Target

NGM120 is anantagonist antibody that binds glial cell-derived neurotrophic factor receptor alpha-like (GFRAL) and inhibits growth differentiation factor 15 (GDF15) signaling.

NGM scientists have made several important discoveries related to GDF15, including identification of its cognate receptor, GFRAL. GFRAL is expressed in a specific region of the hindbrain, partially outside the blood brain barrier, and is believed to initiate signaling through multiple pathways, including the autonomic nervous system. Evidence has shown that serum levels of GDF15 are elevated in patients with a number of tumor types, including non-small cell lung cancer, melanoma, pancreatic, prostate, colorectal, gastric, esophageal and ovarian cancer, and are associated with a worse prognosis in multiple cancers.

Clinical Development Status

NGM is currently underway with a Phase 1a/1b multi-site, open-label, dose escalation clinical study, initiated in February 2020, to assess the safety and tolerability of NGM120 30 mg and 100 mg as monotherapy in patients with advanced solid tumors (Phase 1a, n=20) or in combination with gemcitabine + Nab-paclitaxel (Phase 1b, n=8) in patients with metastatic pancreatic cancer. Patients are dosed once every three weeks in the Phase 1a cohort and once every four weeks in the Phase 1b cohort. Secondary endpoints include pharmacokinetics, overall response rate¹, progression-free survival and changes in lean body mass and body weight. Entry criteria for both cohorts included elevated serum levels of GDF15. Both the Phase 1a and 1b cohorts are fully enrolled.

NGM presented preliminary findings from the Phase 1a/1b study at the European Society of Medical Oncology (ESMO) Virtual Congress in September 2021. Link here to read the press release.

NGM plans to report final results from the Phase 1a and Phase 1b cohorts once all patients have completed treatment and follow-up per protocol.

1 = Assessed using the RECIST Version 1.1 criteria

Target

NGM120 is an antagonist antibody that binds glial cell-derived neurotrophic factor receptor alpha-like (GFRAL) and inhibits growth differentiation factor 15 (GDF15) signaling.

NGM scientists have made several important discoveries related to GDF15, including identification of its cognate receptor, GFRAL. GFRAL is expressed in a specific region of the hindbrain, partially outside the blood brain barrier, and is believed to initiate signaling through multiple pathways, including the autonomic nervous system. Evidence has shown that serum levels of GDF15 are elevated in patients with a number of tumor types, including non-small cell lung cancer, melanoma, pancreatic, prostate, colorectal, gastric, esophageal and ovarian cancer, and are associated with a worse prognosis in multiple cancers.

Clinical Development Status

NGM is underway with a Phase 1a/1b multi-site, open-label, dose escalation clinical study, initiated in February 2020, to assess the safety and tolerability of NGM120 30 mg and 100 mg as monotherapy in patients with advanced solid tumors (Phase 1a, n=20) or in combination with gemcitabine + Nab-paclitaxel (Phase 1b, n=8) in patients with metastatic pancreatic cancer. Both the Phase 1a and 1b cohorts are fully enrolled and the study is ongoing.

NGM initiated a Phase 2 randomized, single-blind (investigator-blinded), placebo-controlled, multi-center expansion study (PINNACLES) in March 2021 to evaluate NGM120 as a first-line treatment in 60 patients with metastatic pancreatic cancer. In the ongoing study, patients will be randomized to either NGM120 or placebo in combination with gemcitabine/Nab-paclitaxel. The study will evaluate the effects of NGM120 on both cancer and cancer-related cachexia.

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

NGM831 is a novel antagonist antibody designed to block the interaction of ILT3 of fibronectin, as well as with other ligands.

In August 2021, NGM published a paper in Cancer Immunology Research, a journal of the American Association for Cancer Research,¹ describing the company’s discovery of ILT3’s functional ligand, fibronectin, an extracellular matrix protein that forms a fibrillar network within the tumor stroma.

As detailed in the publication, ILT3 is a fibronectin-binding inhibitory immune receptor that receives signals from the extracellular matrix to directly promote myeloid cell suppression. ILT3 is expressed specifically on tumor-associated myeloid cells, with particularly high expression on tolerogenic dendritic cells (DCs), myeloid-derived suppressor cells and M2 macrophages. This receptor is upregulated in several tumor types and is associated with poor survival^2,3. Moreover, fibronectin has been shown to be upregulated in multiple cancers and associated with tumor progression^4,5. For tumors in which both ILT3 and fibronectin are upregulated, the ILT3-fibronectin pathway may act as a stromal checkpoint to repress myeloid cell function.

Designed to inhibit ILT3 interactions with fibronectin and other ligands, NGM831 is expected to reprogram tolerogenic DCs into stimulatory cells with enhanced Fc receptor activity as well as to enhance T cell infiltration and activation.

Clinical Development Status

NGM anticipates initiating first-in-human testing of NGM831 in the first half of 2022

References:

1. Paavola et al, Cancer Immunology Research, 2021
2. L de Goeje et al, OncoImmunology 2015
3. Liu et al, Pathology – Research and Practice, 2018
4. Saito et al, Molecular Medicine Reports, 2008
5. Niknami et al, EXCLI Journal, 2017

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.