In an interview with Pharmacy Times®, Richard Furie, MD, chief of the division of rheumatology at Northwell Health, discusses the observed efficacy of obinutuzumab (Gazyva, Gazyvaro; Genentech) in patients with lupus nephritis as seen in the phase 3 REGENCY clinical trial. In REGENCY, obinutuzumab effectively reduced proteinuria while maintaining kidney function in patients with lupus, offering hope for a new treatment that can be effective in patients with varying levels of disease activity. According to Furie, obinutuzumab performed well in patients with high disease activity, solidifying the therapy as a promising option for these populations.
Furie also notes possible directions for future research while emphasizing the need for further study on the risk of infections in patients with lupus nephritis, who face a heightened risk as they often present as immunocompromised.
Pharmacy Times: Could you elaborate on the clinical significance of the findings in the REGENCY trial of obinutuzimab and its potential impact on current treatment protocols for lupus nephritis?
Key Takeaways
1. Obinutuzumab demonstrated significant efficacy in achieving complete response in lupus nephritis patients, reducing proteinuria while preserving kidney function.
2. Lupus patients, already immunocompromised, face heightened infection risks from immunosuppressive therapies; obinutuzumab’s role as a B-cell depleting therapy warrants close monitoring.
3. Patients with severe disease markers—such as high proteinuria, low complement levels, and class 4 lupus nephritis—showed particularly strong responses to obinutuzumab.
Richard Furie, MD: Well, first of all, it was a positive trial. That may sound trite, but we have struggled in our SLE and lupus nephritis trials, though in the last several years, we've had some successes, including the phase 2 NOBILITY trial, which was a study of obinutuzimab, and that served as the foundation for the REGENCY trial. Our end point is a complete response, and it's a pretty rigorous end point. Our desire is to reduce proteinuria in patients with lupus nephritis and, at the same time, make sure that their kidney function is not getting worse. This has implications for long-term kidney survival.
Pharmacy Times: What specific adverse events should pharmacists be vigilant about when monitoring patients with lupus nephritis undergoing treatment with obinutuzimab?
Furie: Well, before we get into the specifics of obinutuzimab, let me just say that patients with lupus in general are more predisposed to certain events. We worry about infections, in part because of the underlying disease but also because of the medicines that they're being treated with. For example, steroids. We've had a love-hate relationship with steroids since 1948. They have been lifesaving, no question about that, but we see a higher risk of infections, and we see many other types of side effects as well. And then along came immunosuppressive therapies, and it's the same situation; we worry about infections. With obinutuzimab, which is a B-cell-depleting antibody... Well, actually, if you go back to when we first started depleting B cells, not with obinutuzimab, but first with rituximab [Rituxan; Genentech], we were very frightened about what would happen to patients without B cells—would they succumb to infections? That was not the case. It's actually very interesting that we do well without having a lot of B cells in our blood. Specifically, with obinutuzimab, in the phase 2 study called NOBILITY, we didn't really see much in the way of adverse effects compared with the placebo group. Let me just say that when we talk about placebo, it's not just placebo. Patients are coming in on standard of care, and that usually means some steroids. It means hydroxychloroquine for most of them. And then in the study, they're receiving mycophenolate. These are all immunosuppressive therapies. Now in REGENCY, this was conducted during the height of the COVID pandemic. It's not an opportune time to study an immunosuppressive drug. In fact, we did see more COVID infections in the obinutuzimab group than we did in the placebo group. But it was also at a time when we didn't really know how to handle COVID. Vaccines weren't available, some of the biologics that we use. Actually, if you look at the paper in the supplementary materials, we compare the adverse event rate in the first half of the study to the second half of the study, when we had a better handle on COVID. With any B-cell depleting antibody, it's not just obinutuzimab; you do have to be concerned about infections.
Pharmacy Times: How do the consistent CRR benefits across various patient subgroups influence the selection criteria for obinutuzumab therapy in diverse patient populations?
Furie: Well, something we always do is a subgroup analysis. But you have to look at those results with a bit of caution because the studies are not powered to slice up the cohort into all these small subgroups, and sometimes you see some things that defy explanation. So, for example, we always look at differences in gender, we look at regional differences, we look at baseline laboratory values, and so forth. And all of that was done in the REGENCY trial. There are certain things that I can't explain, [and] I'm not sure anybody can explain; for example, we saw a really high placebo response. Now, males were outnumbered by females; it's always the case in lupus, and it was the case in the REGENCY study. But we don't know why there was such a high placebo response rate. It didn't really make sense. Other subgroups that we looked at were, as you just mentioned, patients who seemed to have a higher degree of disease activity. These would be patients with low complement levels, high DNA antibodies, a biopsy showing diffuse-proliferative disease that is class 4 disease, [and] patients with high levels of proteinuria. It was very gratifying to see that obinutuzimab performed well in these high-disease activity subgroups. What would be even better is to combine some of those baseline characteristics, though when you start combining, your numbers may get even smaller. But sort of the classic patient who's active would be a class 4 patient with low complements and high DNA antibodies and a lot of proteinuria. You could combine all those baseline characteristics, and that would certainly put obinutuzimab to the test. Those kinds of analyses will be done; just give us some time.
