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13.8 Notices. |
13.8.1 Notice Requirements. Any notice, request, demand, waiver, consent, approval, or other communication permitted or required under this Agreement shall be in writing, shall refer specifically to this Agreement and shall be deemed given only if (a) delivered by hand, (b) sent by facsimile transmission (with transmis... |
13.8.2 Address for Notice. |
If to AbbVie, to: AbbVie Biotechnology Ltd. c/o AbbVie Inc. 1 N Waukegan Road North Chicago, IL 60064 Attention: Executive Vice President, External Affairs; General Counsel Facsimile: (847) 935-3294 |
with a copy (which shall not constitute notice) to: AbbVie, Inc. 1 North Waukegan Road North Chicago, IL 60064 Attention: Vice President, Legal Facsimile: (847) 935-9644 |
If to Licensor, to: Alector, Inc. 151 Oyster Point Blvd., Ste 300 South San Francisco, CA 94080 Attention: CEO |
with a copy (which shall not constitute notice) to: Wilson Sonsini Goodrich & Rosati 650 Page Mill Road Palo Alto, CA 94304 Attention: Kenneth A. Clark Facsimile: (650) 493-6811 |
13.9 Entire Agreement; Amendments. This Agreement, together with the Schedules attached hereto, set forth and constitutes the entire agreement and understanding between the Parties with respect to the subject matter hereof and all prior agreements, understandings, promises, and representations, whether written or oral,... |
13.10 English Language. This Agreement shall be written and executed in, and all other communications under or in connection with this Agreement shall be in, the English language. Any translation into any other language shall not be an official version thereof, and in the event of any conflict in interpretation between... |
13.11 Equitable Relief. Each Party acknowledges and agrees that the restrictions set forth in Section 5.10, ARTICLE 7 and ARTICLE 9 are reasonable and necessary to protect the legitimate interests of the other Party and that such other Party would not have entered into this Agreement in the absence of such restrictions... |
13.12 Waiver and Non-Exclusion of Remedies. Any term or condition of this Agreement may be waived at any time by the Party that is entitled to the benefit thereof, but no such waiver shall be effective unless set forth in a written instrument duly executed by or on behalf of the Party waiving such term or condition. Th... |
13.13 No Benefit to Third Parties. Except as provided in ARTICLE 11, covenants and agreements set forth in this Agreement are for the sole benefit of the Parties hereto and their successors and permitted assigns, and they shall not be construed as conferring any rights on any other Persons. |
13.14 Further Assurance. Each Party shall duly execute and deliver, or cause to be duly executed and delivered, such further instruments and do and cause to be done such further acts and things, including the filing of such assignments, agreements, documents, and instruments, as may be necessary or as the other Party m... |
13.15 Relationship of the Parties. It is expressly agreed that Licensor, on the one hand, and AbbVie, on the other hand, shall be independent contractors and that the relationship between the Parties shall not constitute a partnership, joint venture, or agency, including for all tax purposes. Neither Licensor, on the o... |
13.16 Performance by Affiliates. AbbVie may use one (1) or more of its Affiliates to perform its obligations and duties hereunder and such AbbVie Affiliates are expressly granted certain rights herein; provided that each such Affiliate shall be bound by the corresponding obligations of AbbVie and, AbbVie shall remain l... |
13.17 Counterparts; Facsimile Execution. This Agreement may be executed in two (2) or more counterparts, each of which shall be deemed an original, but all of which together shall constitute one (1) and the same instrument. This Agreement may be executed by facsimile or electronically transmitted signatures and such si... |
13.18 References. Unless otherwise specified, (a) references in this Agreement to any Article, Section or Schedule shall mean references to such Article, Section or Schedule of this Agreement, (b) references in any Section to any clause or paragraph are references to such clause or paragraph of such Section, and (c) re... |
13.19 Construction. Except where the context otherwise requires, wherever used, the singular shall include the plural, the plural the singular, the use of any gender shall be applicable to all genders and the word "or" is used in the inclusive sense (and/or). Whenever this Agreement refers to a number of days, unless o... |
Schedule 1.90 |
Corporate Names |
1. Alector LLC |
2. Alector, Inc. |
Schedule 1.90 |
Existing In-License Agreements |
Third Amended and Restated Collaboration Agreement, dated September 19, 2016, between Adimab, LLC ("Adimab") and Alector LLC (the "Adimab Agreement"). |
Development and Manufacturing Services Agreement, dated July 3, 2017, between Lonza Sales AG ("Lonza") and Alector LLC (the "Lonza Agreement"). |
The license agreement under which Lonza will grant Licensor a non-exclusive license under certain intellectual property (including patents and know-how) pertaining to GS (as defined in the Lonza Agreement) controlled by Lonza and its Affiliates (the "GS License"); provided that Lonza and Licensor enter into the license... |
Development and GMP Manufacturing Master Services Agreement, dated May 30, 2017, between Celonic AG ("Celonic") and Alector LLC (the "Celonic Agreement"). |
Schedule 1.127 |
AL003 and Backups |
[Table containing Full Adimab Royalty Human and optimized CD33, Independent of Adimab Murine/Humanized Antibody CD33, 50% Adimab Royalty Optimized Murine CD33] |
Schedule 1.129 |
AL002 and Backups |
[Table containing Full Adimab Royalty Human and optimized TREM2, Independent of Adimab Murine/Humanized Antibody TREM2, 50% Adimab Royalty Optimized Murine TREM2] |
Schedule 1.150 |
Manufacturing Cost |
For purposes of the Agreement, "Manufacturing Costs" means costs that relate to a Licensed Antibody or Licensed Product that is either (a) supplied by a Third Party, or (b) manufactured directly by a Party or an Affiliate of a Party, determined as follows: |
In the case of clause (a) above, Manufacturing Costs means (i) those amounts that are paid to a Third Party by a Party in connection with the Manufacture of a Licensed Antibody or Licensed Product, including process improvements, storage, manufacturing scale-up, manufacturing site qualification, QA and QC (including te... |
In the case of clause (b) above, Manufacturing Costs means those direct costs (including raw materials, equipment and labor and costs of plant operations and plant support services (including utilities, maintenance, engineering, safety, human resources, finance, plant management and other similar activities)) and a rea... |
Schedule 1.188 |
PoC Trial Parameters |
The PoC Trial will have the following parameters: |
• 265 patients with early AD |
• 55 – 60 sites in multiple regions |
• Monthly dosing IV |
• Treatment duration up to 24 months (12 months for low dose cohort) |
• 4 dose groups (3 active, one placebo, n=60-75 each) |
• Dynamic randomization to allocate more patients to high dose cohorts first |
• First interim analysis (IA) when the first 60 patients that are enrolled in high dose cohort have completed 12 months of dosing |
• Second IA when the first 60 patients that are enrolled in the mid-dose cohort have completed 12 months of dosing; will include long-term data from high dose cohort |
• Final analysis when the last patient of the low dose cohort has completed 12 months of dosing; will include long-term data from high and mid dose cohorts. |
Schedule 1.193 |
Pre Exercise Development Plan and Budget (Parts 1 and 2: Preclinical & Clinical Activities) |
[Follows on next page.] |
Preclinical Plans to IND |
A number of studies are currently ongoing or planned to advance lead AL002 and AL003 mAbs towards IND. |
These studies include additional efficacy studies, PK studies, PK-PD studies and additional work on translational/biomarkers. In addition, CMC characterization and generation of clinical supply, along with toxicology studies are planned / underway. In addition, characterization of alternate antibodies will be undertake... |
Outline of Study Plans (ongoing / planned) 1. Preclinical Pharmacology: in vivo / in vitro studies (see below) 2. PK and PK-PD studies (see below) 3. Translational Sciences: Continued studies of biomarkers and other translational approaches for assessment of target engagement and patient selection 4. Further characteri... |
Anticipated Outcome: Successful submission and acceptance of IND packages for AL002 and AL003 by regulatory authorities to initiate Phase 1 trials |
AL002 PROGRAM – PLANNED ACTIVITIES |
PK/PD Studies: 1. PK/PD huT2 Bac Tg mice 2. Cyno PK Study 3. Cyno PK/tox Study 4. In vivo Signaling |
Efficacy Studies: 1. Tau P301S 2. APP/PS1/5xFAD IC 3. 5xFAD IP 4. huT2(R47H)-Bac x 5xFAD 5. huT2-Bac x 5xFAD 6. Optic Nerve Crush 7. Cuprizone MS Model |
AL003 PROGRAM – PLANNED ACTIVITIES |
PK/PD Studies: 1. CD33 hBac PD Microglia 2. CD33 hBac PD microglia with AL003 Lead 3. CD33 hBac dose range finder TK/PD with AL003 Lead |
Neurology Efficacy Studies: 1. CD33 hBac x 5xFAD |
Exploratory Studies: 1. CD33 hBac VS WT-LPS, cuprizone mediated glial activation 2. Slice culture of hBac Tgx 5xFAD Mice 3. Brain injections of CD33 in hBac Tg x 5xFAD mice 4. BAC-Tg mice – monotherapy |
Pre-Exercise Clinical Development Plan |
Clinical studies are intended to provide data to support decision making for opt-in and to inform planning and execution of Phase 3 registration studies. |
Clinical Development Plan Goals for Phase 1 and 2: 1. Phase 1: Collect sufficient safety data and PK data from SAD/MAD study to support initiation of Phase 2 and selection of the dose levels in the Phase 2 study 2. Phase 2: Achieve decision criteria on CDR-SOB and other clinical and biomarker endpoints for at least one... |
Clinical development plans to achieve proof of concept (PoC) will include: • Phase 1 Single Ascending Dose (SAD) study in Healthy Volunteers (depending on regulatory agreement) and Multiple Ascending Dose (MAD) study in Alzheimer Disease Patients |
Phase 1 (Single Ascending Dose, Multiple Ascending Dose) |
Phase 1 Study Design [Contains diagram showing study design with cohorts A-G and dose escalation] |
• 4 weekly doses in mild/moderate AD • Exposure ~ 4x of highest monthly dose in Phase 2 • AD cohort include CSF and TSPO-PET |
• Single dose in HV • 14 days safety window for dose escalation |
Phase 2 (PoC) |
• Study uses dynamic allocating to randomize more patients to high dose cohorts first • First IA when 60 subjects from high dose cohort have completed 12 months of dosing • Second IA when 60 subjects from the mid dose cohort have completed 12 months of dosing; will include data from later time points of high dose cohor... |
Key Study Elements |
Activity Sample size1) No of sites2) Tx frequency and duration3) Comments |
Phase 1 • 40 HV • 24 AD (M2M) • 1 – 2 sites for SD • 2 – 4 sites for AD • SD: one dose • MD: 4 doses, one dose per week • 5 dose groups in SD • 2 AD cohorts @ 2 dose levels in MD • Total drug exposure in MD estimated to cover 4 x anticipated monthly exposure at highest dose in Phase 2 • MD cohorts will include CSF and ... |
Phase 2 • 265 patients with early AD • 50 – 60 sites in multiple regions • Monthly dosing IV • Up to 24 months • 12 months for low dose cohort • 4 dose groups (3 active, one placebo, n=60-75) • Dynamic randomization to allocate more patients to high dose cohorts first • First IA when the first 60 pts that were enrolled... |
1) Final sample size and patients population will be determined on response from regulatory authorities and ethic committees 2) Final number of sites will depend on actual enrollment rate 3) Final treatment frequency will be based in pharmacokinetics and pharmacodynamics observed in SD of Phase 1 |
Phase 2 key assumptions for time line estimates: • Total 265 patients • Total number of sites: 50 - 60 sites • Enrollment rate: 0.2 pts/site/month • 12 months for enrollment to get to 130 patients for interim analysis • First interim when the 130 (60 high dose) patients reach 12 months treatment = 24 months • For enrol... |
• First IA when the first 60 pts that were enrolled in high dose cohort have completed 12 months of dosing • Second IA when the first 60 pts that were enrolled in the mid dose cohort have completed 12 month of dosing and will include long-term data from high dose cohort • Final analysis when the last patient of the low... |
Data Analysis and Interpretation – General Principles |
Approach: Interim analyses (IAs) will be performed at the intervals noted previously. A Bayesian framework will be used to guide decision-making, with a posterior probability distribution calculated based on both the prior probability distributions for placebo and treatment groups and the observed data in the POC study... |
1. Establish prior probability distribution for the placebo group: Prior to the first IA, The JDC will define datasets that can be used to inform the placebo prior probability distribution. Datasets will include the placebo arm from studies of disease modifying drugs in a patient population with similar criteria used t... |
2. Establish prior probability distribution for the treatment group: The prior probability distribution for the treatment group will be centered at an effect size that reflects the TPP at the time of the interim analysis with a distribution determined from treatment arms of trials where the therapeutic agent demonstrat... |
3. Calculate the posterior distribution: For CDR-SOB, COGN (cognition end points) and Amyloid PET SUVR, and other efficacy endpoints the posterior distribution of the placebo group, treatment group and treatment difference will be calculated by updating the priors with the observed data at each interim or final analysi... |
4. JDC will determine the TPP and the final efficacy endpoints taking into the account the efficacy and safety profile of potentially marketed products at the time of the analysis |
Draft Framework for Interim & Final Analysis • Prior to IA, we need to: • Determine what ES to focus on • Identify thresholds for posterior probabilities: e.g., • At IA 1: biomarker > clinical • At IA 2: biomarker ~ clinical • At final IA: clinical > biomarker • Abbreviation: ES, effect size |
CMC ACTIVITIES |
CMC activities (pre-Phase I to Early Phase 2) |
Key activities and Deliverables |
Drug Substance & Analytical • Cell line Generation • Cell Line clone screening and selection • Master Cell Bank production and characterization • Cell Culture Process Development • Purification Process Development • DS Analytical methods development and validation • Bioassay • Identification and qualification of impuri... |
Drug Product & Analytical • Pre-formulation studies • Formulation /liquid or lyo process development for Phase I/2 • Formulation analytical methods development • Degradation product qualification as required • Stability of formulations and clinical supplies • Package selection • Compatibility with administration sets •... |
Clinical supply package/label/and distribution • Package/label and distribution of clinical supplies • Placebo blinding activities • QP Release/import CTA |
Regulatory documentation: • Regulatory content for Quality sections of INDs/IMPDs and updates • Investigator Brochure sections |
CMC Activities – mid Phase 2 through Submission |
Key activities and Deliverables |
Drug Substance & Analytical • Cell Culture and Purification process improvements • Commercial Master Cell Bank production and characterization if needed as decided by the JDC • Working Cell Bank production and characterization • Upgrade upstream and downstream processes • DS specifications justification • DS stability*... |
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