Powerful Biology, Transformative Impact
Through our seamless, in-house integration of biology and biologics, we are building a robust pipeline of first-in-class and best-in-class drug candidates. Regardless of therapeutic area or disease, our drug candidates each target powerful disease-driving biology with the intent of delivering a transformative impact for patients.
NGM Bio has worldwide commercial rights to aldafermin.
Our most advanced program, aldafermin (previously NGM282), is an engineered variant of the human hormone FGF19, which we are developing as a once-daily injection for the treatment of non-alcoholic steatohepatitis (NASH). FGF19 is a highly specific and potent regulator of liver fat metabolism and bile acid synthesis that we believe is responsible for some of the beneficial effects of gastric bypass surgery on NASH.
In February 2020, we announced positive preliminary topline results from a 24-week double-blind, randomized, placebo-controlled Phase 2 clinical study (Cohort 4) of aldafermin in NASH patients with F2-F3 fibrosis. Cohort 4 was the final reported cohort from our adaptive Phase 2 clinical study of aldafermin in NASH.
Cohort 4 was powered to demonstrate the effect of 1 mg aldafermin treatment versus placebo on the primary endpoint of change in absolute liver fat content, which achieved statistical significance. In addition, the study assessed secondary and exploratory endpoints of liver histology and biomarkers of disease activity.
The histology results revealed that treatment with aldafermin led to clinically meaningful improvements at 24 weeks versus placebo in fibrosis improvement of ≥1 stage with no worsening of NASH (38% of aldafermin-treated patients vs. 18% placebo) and in resolution of NASH with no worsening of liver fibrosis (24% of aldafermin-treated patients vs. 9% placebo). The study also demonstrated a statistically significant impact on the composite endpoint of both fibrosis improvement and resolution of NASH (22% in aldafermin-treated patients vs. 0% placebo).
In the study, aldafermin continued to demonstrate a favorable tolerability profile.
Clinical Development Status
Our ongoing Phase 2b clinical development program for aldafermin includes:
- Phase 2b ALPINE 2/3: The 24-week study is designed to enroll approximately 150 patients with biopsy-confirmed NASH and F2-F3 and will assess the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg doses of aldafermin compared to placebo.
- Phase 2b ALPINE 4: The 48-week study is designed to enroll approximately 150 patients with biopsy-confirmed NASH cirrhosis (F4) and will assess the treatment effect on histology, defined as fibrosis regression of at least one stage without worsening of NASH of aldafermin compared to placebo.
FGFR1c/KLB Agonistic Antibody
NASH, Type 2 Diabetes
Merck licensed NGM313 and plans to conduct a Phase 2b study to evaluate the effect of NGM313 on liver histology and glucose control in NASH patients with or without diabetes.
NGM313 is an agonistic antibody binding to fibroblast growth factor receptor 1c-beta-klotho, or FGFR1c/KLB, which regulates insulin sensitivity, blood glucose and liver fat. NGM313, being developed as a once-monthly injection, has the potential to be a best-in-class insulin sensitizer for the treatment of type 2 diabetes (T2D) and NASH. NGM313 works by selectively activating the FGFR1c/KLB co-receptor complex, which regulates energy expenditure and glucose uptake in fat cells and other tissues.
In November 2018, NGM presented preliminary data at AASLD’s The Liver Meeting® in San Francisco from a Phase 1b proof-of-concept clinical trial of NGM313 in obese, insulin resistant subjects with nonalcoholic fatty liver disease, or NAFLD. The data demonstrated that a single dose of NGM313 resulted in a statistically significant reduction in liver fat content and improvements in multiple metabolic parameters.
Program Status and Upcoming Milestone
In January 2019, Merck exercised its option to license NGM313 (now renamed MK-3655). This one-time option to license NGM313, part of the original agreement announced by NGM and Merck in 2015, was triggered by NGM’s completion of the Phase 1b clinical study of NGM313. Based on the findings of this study, Merck intends to advance MK-3655 into a Phase 2b study to evaluate the effect of MK-3655 on liver histology and glucose control in NASH patients with or without diabetes.
Complement C3 Inhibitory Antibody
Merck has a one-time option to license NGM621 upon our completion of a proof-of-concept study in humans.
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 geographic atrophy (GA), and with the potential for every eight week dosing without pegylation.
GA is an advanced form of age-related macular degeneration (AMD), the leading cause of vision loss and blindness in people over the age of 65 in the US and other industrialized countries.
A progressive retinal degenerative disease, GA is associated with irreversible loss of vision, diminished quality of life, and eventual blindness. Dysregulated activation of the complement system, a key component of the immune system, has been implicated in the onset and progression of GA. There are currently no approved treatments for this disease.
NGM is currently conducting the Phase 2 CATALINA study, a multicenter, randomized, double-masked, sham-controlled clinical trial, to evaluate the safety and efficacy of intravitreal injections (IVT) of NGM621 in patients with GA secondary to AMD. Designed as a Phase 3-enabling study, the CATALINA study will enroll 240 patients diagnosed with GA in one or both eyes.
NGM successfully completed a first-in-human open-label Phase 1 study in which treatment with single- and multiple-dose IVT injections of NGM621 in patients with GA was well tolerated, supporting continued development. NGM presented NGM621 preclinical findings at The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, held virtually in June 2020. The presentations can be viewed here.Learn more about NGM621
GFRAL Antagonistic Antibody
Cancer and Cancer Anorexia / Cachexia Syndrome
Merck has a one-time option to license NGM120 upon our completion of a proof-of-concept study in humans.
NGM120 is a first-in-class antagonistic 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.
NGM Bio has worldwide commercial rights to NGM395.
NGM395 is an engineered long-acting variant of the human hormone known as growth differentiation factor 15, or GDF15. GDF15 drives profound metabolic activity by regulating fuel flux and has been considered a challenging therapeutic target. NGM discovered that metabolic activity of GDF15 is mediated by glial cell-derived neurotrophic factor receptor alpha-like, or GFRAL, which is located in a region of the brain stem outside of the blood-brain barrier. NGM395 is designed to stimulate a pathway that modulates the autonomic nervous system and, possibly, the neuroendocrine axis to modify body weight and fat levels in the body.
A Phase 1 study single ascending dose clinical study is underway evaluating the safety, tolerability and pharmacokinetics of NGM395 in obese but otherwise healthy adults.
"We are a biology-based company, not a disease-focused company. While we started off in metabolic diseases, we weren't afraid to explore other disease areas and learn from those. The opportunity to go into different diseases really interested me. It just makes it very diverse from the biology standpoint."