Target

NGM120 is a first-in-class antagonist antibody that binds glial cell-derived neurotrophic factor receptor alpha-like (GFRAL) and inhibits growth differentiation factor 15 (GDF15) signaling for the potential treatment of cancer and cancer anorexia/cachexia syndrome (CACS).

NGM’s preclinical research suggests the central role of the GDF15/GFRAL pathway in promoting tumor-associated appetite suppression and weight loss. In addition, GDF15 levels are elevated in numerous tumor types and, based on available scientific literature, increased serum GDF15 levels are associated with worse prognosis in prostate, colorectal, esophageal and ovarian cancers. In preclinical studies of NGM120, our team has demonstrated that blocking the interaction between GFRAL and GDF15 is able to both reduce tumor-associated weight loss and slow tumor growth and could potentially provide a novel treatment for CACS and cancer.

Clinical Development Status

In February 2020, we announced the initiation of a Phase 1a/1b multi-site clinical study to evaluate the safety, tolerability and pharmacokinetics of NGM120 as a monotherapy in patients with select advanced solid tumors (Cohort 1) and of NGM120 in combination with gemcitabine and Abraxane® in patients with metastatic pancreatic cancer (Cohort 2). Each cohort will consist of an open-label dose-escalation portion followed by a dose-expansion portion. Approximately 90 patients with elevated serum levels of GDF15 are expected to be enrolled in the concurrently run cohorts. Preliminary evidence of anti-tumor and anti-cachexia activity will be assessed by measuring tumor response rates, body mass and composition, patient-reported outcomes and functional status.

The Phase 1a/1b study followed the successful completion of a Phase 1 safety, tolerability and pharmacokinetics study of NGM120 in healthy adult subjects in 2019.

Target

NGM707 is a novel dual antagonist antibody inhibiting ILT2 and ILT4 being advanced by NGM with the goal of improving patient immune responses to tumors.

ILT2 (Immunoglobulin-like transcript 2) and Immunoglobulin-like transcript 4 (ILT4) are members of the leukocyte Ig-like receptor (LILR) family of immunosuppressive receptors. ILT2 and ILT4, which are expressed on myeloid cells in the tumor microenvironment, are implicated in suppressing anti-tumor immune response and may represent checkpoints that enable tumors to evade immune detection. Suppressive myeloid cells enriched with ILT2 and ILT4 receptors are upregulated in certain cancer types^1-5, while ILT2 is also expressed on natural killer (NK) cells, B cells and a subset of highly cytolytic T cells. Of note, ILT2 and ILT4 are upregulated on macrophages in the tumor microenvironment of certain cancer patients that are non-responders to T cell checkpoint inhibitor therapy and, therefore, may serve as T cell checkpoint inhibitor resistance mechanisms⁶. Reversing myeloid suppression, or myeloid reprogramming, represents a promising new therapeutic area of immuno-oncology.

NGM707 is designed to potentially improve patient immune responses to tumors by inhibiting both the ILT2 and ILT4 receptors. In preclinical studies of NGM707, NGM has demonstrated that an ILT4-mediated blockade reverses myeloid cell immune suppression, while an ILT2-mediated blockade promotes NK and CD8⁺ T cell killing of tumor cells and activates macrophage phagocytosis of tumor cells. In addition, preclinical studies of NGM707 have shown that the dual blockade of ILT2 and ILT4 act synergistically to reverse suppression of Fc receptor signaling.

Clinical Development Status

NGM is currently enrolling patients in a Phase 1/2 study of NGM707 for the treatment of advanced solid tumors.

Target:

NGM438 is a novel antagonist antibody being developed by NGM to inhibit Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) for the treatment of advanced solid tumors.

LAIR1 is a collagen-binding inhibitory receptor expressed on immune cells^1-2 that is implicated in immune suppression. LAIR1 and collagens are upregulated in multiple cancer types^3-7 where collagens are produced by activated stromal cells. These stromal-derived suppressive factors are associated with poor responses to checkpoint inhibitors. For such tumors, formation of the LAIR1-collagen complex may act as a stromal checkpoint to both physically exclude immune cells from the tumor and impose signaling-based immune suppression^8-9. Consequently, inhibiting this stromal checkpoint represents a potentially promising new therapeutic strategy to treat cancer by promoting the remodeling of the tumor architecture that restricts T cell infiltration of the tumor cell mass and reversing immune suppression in the tumor microenvironment.

Designed to inhibit LAIR1 interactions with stromal-derived collagens, NGM438 has the potential to block this stromal checkpoint and restore anti-tumor immune responses. In preclinical studies, NGM438 demonstrated the ability to reprogram collagen-suppressed myeloid cells to a stimulatory phenotype, induce inflammatory cytokine production by myeloid and T cells, and relieve collagen-based suppression of T cell proliferation. Reinvigoration of collagen-suppressed immune cells may address a key resistance mechanism that limits responses to current immunotherapies.

Clinical Development Status:

NGM plans to initiate first-in-human testing of NGM438 in the first half of 2022.