A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis
Authors: Howard Trachtman, Fernando C. Fervenza, Debbie S. Gipson, Peter Heering, David R.W. Jayne, Harm Peters, Stefano Rota, Giuseppe Remuzzi, L. Christian Rump, Lorenz K. Sellin, Jeremy P.W. Heaton, James B. Streisand, Marjie L. Hard, Steven R. Ledbetter, Flavio Vincenti
Journal: Kidney International (2011)

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2, and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m2). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary. Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2, and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m2). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary. 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.Barisoni L. Schnaper H.W. Kopp J.B. Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy.Arch Pathol Lab Med. 2009; 133: 201-216PubMed Google Scholar 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.2Levey A.S. Coresh J. 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González E. et al.Rituximab treatment of adult patients with steroid-resistant focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2009; 4: 1317-1323Crossref PubMed Scopus (102) Google Scholar 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.Cameron J.S. Focal segmental glomerulosclerosis in adults.Nephrol Dial Transplant. 2003; 18: vi45-vi51Crossref PubMed Google Scholar This may be especially true in patients with genetic mutations leading to FSGS.1.Barisoni L. Schnaper H.W. Kopp J.B. Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy.Arch Pathol Lab Med. 2009; 133: 201-216PubMed Google Scholar, 27.Ruf R.G. Schultheiss M. Lichtenberger A. et al.Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome.Kidney Int. 2004; 66: 564-570Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar 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.Rosenbloom J. Castro S.V. Jimenez S.A. 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Moon K.C. et al.Activation of the TGF-β/Smad signaling pathway in focal segmental glomerulosclerosis.Kidney Int. 2003; 64: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar 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.Gagliardini E. Benigni A. 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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. All 16 patients who were enrolled completed the study, 4 at each dose level. Of the 16 patients, 9 (4 patients in the 1 mg/kg group, 2 patients in the 2 mg/kg group, and 3 patients in the 4 mg/kg group) had detectable levels of fresolimumab at day 112. They returned for follow-up visits until fresolimumab was no longer detectable in the blood. The longest duration of additional follow-up after day 112 was 141 days. The mean age of the patients was 37±12 years, mean FSGS duration was 3.0±2.1 years, half were male, 13 were White, and 3 were Black. Overall, the baseline characteristics of the patients were similar between dose groups (Table 1 and Supplementary Table S1 online).Table 1Patient demographics in patients receiving fresolimumab by dose0.3 mg/kg (N=4)1 mg/kg (N=4)2 mg/kg (N=4)4 mg/kg (N=4)Total (N=16)Age (years), mean±s.d.33.0±12.433.8±14.344.3±6.738.5±13.437.4±11.8Male gender, n (%)1 (25.0)3 (75.0)1 (25.0)3 (75.0)8 (50.0)Race, n (%) Black02 (50.0)1 (25.0)03 (18.8) White4 (100.0)2 (50.0)3 (75.0)4 (100.0)13 (81.3)Duration since FSGS diagnosis (years), mean±s.d.3.9±3.41.8±1.53.2±1.23.0±1.63.0±2.1Baseline Up/c ratio (mg/mmol), median845.0666.1376.2713.5736.5Baseline eGFR (ml/min per 1.73 m2), median36.238.839.362.438.6Abbreviations: eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; Up/c, urine protein : creatinine ratio.To convert mg/mmol to mg/mg, divide by 113.11. Open table in a new tab Download .doc (.07 MB) Help with doc files Supplementary Information Abbreviations: eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; Up/c, urine protein : creatinine ratio. To convert mg/mmol to mg/mg, divide by 113.11. At the time of enrollment, 15 out of 16 (94%) patients were on a concomitant medication. The most commonly prescribed drugs were agents acting on the renin-angiotensin system in 14 cases. A total of 12 subjects were receiving a lipid-lowering agent, 11 were given a diuretic, and 4 were receiving aspirin. The use of these agents was comparable in the four patient cohorts. Fresolimumab was well tolerated at single doses up to the maximum level of 4 mg/kg in patients with FSGS. No patient withdrew consent or discontinued participation before completing the study. No profound immunologic or systemic inflammatory reactions were seen in any patient. The DMC (Data Monitoring Committee) recommended continued dosing following each dosing cohort. Infusion-associated reactions, defined as events that occurred within 24 h of infusion and assessed by the investigator as related to fresolimumab, were noted in only one patient who had a cough during infusion of the antibody. The frequencies of reported treatment-emergent adverse events (TEAEs) were similar across the dose groups. Of the 16 patients, 15 (93.8%) reported a total of 73 TEAEs. The most frequent TEAEs reported were peripheral edema (4 patients) and nasopharyngitis (3 patients); all other TEAEs were reported by ≤2 patients. All TEAEs except 1 (grade 3 urticaria in a patient with a history of urticaria) were of grade 1 or 2 intensity (mild or moderate). Overall, 7 patients (43.8%) experienced at least 1 TEAE that was considered by the investigator to be related to the study drug (Table 2). Pustular rash, reported by 2 (12.5%) patients, was the most frequently reported related TEAE. All other drug-related events were single occurrences experienced by individual patients. All related TEAEs resolved by the end of the patient's participation in the study. No patients experienced a serious TEAE or died during the study. Following completion of the study, 1 patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years posttreatment.Table 2Treatment-related adverse eventsSystem organ class/preferred term0.3 mg/kg (N=4), n (%)1 mg/kg (N=4), n (%)2 mg/kg (N=4), n (%)4 mg/kg (N=4), n (%)Total (N=16), n (%)Any related adverse event (AE)1 (25)3 (75)1 (25)2 (50)7 (43.8)Gastrointestinal disorders001 (25)1 (25)2 (12.5) Gingival bleeding001 (25)01 (6.3) Vomiting0001 (25)1 (6.3)Infections and infestations0002 (50)2 (12.5) Rash pustular0002 (50)2 (12.5)Musculoskeletal and connective tissue disorders1 (25)0001 (6.3) Growing pains1 (25)0001 (6.3)Renal and urinary disorders01 (25)001 (6.3) Renal impairment01 (25)001 (6.3)Respiratory, thoracic and mediastinal disorders01 (25)001 (6.3) Cough01 (25)001 (6.3)Skin and subcutaneous tissue disorders01 (25)01 (25)2 (12.5) Pruritus0001 (25)1 (6.3) Vitiligo01 (25)001 (6.3)If a patient had more than one event for a particular system organ class or preferred term, he/she is counted only once for that system organ class of preferred term. Open table in a new tab If a patient had more than one event for a particular system organ class or preferred term, he/she is counted only once for that system organ class of preferred term. No pattern in differences between dose cohorts was observed for vital signs, physical examination findings, gingival examination findings, electrocardiograph findings, or renal function. Changes from baseline in safety laboratory parameters fluctuated over the course of the study and no consistent differences between dose cohorts were noted for laboratory evaluation results. In three patients (two patients in the 1 mg/kg group and one in the 2 mg/kg group), the anti-fresolimumab antibody assay showed positive results when fresolimumab was no longer detectable in the blood. No clinical consequences were noted in the patients with detectable antibody response to fresolimumab. Mean serum concentrations of fresolimumab over time are presented by dose in Figure 1. The pharmacokinetics of fresolimumab were best described using a two-compartment linear model. There was no difference in the pharmacokinetic behavior of fresolimumab in the FSGS cohort compared with the results observed in two other disease populations (idiopathic pulmonary fibrosis and advanced malignancy).42.Brown K.K. Flaherty K.R. Daniels C. et al.Safety and tolerability of GC1008, a human monoclonal antibody against TGFbeta, in patients with idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 177: A768Google Scholar, 43.Morris J.C. Shapiro G.I. Tan A.R. et al.Phase I study of GC1008: A human anti-transforming growth factor-beta (TGFβ) monoclonal antibody (MAb) in patients with advanced malignant melanoma (MM) or renal cell carcinoma (RCC).J Clin Oncol. 2008; 26: 9028Crossref Scopus (9) Google Scholar Patient weight was the only significant covariate identified as being predictive of pharmacokinetic variability. Derived pharmacokinetic parameters for fresolimumab in FSGS patients are presented in Table 3. The half-life of fresolimumab in this patient population was ∼14 days. Values of mean dose-normalized Cmax and area under the curve values ranged from 0.27 to 0.37 μg/ml/mg and from 48.3 to 88.1 ng*h/ml/mg, respectively, and appeared to be independent of dose (Table 3).Table 3Pharmacokinetic parameters after a single dose of fresolimumabDose (mg/kg)Cmax (μg/ml)Cmax/dose (μg/ml/mg)AUC (ng*h/ml)AUC/dose (ng*h/ml/mg)T1/2α (day)T1/2β (day)CL (ml/h)Vss (ml)0.35.70±1.850.31±0.111162±49263.9±27.22.73±1.1510.9±5.119.7±13.04.48±2.14119.3±3.590.27±0.053484±40548.3±9.02.73±1.9317.0±8.721.1±3.96.65±2.06247.5±5.540.32±0.0313,016±281488.1±16.02.61±1.7317.7±3.711.6±2.25.17±1.474114±16.30.37±0.0226,175±796482.9±19.72.92±1.7934.6±47.7aValue appears to be elevated because of one patient. Median half-life was 12.5 days.12.6±2.83.56±0.60Abbreviations: AUC, area under the curve; CL, clearance; Cmax, maximum concentration; T1/2α, distribution half-life; T1/2β, elimination half-life; Vss, volume of distribution at steady state.Values are presented as mean±s.d.a Value appears to be elevated because of one patient. Median half-life was 12.5 days. Open table in a new tab Abbreviations: AUC, area under the curve; CL, clearance; Cmax, maximum concentration; T1/2α, distribution half-life; T1/2β, elimination half-life; Vss, volume of distribution at steady state. Values are presented as mean±s.d. Proteinuria fluctuated during the study period and the median change from baseline to the final study visit in urine protein : creatinine ratio (PCR) for entire patient cohort was -133.31 mg/mmol (-1.2 mg/mg; Table 4). A graphic illustration of the time course of the response for each cohort is available as Figure 2. A clinically significant improvement in proteinuria was observed in the three Black patients (two from the fresolimumab 1 mg/kg cohort and one from the 2 mg/kg cohort). These three individuals demonstrated a mean decrease of 65% in urine PCR levels at the final study visit compared with baseline (Table 5).Table 4Median change from baseline to final study visit in estimated glomerular filtration rate (eGFR), urine protein/creatinine ratio, urine albumin/creatinine ratio, serum creatinine, and serum albumin0.3 mg/kg (N=4)1 mg/kg (N=4)2 mg/kg (N=4)4 mg/kg (N=4)Total (N=16)eGFR (ml/min per 1.73 m2)−5.65−6.25−3.05−9.25−5.85Urine protein/creatinine ratio (mg/mmol)−140.1−331.277.4−126.5−133.3Urine albumin/creatinine ratio (mg/mmol)−93.8−101.9105.2−122.3−57.8Serum creatinine (μmol/l)7.023.516.027.017.5Serum albumin (g/l)0.01.52.02.01.5To convert mg/mmol to mg/mg, divide by 113.11. Open table in a new tab Table 5Urine protein to creatinine ratio for patients with a reduction from baselinePatient100310042004Dose1 mg/kg1 mg/kg2 mg/kgRaceBlackBlackBlackPreinfusion (mg/mmol)559.28772.81402.52End of study (mg/mmol)228.1261.75231.97To convert mg/mmol to mg/mg, divide by 113.11. Open table in a new tab To convert mg/mmol to mg/mg, divide by 113.11. To convert mg/mmol to mg/mg, divide by 113.11. The overall trend was for a slight decline in estimated glomerular filtration rate (eGFR): the median change from baseline at the final study visit was -5.85 ml/min per 1.73 m2 (annualized: -19.0 ml/min per 1.73 m2) with no dose-related differences. For the other efficacy measures assessed, results tended to fluctuate over the course of the study with no treatment-related changes noted (Table 4). This report describes a phase 1, open-label study conducted in patients with treatment-resistant primary FSGS that was designed to assess the safety, tolerability, and pharmacokinetics of single-dose infusions of fresolimumab. The study agent was safely administered to four patients in each of four dose cohorts: 0.3, 1, 2 and 4 mg/kg body weight. All 16 patients who received a single dose of the antibody completed the study. This trial represents the first description of the use of an anti-TGF-β antibody that has appeared in a peer-reviewed publication. It is important to emphasize that this phase I study involved patients with fairly advanced disease based on their resistance to previous treatments and the low eGFR criterion for eligibility. Thus, like patients with oncological diseases, the expectation of therapeutic benefit from a single dose of the anti-TGF-β antibody was low. The primary objective was to evaluate the safety and pharmacokinetics of fresolimumab. The assessment of clinical response was a secondary objective and the findings in this regard should be considered preliminary and proof-of-concept only. There were no complications related to the infusion or that occurred within the 24-h observation period after administration of the antibody. Reporting of long-term adverse events and related adverse events was similar across the dose cohorts. All adverse events except one were of mild or moderate intensity. No patients ex