GFB-024 for CB1-mediated kidney diseases

GFB-024 is a potential best-in-class, peripherally restricted cannabinoid 1 (CB1) inverse agonist monoclonal antibody, which we believe will benefit a subset of DN patients whose disease is caused by severe insulin resistant diabetes (SIRD). We believe that by targeting only peripheral receptors, GFB-024 minimizes the risk for CNS-associated adverse effects as was previously seen with first-generation CB1 small molecule inverse agonists.

GFB-024’s differentiating attributes

Clinically validated biological pathway that improved metabolic profile in obese patients

Improved podocyte and renal tubular function in preclinical models

CB1 pathway-specific biomarkers to potentially predict target engagement, treatment responses, and patient selection

Low risk of drug-drug interactions in patient population with high medication burden

Mechanism of GFB-024

The endocannabinoid (EC) system plays an important role in the regulation of energy balance by acting both at the central nervous system level and in peripheral tissues. CB1 and the enzymes involved in EC biosynthesis and degradation are present in key metabolic organs, including the liver, white and brown fat, pancreas, and kidney. Toggle

In normal kidneys, ECs and CB1 are both expressed at low levels in podocytes, mesangial cells, and proximal tubular cells. ECs are endogenous ligands for CB1 receptors in humans. In obese diabetic rodents, CB1 expression in the kidney is predominantly upregulated in podocytes and tubular cells. Podocyte-specific deletion of CB1 decreases albuminuria and podocyte cell death and protects renal proximal tubular cells from injury possibly by decreasing podocyte EC production. In addition, pharmacologic blockade of CB1 has been shown to improve renal function and reduce albuminuria and glomerular lesions in obese and diabetic mouse models.

In patients with DN, elevated circulating ECs and autocrine CB1 activation stimulate CB1 signaling in podocytes and proximal tubular cells. CB1 signaling induces mitochondrial dysfunction, resulting in podocyte apoptotic cell death and proteinuria. In proximal tubular cells, CB1 signaling impairs mitochondrial fatty acid oxidation, leading to cellular injury. Elevated plasma concentrations of free fatty acids and hyperglycemia enhance mitochondrial damage in podocytes and proximal tubular cells. Stimulation of CB1 signaling in proximal tubular cells upregulates glucose transporter 2 expression, resulting in increased glucose reabsorption and hyperglycemia.

Patients with SIRD are at higher risk of progression to CKD and macroalbuminuria and have a five times higher risk of ESKD progression compared to other patient subsets. SIRD patients are characterized by high BMI and greater insulin resistance compared with other patient subsets, and we believe both are associated with increased CB1 pathway activity.

Development status