If you look at the adverse events, though, the higher dose had more for shingles than the lower dose – 2 percent for placebo, 5 percent for low dose, and 10 percent for high dose. The higher dose also did worse for viral infections. Going forward with a Phase 3 trial, we’ve decided to look at the lower dose as the maximal dose.
Q: What are the main benefits of using anifrolumab for treatment?
A: It takes care of all interferons. If you’re going to inhibit something, generally, the more inhibition you accomplish, the better. Anifrolumab does this. Compared to sifalimumab, inhibition is 50 percent greater with anifrolumab. It approaches 90 percent inhibition while sifalimumab is around 40 percent to 50 percent.
Q: What do you use to define success with this treatment?
A: Lupus is about the most heterogeneous disease there is. A patient can sometimes respond in one domain, but worsen in another. For example, a patient’s skin could get better, but they could go into renal failure. With anifrolumab, patients entered the study with a certain number of SLEDAI points. They also had lab and clinical abnormalities. We tracked their injections, and the results were really dramatic with the skin. Patients with the worst skin disease had an amazing response. We knew from data about alpha interferon inhibitors the skin could be responsive to this approach.
Q: Are there any drawbacks to using anifrolumab?
A: If you look at adverse events, there’s a higher frequency of certain viral infections. This isn’t surprising because interferon pathways help fight viruses. There’s a higher shingles incidence, as well as an increase in upper respiratory infections and influenza. The rates of infection were higher as the dose went up. Other than that, it was well tolerated.
Q: Did you encounter any surprises or unanticipated results throughout the study?
A: The only unanticipated thing was the inverse dose relationship. The lower dose outperformed the higher dose. Is it just a ceiling effect or did we see different numbers because of the low number in each of the arms? I think the latter. The pharmacodynamics showed the doses behave about the same.
We determined 75 percent of the patients at enrollment had interferon gene activity, and 25 percent did not. Looking at the results, we saw a greater effect in patients with a high interferon gene signature. It makes sense anifrolumab would work better in those with active interferon pathways.
Q: How would you anticipate these results to be applied in a patient care environment?
A: Hopefully, this will promote the drug and the studies so people will take a greater interest in looking to participate in research. It’s a lot easier to have this conversation with a patient who has acute lupus and enroll them in a study where you have confidence in the drug. That’s where we stand right now.
Q: What are the main take-away messages about this research?
A: First, the interferon pathway is active in most lupus patients, and we were losing faith after some negative studies that this might be a viable strategy. But, it seems to be now.
Second, anifrolumab is effective for patients with skin disease. It’s especially impactful in those with high interferon gene signatures. Phase 3 studies with more patients will be necessary.
Third, there was a higher shingles frequency, but going forward the lower dose is being studied. Hopefully, we’ll develop a shingles vaccine lupus patients can take.
Richard Furie, Munther Khamashta, Joan T. Merrill, et al. "Anifrolumab, an Anti–Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus," Arthritis and Rheumatology. First published: 28 January 2017. DOI: 10.1002/art.39962