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Medicine Matters rheumatology

I think the most major unmet need in the treatment of lupus is actually lupus nephritis. We do not do a good job with our patients who have lupus nephritis. If complete response is our goal-- and complete response is generally defined by a reduction in proteinuria-- we're achieving complete response rates of about 30% to 35%.

And what we do know from some recent studies is that the people who do best long term are those who do best short term. Meaning those who get a complete response with their initial treatment for lupus nephritis are more apt to do better down the line, you know, 7, 10 years down the line, than patients who don't achieve a complete response. So 1/3 of patients achieving a complete response is not good. It's just not acceptable. So there's no question that we need better therapies if we're only achieving complete response in about 35% of our patients.

So the impetus to do this study is based upon three things. So number one, the successful Phase 3 program with belimumab; number two, data showing that there's increased BAFF production in the patients who have lupus nephritis, so there are higher circulating levels, so just a biologic principle. And then, probably most important, was a post-hoc analysis of the Phase 3 data.

Now the Phase 3 program was for patients with systemic lupus, not patients with active proliferate nephritis. Because the treatment paradigm for lupus nephritis is very different than for extra renal lupus. But be that as it may, about 15% of the patients enrolled in the Phase 3 program-- and that came out to about 200 patients or so-- had some abnormality in the renal domains of their SLEDAI scores.

And so we looked post-hoc at those patients and established that there's a reason, perhaps, to think that belimumab works in renal disease, even though full-blown lupus nephritis was an exclusion in the Phase 3 program. Hence, the development of this particular study, BLISS-LN. The goal of this study was in some ways twofold-- number one, to reduce disease activity, and number two, show durability of effect.

The end point was at two years. And it was an endpoint that was called PERR, primary endpoint of renal response. And like typical endpoints for other studies, though this end point was at two years and most of the lupus nephritis end points had been at either six months or 12 months, the endpoint was defined by a reduction in the protein in the urine, so a urine protein creatinine ratio to 0.7 or less. The second component of the response was that the glomerular filtration rate, the EGFR, couldn't be any worse than 20% below the pre-flare value, or it had to be greater than 60 mL per minute. 60 mL per minute is considered normal. And of course, they couldn't take medicines that were prohibited by the protocol.

So again, like other studies, the end point was driven by a reduction in proteinuria with protection against that end point with restrictions on the creatinine or the EGFR. But what was unique here is the two year endpoint. And there were a couple of other unique features. So one was that the prednisone dose had to be less than 10 milligrams by week 24. And the other unique feature of this protocol was the fact that patients had to hit the end point at consecutive visits.

Unfortunately in our lupus studies, whether it's extra renal lupus or lupus nephritis, there can be a lot of noise when you're collecting urine for protein creatinine ratio. One time it might be 0.8 and then another time it could be 0.6. So is that person a success or a failure?

Well, in this particular study, they had to have consecutive visits where they hit the end point. And that just helps reduce the noise.

And so as far as the results, the primary and all the key secondaries were statistically significant. And I don't know how much you followed our lupus and lupus nephritis trials, but we have struggled. I mean, belimumab is actually the only drug that has conquered these challenges, getting an approval in 2011 by the FDA for the two positive Phase 3 studies. But again, those were extra renal studies. And there have been some additional positive studies with belimumab.

But we have wrestled with lupus clinical trials for, now, 25 years. This is the first lupus nephritis trial to be successful. So it's very refreshing.

We can run through the results. But I'll condense it. The primary end point, the so-called PERR, had about an 11 percentage point difference between placebo and belimumab. And that same effect size was seen with the complete renal response and then the PERR at week 52.

The time to renal-related event or death had a hazard ratio of 0.5, roughly. So that just means a 50% reduction in the rate of these events. Again, that's had a four-item component.

And to me, that means a lot. Because again, this is getting at the prevention of flare, the prevention of renal worsening, what the whole game is all about. And that had a very significant p value of 0.001. And then the ordinal renal response also was statistically significant. So to hit on every single primary and key secondary is so refreshing in this field.

So my view is that I would use this in patients who have proliferative nephritis and/or membranous nephritis. So when asked for the last 15 or 20 years what kind of minimal effect size would I like to see in lupus nephritis trials, my answer was always 10%, barring any safety issues. So a 10% spread means that 1 out of 10 patients will benefit. And we achieved more than that with this particular study.

So I would treat my patients in the real world just like the patients were treated in this particular study. If they have proliferative nephritis, proliferative and membranous, or just membranous, I typically treat with mycophenolate and steroids. And I would add in belimumab, especially since the safety profile was excellent. I mean, there really were no issues.

And that's what we've seen all along. I mean, we started studying this drug in Phase 1, back around the year 2000. And I must say, in all the studies that have been done, the safety profile has been excellent. So I would go for the combination of prednisone, mycophenolate, and belimumab.