CB4211

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Key Highlights - CB4211

  •   Is a novel and improved analog of MOTS-c, a naturally occurring mitochondrial derived peptide (MDP) that plays a key role in regulating metabolism
  •   Has resulted in significant impacts on NASH and obesity in multiple preclinical models
  •   Has been shown in a clinical study to significantly reduce ALT and AST, key biomarkers of liver damage, as well as glucose levels compared to placebo
  •   Resulted in a trend towards lower body weight compared to placebo in a clinical trial

Clinical Development

In August 2021, we announced positive topline data from our Phase 1a/1b study of CB4211 under development for NASH and obesity. The Phase 1b portion of trial was a 4 week, multi-center, randomized, double blind, placebo-controlled clinical study in 20 obese subjects with fatty liver disease.

Results: The study met its primary endpoint showing that CB4211 was well-tolerated and appeared safe with no serious adverse events. Evaluation of the exploratory pharmacodynamic endpoints from the Phase 1b stage of the study comparing CB4211 to placebo demonstrated robust and significant reductions in key biomarkers of liver damage, ALT and AST, a significant decrease in glucose levels, and a trend towards lower body weight after four weeks of treatment. Both the CB4211 and placebo groups had substantial reductions in liver fat content compared to baseline.

Key findings from the study are summarized below.

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CB4211 Phase 1a/1b Topline Results

Biomarker CB4211 (25 mg)
(n = 11)		 Placebo
(n = 9)		 Difference from Placebo
ALT
(% reduction from baseline)		 -21% 4% -251
Proportion of subjects with >17 U/L decrease in ALT2 27% 11% 16%
AST
(% reduction from baseline)		 -28% -11% -17%1
Glucose
(% reduction from baseline)		 -6% 0% -6%1

ALT: Alanine aminotransferase. AST: Aspartate aminotransferase.

1 Statistically significant versus placebo, p<0.05 by unpaired t test

2 A decrease in ALT by 17 U/L or more is significantly associated with histologic response in NASH (Loomba R et al. Gastroenterology, 2019; 156 (1): 88-95)

MRI-PDFF Data1 CB4211 (25 mg)
(n = 11)		 Placebo
(n = 9)
Baseline Liver Fat Content (LFC) 21.1% 15.9%
Percent Reduction in LFC (Absolute) -5.03% -4.88%
Proportion of Responders Achieving >30% Relative Reduction in LFC2 36% 33%

1 MRI-PDFF: Magnetic resonance imaging – proton density fat fraction.

2 A relative reduction of 30% in liver fat is associated with a histological response in NASH (Patel J et al. Therap Adv Gastroenterol 2016, 9(5): 692-701)

MOTS-c: The Natural Starting Point

MOTS-c, a natural peptide encoded with in the mitochondrial genome, has been shown to impact a variety of processes relevant to NASH, including metabolic homeostasis, stimulation of glucose metabolism, insulin sensitivity, and obesity. CB4211 is a novel analog of MOTS-c with improved properties compared to the natural peptide.

CB4211: A Potential Role in Metabolic Homeostasis

We investigated the mechanism of action of CB4211 in regulating fatty acid metabolism, glucose homeostasis, and insulin sensitivity. These studies demonstrated that CB4211 potentiates insulin effects on fatty acid metabolism and glucose homeostasis by extending the duration of insulin receptor (IR) activation without altering the magnitude of the response or activation of highly related receptors. For example, CB4211 potentiated insulin-mediated inhibition of lipolysis in isoproterenol-stimulated adipocyte cultures without changing maximal response, while CB4211 alone had no effect. Subsequent de-phosphorylation of IR and downstream targets (IRS-1 and Akt) was markedly slowed in the presence of insulin with CB4211 compared to insulin alone. Inhibitors of IR auto-phosphorylation (GSK183705A) or downstream PI3K/Akt signaling pathway components (wortmannin, Akti-1/2) abolished the antilipolytic effects of insulin alone and in combination with CB4211. Further supporting specificity of insulin signaling, CB4211 enhanced insulin-mediated phosphorylation of IR, IRS-1, and Akt, without affecting IGF mediated phosphorylation of IGF-1R. Consistent with activity through IR, CB4211 potentiated insulin-induced reduction in glucose production in H4-IIE cells. The acute in vivo effect of CB4211 on insulin tolerance was determined in fasted DIO mice. Administration of CB4211 with insulin enhanced insulin sensitivity, prolonging the reduction in blood glucose levels compared to insulin alone.