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• General study progress update Quarterly reports are to contain the following as available: |
• Program conduct and metrics o Site activation status, recruitment updates, screening data, follow-up visits and subject dispositions, number of open queries, number of forms completed, number of SDV done, number of forms locked) |
• Raw (unmonitored) data, including: o Safety (e.g., SAEs) o PK, ADA, pharmacodynamic and exploratory biomarker data |
• Any new CMC information received by Cugene o CMC timelines provided with any changes o Stability and characterization data, quality issues |
• Note: All analyses shall be performed using SAS version 9.4 or later (SAS Institute Inc., Cary, NC 2726) under the UNIX operating system. |
• Any new regulatory information with Regulatory Authorities and IP |
• Open meeting minutes and outputs of Safety Data Monitoring Committee (DSMB) |
Exception from monthly updates is any clinical safety issues (e.g., SUSARs, IND annual reports, DSURs) or safety signals (e.g., hypersensitivity reactions) to be shared immediately with IRBs and/or Regulatory Authorities. |
Semiannual reports are to contain the following as available: |
• Efficacy clinical data (SDTM-Study Data Tabulation Model SAS data sets) |
• Analysis Data Model (ADAM) SAS data sets and summarized data outputs (Tables, Listings and Figures) based on pre-specified SAP (Statistical Analysis Plan) and timelines for the Phase Ib Clinical Trial and, to the extent available, for the Phase Ia Clinical Trial |
B. Cugene Readiness and Operational Plan |
Cugene shall provide an operational plan that contains elements to reasonably demonstrate that Cugene shall have adequate resources and expertise to execute the Initial Development Plan and Budget. This includes: |
Profiles of staff and hiring profiles of needed staff along with consultants that are consistent with industry practice for similar preclinical and clinical representative positions for a program at this stage of Development. |
Reasonably detailed timelines and budgets (including FTE-based staffing costs) for the Development activities along the timelines agreed to by the Parties. |
Copies of Cugene's quality training program documentation, quality standard operating procedures and quality information systems documentation, which AbbVie shall have the right, during normal business hours and upon at least five Business Days' notice, to inspect and to discuss with appropriate employees and represent... |
CRO proposals outlining study objectives, plans and deliverables. |
Operational Plan |
Activity/Objective Deliverables Timeline |
Business and Operational Plan (BO Plan) Cugene will have adequate resources and expertise to execute the Initial Development Plan and Budget. The BO Plan provided to AbbVie will include: Profiles of staff and hiring profiles of needed staff along with consultants that are consistent with industry practice for similar p... |
Quality Program During the conduct of the activities under the Initial Development Plan and Budget, Cugene will retain QA consultants to monitor the ongoing activities to ensure compliance with SOPs and relevant regulations: Code of Federal Regulations (CFR) Title 21, Part 210: Current Good Manufacturing Practice CFR T... |
Responsibility Matrix |
Party for execution of activities Advisory |
IND 152972 Sponsor Cugene |
CMC AbbVie (on Items identified below) |
1. DS/DP Process and Formulation Development Cugene (subcontracted to WuXi) AbbVie |
2. DS Manufacture (GLP and GMP batches) Cugene (subcontracted to WuXi) AbbVie |
3. DP Manufacture (GLP and GMP batches) Cugene (subcontracted to WuXi) AbbVie |
4. DS/DP Analytical method development, product characterization and stability testing. Cugene (subcontracted to WuXi) AbbVie |
5. Fill/Finish; NOTE: a formal RFP process will happen to select the DP CMO Cugene (to be subcontracted in accordance with the Agreement and operating under cGMP conditions) |
6. GMP Write-up IND Cugene (subcontracted to WuXi) AbbVie |
Toxicology Cugene (may be subcontracted to CRO) AbbVie (on Items identified below) |
1. Protocol Development Cugene (may be subcontracted to CRO) AbbVie |
2. Assay Development Cugene (may be subcontracted to CRO) AbbVie |
a. Product identification b. TK assay in NHP matrix c. Anti-drug IL-2 mutein Fc |
3. 6-month GLP toxicology study Cugene (may be subcontracted to CRO) AbbVie |
a. Supplemental toxicokinetic report b. GLP write up to file to IND |
4. QA Cugene (may be subcontracted to CRO) |
Clinical Cugene (subcontracted to CROs) |
1. Conduct of Phase Ia Clinical Trial SAD in HV Cugene (subcontracted to IQVIA) |
2. Develop, validate and perform PK, ADA, nAb assays Cugene (subcontracted to Labcorp) |
3. Plan and execute Phase Ia Clinical Trial Cugene (subcontracted to IQVIA & Altasciences) |
a. Write protocol and file to IND b. CRF c. SAP d. Database construction e. Obtain IRB approvals f. Enrollment g. Data collection h. Safety analysis i. Pharmacovigilance/SAE reporting j. PK analysis and report k. ADA analysis and report l. PD analysis and report m. Write and approve CSR, file to IND n. CQA |
4. Plan and execute ePoC MAD Phase Ib Clinical Trial in SLE Cugene (to be subcontracted to CROs) AbbVie (on Items identified below) |
a. Convene DRC, CAB, SAB on SLE b. Write protocol and/or amend to IND AbbVie c. Select vendors supporting study procedures and assessments CRO AbbVie d. CRF e. SAP f. Database construction g. Select clinical sites AbbVie h. Obtain IRB approvals i. Enrollment j. Data collection k. Safety analysis l. Efficacy analysis m.... |
5. Final Data Package Cugene AbbVie |
6. Business and Operational Plan Cugene |
7. Quality Program Cugene |
All references to an approval by the Joint Governance Committee shall mean an approval by the Joint Governance Committee pursuant to the terms of the Agreement. |
II. DEVELOPMENT PLAN |
A. Clinical Plan for SAD Phase Ia Clinical Trial and ePoC MAD Phase Ib Clinical Trial |
(To be discussed and approved by the Joint Governance Committee.) |
The following are the Clinical Studies contemplated by the Parties for successful Development of CUG252 for the treatment of SLE through ePoC. |
A placebo-controlled, double-blind randomized SAD Phase Ia Clinical Trial of CUG252 in adult healthy volunteers (18-65 years old) will be conducted. The SAD Clinical Study will assess the safety, tolerability, pharmacokinetics, pharmacodynamics of single-dose of SC of CUG252. A maximum of 6 SC dose levels (with 6 subje... |
The placebo-controlled, double-blind randomized ePoC MAD Phase Ib Clinical Trial is a dose escalation study that would assess the safety, tolerability, pharmacokinetics, pharmacodynamics of multiple doses of SC of CUG252 in adult patients (age range to be reviewed with AbbVie) with rheumatologist-confirmed diagnosis of... |
Safety would be evaluated and will include evaluation of adverse events, physical examinations, vital signs, ECGs, immunogenicity, and safety laboratory parameters. The Clinical Study would be monitored by a Safety Data Review Committee (DRC) that includes AbbVie participation. |
The aforementioned Clinical Study narrative is shown diagrammatically as follows: |
[Chart described but not fully visible in text form] |
Key study objectives, activities and timeline are listed as follows: |
Item Clinical Objectives (Responsibility-Cugene) Activities Timeline |
1 SAD Phase Ia Clinical Trial in HV Cugene will conduct the SAD Phase Ia Clinical Trial, in accordance with the protocol submitted as part of the IND. A summary of such protocol is set forth in this Item below. - Establish safety and tolerability - Characterize PK and ADA profile - Evaluate pharmacodynamic (PD) and det... |
2 ePoC MAD Phase Ib Clinical Trial in SLE patients Cugene will conduct the ePoC MAD Phase Ib Clinical Trial in accordance with the protocol submitted and/or as an update to the IND. A summary of such protocol is set forth in this Item below. - Establish safety and tolerability - Explore the ePoC of the administered dos... |
3 Review MAD Eligibility Criteria with AbbVie Review eligibility criteria for ePoC MAD Phase Ib Clinical Trial to ensure enrollment of the correct patient population (i.e., age upon entry, active SLE not required, SLEDAI/CLASI, history of VTE) Prior to Initiation of ePoC MAD Phase Ib Clinical Trial |
4 DRC Charter Provide a copy of the SAD/MAD DRC Charter After the Effective Date |
5 Clinical PK & Pharmacology Deliverable Assessment of single-dose and multiple-dose PK Dose selection based on PK, biomarker data and acceptable safety in terms of injection-site reactions, infections and immunogenicity including hypersensitivity reactions prior to ePoC as well as for Phase II Clinical Trial During Ph... |
B. Development of Pharmacodynamic (PD) Markers to End of Phase Ib Clinical Trial |
PD markers that will confirm the hypothesized selective expansion of high affinity IL-2 receptor expressing CD4 Regulatory T (Treg) immune cells relative to immune subsets that are dependent on IL-2 signaling through the intermediate affinity IL-2 receptor (e.g., CD4 and CD8 effector, NK cells) will be explored in the ... |
To the extent permitted under the relevant ICFs and study protocol and in compliance with Applicable Laws, Cugene, through its contractors, will isolate PBMC or collect whole blood samples from consenting patients at selective timepoints in the Phase Ib Clinical Trial. Samples will be frozen appropriately for future MO... |
Item Translational Medicine / Biomarker Objectives Activities Timeline |
1 Immuno-monitoring Longitudinal numbers of major leukocyte populations (including eosinophils) in HV by differential CBC Longitudinal numbers of blood T, B, and NK cells in HV using FACS (percentages and cell counts), performed at Labcorp using validated methods Prior to Initiation of ePoC MAD Phase Ib Clinical Trial |
2 Longitudinal numbers of major leukocyte populations (including eosinophils) in SLE patients by differential CBC Longitudinal numbers of blood T, B, and NK cells, in SLE patients using FACS, performed at Labcorp using validated methods Completion of ePoC MAD Phase Ib Clinical Trial |
3 Target engagement / proximal PD Monitoring of percentages and cell counts of CD4+FoxP3+/CD25high/CD127low Tregs relative to intermediate affinity IL-2 receptor expressing immune cells using FACS, performed at Labcorp using validated methods Characterized method for measurement of soluble CD25 IL-2R in serum, includin... |
4 Longitudinal numbers of circulating Tregs in HV exposed to CUG252 or PBO (SAD) using FACS, performed at Labcorp using validated methods Longitudinal quantitation of soluble CD25 IL-2R in HV exposed to CUG252 or PBO (SAD) Prior to Initiation of ePoC MAD Phase Ib Clinical Trial |
5 Longitudinal numbers of circulating Tregs in SLE Patients exposed to CUG252 or PBO (PoC) Longitudinal quantitation of soluble CD25 IL-2R in SLE Patients exposed to CUG252 or PBO (PoC) Completion of ePoC MAD Phase Ib Clinical Trial |
6 PD effects: Treg/Tconv Longitudinal ratios of total Treg/Tconv in HV in blood, using FACS, performed at Labcorp using validated methods Prior to Initiation of ePoC MAD Phase Ib Clinical Trial |
7 Longitudinal ratios of total Treg/Tconv in SLE patient blood, using FACS, performed at LabCorp or equivalent lab using validated methods Completion of ePoC MAD Phase Ib Clinical Trial |
8 To the extent permitted by applicable ICF and study protocol, collecting, aadditional Biomarkers samples for the exploration of CUG252 MoA in consenting SLE patients Availability of serum samples from consenting HVs exposed to CUG252 or PBO Prior to Initation of ePoC MAD Phase Ib Clinical Trial |
9 Availability of serum samples from consenting SLE patients exposed to CUG252 or PBO (PoC) at selective timepoints Completion of ePoC MAD Phase Ib Clinical Trial |
10 Availability of WB in Proteomic Stabilizer from consenting SLE patients at selective timepoint exposed to CUG252 or PBO (PoC) Completion of ePoC MAD Phase Ib Clinical Trial |
11 Availability of cryopreserved PBMCs samples from consenting SLE patients at selective timepoints exposed to CUG252 or PBO (PoC) Completion of ePoC MAD Phase Ib Clinical Trial |
C. Initial CMC Activities |
The overall objective of the CMC activities is to evaluate the feasibility of a lyophilized drug product presentation as a clinical service form in support of the global Phase II Clinical Trial. In order to derisk the program and to support the clinical timeline focus of the CMC Development, work should be to: |
address the observed aggregation propensity of the molecule, |
use the current DS inventory for formulation work, |
stay as closely as possible to the current formulation matrix, and |
leverage historical Phase I formulation development data. |
In addition, sufficient DS supplies in the existing formulation should be provided to support non-clinical activities (26-week GLP long term Cyno tox, Cyno PK). |
Development work |
Cugene will perform a feasibility study to identify a lyophilized formulation of DP that may be suitable for initiation of subcutaneous injections of the recommended Phase II Clinical Trial dose. |
Item CMC Objectives and Notes (Responsibility-Cugene) Activities Timeline |
1 CMC Working Group A CMC subteam will be formed by the Joint Governance Committee to discuss project updates, deliverables, and future plans. The CMC subteam will meet at least once per quarter. Discussion, agreements and next steps will be documented through meeting minutes. Upon formation of the Joint Governance Com... |
2 Phase II Clinical Trial enabling lyophilization formulation identification (active/placebo); Formulation development to target a lyophilized dosage form at 1 mg protein/vial sufficiently stable at 2-8°C to support global Phase II Clinical Trials Perform a formulation screening using the current deep frozen Phase I Cl... |
3 Lyophilization process development; Select one lead and back up formulation and perform lyophilization experiments to identify a Phase II Clinical Trial appropriate lyo process Evaluate appearance of lyo cake and reconstituted solution, reconstitution time, residual moisture content, visible/subvisible particle load,... |
4 Stability, comparability, analytical work; Evaluate stability of both formulations using the selected lyo process for 1 month (at least 5 time points) at 2-8°C, 25°C and 40°C by SEC, visible and subvisible particles, iCIEF Select lead formulation and manufacture a suffcient amount of vials to perform a confirmatory s... |
5 GMP manufacture of Phase IIa Clinical Trial enabling drug product and placebo Transfer lyoprocess/product into a GMP facility at a reasonable scale to support global Phase II Clinical Trials according to the clinical development plan Manufacture a GMP lyo batch in support of Phase II Clinical Trial GMP DP Fill (inclu... |
6 Regulatory supporting document transfer Verified data and reports as needed to support IND, IMPD, BLA to be provided by Cugene to AbbVie Including, but not limited to data and reports supporting: - Cell line development - MCB/WCB manufacture and characterization - DS/DP Process development reports - Viral Clearance s... |
7 Manufacturing Technology Transfer to AbbVie or AbbVie's selected CDMO(s) Upon AbbVie's request, Cugene will perform a Manufacturing Technology Transfer after the License Option Effective Date in accordance with the Agreement, including as follows: - Coordinate 3-way CDA with Cugene's manufacturing, testing, storage, ... |
8 Quality Tasks AbbVie/Cugene - If AbbVie requires Cugene to supply requirements of CUG252, Licensed Products containing CUG252 as the sole active ingredient and placebos, the Parties will establish quality agreement to enable Cugene to supply such requirements for conduct by AbbVie of Phase II Clinical Trials Within 2... |
9 Post-License Option Effective Date support from Cugene If required by AbbVie and in accordance with the Agreement, Cugene will provide support for AbbVie to manufacture, test, and release sufficient quantities of Cugene clinical drug supplies to initiate Phase II Clinical Trials until such time as AbbVie sourced drug... |
10 Manufacturing Initial Development Activities, know-how transfer If Manufacturing Technology Transfer to AbbVie or AbbVie's selected CDMO(s) has not yet been initiated, prior to the License Option Effective Date and as jointly agreed upon, the Parties will engage in preparing for transfer of CMC activities - Cugene w... |
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