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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. |
2. License. In the event Licensor or AbbVie elects to use Licensed Antibody or Licensed Product manufactured with a cell line that uses Lonza's glutamine synthetase expression system ("GS") in Clinical Studies or any commercial use or sale of any Licensed Antibody or Licensed Product, a non-exclusive license to such GS... |
Schedule 10.2 |
Schedule of Exceptions |
Notwithstanding anything to the contrary herein, with respect Licensor Background Patents and/or Licensor Background Know-How, that are: |
1. licensed to Licensor non-exclusively by Adimab under Adimab Platform/Background Patents, Program Know-How and other Know-How transferred by Adimab to Licensor in the context of any Licensed Antibody as set forth in the Adimab Agreement (as such terms are defined therein); |
2. licensed to Licensor non-exclusively by Lonza under the New General Application Intellectual Property as set forth in the Lonza Agreement (as such term is defined therein); |
3. will be licensed to Licensor non-exclusively by Lonza under intellectual property (including patents and know-how) pertaining to GS controlled by Lonza and its Affiliates provided that Lonza and Licensor enter into the GS License as contemplated in the Lonza Agreement (as such terms are defined therein); |
4. licensed to Licensor non-exclusively by Celonic under the Licensed Celonic Existing Technology and Celonic Project Technology as set forth in the Celonic Agreement (as such terms are defined therein); or |
5. licensed non-exclusively and royalty free under other third-party agreements entered into in the standard course |
(collectively "Non-Exclusive Licensor Technology"), Licensor only represents that to Licensor's Knowledge the statements in Sections 10.2.6 and 10.2.23 are true and correct. For clarity, Patents within the Non-Exclusive Licensor Technology are Existing Patents and Existing Patents are deemed to include Patents within t... |
This Schedule of Exceptions is arranged in separate parts corresponding to the numbered subsections contained in the Agreement, however the information disclosed in any numbered part shall be deemed to relate to and to qualify not only the particular representation or warranty of the Licensor set forth in the correspon... |
10.2.1 |
The Patents comprising Non-Exclusive Licensor Technology have not been listed in Schedule 10.2.1 and Licensor makes no representation or warranty as to whether such Patents are subsisting or as to the validity or enforceability of these Patents. |
10.2.2 |
• Except to Licensor's Knowledge, Licensor makes no representation or warranty that no claim or litigation has been brought by any Person alleging, that (a) the Existing Patents comprising Non-Exclusive Licensor Technology are invalid or unenforceable, or (b) the Existing Patents or Licensor Background Know-How, in eac... |
• Reference is made to that certain letter from Licensor to AbbVie dated October 16, 2017. |
10.2.3 |
Adimab reserves a limited, non-exclusive right to include Program Antibodies (as defined therein) in antibody libraries as further described in 5.2(c)(i) of the Adimab Agreement. |
Licensor is a non-exclusive licensee of the Patents within the Non-Exclusive Licensor Technology and makes no representation or warranty as to whether such Patents are free of encumbrances. |
The Patents within the Non-Exclusive Licensor Technology have not been listed on Schedule 10.2.1 and therefore while they are "Existing Patents," they are neither "Owned Patents" nor "In-Licensed Patents." |
10.2.4 |
Reference is made to that certain letter from Licensor to AbbVie dated October 16, 2017. |
10.2.9 |
The file wrapper and other documents and materials relating to the prosecution, defense, maintenance, validity, and enforceability of the Patents within the Non-Exclusive Licensor Technology have not been provided to AbbVie. |
10.2.11 |
Reference is made to that certain letter from Licensor to AbbVie dated October 16, 2017. |
10.2.17 |
Except to Licensor's Knowledge, Licensor makes no representation or warranty that all Licensor Background Know-How comprising Non-Exclusive Licensor Technology that has been made (or will be made) available by Licensor to AbbVie is (and, if made available after the Execution Date, will be) true, complete, and correct. |
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