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5.0 Manufacturing and Supply |
Manufacturing activities to support IND-enabling studies and POC studies will be conducted by Capsida. This includes packaging and distribution. |
6.0 Budget (PoC Plan) |
POC Plan (TDP43 Only) Description Tot. Patient Drug Placebo Cost Per Pat. Total Cost $M Cohort 1 10 6 4 250,000 2.50 Cohort 2 16 10 6 250,000 4.00 5-year long term follow up 26 16 10 150,000 3.90 10.40 |
Per Year # of Years $ millions Clinical Trial Costs (Site, Patient costs and Monitoring) 10.4 IND Enabling GLP Tox in NHPs 2.8 IND Enabling Mouse Pharmacology 0.8 All Manufacturing Production, Packaging, Distribution and Stability 7.5 Direct FTE Costs (primarily clin/reg with R&D supporting IND) 1.5 3 4.5 Indirect FTE ... |
Draft Research Program Background and Research Plans Not a Legal Document; For Discussion Purposes Only |
1 |
Exhibit D Ophthalmology Research Plan |
AbbVie Capsida Ophthalmology Collaboration Background and Capsid Program Research Plan |
Collaboration Background |
AbbVie and Capsida are collaborating on research activities aimed at identifying and optimizing capsids using the Capsida Platform to deliver AbbVie Ophthalmology Cargo to cells in and around the eye as appropriate based on the Ophthalmology Target Capsid Profile (TCP). |
Capsida will harness its biologically driven, high-throughput non-human primate (NHP) screening platform to develop and validate novel IVT, SCS, and IC delivered AAV capsids enabling increased cargo expression and optimal targeting for ocular tissues and cells directed towards the TCP (Table 1) compared with wild type ... |
The activities in this Research Plan focus on the development and engineering of capsids directed towards TCPs provided in Table 1. Each of IVT, SCS and IC as described in Table 1 are distinct ROAs. Combined with AbbVie's differentiated capabilities in the ophthalmology space, the two organizations will collaborate to ... |
Table 1: Preliminary Target Capsid Profiles for de novo Eye Care Capsid Selection* |
Attributes IVT Retina SCS Retina IC Anterior Route of Administration Intravitreal (IVT) Suprachoroidal Space (SCS) Intracameral (IC) |
Distribution Broad retinal tropism extending to outer retina & retinal pigment epithelium (RPE); optic nerve head Sclera and choroid extending to RPE and into outer retina Broad anterior including Trabecular Meshwork, Schlemm's canal |
Transduction Efficiency (average across gradient in distribution area) >70% >30% >70% |
Specificity / Tropism Broad (retinal ganglion cell (RGCs), Mueller cells (Mueller glia), photoreceptor (PR) cells, retinal pigment epithelium (RPE), etc) Broad (retinal ganglion cell (RGCs), Mueller cells (Mueller glia), photoreceptor (PR) cells, retinal pigment epithelium (RPE), etc) Trabecular meshwork (TM) cells, Sc... |
Manufacturability Similar or better than parental serotype (e.g., AAV2, AAV8) Volumetric requirements (max) @ titer 10^13 vg/ml: 50 µl IVT; 100 µl SCS; 20 µl IC |
* Target capsid profiles are subject to change based on recommendations by the Research Working Group and approval by JGC |
Research Plan Scope and Framework |
This Research Plan outlines activities and estimated timelines to be conducted by Capsida or AbbVie, as specified below. These activities are designed to generate and optimize capsids using the Capsida Platform to deliver AbbVie Cargo to the relevant ocular cells as described by the TCPs for this Research Plan. The TCP... |
Changes to the TCP must be approved by the Joint Governance Committee (JGC) in accordance with the Agreement. 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 c... |
Capsida plans to focus engineering efforts on AAV2 and AAV8, subject to reconsideration based on best available internal and external data and Research Working Group recommendation. |
AbbVie target and cargo development will be ongoing throughout the duration of the Research Plan but with activities related thereto falling outside of the scope of this Research Plan. It is the parties' intent that all cargo optimization, including post-transcriptional regulatory elements (PREs), promoters, etc., will... |
High Level Roles and Responsibilities |
Capsida activities |
• Engineering strategy • Proprietary cargo for Library Screening, Variant Optimization, and Final Variant Optimization • Developing and optimizing methods for extraction of high quality and quantity nucleic acids from ocular tissue • Evaluating cross-ocular transduction and safety/efficacy impact of dosing simultaneous... |
• AAV8 capsid generation, screening and variant optimization in NHPs toward SCS TCP • AAV8 capsid generation, screening and variant optimization in NHPs toward IVT TCP • AAV8 capsid generation, screening and variant optimization in NHPs toward IC TCP • FTO screening prior to or in parallel with Secondary and Final Pool... |
AbbVie activities |
• Non-proprietary tool cargo (GFP) for platform build activities provided to Capsida • Representative cargo (plasmid and sequence) for first pooled candidate identification study provided by at least four months prior to initiation of study • Optimized therapeutic cargo for single variant study, if ready, provided by a... |
AbbVie is responsible for making decisions related to animal welfare (e.g. early euthanasia due to animal welfare concerns). When possible, AbbVie will discuss these decisions with Capsida in advance, but for clarity, animal welfare will take priority and such decisions may require prompt action without advance notice ... |
AbbVie does not anticipate using CROs for animal studies and can fully support in-house. Should AbbVie contemplate the need to engage with a CRO, AbbVie will discuss its decision with the Research Working Group. |
Figure 1: High Level Timeline of Capsid Development Activities |
Serotype/ROA screening will inform ROA (e.g., IC administration), serotype, or other focus of the 3rd research plan workstream. |
*The baseline assumption is that IVT injections may be used as surrogate route in some instances for selecting capsids intended for the IC->anterior route, but this will only be done in consultation with, and with the approval of, the JGC. The rationale for this is that there are no major anatomic barriers between the ... |
** Current timelines assume engineered capsids for SCS route of administration will progress to a Final Pooled Candidate Identification Study after Variant Optimization, subject to RWG decision. Alternatively, the RWG may opt to progress to Final Variant Optimization and Secondary Pooled Candidate Identification Study ... |
**Current timelines assume 1 week turnaround time for ocular tissue dissection and pre-processing by AbbVie, non-proprietary tool cargo (GFP) for platform build activities provided to Capsida by AbbVie within one month of signing, and tissues for developing and optimizing methods for extraction of high quality and quan... |
Figure 2: High Level Timeline of Roles / Responsibilities: |
Description of Program Activities |
I. Build and Platform Development |
Preliminary activities will focus on method validation, process optimization, non-NHP screening and method development prior to NHP screening. Activities include: |
1. Developing and optimizing methods for extraction of high quality and quantity nucleic acids from ocular tissue (AbbVie to provide existing tissues for rabbit and/or rodent in the form agreed by the RWG. a. Rationale: Capsida has found different tissues to have different nucleic acid yields and processing requirement... |
2. Dosing rabbits simultaneously with two wildtype serotypes (and potentially novel capsids from bullet #4) and/or two or more ROAs (dose alternate eyes) to evaluate cross-ocular transduction and safety/efficacy impact (AbbVie providing in-life and ocular tissue dissection at the time in the form agreed by the RWG) a. ... |
3. Evaluating different mutagenesis strategies (e.g., peptide insertion site) and screening constructs (e.g., utilizing different ubiquitous or ocular-specific promoters) on parental serotypes for impact on library manufacturability and quality (AbbVie to supply plasmids encoding test genome including, promoters, expre... |
4. Dosing rabbits with exploratory libraries (non-CNS) or capsids to evaluate potential of different engineering strategies and/or establish capsid benchmarks (Similar to bullet #2) (AbbVie providing in-life and ocular tissue dissection at the time and in the form agreed by the RWG) a. Rationale: Transduction baselines... |
5. Process tissues from above study(ies) with Capsida's scRNAseq method, evaluate existing AbbVie scRNAseq data, and use this to develop bioinformatic tools for quantifying viral transcripts and mapping them to particular cell types (AbbVie provide tissue & data at the time and in the form agreed by the RWG) a. Rationa... |
II. Initial Library Screening (Round 1 and Round 2) – IVT and SCS |
All library screening will be conducted in NHPs. Initial library screening efforts (i.e., de novo) begin with peptide substitutions and / or insertions into capsid variants based on (1) AAV2 and (2) AAV8 serotypes with Capsida proprietary cargo delivered via (1) IVT and (2) SCS (and possibly (3) IC) administration. It ... |
AbbVie will perform routine gross ophthalmic and animal welfare evaluations throughout the in-life portion of the studies. More detailed methods of ophthalmic evaluation, including slit lamp biomicroscopy, indirect ophthalmoscopy, color fundus imaging, optical coherence tomography, as well as aqueous or vitreous inflam... |
Capsida will be responsible for engineering strategy, virus library generation, vector production and QC, benchmarked vector genome residence, and analysis of DNA biodistribution in the tissues. AbbVie will be responsible for in-life activities including IVT and SCS administration, and ocular tissue dissection and pre-... |
Based upon the data package from Initial Library Screening, the RWG will recommend to the Joint Governance Committee (JGC) moving to First Pooled Candidate Identification studies or continued library screening. AbbVie can select up to 5 Reserved Capsids per route of administration (IVT, SCS, and IC) from this initial s... |
III. First Pooled Candidate Identification Studies – IVT, SCS and IC as agreed by the JGC |
JGC will agree on the top performing capsid variants from AAV2 and AAV8 backbones as well as relevant control capsids from the engineering platform that will be tested in Pooled Candidate Identification studies with a tagged cargo that is representative of the final cargo (either the final cargo or a surrogate/lead). U... |
AbbVie and Capsida will screen capsids in rodents (n=3-10) and rabbits (n=3-10) (as agreed by the RWG); continued screening in these animals will be further evaluated and refined by the RWG. Animals will be dosed at AbbVie facility, with vector provided by Capsida. NHP (n=3) in-life to be 3-8 weeks. |
Each First Pooled Candidate Identification Study will assess DNA biodistribution, benchmarked vector genome residence, single cell RNA expression as appropriate, gross transduction in target tissues, and capsid quality attributes. Teams to further clarify in vivo protein expression evaluation and assessment of in vitro... |
Capsida will be responsible for vector production and QC, benchmarked vector genome residence, analysis of DNA biodistribution in the tissues, and capsid quality attribute assessments. Capsida and AbbVie will be responsible for their respective activities related to the ex vivo immunogenicity assays if needed as descri... |
Based upon the data package from the candidate identification study, the RWG will recommend to the JGC moving to Variant Optimization or continued library screening. The RWG will evaluate if available data support that engineering efforts in variant optimization should be focused on a single serotype. |
Following data readout from this study, AbbVie can select up to 5 Reserved Capsids per route of administration (IVT, SCS, and IC). For clarity, if IVT route is used at this stage as a surrogate for IC, Reserved Capsids for IC route of administration will be selected based on anterior distribution of IVT-delivered capsi... |
IV. Variant Optimization (Round 1 and Round 2) – IVT and SCS (IC as agreed by the JGC) |
Top performing capsids from the Pooled Candidate Identification Study, as determined by the JGC, will be moved into re-diversification and library screening in NHPs (n=3) aimed at increasing efficacy and/or specificity in ocular cells as relevant for the TCPs. Variant optimization will encompass two rounds. Capsids wit... |
Capsida will be responsible for engineering strategy, virus library generation, vector production and QC, benchmarked vector genome residence, analysis of DNA biodistribution in the tissues, and FTO search of capsids nominated for Secondary or Final Pooled Candidate Identification Study. FTO search may occur prior to o... |
Based upon the data package from Variant Optimization, the RWG will recommend to the JGC whether to progress to Secondary Pooled Candidate Identification studies, Final Pooled Candidate Identification Study, Final Variant Optimization, or continued library screening Currently, parties anticipate engineered capsids for ... |
Following data readout from this study, AbbVie can select up to 5 Reserved Capsids per route of administration (IVT, SCS, and IC). For clarity, if IVT route is used at this stage as a surrogate for IC, Reserved Capsids for IC route of administration will be selected based on anterior distribution of IVT-delivered capsi... |
V. Secondary Pooled Candidate Identification Studies – SCS, IVT, and/or IC as agreed by the JGC |
JGC will agree on top performing capsid variants identified from Variant Optimization (and potentially Initial Library Screening) that will be tested in a Pooled Candidate Identification study with a tagged cargo that is representative of the final cargo (either the final cargo or a surrogate/lead). Unless otherwise ag... |
AbbVie and Capsida will screen capsids in rodents (n=3) and rabbits (n=3); continued screening in these animals will be further refined by RWG. Animals will be dosed at AbbVie facility, with vector provided by Capsida. NHP (n=3) in-life to be 3-8 weeks. |
Each study will assess DNA biodistribution, benchmarked vector genome residence, single cell RNA expression as appropriate, gross transduction in target tissues, and capsid quality attributes. Teams to further clarify in vivo protein expression evaluation and assessment of in vitro mRNA and protein expression as part o... |
Capsida will be responsible for vector production and QC, benchmarked vector genome residence, analysis of DNA biodistribution in the tissues, and capsid quality attribute assessments. Capsida and AbbVie will be responsible for their respective activities related to the ex vivo immunogenicity assays if needed as descri... |
Based on the data package for this study, the Research Working Group shall recommend to the JGC whether to continue the Variant Optimization Research Stage or to progress to the Final Variant Optimization Research Stage and which capsids to further optimize in the Final Variant Optimization Research Stage or to continu... |
VI. Final Variant Optimization (Round 1 and Round 2) – IVT, SCS, and/or IC agreed by the JGC |
Depending on RWG recommendation and JGC determination, top performing capsids with Capsida proprietary cargo delivered via IVT, SCS, and IC administration (unless otherwise agreed by the JGC) will each undergo two additional rounds of variant optimization to increase efficacy and/or specificity toward TCP (unless the R... |
Dependent on prior activities, AAV2 and/or AAV8 engineered capsids may be included in this step. AbbVie will also screen capsids in rodents (n=3-10) and rabbits (n=3-10); continued screening in these animals will be further evaluated and refined by RWG. Animals will be dosed at AbbVie facility, with vector provided by ... |
Capsida will be responsible for engineering strategy, virus library generation, vector production and QC, benchmarked vector genome residence, analysis of DNA biodistribution in the tissues, and FTO search of capsids nominated for the Final Pooled Candidate Identification Study. FTO search may occur prior to or in para... |
Capsida anticipates that top performing capsids from Final Variant Optimization could be sufficiently optimized to move into a third Pooled Candidate Identification study. Decision to move to the Final Pooled Candidate Identification study will be based on available data. The RWG will recommend to JGC whether to move t... |
Following data readout from this study, AbbVie can select up to 5 Reserved Capsids per route of administration (IVT, SCS, and IC). For clarity, if IVT route is used at this stage as a surrogate for IC, Reserved Capsids for IC route of administration will be selected based on anterior distribution of IVT-delivered capsi... |
VII. Final Pooled Candidate Identification Studies – IVT, SCS, and/or IC as agreed by the JGC |
JGC will agree on the top performing capsid variants from Final Variant Optimization (and potentially earlier rounds) delivered via IVT administration which will be tested in a Final Pooled Candidate Identification Study with a tagged cargo that is representative of the final cargo (either the final cargo or a surrogat... |
AbbVie and Capsida will screen capsids in rodents (n=3-10) and rabbits (n=3-10); continued screening in these animals will be further evaluated and refined by RWG. Animals will be dosed at AbbVie facility, with vector provided by Capsida. NHP (n=3) in-life to be 3-8 weeks. |
Each study will assess DNA biodistribution, benchmarked vector genome residence, single cell RNA expression as appropriate, gross transduction in target tissues, capsid quality attributes, and ocular tolerability / safety as appropriate. Teams to further clarify in vivo protein expression evaluation and assessment of i... |
Capsida will be responsible for vector production and QC, benchmarked vector genome residence, analysis of DNA biodistribution in the tissues, capsid quality attribute assessments, and in vitro immunogenicity assays. Capsida and AbbVie will be responsible for ex vivo immunogenicity assays if needed as described in Tabl... |
Following data readout from this study, AbbVie can select up to 5 Reserved Capsids per route of administration (IVT, SCS, and IC). For clarity, if IVT route is used at this stage as a surrogate for IC, Reserved Capsids for IC route of administration will be selected based on anterior distribution of IVT-delivered capsi... |
VIII. Single Variant Characterization Studies – SCS, IVT, IC |
A subset of reserve capsids will be evaluated in a Single Variant Characterization study delivered via SCS, IVT, and IC administration with a tagged cargo representative of the final cargo or optimized therapeutic cargo if available. |
It may be possible to evaluate one capsid in each eye. The Single Variant Characterization Studies will have an objective to confirm properties of capsid candidates including but not limited to the tissue biodistribution, cell type specificity, transduction, duration of expression, and immunogenicity. In some cases the... |
Animals will be dosed at AbbVie facility, with vector provided by Capsida. This study will evaluate up to 5 engineered capsids and parental serotype(s) in NHPs, i.e., n=up to 18 per route of administration. In-life to be 3-8 weeks. RWG may decide to conduct Single Variant Characterization study in rodents and/or rabbit... |
Data to be assessed include DNA biodistribution, single cell RNA expression in NHPs, transduction in target tissues in NHPs, ocular tolerability/safety, ex vivo immunogenicity assays, and clinical pathology in NHPs. Teams to further clarify in vivo protein expression evaluation as part of RWG discussions. Histopatholog... |
Capsida will be responsible for vector production and QC, analysis of DNA biodistribution in the tissues, capsid quality attribute assessment, and packaging efficiency and stability assays. Capsida and AbbVie will be responsible for their respective activities related to the ex vivo immunogenicity assays as described i... |
Data generated by Single Variant Characterization Study on capsids delivered via SCS, IVT, and IC will inform AbbVie's determination of AbbVie Selected Ophthalmology Capsids. |
IX. AbbVie Cargo and Expression Elements Improvement Activities |
During the Research Plan, AbbVie may further improve the AbbVie Ophthalmology Cargo and Expression Elements as necessary. In support of these activities, Capsida will provide vector for these evaluations and expert opinion. |
X. Vector Optimization |
AbbVie may conduct preliminary assessment of the efficacy of various vector designs to inform the choice of cargo for the Single Variant Characterization Studies. AbbVie will transfer the AbbVie Cargo sequence to Capsida for research grade production with different gene regulatory elements. Packaged virus will be trans... |
XI. 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 of AbbVie Selected Ophthalmology Capsids, Capsida will initiate process development activities shown below for up to a total of 3 programs (one per target, i.e. the lead) in support and as required to gener... |
The FDA guidelines for cellular and gene therapy products recommends multiple CMC-related activities to characterize product quality and manufacturing controls, to assure identity, purity, sterility and stability of products to certify lot release and establish product dating and shelf life. If Capsida is the site of m... |
AbbVie will take primary responsibility for developing the potency assay for quantifying the transducibility and efficacy of the protein produced from a specific lot of product. If Capsida produces material for clinical supply, AbbVie will transfer the assay and reagents to Capsida for validation. Other assays necessar... |
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 ... |
Table 2 - Data Package Elements - Library Screening and Variant Optimization (Round 1 and Round 2)* |
Category Analysis Assay Results Responsible Party NHP Benchmarked vector genome residence -target tissues Viral DNA amplified for NGS by PCR Capsida Biodistribution -target tissues Viral DNA assayed for total copy number via qPCR or ddPCR, with a preference for ddPCR in later studies Capsida Rodent Benchmarked vector g... |
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