Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies

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

doi:10.1159/000527167

Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies

Carla Nester^*, Gerald B. Appel, Andrew S. Bomback, Koenraad Peter Bouman, H. Terence Cook, Erica Daina, Bradley P. Dixon, Kara Rice, Nader Najafian, James Hui, Steven D. Podos, Craig B. Langman, Liz Lightstone, Samir V. Parikh, Matthew C. Pickering, C. John Sperati, Howard Trachtman, James Tumlin, Aiko P.J. De Vries, Jack F.M. WetzelsGiuseppe Remuzzi

^*Corresponding author for this work

Pediatrics

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

31 Scopus citations

Abstract

Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

Original language	English (US)
Pages (from-to)	687-700
Number of pages	14
Journal	American Journal of Nephrology
Volume	53
Issue number	10
DOIs	https://doi.org/10.1159/000527167
State	Published - Jan 1 2023

Funding

The authors would like to thank the patients who have enrolled in the two clinical trials and their families. In addition, we are grateful to Hetal Kocinsky and Mark Uknis of prior Achillion Pharmaceuticals, Inc., who participated in the early stages of the study, and Dr C. Duineveld, nephrology fellow at Radboud UMC, Nijmegen, for her assistance with clinical trial monitoring. Our gratitude also goes to Dr. Tom Barbour (who passed away) for his substantial contributions to these studies. The sponsor provided a formal review of the publication; however, the authors had final authority over the content. Medical writing support was provided by Alexandra Balaceanu of Bioscript, Macclesfield, UK, which was funded by Alexion, AstraZeneca Rare Disease, Inc. Steven Podos, Kara Rice, and Nader Najafian are employees of Alexion, AstraZeneca Rare Diseases, and are shareholders in the company. James Hui was an employee and shareholder of Alexion, AstraZeneca Rare Disease, at the time this study was conducted. 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 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 P. Dixon has received consultancy fees from Alexion Pharmaceuticals and Apellis Pharmaceuticals. Craig B 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. Liz Lightstone 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 clinical trials and research grant/contract support from Achillion Pharmaceuticals, Alnylam Pharmaceuticals, and Novartis Pharmaceuticals (paid to institution). C. John Sperati 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, Aiko PJ de Vries, and James Tumlin have no conflicts to declare. Achillion Pharmaceuticals Inc. was acquired by Alexion Pharmaceuticals. Alexion Pharmaceuticals is now Alexion, AstraZeneca Rare Diseases. This analysis and publication were funded by Alexion, Astra- Zeneca Rare Disease, Inc. (and formerly by Achillion Pharmaceuticals, Inc.), who provided overall study management, performed the statistical analyses, and verified data accuracy

Keywords

C3 glomerulopathy
Clinical trial
Complement alternative pathway
Danicopan
Factor D inhibitor

ASJC Scopus subject areas

Nephrology

Access to Document

10.1159/000527167

Cite this

Nester, C., Appel, G. B., Bomback, A. S., Bouman, K. P., Cook, H. T., Daina, E., Dixon, B. P., Rice, K., Najafian, N., Hui, J., Podos, S. D., Langman, C. B., Lightstone, L., Parikh, S. V., Pickering, M. C., Sperati, C. J., Trachtman, H., Tumlin, J., De Vries, A. P. J., ... Remuzzi, G. (2023). Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies. American Journal of Nephrology, 53(10), 687-700. https://doi.org/10.1159/000527167

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title = "Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies",

abstract = "Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.",

keywords = "C3 glomerulopathy, Clinical trial, Complement alternative pathway, Danicopan, Factor D inhibitor",

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

year = "2023",

month = jan,

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doi = "10.1159/000527167",

language = "English (US)",

volume = "53",

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Nester, C, Appel, GB, Bomback, AS, Bouman, KP, Cook, HT, Daina, E, Dixon, BP, Rice, K, Najafian, N, Hui, J, Podos, SD, Langman, CB, Lightstone, L, Parikh, SV, Pickering, MC, Sperati, CJ, Trachtman, H, Tumlin, J, De Vries, APJ, Wetzels, JFM & Remuzzi, G 2023, 'Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies', American Journal of Nephrology, vol. 53, no. 10, pp. 687-700. https://doi.org/10.1159/000527167

TY - JOUR

T1 - Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan

T2 - Final Results from Two Phase 2 Studies

AU - Nester, Carla

AU - Appel, Gerald B.

AU - Bomback, Andrew S.

AU - Bouman, Koenraad Peter

AU - Cook, H. Terence

AU - Daina, Erica

AU - Dixon, Bradley P.

AU - Rice, Kara

AU - Najafian, Nader

AU - Hui, James

AU - Podos, Steven D.

AU - Langman, Craig B.

AU - Lightstone, Liz

AU - Parikh, Samir V.

AU - Pickering, Matthew C.

AU - Sperati, C. John

AU - Trachtman, Howard

AU - Tumlin, James

AU - De Vries, Aiko P.J.

AU - Wetzels, Jack F.M.

AU - Remuzzi, Giuseppe

PY - 2023/1/1

Y1 - 2023/1/1

N2 - Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

AB - Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

KW - C3 glomerulopathy

KW - Clinical trial

KW - Complement alternative pathway

KW - Danicopan

KW - Factor D inhibitor

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Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies

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Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies

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Supplementary Material for: Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies

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