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Drug Product & Analytical • Manufacture and testing of GMP Clinical supplies for Phase 2/OLE including placebo • Selection of Ph3/commercial manufacturer as approved by the JDC • Transfer and Scale up of drug product process • DP Analytical methods optimization & validation • In Use compatibility/Stability • DP methods... |
Clinical supply package/Distribution: • Package/label and distribution of clinical supplies • Qualification of shipment in conjunction with stability data |
Regulatory documentation: • Regulatory CTD documents • IMPD, IND and CTN updates • Briefing books and other Agency SA documents • Investigator Brochure sections |
** Activities that start pre opt-in and continue post opt-in |
NOTE: The pre opt-in budget will cover all activities including those designated by **. AbbVie activities post-opt in are provided in the Post-Opt in Development Plan Schedule. |
Pre-Exercise Estimated Budget |
Based on the proposed study design, Licensor estimates the following pre-exercise development plan budget. These are preliminary budgets based upon current estimates and projections. These may be subject to change as more information and learnings emerge from the two programs and be adjusted in accordance with the term... |
AL002 PROGRAM (TREM2) Cost by Phase / Activity USD ($ Million) |
Year 2017 2018 2019 2020 2021 2022 2023 Pre-Clinical & Research 1.1 2.1 1.7 1.8 1.9 1.9 - Phase I - 1.1 2.4 - - - - Phase II (PoC) - - 5.5 9.0 18.0 29.0 - CMC-1 (pre-opt in activities) 1.0 7.0 4.6 2.8 5.0 5.0 - CMC-2 (** Activities that start pre opt-in and continue post opt-in) 1.5 .750 .750 Grand Total ($103.9 Millio... |
AL003 PROGRAM (CD33) Cost by Phase / Activity USD ($ Million) |
Year 2017 2018 2019 2020 2021 2022 2023 Pre-Clinical & Research 1.0 2.1 1.7 1.8 1.9 1.9 - Phase I - 1.1 1.6 0.8 - - - Phase II (PoC) - - 3.5 9.0 19.0 29.0 - CMC-1 (pre-opt-in activities) 1.2 6.1 3.8 4.3 7.0 7.0 - CMC-2 (** Activities that start pre opt-in and continue post opt-in) 1.5 .750 .750 Grand Total ($106.8 Mill... |
Cost Estimation Key Assumptions: • Cost estimates are based on Licensor's estimates to conduct work as detailed in preclinical and clinical development plan (Phase 1 and Phase 2). • Cost also includes CMC – drug substance and drug product manufacture and transfer • Costs include Initial supply of DS and DP for Phase 3 ... |
Phase 2 / OPEN LABEL EXTENSION STUDY |
For both TREM2 and CD33 programs, study will also include an open-label extension (OLE) to evaluate the long-term safety and tolerability to be offered to eligible patients who have participated in and completed the treatment period of the Phase 2. Below are assumptions for the open label extension studies: |
• Total patients: 190 (Approx. 71% of the patients from the Phase 2 study) o Assume 85% complete Phase 2 across all dose cohorts, and 85% roll over in to the extension study. • All patients in the OLE will be dosed at the highest Phase 2 dose, i.e., the patients from the lower dose arms (and placebo) will receive the h... |
Unless otherwise agreed by the JDC, the only required portion of the OLE studies to be conducted is for one year following completion of the Phase II Study. |
Estimated Budget: Phase 2 / OPEN LABEL EXTENSION STUDIES |
• High level fully burdened cost estimate for the study is about $35.5M. o This includes CMC estimates assuming we will be going to a 10,000L scale with at least 2 runs to support the patients being treated in the open label study • Assume CMC costs to begin when phase 2 dose is determined from the Phase 1 study. • Bel... |
OLE COSTS: AL002 & AL003 PROGRAMS EACH Cost by Phase / Activity USD ($ Million) 2021 2022 2023 2024 |
Phase 2 Open label extension 5.0 10.0 10.5 CMC 5.0 5.0 - - Grand Total ($35.5 Million) |
Drug Substance (DS) & Drug Product (DP) Scale up and Transfer Requirements |
CMC Requirements at Opt-in: |
Licensor will conduct the defined development activities prior to Opt-in to ensure that Phase 3 supplies, representative of the proposed commercial processes for DS and DP, are available for the initiation of Phase 3, according to the Clinical Development Plan (1Q 2023). |
Transfer Requirements: |
To ensure both the quality and quantity of both clinical and commercial supply, the following drug substance and drug product scale up and transfer plan will be used. The supplier selection and transfer will occur in a timely fashion to support a smooth transition of suppliers to guarantee an uninterrupted supply of cl... |
TREM 2: AL002 Pre-clinical and clinical suppliers Commercial suppliers |
Pre-clinical FIH /Ph 1 Ph 2 Ph 3 Launch Year 2017- 2018 2019- 2020 2021-2022 2023 2028 DS site 1 Lonza Lonza 1000 L Lonza 10,000 L Lonza 10,000L Lonza 10,000 L DS site 2 Second site Second site DP Clinical Baccinex Baccinex DP Commercial TBD TBD TBD |
CD33: AL003 Pre-clinical and clinical suppliers Commercial suppliers |
Pre-clinical Tox /FIH / Ph1 Ph 2 Ph 3 Launch Year 2017-2018 2019-2020 2021-2022 2023 2028 DS site 1 Celonic 200L Celonic 1000 L DS Commercial site CMO Site and scale change CMO & Second site CMO & Second site DP Clinical Halix Halix DP Commercial TBD TBD TBD |
TREM 2 CD33 TREM 2: DS Scale up (stays @ Lonza) CD33: DS Scale up and site transfer (Ph 2 through launch) TREM 2: DP Transfer CD33: DP Transfer TREM 2: DS Second site transfer* CD33: DS Second site transfer* |
The foregoing transfer is based on the following: • Celonic is not a commercial DS manufacturer and another CMO will be needed to support Ph 2 and beyond • Baccinex and Halix are not commercial DP manufacturers and other CMOs will be needed to support Ph 2 and beyond • Commercial supplier evaluation and selection will ... |
Tech transfer for DS: • 4 mon. (min.) site search/finalization • 3 mon. contract negotiation • 6 mon. transfer time |
Tech transfer for DP: • 4 mon. (min.) site search/finalization • 3 mon. contract negotiation • 6 mon. transfer time |
Schedule 3.1.3 |
PoC Trial Report Requirements |
Clinical Data Package |
For Phase 1 (to the extent applicable) and Phase 2 (interim analysis I, II or any additional interim analysis performed, and final analysis), the trial report requirements include the following: |
A. Finalized statistical analysis plan and Data Monitoring Committee charter. |
B. Table(s) of key clinical data provided in a MS Word or pdf format of SAS outputs including (but not limited to) the following, as specified in the trial protocol and statistical analysis plan: |
1. Final table and patient level data (data listings) for patient demographics, baseline characteristics and patient dispositions 2. Final tables and patient level data (data listings) for endpoints / efficacy parameters measured including CDR-SOB, COGN (cognitive endpoints) and other efficacy endpoints 3. Summary tabl... |
C. Access to Raw Data 1. Case report forms and database specification 2. SAS datasets and defined files for all the variables listed in Section B above. |
D. Quality assurance Considerations Quality Assurance Plan for the Phase 1 and Phase II trials, together with any findings with respect to the results described in B and C above based on the Quality Assurance Plan. |
For clarity, the ninety (90) day period that determines the end of the Option Period will not commence until all of the above and any other items expressly required to be included in the PoC Trial Report (as specified in the definition of PoC Trial Report in Section 3.1.3) are provided to AbbVie. |
Schedule 3.2.1 |
Initial Post Exercise Development Plan and Budget |
Phase 3 Planning Assumptions |
Both AL002 and AL003 programs are being advanced as potential disease modifying approaches for delaying the progression of disease in patients with prodromal and mild Alzheimer's disease (Early AD"). The target product profile and efficacy endpoint(s) used in the Phase 3 study will be determined by the JDC taking into ... |
The Phase 3 study should be designed to collect sufficient data for regulatory approval in the desired indication. In addition, the Phase 3 clinical development should generate data for other stakeholders (e.g., payers, physicians) to ensure a competitive and differentiated product at the time of launch. |
Based on current projections, a Phase 3 total sample size of n = 2000 (for 2 pivotal studies) is required, but the actual sample size will be adjusted based on the observed effect size and safety profile in Phase 2; and the target product profile. |
Phase 3 Clinical Development Plan: Powering Assumptions • Treatment duration: 104 weeks • Drop-out rate 35% • Placebo decline in CDR-SOB over 104 weeks: 2.6 ± 3.1 (CV = 119%) • 1:1 randomization; ⍺ = 0.05 |
Patients needed per arm to demonstrate % treatment effect at β of 0.8 and 0.9: |
Two arm study with ~500 subjects per arm (total of 1000 subjects) has ~90% power to detect treatment effect of 30% on the primary endpoint (CDR-SOB) and would be adequately powered for key secondary outcomes (e.g., FAQ, RBANS) considering multiplicity. |
Phase 3 Key assumptions for time line estimates • 2,000 subjects (1,000 per study) • Both studies run in parallel • Total number of sites ~380. No or minimal overlap of sites to avoid competition between the two studies • Enrollment rate: 0.25 pts/site/month enrollment • 20 months enrollment • 24 months treatment • Tot... |
AL002: Estimated Timelines for approval for AD indication* |
*Timelines are based on current high level estimates and will be adjusted as additional information becomes available. |
AL003: Estimated Timelines for approval for AD indication* |
*Timelines are based on current high level estimates and will be adjusted as additional information becomes available. |
CMC ACTIVITIES |
CMC Activities – Phase 3 through submission (Post opt-in Activities to be completed by AbbVie & Activities that start pre opt-in and continue post opt-in are noted below) |
Key activities and Deliverables: |
Drug Substance & Analytical • DS stability** • Reference standard stability** • Process Characterization and Justification (acceptable operating ranges, identification & qualification of impurities/degradation products)* • DS Process Validation* • DS Registration Stability from Validation* |
Drug Product & Analytical • DP stability** • Final DP Process justification, process range studies* • DP Process Validation* • DP Stability from Validation* • DP Process Validation at Commercial site* |
Clinical supply package/Distribution: • Validation of shippers and shipping conditions* |
__________________ * Post-opt-in activity to be completed by AbbVie ** Activities that start pre opt-in and continue post opt-in |
Post- Exercise Estimated Budget |
Based on the proposed Phase 3 study design, AbbVie estimates the following post-exercise development plan budget for each program. These are preliminary budgets based upon current estimates and projections. These may subject to change as more information and learnings emerge from the two programs and be adjusted in acc... |
Cost Estimation Key Assumptions: • Estimate is for one mAb asset only • Option Exercise assumed to occur in 2H 2022 for both programs |
*The budget reflected in 2022 for AbbVie - 7.1 USD $ Million- includes estimated lot charges of $4.639 USD $Million |
ABBVIE Post - Exercise Estimated Budget USD ($ Million)" |
Total R&D Cost by Phase (Internal+External) 2022 2023 2024 2025 2026 2027 2028 2029 2031 Total |
Pre-Clinical ... ... ... ... ... ... ... ... ... ... Phase I ... 2.9 ... ... ... ... ... ... ... 2.9 Phase II 28.4 13.5 ... ... ... ... ... ... 42.0 Phase III 3.4 57.0 65.6 99.8 124.2 85.9 58.6 9.8 ... 504.3 Registration 0.4 0.4 0.4 0.4 8.1 ... ... ... 9.5 Ph IV ... ... ... ... ... ... ... ... ... CMC 7.1* 17.3 25.4 40... |
Schedule 3.3.2 |
Antibody Approved for Additional Licensor Development Activities |
CD33 |
1. 6C7-3m24 |
Schedule 3.5.5 |
Pre-Approved Subcontractors |
CLINICAL CROs: 1. Quintiles 2. PPD 3. Covance 4. PRA |
Schedule 5.7.1 |
Example Calculations of Third Party Payment Responsibilities |
If Net Sales are $1,000,000 in the US and $500,000 in the ROW and a royalty of 3% is owed to a Third Party under an Existing License Agreement, (and assuming a royalty of 20% is owed by AbbVie to Licensor in Example 2 below), then the following illustrates how such payment shall be made and reimbursed: |
Example 1. Following AbbVie's exercise of its Option for the Collaboration Program for which such Existing In-License Agreement applies, if Licensor has not exercised a Licensor Opt-Out with respect to such Collaboration Program, then: • Licensor shall pay to the Third Party the sum of $45,000 (3% of $1,500,000); • Lic... |
Example 2. Following AbbVie's exercise of its Option for the Collaboration Program for which such Existing In-License Agreement applies, if Licensor has exercised a Licensor Opt-Out with respect to such Collaboration Program, then: • Licensor shall pay to the Third Party the sum of $45,000 (3% of $1,500,000); • AbbVie ... |
Schedule 6.4.4 |
FTE Rates |
$US 425,000 for employees performing discovery and research work; |
$US 375,000 for employees performing Development activities (other than discovery and research); |
$US 375,000 for employees performing Commercialization activities. |
Schedule 7.6.5 |
Existing In-License Agreement Obligations |
AbbVie agrees that the Agreement is subject the obligations set forth below in Part I, for the Adimab Agreement, and Part II, for the Lonza Agreement. Further, it agrees that AbbVie's rights set forth in Sections 7.2, 7.3 and 7.5 shall not apply with respect to Patents comprising Non-Exclusive Licensor Technology (as d... |
Part I: Adimab Agreement. |
1. Progress Reports. AbbVie will provide Licensor annually with a written report summarizing progress in the Development and Commercialization of Licensed Products, and AbbVie's and its Affiliates' significant activities in that regard, for each of CD33 and TREM2, and provide such information as is necessary for Licens... |
2. Audits. AbbVie agrees that Licensor may disclose to Adimab, under conditions of confidentiality, the information set forth in Section 6.13 provided by the accounting firm, to the extent related to the rights granted under the Adimab Agreement and sublicensed to AbbVie under this Agreement (the "Adimab License") or a... |
3. Prosecution. AbbVie agrees that in the event AbbVie exercises its backup prosecution rights set forth in Section 7.2 with respect to any Patent generated under the Adimab Agreement, it will provide Adimab a reasonable opportunity to review and comment on drafts of any material filings or responses to be made to appl... |
4. Enforcement. In the event that AbbVie requests the cooperation of Adimab in any claim, suit, or proceeding set forth in Section 7.3, 7.4 or 7.5, including being joined as a party plaintiff if necessary to obtain standing for such action, the reasonable costs for such Adimab cooperation shall be deemed Out-of-Pocket ... |
5. Recovery. In the event that Licensor has not exercised a Licensor Opt Out with respect to the applicable Collaboration Program, AbbVie agrees that twenty-five percent (25%) of the remainder of any recovery realized from any action by or on behalf of a Party to enforce a Patent within the Adimab License against infri... |
6. Third-Party Beneficiary. To the extent required by Section 3.3 of the Adimab Agreement, Adimab is an intended third party beneficiary of Section 5.7.1 of the Agreement with respect to royalty payments owed to Adimab under the Adimab Agreement; provided however, that in no event shall Adimab's consent be required for... |
Part II: Lonza Agreement. |
1. Manufacturing Process Transfer. The Lonza manufacturing process for Licensed Antibodies directed to CD33 shall not be transferred to facilities located in Korea, China or India. |
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