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Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria - pdf full text attached
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Download the pdf here
Published ahead of print on June 3, 2010
Clinical Journal of the American Society of Nephrology
"In conclusion, this open-label phase 1 trial showed that FG- 3019, a human monoclonal antibody to CTGF, is well tolerated for at least 6 weeks in type 1 and type 2 diabetic subjects with microalbuminuria when administered by sequential intravenous infusion given every other week. Anti-FG-3019 antibodies were not detected in this study, which is consistent with other studies in which FG-3019 was infused. Preliminary efficacy data, to be interpreted with caution because of the uncontrolled open-label design, suggest a rapid and significant decline in urine ACR under treatment, particularly in subjects with higher baseline microalbuminuria, and warrant further clinical trials in subjects with more advanced DKD."
"Analysis of pooled data showed a significant average decline in mean ACR (albumin/creatinine ratio) from baseline to day 56 of 27 (+/-49) mg/g (p=0.027) (Table 6, Figure 2). The subjects with the most pronounced (>50%) decline in ACR (n =6) tended to have higher baseline ACR than those remaining more stable. Their mean baseline ACR was 100 (+/-84) mg/g (range = 42 to 268 mg/g), which fell to 30 mg/g (+/-18) (range 14 to 63 mg/g) on day 56.....During the washout period from the last infusion on day 42 to day 84, urinary ACR returned to baseline in the 3-mg/kg cohort but remained low in the 10-mg/kg cohort....Serum Cr and eGFR were stable in the efficacy population.....HbA1c was measured in 12 subjects (8 receiving FG-3019 at 10 mg/kg and 4 receiving FG-3019 at 3 mg/kg) and remained stable over time"
Sharon G. Adler*, Sherwyn Schwartz{dagger}, Mark E. Williams{ddagger}, Carlos Arauz-Pacheco, Warren K. Bolton||, Tyson Lee , Dongxia Li , Thomas B. Neff , Pedro R. Urquilla , and K. Lea Sewell
* Division of Nephrology and Hypertension, Los Angeles BioMedical Research Institute, Torrance, California; {dagger} Diabetes and Glandular Disease Clinic, San Antonio, Texas; {ddagger} Renal Unit, Joslin Clinic, Boston Massachusetts; Radiant Research, Dallas Texas; || Division of Nephrology, University of Virginia School of Medicine, Charlottesville, Virginia; and FibroGen, Inc., San Francisco, California
Correspondence: Dr. Sharon G. Adler, Los Angeles BioMed Research Institute, 1124 West Carson Street, Building C1 Annex, Torrance, CA 90502. Phone: 310-222-3891; Fax: 310-782-1837; E-mail: sadler@labiomed.org
ABSTRACT
Background and objectives: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins.
Design, setting, participants, and measurements: Microalbuminuric subjects (n = 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively.
Results: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P = 0.027) without evidence for a dose-response relationship.
Conclusions: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.
Patients with diabetic kidney disease (DKD) are at increased risk for cardiovascular complications and early mortality. Those who survive long enough tend to progress to ESRD requiring dialysis or transplantation. Although advances in therapy with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor type II blockers (ARBs) have attenuated the incident rate of ESRD (1), disease progression remains common (2- 4) and diabetes continues to be the leading cause for initiation of dialysis in the United States (1).
Connective tissue growth factor (CTGF) is a 349-amino-acid secreted pleiotropic protein belonging to the cysteine-rich CCN (CTGF/Cyr61/Cef10/NOVH) family. Numerous glomerular, tubulointerstitial, and vascular cells types can produce CTGF, and many factors associated with the diabetic condition can stimulate CTGF expression, including hypertension, hyperglycemia, and hyperlipidemia (5- 24).
CTGF is a critical mediator of extracellular matrix accumulation and coordinates a final common pathway of fibrosis (5,25,26). CTGF has been shown to amplify the fibrogenic activity of TGF_ (27) and IGF-1 (17) and to inhibit the action of antifibrotic and regenerative factors bone morphogenic protein-7 (27,28) and vascular endothelial growth factor (29,30).
In type 1 diabetes, plasma and urine CTGF levels correlate with the level of albuminuria and the stage of progressive renal insufficiency (31- 34), and the plasma CTGF level is an independent predictor of vascular disease as assessed by intimal medial thickness (35) and of mortality and progression to ESRD (36). In renal biopsy specimens from patients with diabetes, elevated levels of CTGF mRNA are associated with chronic tubulointerstitial damage, albuminuria, and progression of renal insufficiency (37- 39).
FG-3019 is a recombinant human anti-CTGF monoclonal IgG1 antibody that has shown activity in rodent models of kidney dysfunction associated with type 1 and 2 diabetes (40- 42). Here, we report results of an open-label dose-escalation trial of FG-3019 infusions administered biweekly over 56 days in patients with DKD, the first study designed to evaluate safety and potential therapeutic effect of FG-3019 in this patient population.
Discussion
This is the first phase 1, open-label, dose-escalation trial of FG-3019, an investigational human monoclonal antibody to CTGF, in subjects with type 1 or 2 diabetes and microalbuminuria. Both doses of FG-3019 (3 and 10 mg/kg) were well tolerated during four infusions over 42 days.
Pharmacokinetic analysis indicated that drug clearance was saturable. Clearance was slower for the 10-mg/kg dose than for the 3-mg/kg dose and slower for the fourth dose than the first dose. These results suggest a high-affinity, low-capacity clearance mechanism such as binding to target CTGF, superimposed on the background low-affinity clearance of antibody. T1/2 was approximately 5 to 6 days after four doses of FG-3019, which is shorter than the typical IgG T1/2 of 10 to 14 days. This is unlikely to reflect antigen-mediated clearance because the assay for FG-3019 measures free (not antigen-bound) antibody, and FG-3019 was present in significant molar excess over CTGF N-fragment bound to the antibody. FG-3019 was previously evaluated in an open-label, dose-escalation trial in subjects with moderately severe idiopathic pulmonary fibrosis, and the single- dose pharmacokinetic data were similar (45).
Although there are varying reports regarding association of urinary CTGF with DKD (32,46), the results reported here show that diabetic subjects with microalbuminuria did not have elevated urinary CTGF values. Plasma levels of CTGF-whole were low in these subjects, and changes could not be measured. Plasma levels of CTGF N-fragment significantly increased over a period of 3 to 7 days after each FG-3019 infusion, possibly reflecting slower clearance of the CTGF N-fragment-FG-3019 complex compared with the small (approximately 19 kD) uncomplexed CTGF N-fragment, which may be freely filtered by the kidney.
Our observations are subject to some limitations. This was an exploratory open-label study, underpowered for efficacy and subject to confounding effects that might affect apparent efficacy. Nevertheless, urine albumin excretion and tubular dysfunction as reflected by 2M/Cr decreased at the primary end point (day 56). These declines were not correlated with starting concentrations of CTGF, and there was no clear and consistent correlation between ACR response and starting concentrations of any other biomarker. Both dose groups had apparent responders, and although there was no obvious dose-response relationship, the duration of response trended longer in the 10-mg/kg cohort. Small MAP decrements of approximately 4 mmHg were noted in the 3- and 10-mg/kg dosing groups at day 56, and confounding by blood pressure cannot be completely excluded. However, no meaningful difference between responders and nonresponders in blood pressure or MAP after therapy was found.
Although an antibody to CTGF would be anticipated to modulate extracellular matrix synthesis, it may have additional biologic effects. FG-3019 may block CTGF-mediated effects on glomerular capillary permeability, possibly related to functional and structural changes in podocytes or tubular cells.
Studies using rodent models of diabetes have demonstrated early upregulation of CTGF before TGF with CTGF expression primarily in podocytes, (6) and the development of more severe DKD in mice overexpressing CTGF specifically in podocytes (47). Heterozygous CTGF knockout mice developed less severe albuminuria and glomerular basement membrane thickening with diabetes (48), and a CTGF antisense oligonucleotide decreased albuminuria, mesangial hypertrophy, and the increased serum Cr in murine models (streptozotocin and db/db) of type 1 and 2 diabetes (49).
In conclusion, this open-label phase 1 trial showed that FG- 3019, a human monoclonal antibody to CTGF, is well tolerated for at least 6 weeks in type 1 and type 2 diabetic subjects with microalbuminuria when administered by sequential intravenous infusion given every other week. Anti-FG-3019 antibodies were not detected in this study, which is consistent with other studies in which FG-3019 was infused. Preliminary efficacy data, to be interpreted with caution because of the uncontrolled open-label design, suggest a rapid and significant decline in urine ACR under treatment, particularly in subjects with higher baseline microalbuminuria, and warrant further clinical trials in subjects with more advanced DKD.
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