# Use of avacopan in two patients with ANCA-associated vasculitis undergoing dialysis

Adrien Flahault, Valentin Panisset

► To cite this version:

Adrien Flahault, Valentin Panisset. Use of avacopan in two patients with ANCA-associated vasculitis undergoing dialysis. 2024. hal-04597272

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# Use of avacopan in two patients with ANCA-associated vasculitis undergoing dialysis

Adrien Flahault, Valentin Panisset

<figure><img src="image_1.png" /></figure>

## To cite this version:

Adrien Flahault, Valentin Panisset. Use of avacopan in two patients with ANCA-associated vasculitis undergoing dialysis. 2024. hal-04597272

HAL Id: hal-04597272

https://hal.science/hal-04597272v1

Preprint submitted on 2 Jun 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Use of avacopan in two patients with ANCA-associated vasculitis undergoing dialysis

Adrien Flahault<sup>1,2,*</sup>, Valentin Panisset<sup>1</sup>

1. Centre Hospitalier Régional Universitaire de Nancy, Department of Nephrology, Nancy, France

2. Université de Lorraine, Inserm, UMR INSPIIRE, Inserm, Nancy, France

* Correspondence should be addressed to Adrien Flahault (a.flahault@chru-nancy.fr)

## Introduction

Avacopan, an anti C5-receptor, has been shown in the phase III ADVOCATE trial to be efficient and safe as a replacement of glucocorticoids in the treatment of anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV)¹. Specifically, the incidence of steroid-related adverse events was significantly lower in patients treated with avacopan. In this study, however, patients with an eGFR at initial presentation below 15 ml/min/1.73m² and patients undergoing dialysis were excluded. Of note, avacopan was continued in patients who underwent dialysis during the study in this trial.

While avacopan is useful in patients with expected poor tolerance to steroids, restricting access to this medication to patients with an eGFR above 15 ml/min/1.73m² limits the use of avacopan in a significant number of AAV patients. Indeed, in a retrospective study including 532 AAV patients with renal involvement, 95 (18%) required dialysis at initial presentation². We herein report the use of avacopan in who patients who presented with AAV, with contra-indication to steroid and who required dialysis at avacopan initiation.

## Cases presentation

Case n°1 is a 77 years old female with a history of rheumatoid arthritis treated with Methotrexate and high blood pressure. There was no known history of psychiatric disease. The patient presented with rapidly progressive glomerulonephritis (RPGN) with positive anti-MPO antibodies. A kidney biopsy was performed and showed a diffuse necrotizing crescentic glomerulonephritis, with 6 of 17 glomeruli showing extracapillary proliferation, no endocapillary proliferation, and immunofluorescence staining was negative. Initial management consisted in corticosteroids (pulses, followed by oral prednisone according to the reduced-dose PEXIVAS protocol³) and rituximab (375 mg/m², weekly, repeated 4 times),
# Use of avacopan in two patients with ANCA-associated vasculitis undergoing dialysis

Adrien Flahault<sup>1,2,*</sup>, Valentin Panisset<sup>1</sup>

1. Centre Hospitalier Régional Universitaire de Nancy, Department of Nephrology, Nancy, France

2. Université de Lorraine, Inserm, UMR INSPIIRE, Inserm, Nancy, France

* Correspondence should be addressed to Adrien Flahault (a.flahault@chru-nancy.fr)

## Introduction

Avacopan, an anti C5-receptor, has been shown in the phase III ADVOCATE trial to be efficient and safe as a replacement of glucocorticoids in the treatment of anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV)¹. Specifically, the incidence of steroid-related adverse events was significantly lower in patients treated with avacopan. In this study, however, patients with an eGFR at initial presentation below 15 ml/min/1.73m² and patients undergoing dialysis were excluded. Of note, avacopan was continued in patients who underwent dialysis during the study in this trial.

While avacopan is useful in patients with expected poor tolerance to steroids, restricting access to this medication to patients with an eGFR above 15 ml/min/1.73m² limits the use of avacopan in a significant number of AAV patients. Indeed, in a retrospective study including 532 AAV patients with renal involvement, 95 (18%) required dialysis at initial presentation². We herein report the use of avacopan in who patients who presented with AAV, with contra-indication to steroid and who required dialysis at avacopan initiation.

## Cases presentation

Case n°1 is a 77 years old female with a history of rheumatoid arthritis treated with Methotrexate and high blood pressure. There was no known history of psychiatric disease. The patient presented with rapidly progressive glomerulonephritis (RPGN) with positive anti-MPO antibodies. A kidney biopsy was performed and showed a diffuse necrotizing crescentic glomerulonephritis, with 6 of 17 glomeruli showing extracapillary proliferation, no endocapillary proliferation, and immunofluorescence staining was negative. Initial management consisted in corticosteroids (pulses, followed by oral prednisone according to the reduced-dose PEXIVAS protocol³) and rituximab (375 mg/m², weekly, repeated 4 times),
with an initial modest improvement in kidney function. The patient was re-admitted to the nephrology department one month after initial presentation, due to general deterioration of health. Upon admission, and despite immunosuppressive treatment, kidney function had worsened, leading to hemodialysis initiation on a tunneled catheter. However, the patient's overall condition did not improve despite the initiation of dialysis. She developed severe depressive symptoms characterized by apathy, amimia, clinophilia, and loss of drive. Brain MRI and electroencephalogram were unremarkable. The severe mood alterations occurred one month after high dose corticosteroid initiation and there was no other cause identified. We decided to replace prednisone with avacopan (60 mg/day), with a rapid corticosteroid withdrawal (weaning over 4 days), in addition to paroxetine initiation. We observed an improvement in mood in the days following corticosteroid withdrawal, allowing for discharge home thereafter. There was no recovery of renal function, and the patient remained on dialysis. Avacopan was well tolerated, particularly in terms of infectious aspects, and was continued up to 12 months after initiation of immunosuppressive treatment, together with rituximab 500 mg every 6 month for two years for maintenance therapy.

Case n°2 is a 75 years old male with a history of high blood pressure, who was admitted to the nephrology department for kidney failure. The patient had initially been admitted to the gastroenterology department for anemia (Hb 3.2 g/dl) in the context of rectal bleeding. Computed tomography scanner and endoscopic examinations (colonoscopy, gastroscopy) did not reveal any hemorrhagic lesions. The patient received 10 units of red blood cells. In addition, the patient presented with renal failure, with a serum creatinine level of 800 µmol/L, proteinuria, hematuria, and positive anti-MPO antibodies. Kidney biopsy showed a diffuse necrotizing crescentic glomerulonephritis, with 9 of 12 glomeruli showing extracapillary proliferation, no endocapillary proliferation, and immunofluorescence staining was negative. We hypothesized that gastro-intestinal bleeding was secondary to gastro-intestinal involvement of the AAV, although no gastro-intestinal biopsy was performed to confirm this diagnosis. The CT-scan was suggestive of an ENT (sinuses) involvement of AAV. Initial management consisted in an immunosuppressive regimen with pulse corticosteroids (500 mg, three times) and rituximab (375 mg/m², weekly, repeated 4 times). In the context of life-threatening gastro-intestinal bleeding at presentation, we chose to use avacopan (60
with an initial modest improvement in kidney function. The patient was re-admitted to the nephrology department one month after initial presentation, due to general deterioration of health. Upon admission, and despite immunosuppressive treatment, kidney function had worsened, leading to hemodialysis initiation on a tunneled catheter. However, the patient's overall condition did not improve despite the initiation of dialysis. She developed severe depressive symptoms characterized by apathy, amimia, clinophilia, and loss of drive. Brain MRI and electroencephalogram were unremarkable. The severe mood alterations occurred one month after high dose corticosteroid initiation and there was no other cause identified. We decided to replace prednisone with avacopan (60 mg/day), with a rapid corticosteroid withdrawal (weaning over 4 days), in addition to paroxetine initiation. We observed an improvement in mood in the days following corticosteroid withdrawal, allowing for discharge home thereafter. There was no recovery of renal function, and the patient remained on dialysis. Avacopan was well tolerated, particularly in terms of infectious aspects, and was continued up to 12 months after initiation of immunosuppressive treatment, together with rituximab 500 mg every 6 month for two years for maintenance therapy.

Case n°2 is a 75 years old male with a history of high blood pressure, who was admitted to the nephrology department for kidney failure. The patient had initially been admitted to the gastroenterology department for anemia (Hb 3.2 g/dl) in the context of rectal bleeding. Computed tomography scanner and endoscopic examinations (colonoscopy, gastroscopy) did not reveal any hemorrhagic lesions. The patient received 10 units of red blood cells. In addition, the patient presented with renal failure, with a serum creatinine level of 800 µmol/L, proteinuria, hematuria, and positive anti-MPO antibodies. Kidney biopsy showed a diffuse necrotizing crescentic glomerulonephritis, with 9 of 12 glomeruli showing extracapillary proliferation, no endocapillary proliferation, and immunofluorescence staining was negative. We hypothesized that gastro-intestinal bleeding was secondary to gastro-intestinal involvement of the AAV, although no gastro-intestinal biopsy was performed to confirm this diagnosis. The CT-scan was suggestive of an ENT (sinuses) involvement of AAV. Initial management consisted in an immunosuppressive regimen with pulse corticosteroids (500 mg, three times) and rituximab (375 mg/m², weekly, repeated 4 times). In the context of life-threatening gastro-intestinal bleeding at presentation, we chose to use avacopan (60
mg/day), rather than prednisone tapering, as immunosuppressive agent for induction and maintenance therapy. Avacopan was continued for 12 months, and was well tolerated, with no severe infectious event. There has been no recurrence, to this date, of digestive hemorrhage. Kidney function, however, did not recover and the patient remains currently on dialysis.

## Discussion

We report two cases of anti-MPO AAV in patients under dialysis with either life-threatening corticosteroid adverse reaction (case n°1, severe steroid-induced affective disorder) or major contra-indication to corticosteroids (case n°2, life-threatening gastro-intestinal bleeding of unknown origin), who received treatment with avacopan, replacing oral prednisone as an immunosuppressive agent for induction and maintenance AAV therapy. In both patients, although renal outcomes were unfavorable, as both remained on dialysis, avacopan was well tolerated and could be pursued for one year, without major adverse events.

Avacopan has been evaluated as a replacement of corticosteroids in AAV vasculitis in the ADVOCATE clinical trial, which excluded patients undergoing dialysis at baseline¹. This study showed reduced corticosteroid-related adverse events in patients treated with avacopan, making avacopan an interesting therapeutic alternative to corticosteroids in patients with either corticosteroid-related adverse events, contra-indications to corticosteroids or in patients considered as a high risk of developing corticosteroid-related adverse events. When avacopan was introduced in these two patients, there was no reported cases of patients in whom avacopan was initiated while undergoing dialysis. The ADVOCATE study, however, reports that two patients who were treated with avacopan required dialysis during the study, without mention of treatment discontinuation, dose adaptation or specific adverse events.

Since the publication of the ADVOCATE study, a few authors have reported their experience of the use of avacopan in patients undergoing dialysis at the time of avacopan initiation⁴,⁵, with no reported safety issue, apart for a single case report of thrombopenia in an hemodialysis patient with microscopic polyangiitis treated with avacopan, who developed thrombopenia one week after avacopan administration and in whom platelet count norma⁶. The main route of clearance of avacopan is metabolism, followed by biliary
mg/day), rather than prednisone tapering, as immunosuppressive agent for induction and maintenance therapy. Avacopan was continued for 12 months, and was well tolerated, with no severe infectious event. There has been no recurrence, to this date, of digestive hemorrhage. Kidney function, however, did not recover and the patient remains currently on dialysis.

## Discussion

We report two cases of anti-MPO AAV in patients under dialysis with either life-threatening corticosteroid adverse reaction (case n°1, severe steroid-induced affective disorder) or major contra-indication to corticosteroids (case n°2, life-threatening gastro-intestinal bleeding of unknown origin), who received treatment with avacopan, replacing oral prednisone as an immunosuppressive agent for induction and maintenance AAV therapy. In both patients, although renal outcomes were unfavorable, as both remained on dialysis, avacopan was well tolerated and could be pursued for one year, without major adverse events.

Avacopan has been evaluated as a replacement of corticosteroids in AAV vasculitis in the ADVOCATE clinical trial, which excluded patients undergoing dialysis at baseline¹. This study showed reduced corticosteroid-related adverse events in patients treated with avacopan, making avacopan an interesting therapeutic alternative to corticosteroids in patients with either corticosteroid-related adverse events, contra-indications to corticosteroids or in patients considered as a high risk of developing corticosteroid-related adverse events. When avacopan was introduced in these two patients, there was no reported cases of patients in whom avacopan was initiated while undergoing dialysis. The ADVOCATE study, however, reports that two patients who were treated with avacopan required dialysis during the study, without mention of treatment discontinuation, dose adaptation or specific adverse events.

Since the publication of the ADVOCATE study, a few authors have reported their experience of the use of avacopan in patients undergoing dialysis at the time of avacopan initiation⁴,⁵, with no reported safety issue, apart for a single case report of thrombopenia in an hemodialysis patient with microscopic polyangiitis treated with avacopan, who developed thrombopenia one week after avacopan administration and in whom platelet count norma⁶. The main route of clearance of avacopan is metabolism, followed by biliary
excretion; after administration of radiolabeled avacopan, 77% was found in the feces and 10% in urine, with 7% and 0.1% found as unchanged avacopan in the feces and urine, respectively⁷. Thus, there is no rationale for dose adaptation in patients with impaired renal function treated with avacopan.

The other main concern with the use of avacopan in patients undergoing dialysis at treatment initiation is efficacy. While the ADVOCATE study shows that avacopan was superior to prednisone taper with respect to sustained remission at week 52 in AAV, patients with an eGFR below 15 ml/min/1.73m² were excluded from the study, and no study has demonstrated avacopan efficacy in this specific population. In the two cases reported here, none experienced kidney function improvement following avacopan introduction. However, Barr et al reported the case of four patients with an eGFR below 15 ml/min/1.73m² with favorable renal outcome, including one patient in whom dialysis could be discontinued⁵. While a randomized controlled trial evaluating the efficacy of avacopan in AAV patients undergoing dialysis is unlikely to be performed, it would be interesting to retrospectively analyze the effect of avacopan in a larger number of patients treated with dialysis at initiation.

In conclusion, we report two cases of AAV patients treated with hemodialysis in whom avacopan was introduced for contra-indication to corticosteroids, with beneficial effects on corticosteroid adverse events but without subsequent improvement of renal function. Efficacy of avacopan should be validated in a larger number of patients in this context.

**Funding**: none

**References**

1. Jayne, D. R. W., Merkel, P. A., Schall, T. J., Bekker, P., & ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. *N Engl J Med* **384**, 599–609 (2021).

2. Lionaki, S. *et al*. The clinical course of ANCA small-vessel vasculitis on chronic dialysis. *Kidney International* **76**, 644–651 (2009).

3. Walsh, M. *et al*. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. *N Engl J Med* **382**, 622–631 (2020).
excretion; after administration of radiolabeled avacopan, 77% was found in the feces and 10% in urine, with 7% and 0.1% found as unchanged avacopan in the feces and urine, respectively⁷. Thus, there is no rationale for dose adaptation in patients with impaired renal function treated with avacopan.

The other main concern with the use of avacopan in patients undergoing dialysis at treatment initiation is efficacy. While the ADVOCATE study shows that avacopan was superior to prednisone taper with respect to sustained remission at week 52 in AAV, patients with an eGFR below 15 ml/min/1.73m² were excluded from the study, and no study has demonstrated avacopan efficacy in this specific population. In the two cases reported here, none experienced kidney function improvement following avacopan introduction. However, Barr et al reported the case of four patients with an eGFR below 15 ml/min/1.73m² with favorable renal outcome, including one patient in whom dialysis could be discontinued⁵. While a randomized controlled trial evaluating the efficacy of avacopan in AAV patients undergoing dialysis is unlikely to be performed, it would be interesting to retrospectively analyze the effect of avacopan in a larger number of patients treated with dialysis at initiation.

In conclusion, we report two cases of AAV patients treated with hemodialysis in whom avacopan was introduced for contra-indication to corticosteroids, with beneficial effects on corticosteroid adverse events but without subsequent improvement of renal function. Efficacy of avacopan should be validated in a larger number of patients in this context.

**Funding**: none

**References**

1. Jayne, D. R. W., Merkel, P. A., Schall, T. J., Bekker, P., & ADVOCATE Study Group. Avacopan for the Treatment of ANCA-Associated Vasculitis. *N Engl J Med* **384**, 599–609 (2021).

2. Lionaki, S. *et al*. The clinical course of ANCA small-vessel vasculitis on chronic dialysis. *Kidney International* **76**, 644–651 (2009).

3. Walsh, M. *et al*. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. *N Engl J Med* **382**, 622–631 (2020).
4. Zonozi, R. et al. Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. *Kidney International Reports* (2024)
doi:10.1016/j.ekir.2024.03.022.

5. Barr, B., Cheema, K., Fifi-Mah, A., Garner, S. & Girard, L.-P. Use of Avacopan in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Estimated Glomerular Filtration Rate <15 ml/min per 1.73 m2. *Kidney International Reports* 9, 1115–1118 (2024).

6. Morimoto, N. et al. Thrombocytopenia during avacopan administration: A case report. *Int J Rheum Dis* 26, 1603–1607 (2023).

7. Tavneos | European Medicines Agency.
https://www.ema.europa.eu/en/medicines/human/EPAR/tavneos.
4. Zonozi, R. et al. Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. *Kidney International Reports* (2024)
doi:10.1016/j.ekir.2024.03.022.

5. Barr, B., Cheema, K., Fifi-Mah, A., Garner, S. & Girard, L.-P. Use of Avacopan in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Estimated Glomerular Filtration Rate <15 ml/min per 1.73 m2. *Kidney International Reports* 9, 1115–1118 (2024).

6. Morimoto, N. et al. Thrombocytopenia during avacopan administration: A case report. *Int J Rheum Dis* 26, 1603–1607 (2023).

7. Tavneos | European Medicines Agency.
https://www.ema.europa.eu/en/medicines/human/EPAR/tavneos.