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Freshfields Bruckhaus Deringer 700 13th Street, NW, 10th floor Washington, D.C., 20005 Attention: Kristen O. Riemenschneider Facsimile: +1 202 777 4555 |
If to HotSpot, to: |
HotSpot Therapeutics, Inc. 50 Milk Street, 16th Floor Boston, MA 02109 Attention: Chief Business Officer |
with a copy (which shall not constitute notice) to: |
Ropes & Gray LLP 800 Boylston Street, Prudential Tower Boston, MA 02199 Attention: David M. McIntosh Email: David.McIntosh@ropesgray.com |
13.9. Entire Agreement; Amendments. This Agreement, together with the Schedules attached hereto, sets 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 ora... |
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 betwee... |
13.11. Equitable Relief. Each Party acknowledges and agrees that HotSpot's performance obligations under Article 3 (Initial Development) and the restrictions on HotSpot set forth in Section 6.9 (Exclusivity) and both Parties under Article 8 (Intellectual Property) and Article 9 (Confidentiality and Non-Disclosure) are ... |
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. T... |
13.13. No Benefit to Third Parties. Except as provided in Article 11 (Indemnity), 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 ... |
13.15. Relationship of the Parties. It is expressly agreed that HotSpot, 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 HotSpot, on the on... |
13.16. Performance by Affiliates. Either Party may use one (1) or more of its Affiliates to perform its obligations and duties hereunder and such Affiliates are expressly granted certain rights herein; provided that each such Affiliate shall be bound by the corresponding obligations of the applicable Party and, subject... |
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 s... |
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 are references to such clause of such Section, and (c) references to any agreement... |
13.19. Schedules. In the event of any inconsistencies between this Agreement and any schedules or other attachments hereto, the terms of this Agreement shall control. |
13.20. 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 ... |
[SIGNATURE PAGE FOLLOWS.] |
THIS AGREEMENT IS EXECUTED by the duly authorized representatives of the Parties as of the Effective Date. |
HOTSPOT THERAPEUTICS, INC. |
By: |
Name: Jonathan Montagu |
Title: Chief Executive Officer |
Schedule 1.75 |
Initial Development Plan and Budget |
[See attached.] |
IRF5 DEVELOPMENT PLAN |
I) Outline of development plan |
General Information & Deliverables |
Hotspot Therapeutics and AbbVie have entered into a collaboration and option to license agreement (the "Agreement") with the aim of developing an oral, small molecule inhibitor of interferon regulatory factor 5 (IRF5). The goal of this Development Plan and Budget is to identify and develop a potent and selective IRF5 i... |
II) IRF5 Antagonist Program |
Research Program Details |
Hotspot Therapeutics' efforts will concentrate on computational chemistry, medicinal chemistry, in vitro and in vivo pharmacology, DMPK/toxicology, and structural biology to enable the generation of one Clinical Candidate. |
Primary screening and appropriate secondary screening (selectivity assays, etc.) will be performed by Hotspot Therapeutics. Other activities outlined in this research plan may be outsourced through any subcontractor listed on Schedule 3.2.2 of the Agreement or any other subcontractor that is approved by AbbVie. Activit... |
Stage 1 Activities: Lead Generation to Lead Optimization Activities |
Aim: To generate two (2) distinct lead chemical series and demonstrate in vitro activity in relevant cellular assays with acceptable characteristics that drive SAR |
All Stage 1 Activities are the responsibility of Hotspot Therapeutics unless noted otherwise below. |
Tier 1 testing is focused on molecular design and initial triaging to aid SAR development. This tier has been summarized into four components, each of which involve several key assays that are performed on larger numbers of molecules. |
Design Cycle: One design cycle consists of the SAR driven design and generation of new molecules which are then fed into the in vitro screening assays outlined below. SAR is driven by the SpotBinder™ technologies including computational chemistry and mining of deep screening datasets derived from custom libraries. With... |
IRF5 dimerization assay |
i. TR-FRET or AlphaLISA-based dimerization assay utilizing IRF5 constitutively active protein constructs measuring homodimerization |
ii. Readout: Inhibition of AlphaLISA or FRET signal to demonstrate inhibition of dimerization |
iii. Criteria: dose-dependent inhibition of dimerization |
WT Thp1 R848 Assay |
i. WT Thp1 cell lines stimulated with R848 |
1. Readout: TNFα production |
2. Criteria: Dose dependent inhibition of TNFα production |
ii. Cellular viability to be assessed in parallel (by Cell TiterGlo® assay or related technique) |
IRF5 KO Thp1 Pam3 Assay |
i. IRF5 KO Thp1 cell line stimulated with Pam3CSK4 to induce TNFα to demonstrate cellular selectivity |
1. Readout: TNFα production |
2. Criteria: Identification of a selectivity window between IRF5 and IRF3 or IRF7 |
3. Cellular viability to be assessed in parallel (by Cell TiterGlo® assay or related technique) |
IRF3 & IRF7 Selectivity Assays |
i. Biochemical selectivity assay: TR-FRET or AlphaLISA-based dimerization assay utilizing IRF3 or IRF7 constitutively active protein constructs measuring homodimerization |
1. Readout: Inhibition of AlphaLISA or FRET signal to demonstrate inhibition of dimerization |
2. Criteria: Identification of a selectivity window between IRF5 and IRF3 or IRF7 |
ii. Cell based selectivity assay: Stimulation of Thp1 WT or Thp1 IRF reporter with an IRF3 pathway activator (e.g., 2'3'cGAMP) or an IRF7 pathway activator (e.g., 3p-hpRNA). |
1. Readout: Inhibition of luciferase production. |
2. Criteria: Identification of a selectivity window between IRF5 and IRF3 or IRF7 |
ADME Profiling: After in vitro screening for on-target pharmacology, selected molecules that pass through the in vitro screening funnel, approximately 10 per month for stage 1, will go into in vitro ADME profiling consisting of one or more of the assays listed below. The prioritization of these assays will be based on ... |
Solubility |
LogD |
Plasma stability |
Multispecies metabolic stability (microsomes and hepatocytes) |
Multispecies microsome and hepatocyte protein binding |
Permeability (PAMPA and Caco-2) |
Multispecies plasma protein binding |
CYP induction and CYP inhibition |
Rodent PK Assessment: Progress from in vitro to in vivo studies to facilitate PK-PD correlations |
PK studies are typically performed at 2mpk IV and 10mpk PO as well as at higher oral doses or alternative routes of administration if necessary to reach exposures aligned with cellular EC50. |
Approximately 5 compounds per month will be evaluated during Stage 1 in rodent PK assessments |
Acute PD Assessments: Compounds with an acceptable potency, ADME and PK profile will be tested in an acute PD model. |
The PD model utilizes orally dosed, or other routes of administration, test compounds followed by subcutaneously dosed R848 and measurement of changes in cytokines, including TNFα, IL-6, and IL-12 at 1-2 hours post-stimulation. |
2-6 compounds will be evaluated per quarter during Stage 1 |
Tier 2 testing is focused on further characterization of selected molecules to further refine SAR and provide guidance on potential lead molecules. The body of work in this tier of the testing tree is summarized as follows with the approximate throughput of 3-6 molecules per quarter: |
1. Additional profiling of molecules that show reasonable in vitro profile and in vivo PK-PD in one or more of the following assays: |
a. Eurofins panel to screen for potential off-target liabilities |
b. hERG ion channel testing, patch-clamp |
c. DDI potential (CYP induction/inhibition, transporter usage, preliminary metabolic phenotyping, metabolite ID) to expand understanding of potential PK liabilities |
d. In vitro genetic toxicology risks (Ames/ IVMN tests) |
Tier 3 testing is not necessarily constrained by above testing but instead runs continuously and may use tool and/or advanced lead molecules to further characterize and understand mechanism of action. The approaches included in this tier include the following: |
1. Cellular translational studies: Compounds that show promising activity in biochemical, biophysical, and cellular assays are progressed to further testing in translational assays. |
a. PBMC assay |
i. Healthy donor or patient PBMCs are stimulated with R848 |
ii. Readout: mRNA or protein of TNFα or other disease relevant chemokines and cytokines |
iii. Criteria: Dose dependent inhibition of chemokine or cytokine production |
iv. Cellular viability to be assessed in parallel (by Cell TiterGlo® assay or related technique) |
b. Primary B cells assay |
i. Primary human B cells are stimulated with CpG |
ii. Readout: IL-6, CD86, and total IgG |
iii. Criteria: Dose dependent inhibition of IL-6, CD86, or total IgG |
iv. Cellular viability to be assessed in parallel (by Cell TiterGlo® assay or related technique) |
c. Primary pDC assay |
i. Primary human pDCs are stimulated with either R848 or CpG |
ii. Readout: cytokines measured including type I interferon |
iii. Criteria: Dose dependent inhibition of cytokines |
iv. Cellular viability to be assessed in parallel (by Cell TiterGlo® assay or related technique) |
d. Whole blood assay |
i. Whole blood from healthy controls and/or lupus patients are stimulated with R848 or CpG |
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