Thumbs Up From FDA for Anifrolumab in Lupus

The FDA has approved the type 1 interferon receptor antagonist anifrolumab (Saphnelo) for the treatment of moderate-to-severe systemic lupus erythematosus along with standard therapy, reported manufacturer AstraZeneca.

“This is wonderful, exciting news, and is great for the lupus community — patients, family members, and clinicians who treat patients,” said Richard Furie, MD, chief of rheumatology at Northwell Health in Great Neck, New York, in an interview.

Recent decades have seen approval of only two new treatments for lupus, which were belimumab (Benlysta) in 2011 and voclosporin (Lupkynis) for lupus nephritis earlier this year. “And that represents 25 years of trying,” Furie said.

Among agents that have not been successful are tabalumab, epratuzumab, and atacicept. And the road to approval of anifrolumab has not been entirely smooth.

Significant benefits were seen in a phase IIb trial known as MUSE reported at the annual meeting of the European League Against Rheumatism in 2016. In that trial, 62.6% of patients receiving 300 mg intravenous anifrolumab every 4 weeks had an SLE Responder Index score of 4 (SRI-4) plus a reduction in the steroid dose to less than 10 mg/day compared with only 17.6% of patients in the placebo group, which was a significant difference. At the time, lead investigator Furie told MedPage Today, “These are the best lupus data we’ve ever seen.”

Two pivotal phase III trials, TULIP-1 and TULIP-2, followed, with discordant results.

In TULIP-1, which included more than 450 patients, the primary endpoint of Systemic Lupus Erythematosus Responder Index (SRI-4) was not met. At week 52, an SRI-4 response was seen in 36% of patients receiving anifrolumab and in 40% of those given placebo (P=0.41).

However, some secondary endpoints suggested benefits, including the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA).

TULIP-2 included 362 patients who were randomly assigned to receive 300 mg intravenous anifrolumab or placebo every 4 weeks for 48 weeks, with the primary endpoint being a BICLA response. At week 52, 47.8% of patients in the anifrolumab group achieved a BICLA response compared with 31.5% of patients in the placebo group, for a difference of 16.3 percentage points (95% CI 6.3-26.3, P=0.001), the investigators reported in the New England Journal of Medicine.

“We were all shocked when TULIP-1 failed,” said Furie, who is also a leading member of the Lupus Research Alliance’s Lupus Clinical Investigators Network. “But it didn’t really fail — it depends on how you define failure. It did not reach the primary endpoint, but on the other composite, BICLA, it was successful, as well as on a lot of the key secondary endpoints. The totality of the data, I think, is the key phrase,” he said.

“I think the two studies were more similar than dissimilar. You have to have an appreciation of how difficult it is doing clinical trials in lupus. For every one trial that has been successful, there have probably been 10 that were unsuccessful,” he said.

It’s also not the first time there has been discordance between the composite indices in lupus trials. “We also saw discordance between the BICLA and SRI in the ustekinumab phase II trial,” he noted.

Type 1 interferon is a central player in the pathophysiology of lupus, with increased signaling being associated with worse disease activity and severity.

The most common adverse events associated with anifrolumab in the clinical trials included nasopharyngitis, upper respiratory tract infections, infusion-related reactions, and herpes zoster.