C5a agonist therapy may be a 'game changer' in ANCA vasculitis
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Targeting the complement pathway using a C5a agonist may be a “game changer” in anti-neutrophil cytoplasmic autoantibody vasculitis, according to a speaker at the Basic and Clinical Immunology for the Busy Clinician symposium.
“We know ANCA vasculitis is a multisystemic disease primarily targeting the lungs and kidneys,” Adam Brown, MD, of the department of rheumatologic and immunologic disease at the Cleveland Clinic, said in his presentation. “There is a wide heterogeneity of presentation.”
That wide presentation may include sinus pain, cough and blood in the urine. Patients with microscopic polyangiitis and granulomatosis with polyangiitis may have ANCA-associated disease, with diffuse alveolar hemorrhage as the primary pulmonary complication and necrotizing crescentic pauci-immune glomerulonephritis as the most common renal complication.
Brown, who hosts Healio’s Rheuminations podcast, which often provides historical context for the rheumatic diseases, provided a brief overview of ANCA-associated vasculitis and the journey to the C5a approach. “It was 100% fatal in the 1950s,” he said.
The introduction of glucocorticoids provided some therapeutic benefit, as did cyclophosphamide and azathioprine. “Azathioprine kept some patients relapse-free, but not everybody,” Brown said.
The approval of rituximab (Rituxan, Genentech) in 2011 was a great leap forward. “We have options now, which is extremely exciting,” Brown said. “But it is not all glitter.”
Brown said that ANCA vasculitis still carries a nine-fold risk of mortality in the first year of disease. “The first problem is secondary infections,” he said. “The second problem is persistent vasculitis.”
This can lead to what Brown called the “yin and yang of treatment.” In short, immunosuppression can lead to infections, but allowing the vasculitis to go unchecked can lead to significant morbidity and mortality.
“So, enter the complement system,” Brown said.
This system has a “varied role” as a driver of innate immunity but also complements adaptive immunity, which is how it gets the name, according to Brown. It involves 60 or more proteins and is “mostly synthesized by the liver.”
Functions of the complement system involve clearing apoptotic cell bodies and promoting an inflammatory response via chemotaxis. He added C3a and C5a are proteins involved in this chemotaxis.
Brown described C5a as “a potent chemoattractant for neutrophils, monocytes and macrophages,” which makes it an attractive therapeutic target in ANCA vasculitis. He noted that blocking C5a “totally stopped ANCA vasculitis from occurring” in mouse models.
Moving to the phase 2 CLEAR trial, use of the C5a therapy avacopan (ChemoCentryx, Vifor Fresenius Medical Care Renal Pharma), in 67 patients with ANCA vasculitis yielded an 81% response rate as defined by a reduction of 50% in the Birmingham Vasculitis Activity Score in patients who did not receive concurrent prednisone. Response rates for avacopan as assessed by this parameter were 70% in patients also treated with high-dose prednisone and 86% in those who received moderate prednisone doses.
“Holy moly, this is a game changer,” Brown said of these findings.
The phase 3 ADVOCATE trial had “stricter primary endpoints” of sustained remission at 26 weeks and sustained remission at 52 weeks, according to Brown. Results showed sustained remission rates of 73.3% at 26 weeks and 65.7% at 52 weeks for patients treated with avacopan, which bested prednisone at both time points.
“The researchers were not even looking for a better response than prednisone, just something near what prednisone does,” Brown said. “This is unbelievable.”
Brown described this development as “a whole new dawn in medicine,” for one key reason. “This is a new dawn for diseases to be treated without prednisone,” he said. “But it is also an exciting time to treat this disease that used to be fatal.”
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Brown A. Vasculitis. Presented at Basic and Clinical Immunology for the Busy Clinician; Feb. 5-6, 2021. (virtual meeting).
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