Skip to main content

Medicine Matters rheumatology

So this clinical trial, the ADVOCATE study, was randomized, double-blind, placebo-controlled trial of avacopan versus placebo, but essentially avacopan versus glucocorticoids as additional therapy for treatment of ANCA-associated vasculitis. The rationale is several fold. One, the rationale includes that C5 and C5A, which is a receptor, this drug as a blocker of the receptor.

We know that compliment products are likely very important in the pathophysiology of ANCA-associated vasculitis. And so, the rationale for the mechanism of action was that blocking the action of C5A will help prevent some of the inflammatory mediated damage right at the tissue level and, hopefully, rather quickly when it's given in patients with ANCA-associated vasculitis. And it does so in a mechanism of action different from standard treatments that patients may also be getting, such as Rituximab, cyclophosphamide.

Second rationale is that with rapid onset and efficacy, it is hoped that this drug can actually prevent the need to add glucocorticoids to the regimen. Glucocorticoids have been a standard and backbone of therapy for ANCA-associated vasculitis since the beginning of treatment of this disease. And although glucocorticoids are quite effective, at least, in the short-term at reducing inflammation, they have substantial and significant short, medium, and long-term complications that we'd like to prevent.

And so, the goal is to actually reduce or eliminate the need for glucocorticoids while maintaining the same or a greater degree of efficacy. So as said, this is a randomized, double-blind, placebo-controlled trial. That's what I think about it is that these are patients with active either new or relapsing ANCA-associated vasculitis, either granulomatosis with polyangiitis, GPA, or microscopic polyangiitis, MPA.

And these patients had newer relapsing disease at moderate to severe levels of disease activity. And everybody received either Rituximab or cyclophosphamide as induction of remission agent. In addition, those people in the standard of care arm, which I'll call the prednisone arm, they received prednisone in a tapering fashion over 20 weeks. Those patients who were in the experimental arm, or the avacopan arm, received no additional prednisone, and they received avacopan.

And so we're really testing, in addition to either rituximab or cyclophosphamide, a strategy of using prednisone, which is the standard approach, or avacopan. And this was a dose twice a day, an oral dose. And thus, at the end, those patients who were in the prednisone dose, will receive substantially more glucocorticoids than those patients who were in the avacopan arm.

So the main results were actually terrific. We had two primary outcomes of interest. One was equivalence of the two arms at 26 weeks for induction of remission. And then, the outcome at 52 weeks at one year was both, whether there would be as good, and if so, would avacopan actually be superior. And this trial actually hit all of its primary outcomes at 26 weeks.

The prednisone and avacopan arms were not inferior to each other. The rate was almost identical in terms of remission at 26 weeks. At 52 weeks, the avacopan arm had a superior outcome. They had clinically and significantly increased number of patients, percentage of patients who achieved sustained remission at 52 weeks. And so, this was quite positive.

In addition, we had several important secondary outcomes, including glucocorticoid related toxicity measured by an index called glucocorticoid toxicity index, as well as renal outcomes and other outcomes, all of which favored the avacopan arm over the prednisone arm. So really quite a positive study, very encouraging. And the main results were that remission was maintained better as well or better with patients who got avacopan.

And they were able to do it without glucocorticoids. So it's a so-called steroid sparing approach. Patients did get some before they entered the trial. And they may have gotten some with rituximab, because that's standard. But overall, the amount of steroids were substantially less for patients who got the avacopan.

Additionally, interestingly, the renal function improved in both group, but improved even more in avacopan. And it improved not only by 26 weeks, but it continued to improve by week 52, which is intriguing. Because we think of these patients of being in remission, yet their renal function continues to improve, which is promising.

And so, there were a lot of positives here. And the adverse effect profile was quite good, meaning that there were no significant signals of a particular adverse or serious adverse event for patients getting avacopan. Well, I think this is a major advance in thinking about treatment for ANCA-associated vasculitis.

First of all, it worked. And it's a different mechanism of action. It's complementary, and I don't mean that to be funny, because it's a complimented. But it's truly complementary to the other approaches, whether it be cyclophosphamide or rituximab, or then azathioprine after the cyclophosphamide. And so, it emerges well.

And we know the combination therapy we use in a lot of autoimmune disease, especially rheumatology, but what it means is, well, it really depends on whether or not the drug is approved in the various geographic regions where it be used. But if it is approved for use, it provides not only another option for patients and providers to use to treat, but we think it will be a terrific option for both new and relapsing disease at the onset of the flare, the onset of the activity.

Because it works quickly. And probably the biggest impact is it will allow for not the elimination, but the near elimination, the marked reduction in the use of glucocorticoids, which will be of great benefit to patients. Longer term, after remission's obtained, it appears to help maintain remission. So this is really an advance. And it goes along with the theme that we're trying to do in this field and in rheumatology, in general, was to look for so-called steroid sparing approaches to our therapy for systemic inflammatory diseases.

What's next? Well, what's next will be somewhat determined by what is the nature of the regulatory approval for the drug, so how will the drug be allowed to be used. And that often varies from country to country and region to region. I think there will be significant interest in how does this drug work in so-called real world setting. We will get some experience for how it works in practice.

There's certainly a lot of interest in whether to do studies in different subpopulations, whether to extend the amount of time that is used. So there are various options for studying this drug in this indication. I just would add that this was a study done at a great number of sites around the world. And it was very much a international collaboration.

I get to speak about it, which is terrific. But it is really the work of many people in the vasculitis research community. And I think it demonstrates that we have a very cooperative and collaborative community that really can get this work done.