Data presented at the 42nd Annual Meeting of the American Society of Nephrology
San Francisco, CA, USA | November 2, 2009 | FibroGen, Inc. today announced that new research on its therapeutic development programs in kidney disease involving connective tissue growth factor (anti-CTGF) and hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors (PHI) was reported at the 42nd annual meeting of the American Society of Nephrology (ASN) Renal Week October 27-November 1, 2009, in San Diego, California.
CTGF Research Presented at Renal Week
In three presentations of clinical research, FibroGen and collaborators reported results from (1) a phase 1 study of FG-3019, the company’s human monoclonal antibody against CTGF, in patients with diabetes and advanced albuminuria, (2) a study of the effects of sodium intervention and angiotensin receptor blockade (ARB) on urinary CTGF levels in patients with non-diabetic proteinuria, and (3) a study of how proximal tubular function affects excretion and urinary levels of CTGF. Three other presentations on nonclinical research highlighted new insights into CTGF signaling activity in kidney cells (podocytes and mesangial cells) that may contribute to progression of diabetic kidney disease (DKD).
● A randomized, double blind placebo-controlled, phase 1 study of safety, pharmacokinetics (PK) and pharmacodynamics (PD) of FG-3019 in subjects with type 1 or type 2 diabetes mellitus and DKD on background ACEi and/or ARB therapy (Abstract #F-PO1357)1
The study purpose was to characterize safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of FG-3019 administered intravenously over 10 weeks in subjects with overt nephropathy on a stable background regimen of angiotensin blockade. The results demonstrated that FG-3019 was well tolerated; blood pressure was stable over the course of the trial; PK of FG-3019 was generally comparable in this study of subjects with advanced albuminuria compared to those observed in a previous study of patients with microalbuminuria2; and, as observed in previous trials, treatment with FG-3019 was associated with an increase in levels of CTGF in the plasma, likely due to co-complex formation of CTGF with FG-3019, and appeared to reach a plateau after 8-10 weeks of dosing.
● Sodium restriction, losartan, and hydrochlorothiazide reduce elevated urinary CTGF/CCN-2 levels in patients with non-diabetic proteinuria (Abstract #SA-PO2234)3
Previous research has shown that ARB therapy improves outcomes in human DKD4,5 and reduces urinary levels of CTGF6. This new study examined the effects of a high or low sodium diet in combination with ARB therapy in patients with proteinuria and chronic kidney disease (CKD) but who did not have diabetes. The results showed that plasma and urinary CTGF levels were elevated in non-diabetic proteinuric CKD patients, and urinary CTGF levels were reduced by sodium restriction, losartan, and addition of the diuretic, hydrochlorothiazide, to losartan.
● Renal proximal tubular dysfunction is a major determinant of urinary CTGF excretion (Abstract #SA-PO2976)7
Previous research has shown that urinary CTGF excretion correlates with severity of renal disease and may have prognostic value. This new study examined how the kidney handles CTGF and what mechanisms may lead to abnormal elevations in urinary CTGF excretion. It was found that CTGF is normally reabsorbed almost completely in proximal tubules via megalin (an endocytic receptor involved in protein uptake) and that elevated urinary CTGF excretion largely reflects dysfunction of the proximal tubules. These data suggest that urinary CTGF levels is in part a manifestation of renal handling of CTGF protein.
● CTGF results in Cdc42 activation and altered actin binding protein expression (Abstract #SA-PO2938)8
Overexpression of CTGF in podocytes has been shown to worsen DKD in a rodent model of diabetes9. This new study further elucidates the molecular mechanisms underlying CTGF’s role in podocyte dysfunction, showing that CTGF activates Cdc42, which is associated with disruption of podocyte structure.
● CTGF activates canonical Wnt signaling in mesangial cells through direct interaction with LRP6; implications for the pathogenesis of diabetic nephropathy (Abstract #SA-PO2937)10
The canonical Wnt signaling pathway involves a network of proteins that mediates cellular responses to extracellular stimuli, ultimately through activation of target genes. This new study found in biopsies from patients with DKD, that a significant number of genes directly targeted by the Wnt signaling pathway are differentially activated. The ability of CTGF to stimulate the Wnt signaling pathway in mesangial cells via interaction with the LRP6 cell surface receptor was also demonstrated in this study. Taken together, the findings suggest that Wnt/CTGF signaling may contribute to DKD.
● CTGF/CCN2 and TGFβ superfamily signaling: implications for therapeutic intervention (Abstract #SA-PO2940)11
CTGF has a unique multi-modular structure that enables it to mediate interactions with a variety of other molecules. Understanding how each modular CTGF domain orchestrates signals and controls disease processes may be important to the design of domain-specific anti-CTGF therapeutic agents having the ability to reverse domain-specific effects. Using mesangial cells, this new study demonstrated that CTGF-mediated cell signaling and regulation of transforming growth factor-beta (TGF-β) superfamily signaling acts, at least in part, through the VWC domain of CTGF.
HIF-PHI Research Presented at Renal Week
In an oral presentation, new insights were reported on the kidney stress response to hypoxia involving cross-talk between HIF and another key transcription factor known as signal transducer and activator of transcription (STAT).
● Renal hypoxia inducible factors (HIF) and STAT3 cross-talk in vivo (Abstract #F-FC184)12
Hypoxia response is likely shaped by combined action of several transcription factors, including HIF and STAT3. Both are activated during hypoxia, and induce shared target genes, such as heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF). The new study examined possible cross-talk between HIF and STAT3 in the rodent kidney in vivo. Several lines of evidence, including treatment with the HIF-PHI FG-4497, suggested that HIF activation may lead to enhanced renal STAT3 activation as part of a cellular stress adaptation.
About FibroGen
FibroGen, Inc. is a biotechnology-based drug discovery company using its expertise in the fields of tissue fibrosis, connective tissue growth factor (CTGF), and hypoxia-inducible factor (HIF) biology to discover, develop, and commercialize novel therapeutics for fibrotic disorders, diabetic complications, anemia, conditions associated with tissue damage or injury, cancer, and other areas of unmet medical need. FibroGen also develops and produces recombinant human collagens and gelatins using unique production technology that provides the basis for FibroGen’s proprietary cosmetic dermal filler and biomaterials supply business.
References
1. Singh B, Bernardo MV, Bode B, Berg J, Liaw S, Li G, Lilienfeld D: A randomized, double blind placebo-controlled, phase 1 study of safety, pharmacokinetics (PK) and pharmacodynamics (PD) of FG-3019 in subjects with type 1 or type 2 diabetes mellitus and DKD on background ACEi and/or ARB therapy [Abstract]. J Am Soc Nephrol 20: 423, 2009
2. Schwartz S, Williams ME, Arauz C, Bolton WK, Lee T, Coker G, Sewell KL, Adler SG: Phase I study of FG-3019, an anti-CTGF monoclonal antibody, in type 1/2 diabetes mellitus with microalbuminuria [Abstract]. Diabetes 56: 151, 2007
3. Slagman MCJ, Nguyen TQ, Waanders F, Vogt L, Hemmelder MH, Oliver N, Navis GJ, Goldschmeding R, Laverman GD: Sodium restriction, losartan, and hydrochlorothiazide reduce elevated urinary CTGF/CCN-2 levels in patients with non-diabetic proteinuria [Abstract]. J Am Soc Nephrol 20: 620, 2009
4. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, the Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851-860, 2001
5. Brenner BM, Cooper ME, De Zeeuw D, Keane WF, Mitch WE, Parving H-H, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy: N Engl J Med 345: 861-869, 2001
6. Andersen S, van Nieuwenhoven FA, Tarnow L, Rossing P, Rossing K, Wieten L, Goldschmeding R, Parving HH: Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy. Kidney Int 67: 2325-2329, 2005
7. Gerritsen KG, Peters HP, Nguyen TQ, Koeners MP, Wetzels JF, Joles JA, Christensen EI, Verroust PJ, Li D, Xu L, Oliver N, Kok RJ, Goldschmeding R: Renal proximal tubular dysfunction is a major determinant of urinary CTGF excretion [Abstract]. J Am Soc Nephrol 20: 790, 2009
8. Browne MB, Faherty N, Xu L, Oliver N, Crean JK: Connective tissue growth factor (CTGF) results in Cdc42 activation and altered actin binding protein expression [Abstract]. J Am Soc Nephrol 20: 781, 2009
9. Yokoi H, Mukoyama M, Mori K, Kasahara M, Suganami T, Sawai K, Yoshioka T, Saito Y, Ogawa Y, Kuwabara T, Sugawara A, Nakao K: Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. Kidney Int 73: 446-455.
10. Rooney BV, O’Donovan H, Brazil DP, Xu L, Oliver N, Godson C, Sadlier D, Crean JK: CTGF activates canonical Wnt signaling in mesangial cells through direct interaction with LRP6; implications for the pathogenesis of diabetic nephropathy [Abstract]. J Am Soc Nephrol 20: 781, 2009
11. O’Donovan HC, Faherty N, Xu L, Oliver N, Godson C, Crean JK: CTGF/CCN2 and TGFβ superfamily signaling: implications for therapeutic intervention [Abstract]. J Am Soc Nephrol 20: 782, 2009
12. Nechemia-Arbely Y, Rosenberger C, Khamaisi M, Koesters R, Shina A, Klaus S, Shriki A, Rosen S, Axelrod JH, Heyman SN: Renal hypoxia inducible factors (HIF) and STAT3 cross-talk in vivo [Abstract]. J Am Soc Nephrol 20: 44, 2009
SOURCE: FibroGen, Inc.
