AstraZeneca is planning to file for approval of anifrolumab in systemic lupus erythematosus (SLE) in the second half of next year. The Big Pharma is confident data generated across mid- and late-phase trials show the anti-IFNAR1 antibody works despite a pivotal study missing its primary goal.

Anifrolumab looked to be on the ropes last year when AstraZeneca’s first phase 3 trial missed its primary endpoint. However, AstraZeneca made mid-study tweaks to its second phase 3, switching to a different primary endpoint, and delivered data that paint anifrolumab in a more favorable light. The data have made AstraZeneca bullish about its prospects.

“We’ve got a first-in-class medicine. What we see across the totality of the data … is a very strong consistency along the key endpoints,” AstraZeneca Senior Vice President Richard Marshall said. “If you look at the disease activity index, we do have data supporting the impact on the totality of disease.”

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AstraZeneca shared the first close look at the phase 3 data at the 2019 ACR/ARP Annual Meeting. In the second, successful phase 3, 363 patients with moderate-to-severe SLE were randomized to take either anifrolumab or placebo. After 52 weeks, 47.8% of subjects on anifrolumab had achieved the BICLA composite lupus assessment endpoint compared to 31.5% in the control arm. That resulted in the trial meeting its primary endpoint with a p-value of 0.001.

Anifrolumab also statistically outperformed placebo in terms of oral corticosteroid reduction and a disease area and severity index, leading the researchers to state the study “demonstrates efficacy of anifrolumab in moderate to severe SLE.”

That concrete conclusion is called into question by other results. Anifrolumab failed to outperform placebo against two key secondary endpoints in TULIP-2 and, most critically, was no better than the control against the primary endpoint in the previous phase 3.

In the earlier trial, TULIP-1, 36.2% of participants who received the high, 300 mg dose of anifrolumab achieved the required response on the SRI(4) composite primary endpoint. A numerically higher percentage of people on placebo, 40.4%, achieved the required response. A post hoc analysis that used modified restricted medication rules put anifrolumab ahead of placebo by a few percentage points.

The failure of TULIP-1 prompted AstraZeneca to change the design of TULIP-2, hence the different primary endpoints used in the two clinical trials. However, Marshall thinks BICLA is well accepted by regulators and physicians who treat SLE.

“I think the general consensus is that BICLA is the more stringent measure because it requires an impact across all of the affected tissues,” Marshall said.

In some indications, the failure of one trial and success in another after mid-study changes could yield insufficient evidence to support approval. Regulators may be more amenable toward approving a drug in SLE on the basis of such evidence, though, given the unmet medical need in the indication.

The FDA approved GlaxoSmithKline’s Benlysta in 2011. That approval marked the arrival of the first new lupus drug for 50 years and the first-ever biologic treatment for the disease. Since then, the drought has returned as companies including Ablynx, Biogen and Xencor have swung and missed at lupus.

AstraZeneca plans to file for approval of anifrolumab in the second half of next year, and the team is “doing everything we can to bring that forward,” Marshall said.