NGM Biopharmaceuticals announced preliminary results from a Phase 1b proof-of-concept clinical trial of NGM313 in obese, insulin resistant subjects with nonalcoholic fatty liver disease (NAFLD). The data demonstrated that a single dose of NGM313, a proprietary, investigational agonistic antibody that selectively activates the β-Klotho/FGFR1c receptor complex, resulted in a statistically significant reduction in liver fat content (LFC) and improvements in multiple metabolic parameters.

"With an estimated 17.5 million patients in the United States alone with type 2 diabetes and NASH, there is a substantial unmet medical need for a single treatment that addresses pathophysiological states common to both diseases, including insulin resistance, lipid metabolism dysfunction and lipotoxicity in the liver," said Alex DePaoli, M.D., Senior Vice President and Chief Medical Officer at NGM. "We are encouraged by these results and believe they support NGM313's potential as an insulin sensitizer for use as a monotherapy or in combination with other drug classes, like incretins, to normalize glucose levels and halt the progression of, and potentially reverse, NASH."

In 2015, NGM entered into a five-year research collaboration, product development and license agreement with Merck. Under the terms of the collaboration, Merck has a one-time option to license NGM313 upon NGM's completion of a proof-of-concept study in humans. Merck is required to make a determination with respect to its option to license NGM313 by the end of 2018.

The Phase 1b randomized, open-label, active-controlled parallel group study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of NGM313 in obese, insulin resistant subjects with NAFLD. Twenty five subjects were randomized 2:1 to either a single subcutaneous 240 mg dose of NGM313 (n=17) or a daily oral dose of 45 mg pioglitazone (n=8) for 36 days. The primary objectives of the study were to evaluate changes from baseline in LFC as measured by MRI-PDFF at day 36 and changes from baseline in insulin sensitivity at day 29 in subjects treated with NGM313 as compared to pioglitazone. MRI-PDFF was performed at day 1, day 23 and day 36 and read centrally by a radiologist blinded to treatment assignment.
Preliminary results indicated that a single dose of NGM313 resulted in a statistically significant least squares mean change from baseline to day 36 of -6.3% and -37% in absolute and relative LFC, respectively (p<0.0001), while the highest approved daily oral dose of 45 mg pioglitazone resulted in a statistically significant least squares mean change from baseline to day 36 of -4.0% and -25%, respectively (p<0.001). Furthermore, 63% of patients in the NGM313-treated group experienced a relative LFC reduction of ≥30% at day 36 after a single dose, as compared to 25% of patients in the pioglitazone treated group. A relative reduction of LFC of approximately 30%, as measured by MRI-PDFF, has translated into a favorable histological response as evidenced by a NAS improvement of two stages or greater.

In addition, preliminary results from the study demonstrated that a single dose of NGM313 resulted in a mean decrease from baseline of 0.24% in HbA1c at day 36, as compared to a mean decrease of 0.11% with a daily dose of pioglitazone. A reduction in HbA1c of the magnitude observed in this study's insulin resistant, non-diabetic patient population in this time frame supports the promise of NGM313 to potentially improve glucose control in type 2 diabetes patients. Neither group experienced hypoglycemia. Treatment with NGM313 also resulted in statistically significant reductions from baseline in the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), serum concentrations of fasting glucose, ALT, AST, triglycerides and LDL cholesterol, and a statistically significant increase in HDL cholesterol levels at day 28 (p<0.05).

Preliminary data indicate that NGM313-treated patients had an increase from baseline in body weight of 1.6 kg at day 36, as compared to a 2.4 kg increase from baseline in body weight with pioglitazone. Patients treated with NGM313 did not experience hemodilution or edema.

NGM313 was well-tolerated, with no serious adverse events. All adverse events observed during the course of the study were deemed mild, with increased appetite (12%) and injection site reactions (12%) being the only adverse events reported in at least 10% of the NGM313-treated subjects.

"Based on these data, NGM313 has demonstrated potential as a potent insulin sensitizer for the treatment of both NASH and type 2 diabetes," said Dr. DePaoli. "In addition, clinically meaningful metabolic changes in NGM313-treated patients were seen after only a single dose. We believe the data support advancing NGM313 into a Phase 2b study to evaluate the effect of NGM313 on liver histology and glucose control in NASH patients with or without diabetes."

NGM313, a proprietary, investigational agonistic antibody discovered by NGM scientists, works by selectively activating the β-Klotho/FGFR1c receptor complex, which regulates energy expenditure and glucose uptake in fat cells and other tissues. NGM313 binds to a unique epitope of β-Klotho, resulting in the selective activation of FGFR1c and signaling through the metabolic pathway utilized by FGF21-based ligand therapies. It does not trigger signaling through other FGF receptors, such as FGFR2c, FGFR3c or FGFR4, potentially minimizing risks associated with FGF21-based ligand therapies. In Phase 1 studies, NGM313 has demonstrated potential as a once-monthly injectable insulin sensitizer that was safe and well-tolerated.

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