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Clinical Ann Eldred Gabriela Alperovich |
PVG Thao Doan |
CPPM Ahmed Nader |
CMC John Morris, Alane Wentz, Hans-Juergen Krause |
Development Sciences Kennan Marsh |
Biologics Blaine Stine, Jane Segal |
Regulatory Lee Muraoka |
Biomarker Plan Heath Guay |
Phase II SLE Clinical Study The following base case 12-week SLE study and optional amended 24-week SLE study Gantts describe the key clinical, pre-clinical, and CMC activities that shall be performed as part of Development Activities as described in the Agreement. Capitalized terms not defined herein shall have the mea... |
MONTHLY UPDATES On a monthly basis during the period during which Licensor is performing Development Activities, Licensor shall provide to AbbVie, and make the relevant experts reasonably available to discuss, the following: |
• Program conduct and metrics (e.g., if clinical: recruitment) • Data metrics (for e.g., if clinical: clinical data, follow-up visits and patient dispositions, open queries, forms completed, SDV done, forms locked) • Raw (unmonitored) data, including: Safety and efficacy clinical data (Tables and listings) PK, ADA, nAb... |
Any new regulatory information with Regulatory Authorities and intellectual property |
For each month, the monthly Information required to be delivered as provided herein, collectively, the "Monthly Update." |
ELEMENTS OF READINESS PLAN Licensor shall provide an operational plan that must contain all of the elements to demonstrate that Licensor shall have adequate resources and expertise to execute the Development Plan. This must include: |
a. Profiles of staff and hiring profiles of needed staff along with consultants that are consistent with standard industry practice for similar preclinical and clinical representative positions for a program at this stage of development; |
b. Have reasonably detailed timelines and budgets (including FTE-based staffing costs) that demonstrate completion of the Development Activities along the timelines agreed to by the Parties; |
c. Licensor shall provide Abbvie access to Training, SOP and Quality information systems documentation to review. This review shall also include an on-site review. Abbvie shall give Licensor 5 working days' notice before the documents would be made available. Review to also include access to individuals responsible for... |
d. CRO proposals outlining study objectives, plans and deliverables. |
NEW SECTION DEVELOPMENT PLAN (continued) |
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. |
CLINICAL |
(A living document to be discussed and approved by the Joint Governance Committee.) |
The following are the Clinical Studies contemplated by the Parties for successful Development of ALPN-101 for the treatment of SLE through Phase II proof of concept. The Parties agree and acknowledge the final Clinical Studies and the final design of such Clinical Studies shall ensure compliance with the minimum requir... |
Placebo-controlled, double-blind randomized study of ALPN-101 in adult patients (18-65 years) fulfilling the American College of Rheumatology (ACR 1997) criteria for SLE for at least 6 months, OR meeting at least 4 of the 2012 SLICC classification criteria, including at least 1 clinical criterion and 1 immunologic crit... |
Key exclusion criteria are listed as follows: Must not have active lupus nephritis (Class IV or Class III or >0.5g/d proteinuria) or have undergone induction therapy within the last 6 months (final renal exclusion shall be discussed and approved by the Joint Governance Committee) CKD-EPI lupus-related neurologic proble... |
or prior exposure within 3 month to anti-interferon therapies. Additional exclusion criteria shall be discussed and approved by the Joint Governance Committee. |
The study would evaluate single ALPN-101 dose level that shall represent an anticipated effect dose based on PK/PD modeling of ALPN-101 relative to PBO exposure in humans and within the safety exposure allowed for ALPN-101. ALPN-101 and placebo would be administered by IV dosing in a parallel design, max n=65 subjects ... |
An initial interim efficacy assessment could occur week 12 and would be based on unblinded evaluation of efficacy and safety signals. The Primary endpoint is SLE Responder Index-4 (SRI-4). The CRO teams responsible for the study conduct shall remain blinded to the study data. Secondary endpoints would include evaluatio... |
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 an Independent Data and Safety Monitoring Board (DSMB). Important safety information eg. SUSARs pertinent to the study that ... |
A Schematic outline of the base 12-week SLE study with key parameters/considerations |
A Schematic outline of the amended 24-week SLE study with key parameters/considerations |
CLINICAL DEVELOPMENT ACTIVITIES |
Item Clinical Deliverable/responsible party Activities Timeline |
1 Phase IIa Clinical Study First Cohort (Week 12 Endpoint [AO3]) Licensor shall conduct the Phase IIa SLE Clinical Study in accordance with the protocol as submitted with IND and within 30 days of FDA notice to proceed. A summary of such protocol is set forth in this item below. - Establish safety and tolerability as m... |
determined by the primary ans key secondary endpoints noted in the protocol, including but not limited to: SRI-4 BICLA LLDAS SLEDAI-2K BILAG 2004 SLENA SLEDAI Flare Index Steroid burden assessed as change from baseline PGA - Characterize PK and ADA profile Determine preliminary efficacy and exposure-response relationsh... |
An interim analysis could occur after the completion of the 6-month GLP tox in cynomologus monkeys and the human PK study with the new subcutaneous formulation if available The interim analysis could lead to amendment of the Phase IIa protocol to include the new formulation, extend the Endpoint to Week 24, and reassess... |
2 Interim PK and exposure-response analyses for Phase IIa Clinical Study First Cohort (Week 12 Endpoint [AO3]) AbbVie Unblinded assessment of PK, ADA, and exposure-response relationship for efficacy and/or safety endpoints. Starts 12 weeks prior to interim database lock for interim efficacy analysis and completes in pa... |
efficacy analysis |
3 Phase IIa Clinical Study Second Cohort (Week 24 Endpoint [AO3a]) If approved by the JGC, the Parties shall cooperate to amend the Development Plan to include an amendment to the protocol for the Second Cohort. AbbVie shall provide data and expertise necessary to support ALPN-101 components of protocol. Licensor shall... |
4 Evaluate target engagement to inform PK-PD Target (combined CD28-ICOS) saturation on T-cells - In conjunction with development of Phase IIa Clinical Study protocol, Joint Governance Committee to determine best way to confirm saturation on T or other cells and incorporate into study as appropriate Concurrent Phase IIa... |
4 Explore changes in biologic activities that may reflect MOA in peripheral blood Absolute counts of CD4, CD8, monocytes, and NK (e.g., Trucount TBNKMo) IgG, IgM, C3, C4, ANA, anti-dsDNA)* Numbers/frequencies of plasmablasts, T follicular helper cells, Th1, Th2 and Th17 cells -, PBMC's, DNA paxgene, RNA paxgene, serum ... |
SC FORMULATION BRIDGING BIOAVAILABILITY STUDY (THE "BRIDGING STUDY") |
Objective: Evaluate relative bioavailability (for clarity, bioequivalence is not sought) of the new high concentration SC formulation to replace the initial formulation used in the 12-Week Phase IIa SLE Clinical Study. |
Impact: The proposed plan and timing would enable introduction of the new SC formulation in subsequent Phase IIb/III SLE studies and mitigate the need for larger BE studies later in development to meet regulatory requirements. The new SC formulation could be introduced in the 24-Week cohorts of the Phase IIa SLE Clinic... |
Item CPPM Deliverable/responsible party Activities Timeline |
1 Randomized open-label single dose parallel-design study in healthy volunteers (N=approx. 60 subjects) Licensor Subjects shall be randomized to receive the IV formulation used in the 12-Week Phase IIa SLE study or the new high concentration SC formulation Assessment and comparison of PK and immunogenicity between the ... |
Target product profile high concentration formulation/presentation |
The new SC formulation planned for the A03a 24-week SLE study should have sufficient concentration and relative bioavailability to enable administering the clinically efficacious dose(s) in a single SC injection of < 1 mL with dosing no more frequently than once weekly. |
Target 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 representative container closure system Acceptable stability profile defined as R... |
CMC DEVELOPMENT PLAN ACTIVITIES |
(A living document to be discussed and approved by the CMC Working Group.) |
Outline |
Manufacture sufficient DS supplies in support of nonclinical activities o 6 month GLP cyno tox o Cyno pk o EFD/ePPD studies o Preformulation and formulation studies |
Develop a new high concentration formulation/presentation suitable for a single subcutaneous injection of the recommended Phase IIb dose to be used in the second Cohort of Phase IIa [AO3a]) |
Develop a controlled DS/DP manufacturing process to enable manufacture of GMP batches o DS: optimize titer and overall production yield, develop robust UF/DF process for new high concentration formulation o Perform preliminary scale up experiments |
Manufacture GMP DS and DP in support of Phase IIa Manufacture high concentration GMP DS and DP for amended Phase IIa (if applicable), human PK study and long-term ICH compliant DS and DP stability Manufacture/establish an adequate high concentration DS/DP inventory to cover Phase IIb study supply after opt-in (Late Pha... |
Analytical work packages ‐ Develop and qualify/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, specifically o Develop a CE-SDS method (reduced/non-reduced) (or equivalent) to replace SDS-PA... |
Provide plans for GMP analytical test method transfer incl. coordination with Third Party Laboratory and provision of necessary materials (critical reagents, bioassay cell bank, reference standards, retain samples for back lot testing/comparability/method bridging) |
Perform coverage assessment for HCP method |
Process development work Complete all cell line development and phase-appropriate genetic characterization studies, provide sufficient vials of MCB and WCB Completion of DS/DP process development studies to support the chosen dosage form and strength for Phase IIa/IIb Support transfer of drug substance and drug product... |
CMC Deliverable, Responsible Party and Notes Activities Timeline |
1 CMC Working Group A CMC Working Group shall be formed by the Joint Governance Committee to discuss project updates, deliverables, and future plans. - The CMC Working Group shall meet monthly. - Discussion, agreements and next steps shall be documented through meeting minutes. Promptly after formation of the Joint Gov... |
2 Cell Line/Licensor Reports for completed activities for cell line development, to include: - Cell line development including plasmid construction and history of the parental cell line - Clonal cell line generation - Cell line screening and selection - MCB production and characterization - MCB Certificate of Analysis ... |
3 Development of Phase I/II GMP manufacturing Process/Licensor Reports for completed activities, to include: - DS/DP manufacturing process development experiments to demonstrate what conditions/resins/parameters were evaluated that led to the Phase I/Ib GMP process - Manufacture and testing of Non-GMP batches (includin... |
4 Biophysical, and biological characterization of ALPN-101 reference standard, initial ALPN-101 GMP drug substance batch and ALPN-101 batch used for 6 mos GLP toxicology study/Licensor - perform side by side characterization of new hc reference standard, GMP drug substance/DP (low concentration), GMP DS and DP high con... |
heavy and light chains before and after enzymatic deglycosylation - Analytical ultracentrifugation and/or size exclusion chromatography with multiangle light scattering - Circular dichroism spectroscopy - Differential scanning calorimetry - CD28-ICOS inhibition activity - QC test methods for cation exchange HPLC, reduc... |
5 Quality control test Methods/Licensor Establish quality control (QC) test methods based on an assessment of critical quality attributes of ALPN-101 sufficient to enable manufacture, in-process testing, release, and stability evaluation of GMP drug substance and GMP drug product for clinical Phase II studies. - SOPs a... |
6 Quality control test Methods/Licensor Generate and qualify sufficient quantities of all critical assay reagents required for QC test methods (e.g., CD28-ICOS antigen for the binding CD28-ICOS binding ELISA) to support of Phase IIb/III until AbbVie sourced reagents are available. - Establish a qualified or validated (... |
7 Cell based bioassay Licensor Assay development plans and progress to be periodically (at least quarterly) reviewed and agreed to by AbbVie. Establish a validated, stability-indicating, cell-based bioassay for potency measurement that is reflective of the proposed mechanism of action of ALPN-101 and is suitable for re... |
8 Inhibition assay / Licensor Assay development plans and progress to be periodically (at least quarterly) reviewed and agreed to by AbbVie. Establish a validated, stability-indicating CD28-ICOS inhibition assay for potency measurement that is reflective of the proposed mechanism of action of ALPN-101 and is suitable f... |
9 Clinical supplies for Phase IIa/Licensor Manufacture of DS/DP for the entire Phase IIa Establish scale-up and manufacturing strategy to align with clinical demand projections for Phase IIa ‐ Retain and store at -80°C a minimum of 200 mL of the GLP toxicology study batch and each GMP DS/DP batch (DP 50 units) for futu... |
solution records for each GMP batch ‐ DS/DP CofAs for each GMP batch ‐ Storage of drug substance inventory ‐ Storage of drug product inventory ‐ Packaging and labeling of drug product ‐ Distribution of drug product to clinical sites ‐ Obtain and store GMP manufacturing reserve samples of each DS and DP lot per regulato... |
9b Clinical supplies for Phase IIb Licensor (Late Phase Development Activities) Manufacture of DS/DP for the entire Phase IIb (Late Phase Development Activities) Establish scale-up and manufacturing strategy to align with clinical demand projections for Phase IIb ‐ Retain and store at -80°C a minimum of 200 mL of the G... |
10 Commercial process optimization Licensor Determine if the current cell line can enable a commercial process. ‐ Confirm cell line stability is suitable for the number of generations needed at the projected commercial scale. ‐ Perform initial process optimization experiments with the curent cell line to enable a poten... |
11 DS/DP stability for Phase I-II Licensor Intended, accelerated, and stressed storage conditions to support stability dating and excursion justifications for DS/DP. ‐ DS/DP shelf-life assignments and extensions ‐ Monitor a minimum of 1 DS and 1 DP lot on stability per campaign or year. Test stability at the intended s... |
12 Charge variant characterization study Licensor Characterize the molecular structure, post-translational modifications, ALPN-101 binding activity, and CD28-ICOS inhibition activity of acidic, basic, and main charge variants of ALPN-101 as follows: ‐ Use ion-exchange chromatography to separate and collect the charge v... |
13 pH screening study and degradants studies Licensor Conduct a more expansive formulation pH screening study (pH 5.0, 5,5, 6,0, 6,5, 7,0) to confirm observed particulate and charge isoform trends ‐ Characterize structure, post-translational modifications, CD28-ICOS binding activity, and CD28-ICOS inhibition activity o... |
14 Regulatory supporting documents Licensor Verified data and reports as needed to support IND, IMPD, BLA to be provided by Licensor to AbbVie Including, but not limited to data and reports supporting: ‐ Cell line development ‐ MCB manufacture ‐ Process development ‐ Formulation development ‐ Dosage form development ‐ ... |
and/or characterize the primary structure, secondary structure, tertiary structure, post-translational modifications, aggregates, fragments, purity, impurities, CD28-ICOS binding properties, Fc receptor binding properties, and MOA-related functional activities of ALPN-101 ‐ Reference standard preparation and qualificat... |
15 Manufacturing Technology Transfer to AbbVie or AbbVie's selected CDMO(s) Licensor Upon AbbVie's request Licensor shall perform a Manufacturing Technology Transfer, including as follows: ‐ Coordinate 3-way CDA with Licensor's manufacturing, testing, storage, and drug supply (labeling/packaging/distribution) CDMO(s) ‐... |
Phase IIb/III studies ‐ Provide AbbVie with a sufficient supply of assay critical reagents to complete test method transfer, DS/DP process transfer, comparability testing, and manufacture GMP batches to supply Phase IIb/III studies ‐ Provide AbbVie with process summary reports, master batch records, process development... |
16 Quality Tasks AbbVie/Licensor Transition plans to be approved by Joint Governance Committee ‐ If AbbVie requires Licensor to supply requirements of lead Licensed Compound, lead Licensed Product and placebos, the Parties shall establish quality agreement to enable Licensor to supply such requirements for conduct by A... |
17 Post-License Option Effective Date support at Licensor If required by AbbVie, Manufacture, test, and release sufficient quantities of Licensor clinical drug supplies to initiate and support Phase IIb/III studies until such time as AbbVie sourced drug is available for use in clinical studies ‐ Supply analytical metho... |
18 Manufacturing Preparatory 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 Option Effective Date and as jointly agreed upon the Parties shall engage in preparing for transfer of CMC activities ‐ Licensor sha... |
NONCLINICAL ACTIVITIES |
(A living document to be discussed and approved by the Joint Governance Committee.) |
Nonclinical safety evaluation studies shall be performed. The currently available general toxicity package administered 10, 100 and 150 mg/kg/week SC doses and 150 mg/kg/week IV doses of ALPN-101 for 13-weeks (followed by a 8-weeks recovery period) in NHP, defining the 150 mg/kg/week dose as the NOAEL (both IV and SC).... |
The 26-week chronic toxicity studies shall be initiated in mature NHP, with doses and design selected based on data from the 13-week study in combination with feedback from the European Medicines Agency (EMA) (Scientific Advice) and the Food and Drug Administration (FDA) (pre-IND meeting) on the preclinical plans and t... |
A pharmacokinetic study (IV/SC single dose) in NHP shall assess the bioavailability and local tolerability of the SC formulation developed for clinical use. |
Segment 2 (embryofetal toxicity) and Segment 1 (fertility, in rats) of the reproductive toxicity program shall be completed prior to initiation of the Phase IIb study in the lowest feasible species. At this time, rabbit is anticipated to be the preferred species, assuming supportive cross-reactivity studies and alignme... |
1 26-wk GLP NHP tox Licensor is in the process of initiating a 6 mo NHP study at Alta Biosciences, the protocol for which AbbVie has had the opportunity to review. Final report available 6 months from the end of the inlife portion of the study. Report as MS Word, executed PDF versions, and SEND data sets. |
2 NHP PK Study IV vs. SC single dose PK study to assess bioavailability and local tolerability of clinical SC formulation. Minimal group size of 3, with sampling timepoints for at least 2 weeks after dosing. Assess PK, ADA and local tolerability. Report available 1 month from last sampling timepoint. |
3 Developmental Tox Studies DRF and GLP Developmental studies in NHP ± rabbit following administration of ALPN-101 to time mated animals through the defined period of gestation. Each study should contain 3 treatment and 1 control group; the high dose should be based on the results from prior GLP studies. - Study endpoi... |
fetal body weights or fetal external, visceral and skeletal examinations, PK, toxicokinetics and ADA. - Study to be conducted at an AALAC accredited, USDA and FDA inspected facility in USA or GLP certification required for EU facility; facility to have experience and robust historical control database. |
4 Fertility Tox Study (species TBD; rabbit or NHP) Fertility study in NHP or rabbit shall determine the toxic effect of ALPN-101 on female estrous cycle, tubal transport, implantation and development of pre- and post-implantation stages of the embryo, and detection of functional effects on male fertility. The high dose... |
5 BA method validation (rabbit) – if species deemed feasible Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation. Validation to be completed prior to initiation of the Developmental Tox studies Validation shall be completed before study initiation |
6 BA method validation (human) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Validation shall be completed before study initiation |
7 ADA method validation (human) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Validation shall be completed before study initiation |
8 nAb method validation (human) Validation in compliance with most recent FDA/EMA guidance documents on Bioanalytical Method Validation Validation shall be completed before study initiation |
Regulatory Affairs |
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