The Unmet Need

Age-related macular degeneration, or AMD, is a leading cause of vision loss and blindness in people 65 years of age and over in the US and other industrialized countries. The two advanced stages of the disease are called neovascular (wet) AMD and geographic atrophy, or GA.

GA is a progressive retinal degenerative disease associated with irreversible loss of vision, diminished quality of life and eventual blindness. GA is estimated to impact about 1 million people in the US and over 5 million people worldwide.

In patients with GA, single or multiple areas in the macular region of the retina become atrophic, forming distinct lesions that expand and coalesce over time. Enlargement of these lesions can lead to loss of vision and irreversible blindness. GA is often bilateral, meaning it occurs in both eyes.

While there are approved treatments for wet AMD, there are currently no approved treatments for GA.

Our Approach

Dysregulated activation of the complement system, a key component of the immune system, has been implicated in the onset and progression of GA. NGM621 is a humanized IgG1 monoclonal antibody engineered to potently inhibit activity of complement C3 with the treatment goal of reducing disease progression in patients with GA, and with the potential for every eight week dosing.

We are currently underway with a Phase 2 Catalina study, a multicenter, randomized, double-masked, sham-controlled clinical trial to evaluate the safety and efficacy of intravitreal injections of NGM621 in patients with GA secondary to AMD.

The Unmet Need

Cancer-related cachexia is the uncontrolled wasting of both skeletal muscle and fat that is a common co-morbidity of cancer. Cachexia is associated with increased hospitalization and shortened survival compared to cancer patients who do not exhibit the syndrome. While cachexia can occur in all types of cancer, particularly high incidence rates are observed in pancreatic, gastric, colorectal and esophageal cancers, as well as non-small cell lung cancer.

Current therapeutics targeting cachexia are primarily directed toward increasing appetite. However, there are limited approved treatments that address the muscle-wasting associated with cachexia, and no approved treatments that address the altered energy metabolism.

Our Approach

NGM is a leader in research elucidating the central role of the growth differentiation factor 15 (GDF15)/glial cell-derived neurotrophic factor receptor alpha-like (GFRAL) pathway in promoting tumor-associated appetite regulation, metabolic regulation and immune modulation. Through systematic screening of human secreted factors in preclinical models, NGM identified that GDF15 expression has the ability to promote an outsized effect in weight loss. Evidence has also 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.

As published in Nature, NGM was the first to identify GDF15’s cognate receptor, GFRAL, and the associated signaling pathway. This discovery enabled the development of NGM120, a proprietary inhibitory antibody binding to GFRAL that is designed to block the effects of elevated GDF15 levels. In preclinical studies, NGM has demonstrated that blocking the interaction between GDF15 and GFRAL both reduces tumor-associated weight loss and slows tumor growth. In a murine pancreatic tumor model, treatment with NGM120s, an anti-GFRAL antibody similar to NGM120, resulted in greater tumor shrinkage as well as improved survival versus the control arm. In a murine cancer cachexia model, NGM120s rapidly reversed tumor-induced weight loss. In addition, in a murine model of chemotherapy-induced weight loss, administration of NGM120s preserved lean mass and muscle function in animals treated with cisplatin, while treatment with cisplatin alone resulted in greater than 20% weight loss.

We are currently underway with a Phase 2 placebo-controlled component of an ongoing Phase 1/2 study evaluating NGM120 as a first-line treatment in combination with gemcitabine and Abraxane® (paclitaxel protein bound) in patients with metastatic pancreatic cancer. This Phase 2 component of the Phase 1/2 study will assess the efficacy, safety and tolerability of NGM120 or placebo in combination with gemcitabine or Abraxane against both cancer and cancer-related cachexia endpoints. The Phase 1a/1b dose-finding portion of the study is still ongoing, and NGM expects to report interim results from that portion of the study in the second half of 2021.

The Unmet Need

While immunotherapy, including checkpoint inhibition, has ushered in a new era of cancer treatment, many patients and types of cancer remain unresponsive to this revolutionary approach. Approved checkpoint inhibitors focus on ‘removing the brakes’ on T cell checkpoints so that they can unleash a more powerful immune attack against cancer. There is an increasing understanding that additional checkpoints may be implicated in blocking anti-tumor immunity.

To that end, Immunoglobulin-like transcript 2 (ILT2) and Immunoglobulin-like transcript 4 (ILT4), are key myeloid and lymphoid checkpoints that may restrict anti-tumor immunity, enable tumors to evade immune detection, and contribute to T cell checkpoint resistance.

ILT2 and ILT4 receptors expressed on myeloid cells in the tumor microenvironment are implicated in suppressing anti-tumor immune responses 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.

Our Approach

NGM scientists have spent several years researching members of the leukocyte Ig-like receptor (LILR) family of immunosuppressive receptors, including ILT2 and ILT4. NGM707, NGM’s first immuno-oncology candidate, is designed to potentially improve patient immune responses to tumors by inhibiting both the ILT2 and ILT4 receptors. NGM is advancing NGM707 toward the clinic and anticipated initiating first-in-human study of this drug in mid-2021.

1. Tirosh et al., Science, 2016
2. Li et al., Nat Genet, 2017
3. Puram et al., Cell, 2017
4. Azizi et al., Cell, 2018
5. Lambrechts et al., Nat Med, 2018
6. Sade-Feldman et al., Cell, 2018

The Unmet Need

NASH and metabolic diseases are among the largest unmet medical needs globally and represent a leading cause of morbidity and mortality and a significant burden for healthcare systems. They also represent areas of underinvestment by the pharmaceutical industry, driven in part by the biological complexity of the diseases and the substantial costs necessary to develop new therapeutics.

Metabolic syndrome is exhibited by 34% of adults in the US and is believed to be at the center of this health epidemic. Metabolic syndrome comprises a constellation of co-morbid conditions, including type 2 diabetes, obesity, high blood pressure, poorly regulated lipids and non-alcoholic fatty liver disease, or NAFLD, a precursor to non-alcoholic steatohepatitis, or NASH.

Our Current Focus

• Fibroblast growth factor 19, or FGF19, which plays a critical role in controlling bile acid, lipid and glucose metabolism
• Fibroblast growth factor receptor 1c-beta-klotho, or FGFR1c/KLB, which regulates insulin sensitivity, blood glucose and liver fat

Based on our novel insights, we believe these hormone pathways work through distinct mechanisms and play an important role in metabolic regulation.