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Prior to opt-in by AbbVie, Hotspot Therapeutics and AbbVie will be responsible for design of the FIH study (SAD/MAD in HVs); Hotspot Therapeutics will be responsible for the conduct of the SAD and MAD studies in healthy volunteers (HV). |
3. Preparation for submission of IND/CTA |
Prior to opt-in by AbbVie, Hotspot Therapeutics will be responsible for submission of an IND or CTA to conduct the FIH study (SAD/MAD in HVs). After opt-in by AbbVie, Hotspot Therapeutics will transfer sponsor responsibilities for the IND or CTA to AbbVie and AbbVie will become responsible for the IND. |
CLINICAL DEVELOPMENT PLAN |
A. Plan for SAD and MAD Phase I Clinical Trial |
All clinical activities are the responsibility of HotSpot Therapeutics unless otherwise noted below. |
The following are the Clinical Studies contemplated by the Parties for successful Development of Hotspot Therapeutics's IRF5 compound for the treatment of SLE through the end of the Phase I MAD. |
A placebo-controlled, double-blind randomized single ascending dose (SAD) Clinical Trial of Hotspot Therapeutics's IRF5 compound in adult healthy volunteers (18-65 years old) will be conducted. The SAD Clinical Study will assess the safety, tolerability, pharmacokinetics, pharmacodynamics of single oral dose of Hotspot... |
The placebo-controlled, double-blind randomized multiple ascending dose (MAD) Clinical Trial is a dose escalation study that would assess the safety, tolerability, pharmacokinetics, pharmacodynamics of multiple oral doses of Hotspot Therapeutics's IRF5 compound in adult healthy volunteers (18-65 years old). It is antic... |
Figure 1. Phase I SAD/MAD Clinical Study Design Scheme |
[Note: Figure not included in text extraction] |
Table 5. Phase 1 Clinical Plan Activities |
Clinical Objectives (Responsibility Hotspot Therapeutics) |
SAD Phase 1 Clinical Trial in Healthy Volunteers (HV) |
MAD Phase 1 Clinical Trial in HV |
B. Development of Pharmacodynamic (PD) Markers to End of Phase 1 Clinical Trial |
Activities to support development of PD markers are outlined in the Table 6 below: |
Table 6. Development of PD Biomarkers |
Translational Medicine / Biomarker Objectives |
Develop and validate target engagement (TE) and PD biomarker |
Evaluation of exploratory biomarkers |
GMP material synthesis |
GMP drug product and placebo sufficient to support the first Phase 1b study of the Licensed Product in the first indication and the first Phase 2 study of the Licensed Product in the first indication will be manufactured by Hotspot Therapeutics and delivered to AbbVie in accordance with Section 3.8 of the Agreement, as... |
Final Data Package Deliverables: |
After completing all of the activities set forth in this Development Plan and Budget, Hotspot Therapeutics will provide a complete data package containing all data, findings, information and results of the development and CMC activities set forth in this Development Plan and Budget and all supporting documentation (inc... |
a) all Information Reports (to the extent not previously provided) |
b) top line data from the 13-week GLP toxicology studies (including histopathology data and slides) |
c) top line results and patient level data for the first single ascending dose Phase I Study sponsored by HotSpot Therapeutics compliant with ICH E3 guidelines, and; |
d) top line results, and if available prior to the Final License Option Expiration Date the complete study report, and patient level data for the first multiple ascending dose Phase I Study sponsored by HotSpot Therapeutics compliant with ICH E3 guidelines |
Budget and Minimal Hotspot Therapeutics FTEs |
The table below represents the budget required (by expense category) to complete each deliverable detailed in this proposal. |
[Table with budget details] |
FTEs |
Stage 1 |
Stage 2 |
Stage 3 |
Stage 4 |
FUNCTIONAL AREA |
Medicinal chemistry |
Biology (in vitro) |
Pharmacology (in vivo) |
Development Sciences (ADME/PK, Tox & Clin Pharm) |
Translational Biology |
CMC |
Clinical |
Operations |
TOTAL |
APPENDICES |
Appendix A: Product-Specific In Vitro Cellular Assays and In Vivo Acute and Chronic Models for Advancement of IRF5 Research Target |
Attribute |
Effects of test compound should be comparable to or superior to listed standards in each of the following assays or models |
In Vitro Screening Assay in addition to Hotspot Therapeutics protein assay for chemical matter identification |
IRF5 dimerization assay |
WT Thp1 R848 Assay |
IRF5 KO Thp1 Pam3 Assay |
IRF5 Binding |
In Vitro Assays to understand mechanism of action |
Biophysical assays |
Cellular functional assay |
Cellular functional assay |
IRF5 nuclear translocation |
Whole blood assay |
In Vivo Acute Efficacy |
Acute TLR agonist R848 model |
Short term efficacy model: |
In Vivo Chronic Efficacy Model |
SLE efficacy model |
Appendix B: CMC Workplan (at time of initiation of collaboration) |
Hotspot Therapeutics/AbbVie CMC Workplan (Pre-IND Activities/Deliverables) |
Deliverable |
Stage 2 Support |
Stage 3 support |
Stage 3/4 support |
Stage 4 and Clinical Development Support |
Deliverable |
OPT-IN Activity Description |
Documentation of drug substance and drug product development in respective development reports (identification, structural confirmation, process development, analytical development, control strategy, reference standard, stability) |
Transfer DS/DP analytical methods by: • Providing written methods for all analytical release and stability assays for non-USP methods which support regulatory filings • Formal transfer methods of product specific methods are required |
Provide consultation to answer questions regarding analytic methods |
Setup contracts with DS/DP CDMOs conducting stability studies to transfer control of studies to AbbVie |
Continue to provide storage of DS/DP GMP stability samples and regulatory retains or coordinate transfer to site determined by AbbVie |
Provide DS/DP release and stability testing of new GMP/clinical lots until transfer of stability studies is complete |
Assume control and costs for DS/DP stability studies and storage of materials |
Hotspot Therapeutics DS/DP materials to be shipped to site TBD by AbbVie at the completion of tech transfer, except for materials needed to complete tech transfer, such as reference standards: • List materials • DS/DP inventory (SM, INT, DS, DP) • Reference standards • Samples in support of tech transfer or manufacturi... |
Note: Inventory may remain at current suppliers until contracts with AbbVie are in place. Material requests will be facilitated by the Hotspot Therapeutics team. |
Provide DS/DP reports which support technology transfer including: • developmental history reports • technical development reports • Executed batch records • CoA's and supporting analytical data • Reports that support CMC section of the IND/CTD • GMP CDMO audit reports and quality agreements |
Provide documentation/communications with Regulatory Agencies |
DS/DP Tech transfer Process • Coordinate 3-way CDAs with mfg. vendors • Setup F2F meetings at mfg. sites • Provide tech transfer support to manufacturing sites of AbbVie's choosing |
Drug Product Deliverable |
Drug Product • GMP drug product sufficient to support the first Phase 1b and Phase 2 study of the Licensed Product in the first indication • Placebo sufficient to support the first Phase 1b and Phase 2 study of the Licensed Product in the first indication |
Appendix C: Nonclinical and CMC reports and documents to be included for an IND |
submission |
Nonclinical reports for an IND (small molecule) should cover, but not limited to, the following topics: |
Pharmacology |
● Primary Pharmacology: in vitro, in vivo |
● Secondary Pharmacology: off target binding assays for receptors, ion channels, enzymes and transporters |
● Safety Pharmacology: CV (hERG, in vivo), CNS, respiratory |
Pharmacokinetics |
● Bioanalytical method validation |
● Absorption: cellular permeability, pharmacokinetics in nonclinical species, dose response, formulation effects (if necessary) |
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