PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis
Introduction: Focal segmental glomerulosclerosis (FSGS) is characterized by proteinuria and a histologic pattern of glomerular lesions of diverse etiology that share features including glomerular scarring and podocyte foot process effacement. Roundabout guidance receptor 2 (ROBO2)/slit guidance liga...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024921010408 |
| _version_ | 1819014250813718528 |
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| author | Laurence H. Beck, Jr. Stephen P. Berasi J. Brian Copley Donal Gorman Daniel I. Levy Chay Ngee Lim Joel M. Henderson David J. Salant Weining Lu |
| author_facet | Laurence H. Beck, Jr. Stephen P. Berasi J. Brian Copley Donal Gorman Daniel I. Levy Chay Ngee Lim Joel M. Henderson David J. Salant Weining Lu |
| author_sort | Laurence H. Beck, Jr. |
| collection | DOAJ |
| description | Introduction: Focal segmental glomerulosclerosis (FSGS) is characterized by proteinuria and a histologic pattern of glomerular lesions of diverse etiology that share features including glomerular scarring and podocyte foot process effacement. Roundabout guidance receptor 2 (ROBO2)/slit guidance ligand 2 (SLIT2) signaling destabilizes the slit diaphragm and reduces podocyte adhesion to the glomerular basement membrane (GBM). Preclinical studies suggest that inhibition of glomerular ROBO2/SLIT2 signaling can stabilize podocyte adhesion and reduce proteinuria. This clinical trial evaluates the preliminary efficacy and safety of ROBO2/SLIT2 inhibition with the ROBO2 fusion protein PF-06730512 in patients with FSGS. Methods: The Study to Evaluate PF-06730512 in Adults With FSGS (PODO; ClinicalTrials.gov identifier NCT03448692), an open-label, phase 2a, multicenter trial in adults with FSGS, will enroll patients into 2 cohorts (n = 22 per cohort) to receive either high- or low-dose PF-06730512 (intravenous) every 2 weeks for 12 weeks. Key inclusion criteria include a confirmed biopsy diagnosis of FSGS, an estimated glomerular filtration rate (eGFR) ≥45 ml/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration formula (30–45 with a recent biopsy), and urinary protein-to-creatinine ratio (UPCR) >1.5 g/g. Key exclusion criteria include collapsing FSGS, serious/active infection, ≥50% tubulointerstitial fibrosis on biopsy, and organ transplantation. The primary endpoint is change from baseline to week 13 in UPCR; secondary endpoints include safety, changes in eGFR, and PF-06730512 serum concentration. Results: This ongoing trial will report the efficacy, safety, pharmacokinetics, and biomarker results of PF-06730512 for patients with FSGS. Conclusion: Findings from this proof-of-concept study may support further development and evaluation of PF-06730512 to treat FSGS and warrant assessment in phase 3 clinical trials. |
| first_indexed | 2024-12-21T02:12:52Z |
| format | Article |
| id | doaj.art-4695a2e5d2284f1c8a194a0de0deb7a6 |
| institution | Directory Open Access Journal |
| issn | 2468-0249 |
| language | English |
| last_indexed | 2024-12-21T02:12:52Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Kidney International Reports |
| spelling | doaj.art-4695a2e5d2284f1c8a194a0de0deb7a62022-12-21T19:19:19ZengElsevierKidney International Reports2468-02492021-06-016616291633PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental GlomerulosclerosisLaurence H. Beck, Jr.0Stephen P. Berasi1J. Brian Copley2Donal Gorman3Daniel I. Levy4Chay Ngee Lim5Joel M. Henderson6David J. Salant7Weining Lu8Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA; Correspondence: Laurence H. Beck Jr., Boston University School of Medicine, Boston Medical Center, 650 Albany St, X-536, Boston, MA 02118, USA.Pfizer Inc., Cambridge, Massachusetts, USAPfizer Inc., Cambridge, Massachusetts, USAPfizer Inc., Cambridge, United KingdomPfizer Inc., Cambridge, Massachusetts, USAPfizer Inc., Cambridge, Massachusetts, USABoston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USABoston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USABoston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA; Weining Lu, Boston University School of Medicine, Boston Medical Center, 650 Albany St, Boston, MA 02118, USA.Introduction: Focal segmental glomerulosclerosis (FSGS) is characterized by proteinuria and a histologic pattern of glomerular lesions of diverse etiology that share features including glomerular scarring and podocyte foot process effacement. Roundabout guidance receptor 2 (ROBO2)/slit guidance ligand 2 (SLIT2) signaling destabilizes the slit diaphragm and reduces podocyte adhesion to the glomerular basement membrane (GBM). Preclinical studies suggest that inhibition of glomerular ROBO2/SLIT2 signaling can stabilize podocyte adhesion and reduce proteinuria. This clinical trial evaluates the preliminary efficacy and safety of ROBO2/SLIT2 inhibition with the ROBO2 fusion protein PF-06730512 in patients with FSGS. Methods: The Study to Evaluate PF-06730512 in Adults With FSGS (PODO; ClinicalTrials.gov identifier NCT03448692), an open-label, phase 2a, multicenter trial in adults with FSGS, will enroll patients into 2 cohorts (n = 22 per cohort) to receive either high- or low-dose PF-06730512 (intravenous) every 2 weeks for 12 weeks. Key inclusion criteria include a confirmed biopsy diagnosis of FSGS, an estimated glomerular filtration rate (eGFR) ≥45 ml/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration formula (30–45 with a recent biopsy), and urinary protein-to-creatinine ratio (UPCR) >1.5 g/g. Key exclusion criteria include collapsing FSGS, serious/active infection, ≥50% tubulointerstitial fibrosis on biopsy, and organ transplantation. The primary endpoint is change from baseline to week 13 in UPCR; secondary endpoints include safety, changes in eGFR, and PF-06730512 serum concentration. Results: This ongoing trial will report the efficacy, safety, pharmacokinetics, and biomarker results of PF-06730512 for patients with FSGS. Conclusion: Findings from this proof-of-concept study may support further development and evaluation of PF-06730512 to treat FSGS and warrant assessment in phase 3 clinical trials.http://www.sciencedirect.com/science/article/pii/S2468024921010408efficacyfocal segmental glomerulosclerosispharmacokineticsROBO2safetytrial in progress |
| spellingShingle | Laurence H. Beck, Jr. Stephen P. Berasi J. Brian Copley Donal Gorman Daniel I. Levy Chay Ngee Lim Joel M. Henderson David J. Salant Weining Lu PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis Kidney International Reports efficacy focal segmental glomerulosclerosis pharmacokinetics ROBO2 safety trial in progress |
| title | PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis |
| title_full | PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis |
| title_fullStr | PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis |
| title_full_unstemmed | PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis |
| title_short | PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis |
| title_sort | podo trial design phase 2 study of pf 06730512 in focal segmental glomerulosclerosis |
| topic | efficacy focal segmental glomerulosclerosis pharmacokinetics ROBO2 safety trial in progress |
| url | http://www.sciencedirect.com/science/article/pii/S2468024921010408 |
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