Kidney360 · 2024
Precision Medicine Proof-of-Concept Study of a TNF Inhibitor in FSGS and Treatment-Resistant Minimal Change Disease.
СтатьяНазвание и аннотация: Перевод в очереди
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Trachtman Howard, Modi Zubin J, Ju Wenjun, Lee Edmond, Chinnakotla Silpa, Massengill Susan, Sedor John, Mariani Laura, Zhai Yan, Hao Wei, Desmond Hailey, Eddy Sean, Ramani Karthik, Spino Cathie, Kretzler Matthias
Аннотация
KEY POINTS: Precision medicine trials are feasible in patients with primary glomerular diseases. Patients with FSGS and the best-preserved kidney parenchyma demonstrated the most favorable biomarker response to short-term adalimumab treatment. Targeted therapies for FSGS are more likely to succeed during the course of disease when the injury pathway is activated and can be modified.
BACKGROUND: FSGS and treatment-resistant minimal change disease (TR-MCD) are heterogeneous disorders with subgroups defined by distinct underlying mechanisms of glomerular and tubulointerstitial injury. A noninvasive urinary biomarker profile has been generated to identify patients with intrakidney TNF activation and to predict response to anti-TNF treatment. We conducted this proof-of-concept, multicenter, open-label clinical trial to test the hypothesis that in patients with FSGS or TR-MCD and evidence of intrarenal TNF activation based on their biomarker profile, short-term treatment with adalimumab would reverse the elevated urinary excretion of monocyte chemoattractant protein-1 (MCP-1) and tissue inhibitor of metalloproteinases 1.
METHODS: Patients with FSGS or TR-MCD, eGFR >30 ml/min per 1.73 m2, urine protein:creatinine ratio ≥1.5 g/g, and age 6–80 years were eligible for this trial. Adalimumab, 20–40 mg, was administered through subcutaneous injection every 2 weeks for five doses. Participants were evaluated at weeks 0 (baseline), 2, 8, and 10. Excretion of urinary monocyte chemoattractant protein-1, urinary tissue inhibitor of metalloproteinases 1, urinary excretion of EGF, and plasma monocyte chemoattractant protein-1 were measured at each visit.
RESULTS: Seven participants were enrolled, with median baseline urine protein:creatinine ratio 12.1 mg/mg (interquartile range [IQR], 2.2–18.6), serum albumin 2.4 g/dl (IQR, 2.0–2.8), and eGFR 57 ml/min per 1.73 m2 (IQR, 44–96). On the basis of self-report, they received all prescribed doses of adalimumab. The patients with the most favorable response on the basis of changes in urinary biomarkers had the best preserved kidney parenchyma based on urinary excretion of EGF.
CONCLUSIONS: Precision medicine trials are feasible in rare glomerular disorders. In this pilot study, adalimumab resulted in a heterogenous response of the candidate mechanistic-predictive biomarkers of TNF-mediated inflammation in patients with FSGS or TR-MCD. A reduction was seen in a subgroup of patients with preserved kidney parenchyma. The findings may reflect the challenge to reverse chronic injury at advanced stages of kidney disease or insufficient intrarenal target engagement with the intervention drug dose.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:: NCT04009668.
BACKGROUND: FSGS and treatment-resistant minimal change disease (TR-MCD) are heterogeneous disorders with subgroups defined by distinct underlying mechanisms of glomerular and tubulointerstitial injury. A noninvasive urinary biomarker profile has been generated to identify patients with intrakidney TNF activation and to predict response to anti-TNF treatment. We conducted this proof-of-concept, multicenter, open-label clinical trial to test the hypothesis that in patients with FSGS or TR-MCD and evidence of intrarenal TNF activation based on their biomarker profile, short-term treatment with adalimumab would reverse the elevated urinary excretion of monocyte chemoattractant protein-1 (MCP-1) and tissue inhibitor of metalloproteinases 1.
METHODS: Patients with FSGS or TR-MCD, eGFR >30 ml/min per 1.73 m2, urine protein:creatinine ratio ≥1.5 g/g, and age 6–80 years were eligible for this trial. Adalimumab, 20–40 mg, was administered through subcutaneous injection every 2 weeks for five doses. Participants were evaluated at weeks 0 (baseline), 2, 8, and 10. Excretion of urinary monocyte chemoattractant protein-1, urinary tissue inhibitor of metalloproteinases 1, urinary excretion of EGF, and plasma monocyte chemoattractant protein-1 were measured at each visit.
RESULTS: Seven participants were enrolled, with median baseline urine protein:creatinine ratio 12.1 mg/mg (interquartile range [IQR], 2.2–18.6), serum albumin 2.4 g/dl (IQR, 2.0–2.8), and eGFR 57 ml/min per 1.73 m2 (IQR, 44–96). On the basis of self-report, they received all prescribed doses of adalimumab. The patients with the most favorable response on the basis of changes in urinary biomarkers had the best preserved kidney parenchyma based on urinary excretion of EGF.
CONCLUSIONS: Precision medicine trials are feasible in rare glomerular disorders. In this pilot study, adalimumab resulted in a heterogenous response of the candidate mechanistic-predictive biomarkers of TNF-mediated inflammation in patients with FSGS or TR-MCD. A reduction was seen in a subgroup of patients with preserved kidney parenchyma. The findings may reflect the challenge to reverse chronic injury at advanced stages of kidney disease or insufficient intrarenal target engagement with the intervention drug dose.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:: NCT04009668.