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MILAN -- An investigational protein drug called dazodalibep with broad-spectrum activity against autoimmune pathways reduced symptoms of Sjögren's syndrome in a two-stage, phase II randomized trial with a unique design.

Called , the placebo-controlled trial targeted two different populations, each reported in separate presentations at the European Alliance of Associations for Rheumatology (EULAR) annual meeting. Dazodalibep is a non-antibody fusion protein that antagonizes the CD40 ligand, disrupting intercellular communication between different immune cell species that together drive autoimmunity in Sjögren's syndrome.

The first, presented by Wan-Fai Ng, PhD, of Newcastle University in England, involved a fairly standard type of patient, those with moderate-to-severe overall symptoms as graded by the standard EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). With a primary endpoint of decline from baseline in ESSDAI score, 24 weeks of treatment led to a mean difference from placebo of 2.2 points (P=0.167).

Perhaps more interesting was the second stage, reported by Chiara Baldini, MD, of the University of Pisa in Italy. It targeted a patient group she described as "typically neglected" in Sjögren's syndrome trials: those with relatively mild disease (ESSDAI score <5) but who describe their symptom burden as "unacceptable." This was assessed via the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), with a score of at least 5 as a separate inclusion criterion.

In this analysis, change in ESSPRI score was the primary outcome. Baldini reported that patients receiving dazodalibep achieved a 1.8-point decline from baseline, versus a 0.5-point reduction with placebo (difference 1.3, P=0.0002) at week 24.

Drugmaker Horizon Therapeutics said it plans to pursue further development of dazodalibep but a phase III trial has not been announced.

Stage 1 Details

In this part of the trial (and stage 2 as well), patients were randomized 1:1 to 24 weeks of either placebo or dazodalibep, followed by a 16-week switchover to the other agent and an additional 12 weeks of treatment-free safety evaluation. A total of 74 patients participated in stage 1. Almost all participants were women; mean age was about 50. ESSDAI scores averaged 10.7 at baseline and the ESSPRI mean was 6.6.

ESSDAI score ≥5 was required for inclusion, making for a standard patient population in a Sjögren's syndrome trial. But while this group responded better to dazodalibep than placebo with ESSDAI, there was no difference in ESSPRI score until the very end of the trial, when a slight separation favoring the active drug appeared. Numerical differences also favored dazodalibep for other secondary outcomes such as fatigue and function but these did not reach statistical significance.

Ng took pains to note that substantially more patients on dazodalibep achieved ESSDAI score reductions of 5 or 6 points -- more than 60%, compared with 35% of the placebo group (P<0.05).

No major safety issues emerged in this part of the study. Treatment-emergent adverse events were somewhat more common with dazodalibep (78% vs 61%); one patient on the drug developed a herpes zoster infection and one patient died, but the fatality occurred weeks after treatment ended in a patient with COVID-19 and a history of respiratory and cardiovascular disease; Ng said the family refused an autopsy and therefore it was judged unrelated to treatment.

Stage 2 Details

This phase involved 109 patients, also randomized to 1:1 to dazodalibep or placebo on the same schedule as in stage 1. In addition to an ESSPRI score of at least 5, patients had to have ESSDAI scores less than 5 to be enrolled. They also needed to have stimulated salivary flow of at least 0.1 mL/min to establish that objective signs were not severe, and extraglandular involvement must have been classified as "limited."

Participant characteristics were similar to those in the stage 1 sample, except, of course, that mean ESSDAI score was much lower at 2.8.

Unlike in stage 1, patients in stage 2 did report markedly more improvement with dazodalibep versus placebo in a range of subjective outcomes. These included the dryness, fatigue, and pain domains within ESSPRI. For each of these, only minimal changes were seen with placebo through week 24, whereas reductions from baseline approaching or exceeding 2 points were seen with the active drug. Additional measures of fatigue and global symptom burden also favored dazodalibep.

Safety findings were similar to those from stage 1, Baldini said. There were no deaths or serious adverse events attributable to treatment.