Dazodalibep seen to ease Sjögren’s syndrome symptoms in Phase 2 trial

Horizon therapy found safe, effective in 2 divergent groups of patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Dazodalibep, Horizon Therapeutics’ experimental therapy for Sjögren’s syndrome, was found to safely and effectively ease disease activity and symptoms across two divergent groups of people with the chronic autoimmune disorder.

These groups included people with Sjögren’s who had generally been excluded from recent clinical trials — patients with “overall unacceptable health status.” Specifically, these patients had either moderate-to-high systemic disease activity or moderate-to-severe symptoms, but minimal systemic disease activity.

These are the results of a completed Phase 2 trial (NCT04129164) that were featured in an oral presentation and a poster at this year’s European Alliance of Associations for Rheumatology (EULAR) European Congress of Rheumatology, which took place June 1-3 in Milan, Italy.

“These presentations demonstrate our research approach at Horizon to recognize the challenges of people living with serious unmet medical needs and deliver solutions that may improve their quality of life,” Elizabeth H.Z. Thompson, PhD, Horizon’s executive vice president of research and development, said in a company press release.

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According to Horizon, dazodalibep is the only therapy in development to meet the main goal of a Phase 2 trial in both Sjögren’s patient populations.

“We look forward to continuing to develop dazodalibep and potentially transform patient care in Sjögren’s,” Thompson said.

Sjögren’s is an autoimmune disease characterized by the abnormal production of self-reactive antibodies that mistakenly attack moisture-producing glands. Symptoms can include dry eyes and mouth as well as pain and fatigue. More severe cases affect internal organs such as the kidneys and lungs.

Administered directly into the bloodstream, dazodalibep works by preventing the binding between CD40, a receptor protein present at the surface of antibody-producing immune B-cells, and its CD40 ligand (CD40L) — present at the surface of immune T-cells.

Given that CD40-CD40L immune signaling is overly activated in Sjögren’s and other autoimmune diseases, the experimental therapy is expected to reduce the autoimmune attacks that drive them. Ultimately, the goal is to ease disease activity and symptoms in patients with the rare disorder.

The global Phase 2 trial tested dazodalibep against a placebo in two populations of adults, ages 18-75, with a diagnosis of Sjögren’s.

The first population included 74 patients with moderate-to-severe organ involvement, or systemic disease activity, as defined by an EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of five points or more.

The second patient population comprised 109 individuals with no organ involvement, but moderate-to-severe symptoms as defined by an EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score of at least five points.

This population represents “a substantial proportion of Sjögren’s patients who have largely been excluded from recent trials despite significant disease burden,” the researchers wrote.

All participants were randomly assigned to receive either dazodalibep (1.5 mg) or a placebo for 24 weeks, or about six months. After that, patients were switched to the opposing regimen for 16 weeks, or about four months.

Treatment in the first six months was given every other week for the first three doses and then once a month for four doses. In the remaining 16 weeks, patients received five doses once a month.

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In the oral presentation, “Efficacy and Safety of Dazodalibep (VIB4920/HZN4920) in Subjects with Sjögren’s Syndrome: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study” (OP0143), researchers shared data from the first patient population.

As previously reported, dazodalibep successfully met the trial’s main goal for this population. Six months of treatment was associated with a significantly greater drop, by 2.2 points, in the ESSDAI score — indicating lower disease activity — relative to a placebo.

Reductions in overall symptoms, based on ESSPRI scores, as well as in fatigue, also favored the experimental therapy. A posterior analysis showed that dazodalibep-treated patients were twice as likely to achieve a greater drop in ESSPRI scores — of 5-6 points — than those on a placebo (61.1%-60.0% vs. 35.1%-34.3%).

“The reported [adverse events] were generally mild through [six months] and similar in frequency between treatment groups,” the researchers wrote.

There were no reports of treatment-related serious adverse events or treatment discontinuations due to adverse events.

The most common adverse events during the trial included COVID-19, diarrhea, dizziness, ligament sprain, and upper respiratory tract infection. One patient in the dazodalibep group experienced herpes zoster as a side effect of special interest and another died 12 days after a COVID-19 diagnosis.

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Less severe symptoms with dazodalibep vs placebo in Sjögren’s syndrome patients

Findings from the second patient population were shared in the poster “Dazodalibep (VIB4920/HZN4920) in Sjögren’s Subjects with an Unacceptable Symptom Burden: Safety and Efficacy from a Phase 2, Randomized, Double-Blind Study” (LB0003).

After six months of treatment, those given dazodalibep showed a significantly greater drop, by 1.27 points, in the ESSPRI scores — reflecting less severe symptoms. That was in comparison with the patients in the placebo group.

Those findings meant that the therapy met the study’s main goal for this patient population.

Compared with the placebo, dazodalibep was linked to significantly greater drops in scores on all three ESSPRI domains: dryness (1.9 vs. 0.8 points), fatigue (1.7 vs. 0.3 points), and pain (1.8 vs. 0.4 points).

About double the proportion of patients in the dazodalibep group achieved a clinically meaningful drop in ESSPRI scores, of at least one point or 15%, relative to those in the placebo group (66.7% vs. 32.7%).

Dazodalibep-treated patients also experienced a significantly greater reduction in the Functional Assessment of Chronic Illness Therapy-Fatigue score (8.1 vs. 2.8) and tended to show greater reductions in validated measures of dry eye disease and self-reported disease severity.

“Safety profiles were similar between the groups, with the most commonly reported adverse events including COVID-19, [the common cold] and anemia,” the release stated.

Serious side effects were reported in three patients in the dazodalibep group, but none were deemed related to treatment.

“Larger trials of DAZ [dazodalibep] therapy for Sjögren’s are warranted to further explore its safety profile and confirm its clinical efficacy,” the researchers wrote.

The Phase 2 trial provides encouraging evidence that those suffering from Sjögren’s could experience significant improvements of their disease with dazodalibep treatment.

In a third poster, “CD40L Blockade with Dazodalibep (VIB4920/HZN4920) Reduces Blood Biomarkers of T and B Cell Co-stimulation in Subjects with Systemic Sjögren’s Syndrome” (POS0815), researchers showed that dazodalibep led to a significant and rapid drop of blood biomarkers of CD40-CD40L signaling in the trial’s first patient population.

“CD40-CD40L blockade with DAZ in patients with [Sjögren’s syndrome] reduces systemic disease activity by inhibiting T and B cell [activation],” the researchers wrote.

Wan-Fai Ng, PhD, one of the study authors, said that “the Phase 2 trial provides encouraging evidence that those suffering from Sjögren’s could experience significant improvements of their disease with dazodalibep treatment.”

“The positive results represent a significant step towards developing a treatment for these patients,” added Ng, a professor of rheumatology at the Translational and Clinical Research Institute of Newcastle University, in the U.K.