Novel Lupus Drug Clears Phase II Hurdle

BARCELONA — A small-molecule oral drug shaping up as a first-in-class to treat various forms of lupus performed well in a phase II trial, despite — or perhaps even because of — missing its primary endpoint, a presentation here suggested.

Called enpatoran, the agent targets the Toll-like receptor (TLR) species 7 and 8. Some 50%-60% of patients with systemic lupus erythematosus (SLE) receiving it at different doses obtained so-called BICLA responses after 24 weeks, compared with 39% of a placebo group, reported Eric Morand, MBBS, PhD, of Monash University in Melbourne, Australia.

Differences from placebo in response rates, however, weren’t the primary endpoint, Morand explained during a late-breaking abstract session at the European Alliance of Associations for Rheumatology annual meeting. Rather, the primary endpoint was a clear dose-response, and that was definitely not seen. The highest numerical rate for BICLA response, 58%, was in the group receiving the lowest dose (25 mg twice daily); two groups receiving higher doses, 50 and 100 mg twice daily, each had response rates of 49%.

This lack of dose-response was because “there was a response at all doses,” Morand said — and that was a good thing and the more important finding, he argued.

He especially stressed outcomes for a second endpoint, BICLA response plus “clinically meaningful” reduction in daily corticosteroid usage, the latter defined as going from ≥10 mg/day to ≤5 mg/day in prednisone equivalents by week 12 and sustained thereafter. That endpoint also showed large differences between the active drug and placebo at week 24:

Placebo: 31.4%Enpatoran 25 mg: 58.8%Enpatoran 50 mg: 55.6%Enpatoran 100 mg: 47.5%
Although these response rates suggest a dose-response relationship opposite of what was expected, Morand suggested that it was simply an artifact of the assessment methods. In lupus trials, he said, “it’s hard to separate placebo from active treatment, and it’s even harder to separate doses.” These problems arise, he added, from the measurements.

As well, he noted that no dose-response was seen with enpatoran in patients with cutaneous lupus, reported in May at a different meeting. The same three dosage levels were equally effective in that disease, and clearly more so than placebo.

TLRs are a novel target in lupus in that, originally, this receptor family was considered to be part of the innate immune system, whereas autoimmune disease like lupus originate with the adaptive system. But research has shown that TLRs’ effects do extend beyond the innate system and play a role in B-cell activation, for example. Type 1 interferon, release of which is triggered by TLR 7/8 stimulation, is a key factor connecting the two systems.

Consequently, Morand highlighted an exploratory analysis restricted to patients with high interferon gene activation, about 80% of the total sample. BICLA responses were seen in 61% of those on the lowest dose, and 49%-52% of the higher-dose groups, versus 31% with placebo.

He also noted with satisfaction that complete suppression of interferon gene activation was observed “not just in some patients, but in all patients.” This demonstrated that, if nothing else, enpatoran was engaging its TLR targets successfully.

For the SLE trial, Morand and colleagues enrolled 294 patients, randomized in two phases. The first 60 were assigned 1:2 to placebo or enpatoran at 100 mg, then the remainder were randomized 1:1:1:1 to placebo or the 25, 50, or 100 mg doses, all taken twice daily.

Mean patient age was about 42 and close to 95% were women. One-half of patients were taking ≥10 mg/day of steroids at baseline; two-thirds had SLE Disease Activity Index scores of 10 or more.

With regard to adverse events (AE) in the trial, “there were no troubling safety signals,” Morand said. No one died and only one severe treatment-emergent AE (TEAE) occurred, and that was in the placebo group. Infections and gastrointestinal AEs were seen at similar rates in all groups, as were TEAEs overall.

“These results support further investigation of enpatoran in people with lupus,” Morand concluded.

Disclosures

The study was funded by Merck KGaA and its EMD Serono unit. Several co-authors are company employees.

Morand and co-authors disclosed multiple relationship with industry including EMD Serono.

Primary Source

European Alliance of Associations for Rheumatology

Source Reference: Morand E, et al “Randomised, placebo-controlled phase II study of oral enpatoran, a first-in-class toll-like receptor 7/8 inhibitor, in systemic lupus erythematosus” EULAR 2025; Abstract LB0004.