Biomarker-centric clinical trial redesign 'coming to ANCA associated vasculitis'
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Despite an ever-growing array of potential candidate biomarkers for antineutrophil cytoplasmic antibody-associated vasculitis, it can be a long journey from “bench work” to bedside, according to a presenter at ACR Convergence 2021.
Peter Grayson, MD, MSc , fellowship assistant director at the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the NIH, acknowledged that with so many potential biomarkers in play in ANCA vasculitis, taking this journey is rarely easy. “Time and time again, biomarkers show promise at the group level but fail to show action at the individual patient level,” he said.
That said, paying closer attention to preclinical and preliminary data can provide insight for the research community that could ultimately lead to effective novel therapeutics, according to Grayson.
The key example of this is avacopan (Tavneos, ChemoCentryx) and the ADVOCATE trial. Preliminary data supported the role of the complement system — specifically, the C5a receptor — as a potential therapeutic target for ANCA vasculitis. “We tend to think of ANCA-associated vasculitis as a disease that does not involve complement because it is a pauci-immune condition and because levels of C3 and C4, members of the classic complement pathway, were not abnormal in the disease,” he said.
But mouse models in C5a led to the successful CLASSIC study and CLEAR trial, which showed the safety and effectiveness of avacopan and allowed the program to move to phase 3. “This is really a remarkable journey over several decades that culminated in the ADVOCATE trial, which led to the first ever drug developed specifically for ANCA-associated vasculitis receiving FDA approval in October of this year,” Grayson said. “This sets the standard for how we can integrate bench work with clinical application in the world of biomarker discovery and development.”
Grayson acknowledged that it can be “quite daunting” to make sense of the biomarker landscape in a disease like ANCA vasculitis.
He noted that in addition to those in the complement system, there is a host of antigens, chemokines, cytokines, immune cell subsets, T- and B-cell subsets, mRNA transcriptomic profiles, urinary markers and metabolites that have been associated with ANCA in some form or another.
“There are challenges in identifying a biomarker first and then actually taking it forward to some sort of clinical application,” he said.
One example of this is a transcriptomic signature that indicates T-cell exhaustion and may predict prognosis in ANCA. While Grayson suggested that it was “remarkable science” that led to this discovery, applying it in the clinic has proven technically challenging.
Similarly, ANCA itself has shown the possibility of being a predictor of relapse risk. “But when it is applied at the individual patient level, it does not hold up well,” he said.
Genome-wide association studies have shed light on the genetic landscape involved in ANCA-associated vasculitis. But Grayson acknowledged that the research community is only just beginning to understand the genetic factors at play in the disease.
All of that said, Grayson believes that ongoing efforts in these directions could prove fruitful and ultimately benefit patients. “The trial of the future is going to be precision based, giving the right patient the right drug at the right time for the right duration,” he said.
The trend toward adaptive trial designs — for example, an umbrella trial — across the spectrum of rheumatologic diseases is likely to find its way to the vasculitides, according to Grayson. “In an umbrella trial, you screen all patients with the disease, then you would stratify them by specific biomarkers,” he said. “Then you would conduct your randomized, controlled trial stratified by these basic biomarkers. These types of designs are what we are going to see coming to ANCA-associated vasculitis.”
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Grayson P. Abstract #6S401. Presented at: ACR Convergence 2021; November 5-9, 2021 (virtual meeting).
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