Dazodalibep Eases Moderate-to-high Disease Activity in Sjögren’s Patients: Trial Data

The investigational therapy dazodalibep markedly eased disease activity in people with Sjögren’s syndrome with moderate-to-high systemic disease activity, meeting the primary goal of a Phase 2 trial.

Ahead of expectations, the therapy’s developer, Horizon Therapeutics, plans to work with the U.S. Food and Drug Administration (FDA) to design a Phase 3 program to further evaluate the therapy in the same patient population starting next year.

“These positive results from the dazodalibep Phase 2 trial are good news for patients with Sjögren’s syndrome,” William St. Clair, MD, chief of the division of rheumatology and immunology at Duke University Medical Center, said in a press release.

Sjögren’s syndrome is a systemic (bodywide) autoimmune disease that primarily affects the salivary and tear glands, and in severe cases, multiple organs. Symptoms include dry mouth, dry eyes, arthritis, and kidney or lung impairment. So far, there is no approved therapy to slow or reverse it.

“Sjögren’s is a devastating autoimmune disease with many unmet treatment needs,” Frederick Vivino, MD, said. “It significantly impacts patient quality of life and leads to numerous serious complications.”

Vivino is the former director of the Penn Sjögren’s Syndrome Center and chief of the division of rheumatology at Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine.

“In addition to arthritis and debilitating fatigue, the internal organs are frequently affected. Dry eyes and dry mouth are not trivial symptoms and, when ignored, can lead to life-changing complications including altered vision, corneal ulcers, accelerated caries and eventual loss of the dentition,” Vivino said.

Several autoimmune diseases, including Sjögren’s, are associated with the overactivation of a pathway related to CD40, a protein found on the surface of antibody-producing immune B-cells, and its receptor on immune modulating T-cells.

Dazodalibep is a protein-based therapeutic designed to block the interaction between CD40 and its receptor, thereby disrupting the overactivation of the pathway and lowering autoimmune disease activity.

The Phase 2 study (NCT04129164) enrolled 74 Sjögren’s patients with moderate-to-high systemic disease activity as defined by a European Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) score of 5 or more.

Participants were randomly assigned to receive either dazodalibep by intravenous (into-the-vein) injection or a placebo for 24 weeks (nearly six months). After that, those who were assigned to receive dazodalibep switched to a placebo, and the patients who were randomized to a placebo were treated with dazodalibep for 16 weeks (about four months). All were followed for at least 12 weeks (three months) after their last dose.

According to Horizon, at 24 weeks, patients treated with dazodalibep had a 6.3-point reduction in their ESSDAI score, whereas those given a placebo achieved a 4.1-point reduction, a statistically significant mean difference of 2.2 points.

“These data are compelling in that dazodalibep achieved the primary endpoint with statistical significance in patients with moderate-to-high systemic disease activity as defined by ESSDAI,” Elizabeth Thompson, PhD, executive vice president of research and development at Horizon, said.

According to Thompson, this “represents a significant step towards developing a treatment for Sjögren’s syndrome, a disease with no FDA-approved treatments available.”

In secondary measures, numerical improvements in dryness, fatigue, and physical functioning were seen with treatment, as were the number of tender and swollen joints. Also, patients showing significant ESSDAI benefits favored dazodalibep over a placebo in a responder analysis.

Dazodalibep was well tolerated in the trial, with the most common side effects reported being COVID-19 infection, dizziness, diarrhea, ligament sprain, and upper respiratory infections.

The Phase 2 trial is also investigating dazodalibep in a second, separate group of patients with moderate-to-severe subjective symptoms, defined by a EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score of 5 or more and a residual stimulated salivary flow, but with mild systemic disease activity (ESSDAI score lower than 5). “We continue to see evidence that dazodalibep’s mechanism of action is potentially effective across many autoimmune diseases and we look forward to working with regulators to further our Sjögren’s clinical development program,” Thompson said.

These findings in Sjögren’s follow positive data from another Phase 2 study (NCT04163991) involving patients with rheumatoid arthritis that showed dazodalibep met its primary goal of reducing disease activity at all tested doses.