Focal segmental glomerulosclerosis (FSGS) is a clinical entity that impacts renal function through progressive fibrosis of the glomerulus. FSGS is not a single disease; rather, it is a heterogeneous clinicopathological process identified in renal biopsies that are generally performed in patients with proteinuria or nephrotic syndrome. Idiopathic or primary FSGS has a distinctive histopathological appearance, characterized by hyalinization and sclerosis of a portion of the glomerular tuft, minimal deposition of immune complexes, and effacement of visceral epithelial cell (podocyte) foot processes. Idiopathic FSGS can be distinguished from secondary causes of FSGS (for example, genetic mutations, medications, infections, reflux nephropathy, or surgical reduction in renal mass) by more widespread podocyte effacement together with the presence of nephrotic syndrome.1
The implication for making the distinctions is that primary FSGS may respond to corticosteroids or other immunosuppression therapy, whereas secondary forms are treated by addressing the underlying cause. Regardless of the etiology of FSGS, the majority of cases are characterized by progressive renal fibrosis and steady deterioration in kidney function.2, 3, 4
In FSGS, the beneficial effects of angiotensin-converting enzyme inhibitor treatment on proteinuria and preservation of renal function have led to their widespread use in this population.5, 6, 7, 8, 9, 10, 11, 12
High-dose and/or prolonged oral corticosteroid therapy has been the primary treatment for FSGS and a treatment response indicates a better long-term outcome in a small percentage of patients.13, 14
Cyclosporine is the only agent that has been documented to be efficacious for reduction of proteinuria in controlled trials in both children and adults with steroid-resistant FSGS.15, 16, 17, 18
There are also uncontrolled studies suggesting that tacrolimus, sirolimus, mycophenolate mofetil, or rituximab may induce remission in patients with primary FSGS.19, 20, 21, 22, 23, 24, 25
However, in the majority of primary FSGS patients, treatment with steroids and other therapeutic interventions result in only transient improvement in proteinuria and does not alter disease course.26
This may be especially true in patients with genetic mutations leading to FSGS.1, 27
Because of the poor prognosis of and the lack of a proven treatment for patients with steroid-resistant FSGS, there is a pressing need for new treatments that can reduce proteinuria and slow down or stop the progression of renal damage.
Several lines of evidence point toward an important role of transforming growth factor-β (TGF-β) in disease pathogenesis and progression of primary FSGS. TGF-β is well known to be a modulator of extracellular matrix production and is associated with interstitial fibrosis in renal disease.28
More recently, TGF-β has been recognized as a key regulator of the glomerular visceral epithelial cell, or podocyte, a pivotal cell in the pathogenesis of FSGS. Overexpression of TGF-β in podocytes leads to podocytopenia and glomerulosclerosis.29
In cultured podocytes, TGF-β influences cell survival29, 30, 31, 32
and induces changes in the cytoskeleton and cell adhesion that are analogous to in vivo
foot process effacement.33
TGF-β also activates several signaling pathways, including the Smad cascade, that have demonstrated roles in glomerular pathogenesis in animal models.34, 35
Both FSGS patients and experimental animal models demonstrate increased expression of TGF-β in the kidney and increased urinary excretion of the growth factor.36
Biopsies of FSGS patients reveal increased immunostaining for TGF-β in glomerular endothelial cells.37
Therefore, these findings suggest that modulation of TGF-β activity within the kidney, with consequent effects on key cell components of the glomerulus and signaling molecules, may be renoprotective and have a beneficial effect on the severity or progression of FSGS.
One strategy for altering TGF-β is by antagonism with a monoclonal antibody. Fresolimumab, a member of the G4 immunoglobulin (IgG4) subclass, is an engineered human monoclonal antibody that neutralizes all three isoforms of TGF-β. This IgG subclass does not activate the complement pathway, a potential favorable feature of the antibody. Data from diverse animal models demonstrate that neutralization of TGF-β can inhibit tissue fibrosis.38
For example, therapeutic administration of a mouse analog of fresolimumab (1D11) to a murine model of chronic cyclosporine nephropathy reduced collagen deposition, epithelial cell apoptosis, and normalized tissue hypoxia.39
1D11 has also been shown to preserve glomerular selectivity and prevent ultrastructural changes to the glomerular filtration barrier during hypertension.40
In a model of diabetic nephropathy, administration of 1D11 combined with enalapril was antihypertensive, antiproteinuric, reduced glomerulosclerosis, and preserved podocyte number.41
These results provide evidence that TGF-β antagonism is effective in preventing and reducing the structural and functional consequences of chronic renal injury.
The primary objectives of this phase I clinical trial in patients with treatment-resistant primary FSGS and nephrotic-range proteinuria were to determine: (1) the safety and tolerability of single-dose infusions of fresolimumab; and (2) the pharmacokinetics of fresolimumab following single-dose infusions of fresolimumab. The secondary objective was to obtain preliminary data about the effect of single-dose infusions of fresolimumab on proteinuria and kidney function.