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- Coordinate face-to-face meetings and teleconference meetings with Opsidio's manufacturing, testing, storage, and drug supply (labeling/packaging/distribution) CDMO(s) - Consult with and assist AbbVie as needed to enable DS/DP process transfer and DS/DP test method transfer - Consult with and assist AbbVie as needed t... |
toxicology batch for comparability testing - Provide AbbVie with process summary reports, master batch records, process development reports and other documents as needed containing all information and know-how required to enable DS/DP process transfer. Test method transfer - Transfer DS/DP in-process, release and stabi... |
15 Quality Tasks AbbVie/Opsidio |
16 Post-License Option Exercise Closing Date support at Opsidio |
- Licensed Antibodies MCB and working cell bank (as applicable) - Licensed Antibodies reference standard(s) |
17 Manufacturing Preparatory Initial Development Activities, know how transfer |
If parties cannot mutually agree to activities where mutual agreement is stated, the matter is to be resolved pursuant Section 13.7 of the Definitive Agreement. |
IV. Pre-Clinical Activities |
A. cGLP Toxicology |
13-week cGLP toxicity studies in rat and NHP will be performed to support the IND and the clinical program through Phase I/IB Trial. |
Opsidio will also initiate a 26-week rat (if required by FDA) and NHP cGLP toxicology study to be completed before the initiation of the Phase I/IB Trial. Planned timing to be concurrent with the Phase 1a study in order to be completed before the start of the Phase 1b study. |
Prior to initiation of the 13-week tox studies, dose finding studies will be performed. |
A human cross reactivity study is a necessary component of the IND submission. This is performed on a standard panel of 32 normal human tissues. Charles River Laboratories has the facilities and personnel to accomplish this cGLP study. |
cGLP toxicology protocols will be developed at JGC, and AbbVie will approve the final cGLP study protocols. |
B. Clinical Assay Development |
Standard and non-standard assays will be needed for PK and PD. The PK, ADA, and nAb assays will be typical monoclonal development assays. |
PD markers will be a combination of routine clinical assays, e.g. eosinophil counts and IgE levels; applications of existing assays, e.g. serum SCF165 assays and flow cytometry for c-kit-positive cells; and purpose-built assays, e.g. tissue cytokine levels. The development of purpose-built assays is described below in ... |
A pharmacokinetic study (IV/SC single dose) in NHP will assess the bioavailability and local tolerability of the SC formulation developed for clinical use. |
1 IND package (responsibility Opsidio) |
2 13-week cGLP toxicity studies in rat and NHP (w/recovery) (responsibility Opsidio) |
- Studies with 13 weeks of dosing. - 3 treatment and 1 control group; the high dose should be based on the results of the dose finding study - Studies to include a recovery phase, duration minimally 6 weeks or long enough to demonstrate any potential findings are recovering. - Recovery phase to minimally include the co... |
3 26-wk cGLP NHP tox (responsibility Opsidio) |
- Study conducted in cynomolgus monkeys - Study with 26 weeks of dosing. - 3 treatment and 1 control group; the high dose should be based on the results of the dose finding study - - Number of animals: 4/sex/group for dose groups; - Study endpoints to include clinical observations, body weight assessments, food consump... |
4 Immunosafety Assays (responsibility Opsidio) |
5 BA method validation (rat and NHP) (responsibility Opsidio) |
6 BA method validation (human) (responsibility Opsidio) |
7 ADA method validation (rat, NHP, human) (responsibility Opsidio) |
8 nAb method validation (human) (responsibility Opsidio) |
9 Tissue cross reactivity assays (responsibility Opsidio) |
10 NHP PK Study (responsibility Opsidio) |
C. Other Preclinical Activities |
Objective |
Anti-SCF248 antibodies |
D. Regulatory Affairs |
1. Health Authority submissions and consultations |
US |
An IND will be opened to allow enrollment of US subjects into the FIH, SAD/MAD Phase I/IA Trial in HV and PoC Phase I/IB Trial in AD subjects. An FDA (Type B (Pre-IND)) meeting will be sought in 2021 before the planned IND submission and start of planned Phase I/IA Trial and Phase I/IB Trial. This interaction will focu... |
EU (as mutually agreed) |
Scientific Advice (SA) from a select national competent authorities (e.g., UK, Germany, Netherlands, or Belgium) may be sought before the start of FIH, SAD/MAD Phase I/IA Trial in HV and PoC Phase I/IB Trial in AD subjects. In the EU these interactions will focus on establishing relationships with EU regulators and to ... |
Regulatory Deliverable (responsibility Opsidio) |
1 Submit IND for the Licensed Antibody FIH, SAD/MAD Phase I/IA Trial in HV and PoC Phase I/IB Trial in AD subjects (US) and, if needed, CTA in appropriate ex-US country(ies) |
2 Submit FDA (Type B (Pre-IND)) meeting and, if needed, national competent authority Sci Advice to seek feedback on development program requirements in order to initiate FIH, SAD/MAD Phase I/IA Trial and PoC Phase I/IB Trial in AD subjects |
3 Transfer responsibilities and obligations of the Licensed Antibodies IND |
4 Regulatory Preparatory Initial Development Activities |
V. Program Target Success Criteria |
A. Success Criteria for IND |
To be achieved within 3 months of timelines corresponding to such activities agreed in this Initial Development Plan and Budget. |
1. CMC |
Generate monoclonal cell line with commercially acceptable production level (~4 g/L) and gene-integration stability (60 generations) |
Develop drug substance process with overall yield ≥70% |
Provide at least 100 mg/mL formulation suitable for subcutaneous administration |
Establish phase-appropriate qualified analytical methods |
Produce sufficient DS/DP inventory to support pre-clinical and clinical studies through Phase I/IB Trial |
• Demonstrate acceptable DS/DP stability profile (at IND at least 6 month real time data development batch) at 2-8°C, 25°C and 40°C, aggregate level not more than 2% at release/monomer not less than 90% (SEC),to support early-phase clinical program. |
2. 13w cGLP Toxicology |
• Toxicology profile consistent with clinical development of a Licensed Antibody. |
• Demonstrate full reversibility of any hematopoietic toxicity, no evidence of an impact on melanogenesis, gametogenesis at a TI (vs predicted human efficacious exposure) of at least 10x. Identify the potential for clinical monitoring of any identified hematopoietic toxicity, with an understanding that cessation of dos... |
3. Regulatory |
FDA provides communication (i.e. verbal, written) that identifies the IND is open and the planned SAD/MAD Phase I/IA Trial in HV will be allowed to proceed within 30 days of the FDA notice. |
B. Success Criteria for End of Phase I/IA Trial |
To be achieved within 3 months of timelines corresponding to such activities agreed in this Initial Development Plan and Budget. |
1. CMC |
If a formulation transition is required, the SC formulation planned for the Phase I/IB Trial in AD subjects should have sufficient concentration (>100 mg/ml) and relative bioavailability to enable administering the clinically efficacious dose(s) in a single commercially feasible SC injection of < 1 mL volume. |
If a formulation transition is required, adequate characterization and demonstration of comparability must be completed to support regulatory updates and accepted by FDA. |
To support transition from IV to SC administration, successful bridging will be established based on: attainment of efficacious drug exposure estimated from the target binding data by the SC formulation, relative bioavailability of the SC formulation based on estimates for Cmax and AUC compared to the IV formulation, c... |
Demonstrate feasibility of pre-filled syringe presentation o Show compatibility of the SC formulation with siliconized surfaces o No significant increase of aggregates |
Qualified cell based potency assay |
Implement quantitative preliminary purity specifications for charge variants (icICF/IEX) |
Perform data trending over all available stability data points to confirm acceptable long term stability profile (SEC trend analysis supports a NMT 5% aggregate level at end of shelf life (2 yrs), subvisible particles within compendial limits without significant trending at 25°C, product practically free from visible p... |
2. 26-week cGLP Toxicology |
• Toxicology profile consistent with full clinical development of a Licensed Antibody and no change in baseline for KIT-related hematopoiesis, melanogenesis, gametogenesis and |
gastrointestinal pacemaker cell activity. If any of these toxicities are unresolved, then the margin vs projected human therapeutic exposure is increased to at least 20x. |
3. Clinical |
Safety rates of adverse events not worse than dupilumab package insert in terms of immunologic reactions i.e. hypersensitivity and injection-site reactions, infections, eye related events and laboratory parameters for treatment in chronic autoimmune and inflammatory diseases like AD. |
PK and immunogenicity(ADA) profiles with a dose-regimen no more frequent than q2wk for treatment in chronic autoimmune and inflammatory diseases like AD. |
4. Regulatory |
Submission of the planned PoC Phase I/IB Trial in AD subjects protocol to the IND within 3 months from the SAD/MAD Phase I/IA Trial study database lock and analysis. |
5. Biomarker Package to Support PoC Phase I/IB Trial in AD Subjects (Biomarker Milestone) |
Statistically significant (p < 0.1) demonstrated reduction in a target cell (e.g. ILC2 or eosinophil) numbers or changes in soluble circulating SCF (SCF165) levels versus pre-dose baseline that is reflecting a dose dependent target engagement of SCF248 in healthy volunteers (unless a statistically significant differenc... |
C. Success Criteria for End of PoC Phase I/IB Trial |
To be achieved within 3 months of timelines corresponding to such activities agreed in this Initial Development Plan and Budget. |
1. Target Product Profile |
Target concentration >100 mg/ml, volume < 1 mL per single dose |
Prefilled syringe with staked needle |
Needle size not larger than G27 |
Max. injection force at 2-8°C not more than 20N, measured at 80 mm/min |
Availability of at least 3-month data on development batch in prefilled syringe |
Acceptable stability profile (24-month expiry date achievable based on 2-8°C and accelerated data, no OOS expected based on 6-month data extrapolation, comparable stability profile of prefilled syringe presentation compared to vial presentation. |
Establish comparability, as needed, to support DS/DP process changes/optimization |
Define critical quality attributes and establish control strategy with phase appropriate validated analytical methods (according to ICH and regulatory guidances), including a cell-based potency assay |
DS/DP supply sufficient to initiate P2 activities |
2. Clinical |
Biomarker data (Target deliverables): |
1 Conclusive evidence of target engagement in AD patients as demonstrated by significant and meaningful (i.e. effect of magnitude and direction that is considered important by a scientist trained in the field of AD) reduction in circulating target cells (i.e. ILC2 and eosinophils) and reduction in levels of soluble SCF... |
2 Conclusive evidence of significant and meaningful biological activity (i.e. effect of magnitude and direction that is considered important by a scientist trained in the field of AD) of Licensed Antibody in AD patients as demonstrated by significant in skin biomarkers (transcript levels, cell number by H&E, or protein... |
3 Provide to AbbVie biomarker samples (as defined in the Clinical Plan Objective Table) for the exploration of Licensed Antibody MoA in AD and other diseases of interest if AbbVie opts-in |
VI. Data Package Delivery Requirements |
Opsidio will deliver the Data Package promptly in accordance with the Definitive Agreement after all of the following conditions are satisfied: |
A. Clinical |
(a) the SAD/MAD Phase I/IA Trial and PoC Phase I/IB Trial each has the minimum number ("n") of Response-Evaluable Patients identified below for each group of such Clinical Study and are otherwise conducted in accordance with this Initial Development Plan and Budget and the Definitive Agreement ("Response-Evaluable Pati... |
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