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ANCA-Associated Vasculitis (AAV)

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Experimental Therapies

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases in which ANCA target and activate neutrophils, causing the inflammation and destruction of small blood vessels.1

Currently, no cure is available for ANCA-associated vasculitis, but researchers are working on different approaches to induce and maintain disease remission.2  Experimental treatments include immunosuppressive agents, biologics, monoclonal antibodies against CD-52, and agents that block the complement system.3

Immunosuppressive Agents

Immunosuppressive agents like Cytoxan® (cyclophosphamide), CellCept® (mycophenolate mofetil), and Imuran® (azathioprine) can be used either to induce remission or to prevent a relapse once remission has been achieved.

Cytoxan

Cytoxan is an alkylating agent that suppresses the immune system.4 Research has shown that the dose of prednisone can be reduced if Cytoxan is used to treat ANCA-associated vasculitis.5 However, the treatment is associated with permanent infertility.4

In a study conducted in 2009, a regimen based on Rituxan® (rituximab) and low-dose Cytoxan was effective in inducing long-term disease-free remission in patients with ANCA-associated vasculitis.6 

ENDURRANCE-1, a phase 3 clinical trial (NCT03942887), is now testing whether adding Cytoxan to the current standard of care with Rituxan alone can induce a favorable clinical and immunological state and therefore reduce the number of tailored re-treatments with Rituxan.7

Read more about AAV treatment

Methotrexate and CellCept 

Methotrexate and CellCept are disease-modifying anti-rheumatic drugs that have been used to induce remission in ANCA-associated vasculitis.8 Research has shown that methotrexate can be substituted for Cytoxan in patients with less-severe disease.9

SATELITE, a phase 2 clinical trial (NCT04871191), is currently testing salvage therapy with Rituxan plus methotrexate, CellCept, or Imuran to induce remission in patients with granulomatosis with polyangiitis (GPA), a type of ANCA-associated vasculitis, who have had an inadequate response to standard-of-care therapy.10

Read more about AAV clinical trials

Biologics

The potential benefits of several biologics are being tested in patients with ANCA-associated vasculitis. 

Nucala

Nucala® (mepoluzimab) is a humanized monoclonal antibody that binds to interleukin 5, which activates eosinophils. In a phase 3 clinical trial, the treatment has been shown to be of clinical benefit in the management of refractory and relapsing eosinophilic granulomatosis with polyangiitis (EGPA), a type of ANCA-associated vasculitis.11.12

E-MERGE, another phase 3 trial (NCT05030155), is currently comparing a Nucala-based regimen with conventional therapy for the induction of remission in patients with EGPA.13

Nucala has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps.14

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Benlysta

Benlysta® (belimumab) is a human monoclonal immunoglobulin G1 antibody against soluble B-lymphocyte-stimulating factor.15

The safety and efficacy of Benlysta in combination with Imuran to maintain remission following a standard induction regimen in patients with GPA or microscopic polyangiitis (MPA), another type of ANCA-associated vasculitis, have been investigated in a phase 3 clinical trial.16 The results showed that the addition of Benlysta to Imuran and low-dose glucocorticoids to maintain remission did not reduce the risk of recurrent vasculitis. In the Benlysta group, all vasculitis relapses occurred following induction of disease remission with Cytoxan in patients with PR3-ANCA. Patients who received Benlysta after induction of remission with Rituxan did not have recurrent vasculitis.17 

COMBIVAS, a phase 2 clinical trial (NCT03967925), is currently evaluating whether Rituxan plus Benlysta can improve biological endpoints, functional outcomes, and clinical status more effectively than Rituxan plus placebo in patients with EGPA or MPA.18

Benlysta has been approved by the FDA to treat systemic lupus and adults with lupus nephritis.19

Read more about AAV prognosis

Orencia

Orencia® (abatacept) is a recombinant fusion protein in which the extracellular domain of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is linked to a modified Fc region of IgG1. Orencia inhibits T-cell activation by blocking the engagement of CD28 with CD80/CD86.20

An open-label phase 1/2 clinical trial tested the safety and effectiveness of Orencia in adult patients with mild relapsing GPA.21 The drug was well tolerated and associated with high rates of disease remission, along with prednisone discontinuation.22

The experimental treatment is now being tested in ABROGATE, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (NCT02108860), to evaluate its efficacy in maintaining a sustained remission in patients with mild relapsing GPA without the use of glucocorticoids.23

Orencia is already approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis.24

Read more about AAV life expectancy

References

  1. ANCA vasculitis. UNC Kidney Center. Updated September 2018. Accessed February 28, 2023.
  2. Monti S, Brandolino F, Milanesi A, Xoxi B, Delvino P, Montecucco C. Novel therapies for ANCA-associated vasculitis. Curr Rheumatol Rep. 2021;23(6):38. doi:10.1007/s11926-021-01010-0
  3. Nozaki Y. New insights into novel therapeutic targets in ANCA-associated vasculitis. Front Immunol. 2021;12:631055. doi:10.3389/fimmu.2021.631055
  4. Cyclophosphamide. MedlinePlus. Updated August 15, 2018. Accessed February 28, 2023.
  5. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670-680. doi:10.7326/0003-4819-150-10-200905190-00004
  6. Mansfield N, Hamour S, Habib AM, et al. Prolonged disease-free remission following rituximab and low-dose cyclophosphamide therapy for renal ANCA-associated vasculitis. Nephrol Dial Transplant. 2011;26(10):3280-3286. doi:10.1093/ndt/gfr127
  7. Exploring durable remission with rituximab in antineutrophil cytoplasmic antibody(ANCA)-associated vasculitis (ENDURRANCE-1). ClinicalTrials.gov. May 8, 2019. Updated May 20, 2022. Accessed February 28, 2023.
  8. Han F, Liu G, Zhang X, et al. Effects of mycophenolate mofetil combined with corticosteroids for induction therapy of microscopic polyangiitis. Am J Nephrol. 2011;33:185-192. doi:10.1159/000324364
  9. Faurschou M, Westman K, Rasmussen N, et al. Brief report: long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012;64(10):3472-3477. doi:10.1002/art.34547
  10. Study of salvage therapy to treat patients with granulomatosis with polyangiitis (SATELITE). ClinicalTrials.gov. May 4, 2021. Updated February 8, 2023. Accessed February 28, 2023.
  11. A study to investigate mepolizumab in the treatment of eosinophilic granulomatosis with polyangiitis. ClinicalTrials.gov. December 25, 2013. Updated January 31, 2018. Accessed February 28, 2023.
  12. Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376:1921-1932. doi:10.1056/NEJMoa1702079
  13. Study of mepolizumab-based regimen compared to conventional therapeutic strategy in patients with eosinophilic granulomatosis with polyangiitis (E-merge). ClinicalTrials.gov. September 1, 2021. Updated June 30, 2022. Accessed February 28, 2023.
  14. GSK announces FDA approval for Nucala (mepolizumab) for use in adults with chronic rhinosinusitis with nasal polyps. News release. GSK; July 29, 2021.
  15. Dennis GJ. Belimumab: a BLyS-specific inhibitor for the treatment of systemic lupus erythematosus. Clin Pharmacol Ther. 2012;91(1):143-9. doi:10.1038/clpt.2011.290
  16. Belimumab in remission of vasculitis (BREVAS). ClinicalTrials.gov. August 13, 2012. Updated April 17, 2018. Accessed February 28, 2023.
  17. Jayne D, Blockmans D, Luqmani R, et al. Efficacy and safety of belimumab and azathioprine for maintenance of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled study. Arthritis Rheumatol. 2019;71(6):952-963. doi:10.1002/art.40802
  18. Rituximab and belimumab combination therapy in PR3 vasculitis (COMBIVAS). ClinicalTrials.gov. May 30, 2019. Updated March 8, 2022. Accessed February 28, 2023. 
  19. FDA approves GSK’s BENLYSTA as the first medicine for adult patients with active lupus nephritis in the US. News release. GSK; December 17, 2020.
  20. Herrero-Beaumont G, Martínez Calatrava MJ, Castañeda S. Abatacept mechanism of action: concordance with its clinical profile. Reumatol Clin. 2012;8(2):78-83. doi:10.1016/j.reuma.2011.08.002
  21. Abatacept in treating adults with mild relapsing Wegener’s granulomatosis. ClinicalTrials.gov. May 2, 2007. Updated January 18, 2016. Accessed February 28, 2023.
  22. Langford CA, Monach PA, Specks U, et al. An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener’s). Ann Rheum Dis. 2014;73(7):1376-1379. doi:10.1136/annrheumdis-2013-204164
  23. Abatacept for the treatment of relapsing, non-severe, granulomatosis with polyangiitis (Wegener’s). ClinicalTrials.gov. April 9, 2014. Updated February 6, 2023. Accessed February 28, 2023.
  24. Abatacept (Orencia®) drug information sheet. Johns Hopkins Arthritis Center. Accessed February 28, 2023. 

Reviewed by Kyle Habet, MD, on 2/28/2023.

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