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First-in-class TREM-1 inhibitors for neovascular retinal diseases

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R44EY034015-01A1
Agency Tracking Number: R44EY034015
Amount: $278,127.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 100
Solicitation Number: PA21-259
Timeline
Solicitation Year: 2021
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-30
Award End Date (Contract End Date): 2024-09-29
Small Business Information
61 FRANK ST, APT 36
Worcester, MA 01604-1000
United States
DUNS: 962285263
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 ALEXANDER SIGALOV
 (203) 505-3807
 sigalov@signablok.com
Business Contact
 ALEXANDER SIGALOV
Phone: (203) 505-3807
Email: sigalov@signablok.com
Research Institution
N/A
Abstract

Project Summary/Abstract
Retinal neovascularization (RNV) is a major cause of vision loss in retinopathy of prematurity (ROP),
diabetic retinopathy (DR) and retinal vein occlusion. In the US, about 16,000 of premature infants are
affected by ROP annually and about 4.1 million adults years have DR. Complications of conventional
treatments suggest an unmet need for new therapies. The long-term objective of this project is to develop a
systemic, new mechanism-based, efficient and well-tolerable therapy for ROP and other RNV diseases.Triggering receptor expressed on myeloid cells (TREM-1) is upregulated upon inflammation and is
involved in angiogenic signaling pathways, suggesting TREM-1 as a promising target for treatment of RNV.Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To
minimize clinical failure risks, we developed well-tolerable TREM-1 inhibitory peptides GF9 and GA31 that
employ a novel, ligand-independent mechanism of action. They can be used in a free form or formulated in
macrophage-specific lipopeptide complexes (LPC) to improve half-life and reduce off-target risks.Previously, we showed that ligand-independent TREM-1 blockade using either a free (GF9) or LPC-
formulated peptide (GA31-LPC): 1) prevents and treats RNV in mice with oxygen-induced retinopathy
(OIR); 2) improves vessel sprouting during hypoxia, 3) inhibits retinal TREM-1 and CSF-1 expression, and
4) reduces cytokine release (TNFα, IL-1β, IL-6 and CSF-1) in vitro, while control peptides have no effect.The goal of the proposed project is to further develop this first-in-class TREM-1 therapy for neovascular
retinal diseases. Considering pros and cons of GF9 and GA31-LPC, we suggest to start with both leads.
Due to differences in the manifestation of vascular phenotypes, we suggest to use both OIR mice and rats.Phase I aims are to: 1) generate GMP-compliant formulations of free GF9 and GA31-LPC and test
them in vitro, and 2) test the developed formulations of GF9 and GA31-LPC in the OIR mouse model.
GMP-friendly tangential flow filtration technique to prepare GA31-LPC will be explored.Phase II aims are to: 1) develop an LC-MS-assay to measure GF9 and GA31 in ocular tissues, 2) test
pharmacokinetics and ocular tissue distribution of GF9 and GA31-LPC in vivo, 3) test the preventative and
therapeutic effects of GF9 and GA31-LPC in two OIR models and select the lead, and 4) test the lead in
non-clinical toxicology studies. Comprehensive histology/IHC will be performed. Cytokines will be tested.Follow-up Phase IIb will include other administration and combination (eg, laser + GF9) regimens, GLP-
TOX, ADME, CMC and other IND-enabling studies. The final product will represent safe and stable
systemic therapy. Its anticipated safety is supported by safety of GF9 therapy in long-term treated healthy,
cancer and arthritic mice. Prototypes of SignaBlok's LPC are well-tolerated in humans. TREM-1 blockade
by SignaBlok competitor's peptide LR12 (Inotrem) is safe and well-tolerated in healthy and septic subjects.

* Information listed above is at the time of submission. *

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