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5. Clinical biomarker plan and Data Package: Opsidio |
Operational Plan and Budget, Product Management and QA: Opsidio |
Preclinical R&D |
1. Non-standard PD assay development |
2. Affinity optimization and fully human MAb generation |
a. Generate MAbs: Specifica |
b. Pharmacologic assessment: Opsidio |
c. Immunogenicity assessment |
III. Initial Research and Development Plans |
A. Readiness and Operational Plan and Budget |
Opsidio will execute on the Operational Plan and Budget to fulfill its obligations under this Initial Development Plan and Budget and the Definitive Agreement. |
B. Clinical Plan |
The following are the Clinical Studies contemplated by the Parties for successful development of a Licensed Antibody for the treatment of AD through PoC Phase I/IB Trial. |
Placebo-controlled, double-blind randomized Phase I/IA Trial of a Licensed Antibody in adult healthy volunteers (18-75 years) will be conducted. The SAD segment of the Phase I/IA Trial will assess the safety, tolerability, and pharmacokinetics of single-dose of IV or SC of a Licensed Antibody. A total of 4 IV dose leve... |
The placebo-controlled, double-blind randomized PoC Phase I/IB Trial study of a Licensed Antibody in adult patients (18-75 years) with dermatologist-confirmed diagnosis of AD. The subjects must have moderate to severe AD. A Licensed Antibody and placebo would be administered by IV or SC dosing in a parallel design, 24 ... |
Primary and key secondary endpoints would be assessed at week 16 and would be based on evaluation of EASI, including the percentage improvement from baseline in EASI and proportions of patients achieving improvement of greater than or equal to 50%/greater than or equal to 75%/greater than or equal to 90% from baseline ... |
Safety would be evaluated and may include evaluation of adverse events, physical examinations, vital signs, ECGs, immunogenicity, and safety laboratory parameters. The study would be monitored by a Safety DSMB that includes AbbVie participation. |
The aforementioned clinical study narrative is shown diagrammatically as follows: |
[Note: There appears to be diagrams in the original document showing the clinical study design] |
Clinical Plan Objective Table. Key study objectives, activities and timeline are listed as follows: |
Item: 1<br>Clinical Objectives (Responsibility-Opsidio): SAD/MAD Phase I/IA Trial in HV clinical protocol<br>Activities: Opsidio will prepare the SAD and MAD Clinical Study protocol in HV for the IND. AbbVie will approve.<br>Timeline: Before IND |
Item: 2<br>Clinical Objectives (Responsibility-Opsidio): PoC Phase I/IB Trial AD protocol<br>Activities: Opsidio will prepare the PoC Phase I/IB Trial Clinical Study protocol. AbbVie will approve.<br>Timeline: Prior to start of Phase I/IB Trial |
Item: 3<br>Clinical Objectives (Responsibility-Opsidio): SAD/MAD Phase I/IA Trial in HV<br>Activities: Opsidio will conduct the SAD/MAD Phase I/IA Trial, in accordance with the protocol submitted as part of the IND. A summary of such protocol is set forth in this item below.<br>- Establish safety and tolerability<br>- ... |
Item: 4<br>Clinical Objectives (Responsibility-Opsidio): PoC Phase I/IB Trial in AD patients<br>Activities: Opsidio will conduct the PoC Phase I/IB Trial in accordance with the protocol submitted as an update to the IND. A summary of such protocol is set forth in this item below.<br>- Establish pharmacokinetics, safety... |
Item: 5<br>Clinical Objectives (Responsibility-Opsidio): Establish DSMB<br>Activities: Monitor trial safety<br>Timeline: Prior to start of Phase I/IB Trial |
Item: 1<br>Translational Medicine / Biomarker objectives: Immuno-monitoring<br>Activities: • Longitudinal numbers of major leukocyte populations (including eosinophils) in HV by differential CBC<br>• Longitudinal numbers of blood T, B, NK cells, and monocytes in HV by flow cytometry<br>Timeline: Prior to start of PoC P... |
Item: 2<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Longitudinal numbers of major leukocyte populations (including eosinophils) in AD patients by differential CBC<br>• Longitudinal numbers of blood T, B, NK cells, and monocytes in AD patients by flow cytometry<br>Timeline: ... |
Item: 3<br>Translational Medicine / Biomarker objectives: Target engagement / proximal PD<br>Activities: • Characterized method for the monitoring of the number of circulating ILC2, including feasibility in HV<br>• Characterized method for the monitoring of the morphology of blood eosinophils, including feasibility in ... |
Item: 4<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Longitudinal numbers of circulating ILC2 in HV exposed to Licensed Antibody or PBO (SAD and MAD)<br>• Longitudinal phenotypic data of circulating eosinophils in HV exposed to Licensed Antibody or PBO (SAD and MAD)<br>• Lon... |
Item: 5<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Longitudinal numbers of circulating ILC2 in AD Patients exposed to Licensed Antibody or PBO (PoC)<br>• Longitudinal phenotypic data of circulating eosinophils in AD Patients exposed to Licensed Antibody or PBO (PoC)<br>• L... |
Item: 6<br>Translational Medicine / Biomarker objectives: PD effects: IgE<br>Activities: • Longitudinal concentration of total IgE in HV<br>Timeline: Prior to start of PoC Phase I/IB Trial |
Item: 7<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Longitudinal concentration of total IgE in AD patients<br>Timeline: End of PoC Phase I/IB Trial |
Item: 8<br>Translational Medicine / Biomarker objectives: Disease molecular modification: skin biology<br>Activities: • Finalized method selection for analysis of change in gene expression in skin biopsies from AD patients<br>• Finalized method selection for the analysis of tissue resident ILC2, Eosinophils, and Mast c... |
Item: 9<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Longitudinal (BL and PA) expression levels for all analyzed transcripts (depending on method) in AD patients skin biopsies<br>• Longitudinal (BL and PA) cell count for tissue resident ILC2, Eosinophils, and Mast cells in s... |
Item: 10<br>Translational Medicine / Biomarker objectives: Additional biomarker samples for the exploration of Licensed Antibody MoA in AD and other diseases of interest<br>Activities: • Availability of serum / plasma samples from HV exposed to Licensed Antibody or PBO (SAD and MAD)<br>Timeline: Prior to PoC Phase I/IB... |
Item: 11<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Availability of serum / plasma samples from AD patients exposed to Licensed Antibody or PBO (PoC)<br>Timeline: End of PoC Phase I/IB Trial |
Item: 12<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Availability of WB for RNA samples from HV exposed to Licensed Antibody or PBO (SAD and MAD)<br>Timeline: Prior to PoC Phase I/IB Trial |
Item: 13<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Availability of WB for RNA samples from AD patients exposed to Licensed Antibody or PBO (PoC)<br>Timeline: End of PoC Phase I/IB Trial |
Item: 14<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Availability of cryopreserved PBMCs from HV exposed to Licensed Antibody or PBO (SAD and MAD)<br>Timeline: Prior to start of PoC Phase I/IB Trial |
Item: 15<br>Translational Medicine / Biomarker objectives: [continued from above]<br>Activities: • Availability of cryopreserved PBMCs samples from AD patients exposed to Licensed Antibody or PBO (PoC)<br>Timeline: End of PoC Phase I/IB Trial |
C. Initial Phase I/IA Trial IV/SC formulation PK Studies |
Objective: An initial SC formulation will be developed for Phase I/IA Trial; all of the necessary PK, bioavailability, tox, and CMC work will be done on that formulation and included in the FIH IND. |
Item Clinical PK & Pharmacology Deliverable (Responsibility-Opsidio) |
D. Phase I/IA Trial IV/SC Formulation PK Bridging Studies |
If the initial SC formulation for Phase I/IA Trial does not meet criteria as defined in the EO Phase I/IA Trial CMC subsection, then this Section would apply. |
Objective: Develop SC formulation to support Phase II Trial development and to evaluate relative bioavailability of the high conc SC formulation |
The proposed plan and timing would enable introduction of a new SC formulation in subsequent Phase II Trials and mitigate the need for larger bioequivalence studies later in development to meet regulatory requirements. |
Item Clinical PK & Pharmacology Deliverable (Responsibility-Opsidio) |
E. Initial CMC Development Plan Activities |
Opsidio is responsible for conducting the following CMC activities until achievement of the success criteria outlined in Section V below, whether such criteria is achieved with the Humanized 5H10 Antibody or a subsequent, additional Licensed Antibody. The program will begin with cell line development based on the DNA a... |
1. cGMP Manufacturing |
KBI Biopharma will use stable cell pools and the RCB developed at Selexis to perform upstream and downstream process development, and to generate material to develop IV and SC formulations. The toxicology batch of formulated bulk drug substance will be shipped in appropriate containers to Charles River Laboratories. Th... |
KBI Biopharma will also initiate accelerated and real time stability on the toxicology DS batch, and the final drug substance and drug product batches. |
Manufacture sufficient DS supplies in support of nonclinical activities |
o 26-week cGLP cyno tox |
o Cyno PK |
Develop a high concentration formulation/presentation suitable for a single subcutaneous injection of the recommended Phase I/IB Trial and Phase II Trial dose (see Target Product Profile) |
(a) Development work |
Complete all cell line development and characterization studies, provide a sufficient number of vials of MCB. A WCB will be developed prior to manufacturing batches for pivotal trials. |
Develop a controlled DS/DP manufacturing process to enable manufacture of cGMP batches. |
o DS: target a titer of 4 g/L and overall production yield of 70%; |
o DP: develop robust process for high concentration formulation |
o Perform appropriate scale up experiments to achieve stated CMC success criteria and in support for late phase development |
Complete DS/DP process development studies to support the chosen dosage form and strength for Phase I and Phase II Trials. |
Complete DS/DP analytical characterization studies, in particular functional relevance of acidic species and glycosylation variants as applicable. |
(b) Analytical work packages |
Develop and validate (phase appropriate) suitable analytical methods covering all critical quality attributes of DS/DP to characterize and monitor quality of drug substance and drug product, including a cell based potency assay reflective of proposed mechanism of action |
Provide plans for cGMP analytical test method at Phase II Trial transfer including coordination with TPL's and provision of necessary materials (critical reagents, bioassay cell bank, reference standards, retain samples for back lot testing/comparability/method bridging) |
Perform phase appropriate coverage assessment for HCP method |
(c) Support of ongoing and initiation of future clinical studies |
Manufacture cGMP DS and DP in support of Phase I/IA Trial, Phase I/IB Trial and Phase II Trial |
Manufacture high concentration cGMP DS and DP for amended Phase I/IA Trial, Phase I/IB Trial and Phase II Trial (if applicable), human PK study and long-term ICH compliant DS and DP stability |
Manufacture/establish an adequate high concentration DS/DP inventory to initiate Phase II Trials |
Establish a high concentration reference standard including characterization and bridging to old reference standard (if applicable) |
Develop a matching placebo for the high concentration SC presentation suitable for blinded studies |
Provide at least 3-month stability data for placebo including data under accelerated conditions |
Supply of placebos, according to study design, with suitable blinding as appropriate |
Complete ongoing stability studies as planned in support of IND/IMPD including data to support Phase I/IA Trial, Phase I/IB Trial and Phase II Trial |
CMC Objectives and Notes (Responsibility-Opsidio) |
1 CMC Working Group |
2 Cell Line |
3 Development of Phase I/IA Trial, Phase I/IB Trial and Phase II Trial cGMP manufacturing Process |
scale engineering batches, at scale engineering batches, and cGLP toxicology batches) - Identification and qualification of major impurities as needed - DS/DP hold-time studies to support at-scale process holds and excursions - Reference standard manufacture, characterization, qualification and stability - Formulation ... |
4 Biophysical, and biological characterization of the Licensed Antibody reference standard, initial cGMP drug substance batch and batch used for IND-enabling cGLP toxicology study |
product variants, product-related impurities, glycosylation profile, SCF248 binding activity, SCF248 cell based functional assay and Fc receptor binding properties of the Licensed Antibody. - At a minimum, characterization tests to include: - Reverse phase LC/MS/MSMS, peptide mapping - Mass spectrometric determination ... |
5 Quality control test Methods |
6 Quality control test Methods |
7 Cell based bioassay development plans and progress to be periodically (at least quarterly) reviewed and agreed to by AbbVie. |
- Reports and documentation supporting establishment of the cell-based bioassay, to include: o Method development report describing assay formats, cell lines, and all other test method parameters evaluated during development of the cell-based bioassay. o Test method SOP o Test method validation protocol o Test method v... |
- Upon AbbVie's request pursuant to (and without limiting), provide AbbVie with the specific know-how to grow and maintain the cells used to perform the bioassay. |
9 Clinical supplies for Phase I/IA and Phase I/IB Trials |
each DS and DP lot per regulatory guidelines |
10 DS/DP stability for Phase I/IB Trial |
11 DS/DP process development, scale-up, transfer for Phase I and Phase II Trial resupplies and, if requested by AbbVie pursuant to initiation of Phase II Trial |
studies as needed to maintain uninterrupted Phase I/IB Trial drug supply and, initial supply drug to begin Phase II Trials - If a site, scale, or process change is to be implemented, conduct a technical run at the selected CDMO to assess process performance and product quality and stability, scale to be determined by C... |
(minimum 6 month), and stressed (minimum 6 month) storage conditions using material from a representative technical batch. Store frozen retains from each stability time point. |
12 Charge variant characterization study |
13 Regulatory supporting documents |
- DS and DP cGMP executed batch records for each cGMP batch - Release data and CofAs for each DS and DP cGMP batch - Stability data and reports for each DS and DP cGMP batch - Results of physicochemical, biophysical, and biological testing of the Licensed Antibody reference standard, nonclinical batches, and cGMP batch... |
14 Manufacturing Technology Transfer to AbbVie or AbbVie's selected CDMO(s) |
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