Compassionate Use of Avacopan in Difficult-to-Treat Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Leeuwen, Jolijn R van; Bredewold, Obbo W.; Dam, Laura van; Werkman, Stella L.; Jonker, Jacqueline T.; Geelhoed, Miranda; Langeveld, Antonius P. M.; Remmelts, Hilde H F; Broecke, Maud M. van de; Ray, Argho; Rabelink, Ton J.; Teng, Y K Onno

doi:10.1016/j.ekir.2021.11.036

Cited by 28 publications

(18 citation statements)

References 6 publications

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“…4 In between the completion of the ADVOCATE study (2019) and the approval of regulatory agencies, 30 patients with a high unmet medical need have been treated with avacopan through the Early Access Program (EAP). 5 , 6 Eligible for the EAP were patients with new or relapsing life- or organ-threatening ANCA-associated vasculitis, requiring an induction treatment, who also had a high risk of steroid-related complications. 5 …”

Section: Introductionmentioning

confidence: 99%

Preliminary Assessment of Safety and Tolerability of Avacopan During the Early Access Program for ANCA-Associated Vasculitis

Leeuwen

Popov

Obergfell

et al. 2023

BTT

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Section: Introductionmentioning

confidence: 99%

Preliminary Assessment of Safety and Tolerability of Avacopan During the Early Access Program for ANCA-Associated Vasculitis

Leeuwen

Popov

Obergfell

et al. 2023

BTT

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“…NDT9513727 is a selective and inverse agonist of the human C5aR1. Avacopan has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of anti-neutrophil cytoplasmic autoantibody-associated vasculitis …”

Section: Introductionmentioning

confidence: 99%

Investigating the Dynamic Binding Behavior of PMX53 Cooperating with Allosteric Antagonist NDT9513727 to C5a Anaphylatoxin Chemotactic Receptor 1 through Gaussian Accelerated Molecular Dynamics and Free-Energy Perturbation Simulations

Niu

Yang

et al. 2022

ACS Chem. Neurosci.

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C5a anaphylatoxin chemotactic receptor 1 (C5aR1) is an important target in anti-inflammatory therapeutics. The cyclic peptide antagonist PMX53 binds to the orthosteric site located in the extracellular vestibule of C5aR1, and the non-peptide antagonist NDT9513727 binds to the allosteric site formed by the middle region of TM3 (trans-membrane helix), TM4, and TM5. We catch a sight of the variational binding mode of PMX53 during the Gaussian accelerated molecular dynamic (GaMD) simulations. In the binary complex of C5aR1 and PMX53, the PMX53 takes a dynamic binding mechanism during the simulation. Namely, the side chain of Arg6 of PMX53 extends to TM6-TM7 (pose 1) or swings to TM5 (pose 2), forming a salt bridge with Glu199. Meanwhile, in the ternary complex of C5aR1 with PMX53 and NDT9513727, the side chain of Arg6 of PMX53 swings to TM5 (pose 2) from extending to TM6–TM7 (pose 1) at the beginning of the GaMD simulation. In subsequent simulation, PMX53 stabilizes in the pose 2 binding mode by forming a stable salt bridge with Glu199. The free-energy perturbation (FEP) calculations demonstrate that pose 1 (ΔG binding = −10.94 kcal/mol) is more stable in the binary complex and pose 2 (ΔG binding = −7.91 kcal/mol) is unstable because of highly dynamic TM5. NDT9513727 interacts directly with TM4 and TM5 and stabilizes the hydrophobic stack between the extracellular sides of the two helices. Therefore, pose 2 (ΔG binding = −16.27 kcal/mol) is notably stable than pose 1 (ΔG binding = −9.78 kcal/mol) in the ternary complex. The identification of a novel binding mode of PMX53 and the detailed structural information of PMX53 interacting with a receptor obtained by GaMD simulations will be helpful in designing potent antagonists of C5aR1.

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“…Fourth, our data reinforce the therapeutic potential of avacopan in real-life practice, as it was recently published only for difficult-to-treat patients. 4 In our series, patients were diagnosed with either de novo or relapsing but not refractory AAV. This could explain why GC tapering was obtained much earlier and therefore why GC toxicity index was not calculated.…”

Section: Discussionmentioning

confidence: 86%

“…Real-life data are now only available in difficult-to-treat patients (refractory or GC dependent). 4 Thus the first aim of this study was to assess the efficacy and tolerance of avacopan in standard patients, with a real GC sparing. As a second objective, we aimed to assess whether quantifying the urinary concentration of the soluble form of CD163 (usCD163), a marker of macrophages, may be a reliable marker of AAV.…”

mentioning

confidence: 99%

Avacopan as First-Line Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Steroid-Sparing Option

Gabilan¹,

Pfirmann

Ribes³

et al. 2022

Kidney International Reports

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Compassionate Use of Avacopan in Difficult-to-Treat Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Cited by 28 publications

References 6 publications

Preliminary Assessment of Safety and Tolerability of Avacopan During the Early Access Program for ANCA-Associated Vasculitis

Preliminary Assessment of Safety and Tolerability of Avacopan During the Early Access Program for ANCA-Associated Vasculitis

Investigating the Dynamic Binding Behavior of PMX53 Cooperating with Allosteric Antagonist NDT9513727 to C5a Anaphylatoxin Chemotactic Receptor 1 through Gaussian Accelerated Molecular Dynamics and Free-Energy Perturbation Simulations

Avacopan as First-Line Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Steroid-Sparing Option

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