Medicine Matters rheumatology

The majority of patients with active lupus will have an interferon gene signature. But the burning question was whether, if one inhibits the interferon pathway, could one see improvement in clinical activity? And that's what this study is all about.

There's a molecule on the surface of plasmacytoid dendritic cells. That's actually unique to PDCs. And PDCs are important targets in this strategy because they produce a lot of interferons. They are found in the skin of lupus patients, but they're also found in other organs like the kidney.

Again, so the strategy here was to try to shut down the synthesis of type 1 interferons. This molecule, BDCA2, which is uniquely expressed on the plasmacytoid dendritic cell, when ligated, gets internalized. And when internalized, type 1 interferon synthesis is shut off, as are a variety of other cytokines and chemokines.

Well, when one does an extrarenal lupus study, it's basically a study of arthritis and cutaneous lupus. Those are the manifestations that are most frequent in this population. The primary endpoint for this particular study that I presented was improvement in arthritis, but we've collected other information pertaining to activity of skin disease and also overall lupus activity.

The drug was given subq, the endpoint was at 24 weeks, and the primary endpoint was the reduction in tender and swollen joints. So again, we're talking about improvement of arthritis. And there was a statistical difference between the two that was about a 22 percentage point difference between placebo and BIIB059.

There were other endpoints that we looked at that were secondary endpoints, and one is the SRI, the SLA Responder Index, which is a composite index that actually is favored by a lot of the clinical trials. So we definitely included that here, and there was really a very robust distinction between the performance of BIIB059 and placebo. It was 57% were responders by the SRI versus 30%. And while that may not seem a lot compared to what we're seeing in rheumatoid arthritis or psoriatic arthritis, that is a very striking difference for a lupus clinical trial.

These were phase II studies, so we have to move to phase III. That's going to take a little time. But for extrarenal lupus, we have relatively few drugs, especially for cutaneous lupus. So there is a major need for effective and safe drugs for skin disease, but there's also a major need for just general lupus.

First, we had the science in the test tube and then its application to a small phase I study that was very heavy on biology, serving as the foundation for moving into a phase II study-- actually, two phase II studies in lupus-- concentrating on where we thought the benefit would be and that was skin disease but also looking at other aspects of lupus, namely, arthritis. And we also saw an overall response in the SRI that was very robust.

So it's-- we've been so challenged with lupus clinical trials. Our foray into lupus started in the early 1990s. And short of the belimumab program, which was successful, all the other programs had failed, and it's not for lack of trying. And lupus has been attacked by at so many different angles. So it's so refreshing to see a very logical progression such as that was taken with BIIB059 and to see two successful phase II studies, and let's hope this success continues into phase III.