, VTA, Spinal Cord |
Route of Administration Intravenous (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 dorsal root ganglion (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 Capsid Engineering, Screening and Characterization |
Drug substance activities assume 3 parallel efforts: capsid engineering, vector optimization (e.g., expression elements - promoter/ Gene Regulatory Elements (GRE)), and cargo development (out of scope of 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 ... |
3.2.1 Selection Process of New Capsids - for Tau and for Ξ±-synuclein |
The steps set forth below will be conducted with respect to each of tau and synuclein and each Research Stage as set forth in the Agreement. |
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... |
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, thou... |
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 takes 3-months to conduct (total period of 6-months). Five capsid variants within the top performing capsids from this screening effort can be opportunistically moved by AbbVie into Reserved Capsids and / or Pooled Screening, which decision may be based by the Working Grou... |
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 experiment with a cargo (e.g. neutral cargo, tool tau / -synuclein cargo or final tau / -sy... |
Five capsid variants within the top performing capsids from the Pooled Screening efforts can be moved into Reserved Capsids by AbbVie, which selection may be based on the Working Group's determination that their fold-enrichment over benchmark capsids meets TCP criteria. Based on these criteria, any or all of these 5 Re... |
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 Capsid - Cargo Characterization. Further capsid optimization and screening involves re-differentiat... |
9.0 Final Pooled Screening (3-months; Activities are 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 experiment with a cargo (e.g. neutral cargo, tool tau / -synucle... |
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 ... |
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 - 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 adult NHPs is the final characterization stage; the Working Group will decide on the age range, depending on animal availabilit... |
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 the stage of engineering, including library screening and/or pooled screening data as described in Appendix 6. This summary will include a rationale for sequence modifications and based on available data sets the re... |
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... |
Capsida shall also provide AbbVie with Existing Capsids for use in the Research Program to assess efficacy and / or target engagement studies, in accordance with Capsid Program Research Plan. |
10.2 Tau Capsid β Cargo Development |
10.2.1 Tau Cargo Development |
Tau cargo development will be led by AbbVie and is generally outside of the scope of this research plan with the exception of the vector optimization strategy which will be designed jointly between AbbVie and Capsida. Vector optimization will include assessment of the efficacy of various expression elements, including ... |
AbbVie will be able to provide a tool tau cargo upon commencing the partnership for use in capsid screening and to begin DNA optimization as described below. The final tau cargo is estimated to be completed and transferred to Capsida by 4Q2021, as described in the timeline below. |
10.2.2 Dose β Efficacy Relationship in Mice |
Dose ranging studies in tau disease models will be conducted by AbbVie for the purpose of establishing a relationship between dose β cargo expression β target engagement - efficacy (i.e., clearance of tau pathology). Disease proof-of-concept can be established using already developed and efficient CNS-targeting rodent ... |
10.2.3 Additional NHP Studies for Target Engagement |
AbbVie will work to translate the rodent efficacy model to NHP to incorporate tau aggregate deposition with PET imaging and biomarker detection. Based on the dose response results in mice, AbbVie will do limited dose response in the NHP models to establish target engagement and develop a model for estimating human dose... |
10.2.4 Tau Cargo β Capsid Optimization: Selection of Research Product |
Vector optimization will be finalized as described in Section 3.3.1 Tau Cargo Development, with AbbVie providing data relating to various vector compositions to efficacy in mouse models at the time of finalizing the gene therapy modules (4Q2021). These elements will be incorporated into the Final Individual Capsid β Ca... |
10.2.5 Tau Capsid β Cargo Program (Research Product) Data Package: Reports and Deliverables |
Upon completion of the tau capsid β cargo studies, all data sets outlined in Appendix 6 and corresponding reports for the top performing capsid variants (i.e., Reserved Capsids, Primary Capsid and Back-Up Capsids) will be provided to AbbVie. These include: |
β’ Cell-type distribution in NHPs and rodents, after peak expression is 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 (e.g., nADA) in NHP and low prevalence of preexisting antibodies (<50%) in the target patient population (sufficient sample size to estimate nADA in AD/PD serum sample, but no more 50 samples) |
β’ Toxicity profiles in adult cynomolgus monkey, including clinical pathology and histopathology at peak expression and later (e.g., look at later timepoints for recovery) |
β’ Sequence of the Research Product, Primary and Back-Ups capsids, including patentability and FTO assessment |
The Target Product Profile for the Research Product for the tau program has the following attributes. |
Meets TCP criteria as agreed by the JGC. |
In vivo activity established with evidence of on-target and sustained effect (e.g., clearance of tau aggregates) in a preclinical model (preferably tauopathy 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 prevalence data in the intended patient population and plan for widespread use in the general population; data supportive of advancement to IND enabling studies. |
Manufacturing executable plan in place including process, scalability, analytical methods etc. |
10.3 Ξ±-Synuclein Capsid β Cargo Development |
10.3.1 Ξ-SYNUCLEIN CARGO DEVELOPMENT |
Ξ±-synuclein cargo development will be led by AbbVie and is generally outside of the scope of this research plan with the exception of the vector optimization strategy which will be designed jointly between AbbVie and Capsida. Vector optimization will include assessment of the efficacy of various promoter elements (e.g.... |
10.3.2 Dose β Efficacy Relationship in Mice |
Dose ranging studies in Ξ±-synuclein disease models will be conducted by AbbVie for the purpose of establishing a relationship between dose β therapeutic protein expression β efficacy (i.e., clearance of Ξ±-synuclein pathology). Disease proof-of-concept can be established using already characterized and efficient CNS-tar... |
10.3.3 Additional NHP Studies for Target Engagement |
In addition, AbbVie will work to translate the rodent efficacy model to NHP to incorporate Ξ±-synuclein aggregate deposition with biomarker detection. A PET imaging approach may be considered upon availability of the -synuclein PET ligand. Based on the dose response results in mice, AbbVie will do limited dose response ... |
10.3.4 Ξ±-synuclein Cargo β Capsid Optimization: Selection of Research Product |
Vector optimization will be finalized as described in Section 3.4.1 -synuclein Cargo Development, with AbbVie providing data relating various vector compositions to efficacy in mouse models at the time of finalizing the gene therapy modules (4Q2022). These elements will be incorporated into the Final Individual Capsid ... |
10.3.5 Ξ±-synuclein Capsid β Cargo Program (Research Product) Data Package: Reports and Deliverables |
Upon completion of the Ξ±-synuclein capsid β cargo studies all data sets outlined in Appendix 6 and 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’ Cell-type distribution in NHPs and rodents, after peak expression is 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 the targeted tissues and in selected peripheral tissues in NHPs and / or rodents |
β’ Acceptable immunogenicity profile (e.g, nADA) in NHP and low prevalence of preexisting antibodies (<50%) in the target patient population (sufficient sample size to estimate nADA in AD/PD 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-Ups capsids, including patentability and FTO assessment |
The Target Product Profile for the Research Product for the -synuclein program has the following attributes: |
Meets TCP criteria as agreed by the JGC. |
In vivo activity established with evidence of on-target and sustained effect (e.g., clearance of -synuclein aggregates) in a preclinical model (preferably synucleinopathy 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 in the intended patient population and plan for widespread use in the general population supportive of advancement to IND enabling studies. |
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