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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... |
Cugene shall be responsible for and shall bear all costs and expenses necessary to perform its obligations set forth above, provided that (a) Item 5 set forth above will be performed at AbbVie's cost and expense and (b) FTE costs and out-of-pocket costs incurred by Cugene related to Items 7 and 10 set forth above are s... |
If the Parties cannot mutually agree to activities where mutual agreement is stated, the matter is to be resolved pursuant to the Agreement. |
III. PRE-CLINICAL ACTIVITIES |
A. GLP Toxicology |
For Initiation of Phase II Clinical Trials, 26-week GLP toxicity studies will be conducted in NHP and mice (unless indicated otherwise by FDA). The GLP Toxicology Protocol will be developed at and approved by the JGC, subject to Section 6.2.4(b) of the Agreement. |
Item Objectives Activities Timeline |
1 26-wk GLP NHP tox (Responsibility-Cugene) Final GLP Toxicology Protocol to be developed and approved at JGC, consistent with the preliminary specifications below. Start date to be determined by JGC based on Clinical Study progression: - Reports as MS Word, executed PDF versions, and SEND data sets for: - Study conduc... |
26-wk GLP Mouse tox (Responsibility-Cugene) Final GLP Toxicology Protocol to be developed and approved at JGC, consistent with the preliminary specifications below. Start date to be determined by JGC based on Clinical Study progression: - Reports as MS Word, executed PDF versions, and SEND data sets for: - Study conduc... |
2 Immunosafety Assays (Responsibility-Cugene) Assays to include ADCC activity, C1Q binding, and cytokine release from PBMC Available reports due within 30 days following the Effective Date |
3 PK method validation (human) (Responsibility-Cugene) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Validation will be available before Initiation of Clinical Study and provided within 10 days of the receipt thereof |
4 ADA method validation (mice, NHP, human) (Responsibility-Cugene) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Reports in mice and NHP will be available before Initiation of Clinical Study and reports in human will be provided within 10 days of the receipt the... |
5 Neutralizing Ab method validation (human) (Responsibility-Cugene) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation To be ready/validated for Phase Ib Clinical Trial |
B. Regulatory Affairs |
Regulatory Authority submissions and consultations |
US |
An IND in SLE is open to allow enrollment of US subjects into the FIH, SAD Phase Ia Clinical Trial in HV and ePOC MAD Phase Ib Clinical Trial in SLE subjects. If any Regulatory Authority interactions are needed/requested during the conduct of the Initial Development Plan and Budget (i.e., before the planned Phase II Cl... |
Item Regulatory Deliverable (Responsibility-Cugene) Activities Target Timeline |
1 Transfer responsibilities and obligations of CUG252 IND 152972 Parties to discuss date of transfer and consider any on-going activities that may impact timing of transfer (i.e., clinical data, non-clinical, CMC activities) From and after the License Option Effective Date |
2 If needed, submit FDA (Type C) meeting (or Request for Advice) to seek feedback on development program requirements (i.e., non-clinical, CMC, clinical) |
IV. DATA PACKAGE |
A. Clinical |
The Clinical Study report for the Phase Ia Clinical Trial and ePoC MAD Phase Ib Clinical Trial as described in the USA FDA IND 152972 and outlined in Section II.A: |
• Clinical disease activity(from Phase Ib Clinical Trial only) and safety information |
• Pharmacokinetic data |
• Immunogenicity (ADA) data |
• Biomarker data |
• Bioanlytical and validation reports for PK and ADA |
B. Non-clinical 6M GLP toxicology reports for activities in Section III |
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