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Avacopan for ANCA Vasculitis: A New Treatment Paradigm?

— Remission rates not inferior to prednisone -- the "unthinkable" achieved

Last Updated February 18, 2021
MedpageToday
The chemical structure of avacopan over a microscope image of Antineutrophil cytoplasmic antibodies (ANCA)

An investigational C5a receptor inhibitor, avacopan, was effective as a steroid-sparing induction treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a , investigators reported.

At week 26, remission was achieved by 72.3% of patients receiving oral avacopan and by 70.1% of those given prednisone, which represented a difference of 3.4 percentage points (95% CI -6.0 to 12.8, P<0.001 for noninferiority, P=0.24 for superiority), according to David Jayne, MD, of Addenbrooke's Hospital in Cambridge, England, and colleagues.

A second primary endpoint of sustained remission at week 52 was met by 65.7% of those receiving avacopan and in 54.9% of those given prednisone, for a difference of 12.5 percentage points (95% CI 2.6-22.3, P<0.001 for noninferiority, P=0.007 for superiority), the investigators reported in the .

Some of the findings were reported last June at the virtual European League Against Rheumatism meeting. On the strength of ADVOCATE's results, drugmaker in July.

"The ADVOCATE trial heralds a change in the treatment of ANCA-associated vasculitis that was previously unthinkable -- the possibility of inducing disease remission without glucocorticoids," wrote Kenneth Warrington, MD, of the Mayo Clinic in Rochester, Minnesota, in an .

"The innovative aspect of the ADVOCATE trial is that with the use of avacopan, the amount of glucocorticoids patients received was much reduced, resulting in fewer glucocorticoid-related side effects while maintaining and even improving on efficacy," Warrington told ľֱ.

"The clinical implications of this trial are profound in that glucocorticoids have been used for decades to treat patients with ANCA-associated vasculitis, and avacopan ushers in a new era in the treatment of this disease," he added.

This study advances the entire concept of "steroid-sparing therapy for the treatment of systemic inflammatory diseases, a longtime goal for both patients and physicians," said co-principal investigator Peter A. Merkel, MD, of the University of Pennsylvania in Philadelphia.

Patients with ANCA-associated vasculitis are at risk for potentially lethal complications, such as glomerulonephritis, as well as organ damage from the long-term use of prednisone.

"Activation of the alternative complement pathway, which results in terminal C5a production, is a component of the pathogenesis of ANCA-associated vasculitis," Jayne and colleagues explained. Blocking the C5a receptor with avacopan inhibits the chemo-attraction and activation of neutrophils, and in an animal model, the effect of this inhibition was prevention of glomerulonephritis.

To evaluate the possibility of replacing the long-term use of glucocorticoids by blocking the C5a receptor in ANCA-associated vasculitis, the investigators enrolled 331 patients from 143 centers, all of whom had either granulomatosis with polyangiitis or microscopic polyangiitis.

The treatment consisted of avacopan 30 mg twice daily or prednisone given on a tapering schedule for 20 weeks. Background therapy consisted of intravenous or oral cyclophosphamide followed by oral azathioprine, or intravenous rituximab (Rituxan) weekly for 4 weeks. During the 14-day screening period before randomization, 75.3% of patients in the avacopan group and 82.3% of those in the prednisone group reported any exposure to glucocorticoids, but following randomization, additional prednisone "was to be avoided as much as possible," the investigators noted.

Participants' mean age was 61, more than half were men, and the majority were white. Two-thirds of patients had newly diagnosed disease and the remainder had relapsing disease. The baseline Birmingham Vasculitis Activity Score (BVAS) was 16.3. The background immunosuppressant regimen consisted of rituximab in 65%, and renal involvement was present in 81%.

Remission was defined as a BVAS of zero, and adverse effects associated with prednisone were measured on the Glucocorticoid Toxicity Index (GTI), which reflects multiple events including weight gain, glucose tolerance, blood pressure, lipid levels, and infection.

At week 26, the least-squares mean GTI cumulative worsening score was 39.7 in the avacopan group and 56.6 in the prednisone group, for a difference of -16.8 points (95% CI -25.6 to -8.0), and the least-squares mean on the GTI aggregate improvement score was 11.2 in the avacopan group and 23.4 in the prednisone group, for a difference of -12.1 points (95% CI -21.1 to -3.2).

On the Short Form 36 health-related quality of life physical component, the least-squares mean change from baseline at week 26 was 4.45 in the avacopan group and 2.63 in the prednisone group, for a difference of 3.10 (95% CI 1.17-5.03).

The hazard ratio for relapse following remission was 0.46 (95% CI 0.25-0.84) for avacopan versus prednisone.

Mean total prednisone doses were 1,349 mg and 3,655 mg in the avacopan and prednisone groups, respectively.

The most common serious adverse event was worsening of vasculitis, reported in 10.2% of the avacopan group and 14% of the prednisone group; serious adverse events other than vasculitis occurred in 37.3% and 39% of patients, respectively.

Two patients receiving avacopan died, one of a vasculitis exacerbation and the other from pneumonia, as did four in the prednisone group (fungal infection, pleural effusion, myocardial infarction, and unknown cause). Serious infections were reported in 13.3% and 15.2% of the avacopan and prednisone groups, respectively, and serious opportunistic infections developed in 3.6% and 6.7%. There were no cases of Neisseria meningitidis, which was an adverse event of special interest because of the risk of infection associated with complement inhibition.

Longer studies will be needed to more fully assess the durability and safety of the drug, the investigators stated. They also noted that a limitation of the trial was its heterogeneous population.

ChemoCentryx also , which missed its primary endpoint but showed efficacy for two key secondary outcomes (all biomarker-based).

  • author['full_name']

    Nancy Walsh earned a BA in English literature from Salve Regina College in Newport, R.I.

Disclosures

The study was funded by ChemoCentryx.

The study authors reported financial relationships with ChemoCentryx, AstraZeneca, Genentech, GlaxoSmithKline, AbbVie, Bristol Myers Squibb, InflaRx, Biogen, Boehringer Ingelheim, CSL Behring, Insmed, Janssen, Kiniksa Pharmaceuticals, Novartis, Sparrow Pharmaceuticals, and Takeda.

Warrington reported financial relationships with Eli Lilly, Kiniksa, Roche/Genentech, Sanofi, and GlaxoSmithKline.

Primary Source

New England Journal of Medicine

Jayne DRW, et al "Avacopan for the treatment of ANCA-associated vasculitis" N Engl J Med 2021; 384: 599-609.

Secondary Source

New England Journal of Medicine

Warrington KJ "Avacopan -- time to replace glucocorticoids?" N Engl J Med 2021; 384: 664-665.