German Hernandez, MD, FASN, FACP, and Ellen Ginzler, MD, MPH, provide insight into the FDA approved therapies for lupus nephritis, belimumab and voclosporin, including an overview of clinical evidence, mechanism of action, and patient selection.
German Hernandez, MD, FASN, FACP: Lupkynis [voclosporin] is a novel calcineurin inhibitor. It basically has 1 modification in the latch region of the calcineurin molecule. It’s thought to have a dual mechanism of action in the sense that it provides some stability to the podocytes—that’s where the proteinuria is happening—but it also acts as an immunosuppressant by inhibiting T-cell activation and decreasing cytokine production. Because of the different pharmacokinetics and pharmacodynamics of Lupkynis, it’s a medication that, unlike tacrolimus or cyclosporine, doesn’t require therapeutic drug monitoring. This is very nice for us as clinicians because we don’t have to be chasing cyclosporine or tacrolimus levels. It’s basically just dosed, and then the dose can be adjusted depending on the patient’s changing GFR [glomerular filtration rate], if there is such a change.
The Lupkynis trial was a 52-week trial that took patients with lupus nephritis—class 3, 4, or 5—and looked at them either alone, or class 3 in combination with class 5, or class 4 in combination with class 5. They were treated with standard of care, corticosteroids as well as MMF [mycophenolate mofetil]. Patients were randomized to receive either Lupkynis or placebo. They were followed for a total of 52 weeks. The primary outcome for this study was a complete renal remission, basically achieving a urine protein to creatinine ratio [UPCR] of less than 500 mg/g of creatinine over the 52-week follow-up period. This was achieved in 40.8% of patients in the Lupkynis group vs only 22.5% in the standard of care group.
The interesting thing about this trial is that they had a very aggressive taper protocol for prednisone, so that by the end of 16 weeks, all the patients were down to a level of 2.5 mg of prednisone, which isquite aggressive, and it turns out very achievable. The positive thing about this is that we’re exposing our patients to a lower risk of developing [adverse] effects related to the prednisone.
The other interesting thing about this trial is that they not only looked at renal responses at 52 weeks, but there was also a halfway point at 24 weeks. They found that 32.4% of patients in the Lupkynis group achieved a complete renal response compared with 19.7% in the active standard of care arm. The thing that’s important in lupus nephritis is achieving a remission, but also achieving it as fast as you can. When we look at how many days it took to get to a complete renal remission, for those in the Lupkynis group, it was only 169 days to get to a UPCR or proteinuria reduction of less than 500 mg/g, compared with 372 days in the MMF and prednisone group.
When they looked at how fast a 50% reduction in proteinuria can be achieved, it was a median of 29 days for the Lupkynis group vs 63 days for the standard of care group with MMF and prednisone. There was a higher efficacy in terms of achieving complete renal response both at 24 and 52 weeks, and also a shorter amount of time to getting to a 50% reduction, at only 29 days in the Lupkynis group. These are promising results with this drug.
Ellen Ginzler, MD, MPH: There are some differences in outcome with the 2 drugs, but they both show an ability to lower the levels of protein excretion in the urine more rapidly when you add those onto the standard of care drugs. They both show that overall, you tend to need less prednisone, less steroids, when you add those drugs, and there’s less likely to be a flare once the disease has gotten under control.
There are minor differences between the 2 drugs, but those effects are similar with both drugs. The major difference is that Benlysta, or belimumab, was approved for treating other features of lupus long ago, in about 2012. As a result, we have a lot of experience with nonrenal lupus with Benlysta. With voclosporin, or Lupkynis, that hasn’t undergone clinical trials for lupus features other than nephritis, so we don’t have as good evidence yet of how that will work for things like arthritis or skin rashes. That’s some experience we need to get.
German Hernandez, MD, FASN, FACP: Benlysta acts by targeting the B cells, whereas Lupkynis acts by targeting the T cells and also providing some podocyte stability within the kidneys. When you look at the trial results of Benlysta, at the end of 104 weeks, the Benlysta group had a 30% complete renal response compared to 20% in the standard of care group. When you look at Lupkynis, which is a T cell-targeting drug as well as a podocyte stability drug, the rates of response at 52 weeks were about 41% in the Lupkynis group vs 22% in the placebo group. That’s how the 2 studies compare. Obviously, there’s no head-to-head comparison study between Benlysta and Lupkynis.
Ellen Ginzler, MD, MPH: I personally would choose voclosporin if I had a patient who was spilling very high amounts of protein, because it tends to work more quickly and it gets directly at the protein part of the clinical effects of lupus nephritis. On the other hand, if I had a patient who had a lot of active arthritis and rashes along with their lupus nephritis, I would probably pick Benlysta first.
Transcript edited for clarity.