A Duke rheumatology and immunology expert was part of a team who discovered a potential treatment for Sjӧgren’s disease (SjD), an autoimmune disorder also associated with a type of blood cancer.
Eugene William St. Clair, W. Lester Brooks Jr. distinguished professor of medicine, published in June the results of a phase 2 clinical trial in which patients with SjD were treated with Dazodalibep (DAZ). DAZ is a novel non-antibody fusion protein that blocks the binding of the CD40 protein to its receptor in a process referred to as the CD40L/CD40 pathway.
According to St. Clair, SjD is an autoimmune disorder characterized by dry eyes and mouth that currently has no disease-modifying treatments. When the disease is present, the body produces autoantibodies that attack proteins in the lacrimal and salivary glands, leading to inflammation.
Patients with SjD commonly experience chronic fatigue and joint pain. The condition can further affect various organ systems, leading to complications including interstitial lung disease and peripheral neuropathy.
SjD patients also display an alarming incidence of lymphoma: cancer of the lymphatic system. St. Clair noted that about five out of every 100 patients in his clinic with the disease also currently have or previously had lymphoma.
The combined burden of the two diseases often leads to a low quality of life. However, the results from St. Clair’s recently published study indicate that DAZ could be a viable treatment option for SjD patients.
The clinical trial enrolled 183 patients from two SjD populations. Population 1 had 74 patients who experienced moderate to severe systemic disease activity, meaning that other organ systems were involved beyond the standard symptoms of salivary and lacrimal dryness and fatigue. Population 2 consisted of 109 patients that still suffered from an unacceptable symptom burden but had limited involvement of other organ systems.
The patients were given either a placebo or DAZ in a randomized and double-blinded fashion. The treatment was initially administered to patients every two weeks but was later changed to every four weeks.
On day 169 of the study, patients’ symptoms were assessed. Treatments were then switched to either the active drug or placebo, and patients were assessed again on day 365.
Patients on DAZ in both SjD populations had statistically significant improvements in their symptoms at either of the study’s endpoints, and improvements relapsed when patients were switched from DAZ back to placebo.
“I'm always surprised and happy when we get positive results. And the reason is, because there have been a lot of negative results,” St. Clair said.
Interestingly, patients from Population 2 — those whose symptoms include limited involvement of other organ systems — have been excluded from most of the recent clinical trials.
“That's the majority of patients, so probably 80% of the patients that we see in [the] clinic,” St. Clair said. “Probably for the first time, we're seeing a signal in [this group of patients] … so, to me, that was surprising but very exciting.”
The CD40L/CD40 pathway that is affected by DAZ was not an obvious target for treatment because, like many other autoimmune diseases, SjD does not have a known cause. St. Clair explained that although the disease causes an observable inflammatory response in the body’s tissue, it can be difficult to isolate the inflammation’s cause because a number of different biological factors are at play.
“The actual drivers of it are hard to find,” St. Clair said. “You hope that one of the therapies that you happen to be studying is focused on a key driver of those inflammatory pathways.”
The observed success of DAZ points to the CD40L/CD40 pathway’s importance in SjD pathology. “Now all we have to do is confirm it in a larger trial,” St. Clair said.
A phase 3 clinical trial that will enroll hundreds more patients is already underway. Following that, DAZ will need to gain approval from regulatory authorities before entering the market.
“I think these were very, very promising phase 2 results,” St. Clair said. “We don't know how this result will generalize to the patient community at large because we just need a lot more patients.”
St. Clair noted that he is “cautiously optimistic” about DAZ as a treatment for SjD. While qualifying that drug development is “unpredictable,” he expressed his belief that a marketable treatment for SjD is approximately five years away.
Such an accomplishment would mark a transformative milestone in the fight against SjD, offering hope and relief to patients at Duke and beyond.
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Ana Despa is a Pratt sophomore and an associate news editor for the news department.