Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

Steven D. Podos; Howard Trachtman; Gerald B. Appel; Andrew S. Bomback; Bradley P. Dixon; Jack F.M. Wetzels; H. Terence Cook; Samir V. Parikh; Matthew C. Pickering; James Tumlin; Craig B. Langman; Liz Lightstone; C. John Sperati; Erica Daina; Koenraad Peter Bouman; Kara Rice; Jane A. Thanassi; Mingjun Huang; Carla Nester; Giuseppe Remuzzi

doi:10.1159/000527166

Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

Steven D. Podos^*, Howard Trachtman, Gerald B. Appel, Andrew S. Bomback, Bradley P. Dixon, Jack F.M. Wetzels, H. Terence Cook, Samir V. Parikh, Matthew C. Pickering, James Tumlin, Craig B. Langman, Liz Lightstone, C. John Sperati, Erica Daina, Koenraad Peter Bouman, Kara Rice, Jane A. Thanassi, Mingjun Huang, Carla Nester, Giuseppe Remuzzi

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and -0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = -0.83 and -0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = -0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = -0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.

Original language	English (US)
Pages (from-to)	675-686
Number of pages	12
Journal	American Journal of Nephrology
Volume	53
Issue number	10
DOIs	https://doi.org/10.1159/000527166
State	Published - Jan 1 2023

Funding

Steven D. Podos, Kara Rice, Jane A Thanassi, and Mingjun Huang are employees of Alexion, AstraZeneca Rare Disease, and are shareholders in the company. Carla Nester is the Associate Director for Molecular Otolaryngology and Renal Research Laboratory and has received a grant/contract from NIH. She has been a site investigator for ChemoCentryx, Achillion Pharmaceuticals, Alexion Pharmaceuticals, Novartis, Apellis Pharmaceuticals, Retrophin/Travere Therapeutics, and BioCryst. In addition, she has received advisory board honorarium from BioCryst and has participated in drug safety monitoring board/advisory board for Alexion Pharmaceuticals, Novartis, and BioCryst. Disclosures including royalties/licenses are provided in www.uptodate.com. Gerald Appel has received a research grant from Alexion Pharmaceuticals/Achillion Pharmaceuticals, which was paid to his institution (Columbia University, College of Physicians and Surgeons), and consultancy fees from Alexion Pharmaceuticals. Andrew S. Bomback has received consultancy fees from Achillion Pharmaceuticals/Alexion Pharmaceuticals, Catalyst, ChemoCentryx, Novartis, and Visterra. Terence Cook has received consultancy fees from Alexion Pharmaceuticals and Novartis and a grant from Alexion Pharmaceuticals, which was provided to his institution. Bradley Dixon has received consultancy fees from Alexion Pharmaceuticals and Apellis Pharmaceuticals. Craig Langman has received study funding and support from Alexion Pharmaceuticals, which was provided to his institution. Liz Lightstone has been a consultant/advisor for Achillion, Alexion Pharmaceuticals, AstraZeneca, Aurinia, Bristol-Myers Squibb, GSK, Kezar Life Sciences, Novartis, and Pfizer. She has received honoraria/travel grants from Alexion Pharmaceuticals, Achillion Pharmaceuticals, GSK, and Novartis and has participated in drug safety monitoring/advisory boards for Novartis. She has received study funding/support from Alexion Pharmaceuticals, which were provided to her institution. LL has also participated as the deputy chair of the Western Europe Regional Board and on ISN ExComm, is a trustee for Kidney Research UK, and a council member for Women in Nephrology (all unpaid). Samir V. Parikh has received grants/funding from NIH-NIDDK, EMD Serono, and Aurinia Pharmaceuticals, which were paid to institution, and consultancy fees from Aurinia Pharmaceuticals, Alexion Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, and Kezar Life Sciences. Disclosures including royalties/licenses are provided in www.uptodate.com. Matthew C. Pickering has received consultancy fees from Alexion Pharmaceuticals, Achillion Pharmaceuticals, and Gyroscope Pharmaceuticals and study funding from Achillion Pharmaceuticals. C. John Sperati has received honoraria from Alexion Pharmaceuticals for serving on the DMC of the clinical trials and research grant/contract support from Achillion Pharmaceuticals, Alnylam Pharmaceuticals, and Novartis Pharmaceuticals (paid to institution). CJS has received consultancy fees from Alnylam Pharmaceuticals and Q32 Bio. Howard Trachtman has received consultancy fees from Travere Therapeutics, Akebia Therapeutics, Goldfinch Bio, Angion, and Natera and support for meeting attendance from Travere Therapeutics. He has participated in data safety monitoring or advisory boards for Otsuka and ChemoCentryx. Jack Wetzels has received consultancy fees from Novartis (paid to institution), Morphosys, and Travere. He has received study funding/support from Alexion Pharmaceuticals, which was provided to his institution, and grant support and honoraria from Alexion Pharmaceuticals. JW is a member of KDIGO guide working groups (unpaid). Giuseppe Remuzzi has received consultancy fees from Akebia Pharmaceuticals Inc., Alexion Pharmaceuticals Inc., AstraZeneca, BioCryst Pharmaceuticals, Janssen Research and Development LLC, Menarini Ricerche Spa, Otsuka, and Silence Therapeutics, which were all paid to his institution. He has also received honoraria and support for meeting attendance from Boehringer Ingelheim. Koenraad Peter Bouman, Erica Daina, and James Tumlin have no conflicts to declare. Achillion Pharmaceuticals Inc. was acquired by Alexion Pharmaceuticals. Alexion Pharmaceuticals is now Alexion, AstraZeneca Rare Disease. The authors would like to thank the patients who have enrolled in the two clinical trials and their families. Our gratitude also goes to Dr. Tom Barbour (who passed away) for his substantial contributions to these studies. In addition, we are grateful to Guillermo del Angel and Nader Najafian of Alexion, AstraZeneca Rare Disease, for their assistance with clinical study monitoring, genetic analysis of patient samples, and review of the manuscript and to Dharaben Patel and Yongsen Zhao of Alexion, AstraZeneca Rare Disease, for their contributions of systemic and urinary complement biomarker data. The sponsor provided a formal review of the publication; however, the authors had final authority over the content. Medical writing support was provided by Helen Swainston, Bioscript Group, Macclesfield, UK, which was funded by Alexion, AstraZeneca Rare Disease. This analysis and publication were funded by Alexion, Astra-Zeneca Rare Disease (and formerly by Achillion Pharmaceuticals, Inc.), who provided overall study management, performed the statistical analyses, and verified data accuracy

Keywords

Biomarkers
Biopsy
C3 glomerulopathy
Clinical trial
Complement system

ASJC Scopus subject areas

Nephrology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1159/000527166

Cite this

Podos, S. D., Trachtman, H., Appel, G. B., Bomback, A. S., Dixon, B. P., Wetzels, J. F. M., Cook, H. T., Parikh, S. V., Pickering, M. C., Tumlin, J., Langman, C. B., Lightstone, L., Sperati, C. J., Daina, E., Bouman, K. P., Rice, K., Thanassi, J. A., Huang, M., Nester, C., & Remuzzi, G. (2023). Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan. American Journal of Nephrology, 53(10), 675-686. https://doi.org/10.1159/000527166

@article{1153dc56bd2745cb823c298198e15c17,

title = "Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan",

abstract = "Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and -0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = -0.83 and -0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = -0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = -0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.",

keywords = "Biomarkers, Biopsy, C3 glomerulopathy, Clinical trial, Complement system",

author = "Podos, {Steven D.} and Howard Trachtman and Appel, {Gerald B.} and Bomback, {Andrew S.} and Dixon, {Bradley P.} and Wetzels, {Jack F.M.} and Cook, {H. Terence} and Parikh, {Samir V.} and Pickering, {Matthew C.} and James Tumlin and Langman, {Craig B.} and Liz Lightstone and Sperati, {C. John} and Erica Daina and Bouman, {Koenraad Peter} and Kara Rice and Thanassi, {Jane A.} and Mingjun Huang and Carla Nester and Giuseppe Remuzzi",

year = "2023",

month = jan,

day = "1",

doi = "10.1159/000527166",

language = "English (US)",

volume = "53",

pages = "675--686",

journal = "American Journal of Nephrology",

issn = "0250-8095",

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Podos, SD, Trachtman, H, Appel, GB, Bomback, AS, Dixon, BP, Wetzels, JFM, Cook, HT, Parikh, SV, Pickering, MC, Tumlin, J, Langman, CB, Lightstone, L, Sperati, CJ, Daina, E, Bouman, KP, Rice, K, Thanassi, JA, Huang, M, Nester, C & Remuzzi, G 2023, 'Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan', American Journal of Nephrology, vol. 53, no. 10, pp. 675-686. https://doi.org/10.1159/000527166

Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan. / Podos, Steven D.; Trachtman, Howard; Appel, Gerald B. et al.
In: American Journal of Nephrology, Vol. 53, No. 10, 01.01.2023, p. 675-686.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

AU - Podos, Steven D.

AU - Trachtman, Howard

AU - Appel, Gerald B.

AU - Bomback, Andrew S.

AU - Dixon, Bradley P.

AU - Wetzels, Jack F.M.

AU - Cook, H. Terence

AU - Parikh, Samir V.

AU - Pickering, Matthew C.

AU - Tumlin, James

AU - Langman, Craig B.

AU - Lightstone, Liz

AU - Sperati, C. John

AU - Daina, Erica

AU - Bouman, Koenraad Peter

AU - Rice, Kara

AU - Thanassi, Jane A.

AU - Huang, Mingjun

AU - Nester, Carla

AU - Remuzzi, Giuseppe

PY - 2023/1/1

Y1 - 2023/1/1

N2 - Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and -0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = -0.83 and -0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = -0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = -0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.

AB - Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and -0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = -0.83 and -0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = -0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = -0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.

KW - Biomarkers

KW - Biopsy

KW - C3 glomerulopathy

KW - Clinical trial

KW - Complement system

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Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

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UN SDGs

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Supplementary Material for: Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

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Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

Abstract

Funding

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ASJC Scopus subject areas

UN SDGs

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Fingerprint

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Supplementary Material for: Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

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