From dry eyes to what feels like a mouth full of cotton, people with Sjögren’s syndrome deal with irritating and painful symptoms every day. While there are some medications that can treat the symptoms of this autoimmune condition — such as eye drops and steroids — none of these drugs treat the underlying immunological cause of the disease.

In many autoimmune diseases including Sjögren’s syndrome, the interaction between the cluster of differentiation 40 (CD40) and its ligand becomes over activated, leading to inflammation (1). The CD40 protein is present on B cells, and the CD40 ligand is on interacting T cells. Recently, researchers have seen some success in clinical trials for Sjögren’s disease with drugs that target this pathway (2). One of these promising therapies is Amgen’s fusion protein drug, dazodalibep.

“The innovation that was demonstrated in developing this molecule as a fusion protein just highlights the expertise of our discovery folks who have worked on this for so many years,” said Sumita Bhatta, Vice President, Global Development Therapeutic Area Head, Rare Disease at Amgen.

With positive Phase 2 data on dazodalibep in people with Sjögren’s disease published last summer, Bhatta and her colleagues are currently enrolling two different groups of Sjögren’s disease patients into two Phase 3 trials for the drug (3). Her team along with people with Sjögren’s syndrome hope to soon have a therapy that halts the actual cause of the disease.

How does Sjögren’s disease manifest in patients?

Sjögren’s disease is a chronic and systemic autoimmune condition. It can be very severe in up to 50  percent of patients where the immune system attacks not only exocrine glands like tear ducts and salivary glands, but also multiple organs within the body (4). This becomes very debilitating for these patients, the majority of whom are women. Despite how frequently this disease occurs, there is no approved medication to treat the underlying cause of this disease or to prevent this autoimmune attack from happening in the first place.

What kind of drug is dazodalibep, and how does it work?

Dazodalibep is a CD40 ligand antagonist, and it's designed to block the CD40/CD40 ligand pathway. Overactivation of this pathway causes immune system activation in an unchecked fashion at times, and that can result in the inflammation that we see in Sjögren’s disease. Blocking this ligand disrupts the ability of T cells to interact with B cells, thereby not activating that immune cell pathway. In fact, when researchers at Horizon Therapeutics (now a part of Amgen) first developed this drug, they explored it in multiple indications, and the results in Sjögren’s disease prompted its further investigation.

There have been many previous attempts to block the CD40 ligand. These included monoclonal antibodies that interacted with the CD40 ligand, but they actually activated it in such a way that led to adverse events, including deep vein thromboses and pulmonary embolisms. These side effects were likely related to the Fc portion of those monoclonal antibodies. What's unique about dazodalibep is that as a fusion protein, it’s bound to serum albumin on one side and CD40 ligand on the other, so it doesn't have that Fc region. As a result, it truly blocks the CD40/CD40 ligand interaction in such a way that it doesn’t cause that accidental immune activation and adverse effects.

What were the results from your recent Phase 2 trial?

The Phase 2 data showed a statistically significant improvement in the endpoints that measured drug effectiveness in this disease in both of the populations that we're studying: people who have moderate-to-severe systemic disease activity (population one), and people who have low systemic disease activity but moderate-to-severe symptoms (population two).

This drug was generally safe and well tolerated, but, as with many trials, there were some adverse events. We will be studying these in the Phase 3 trials as well. For example, since we’re blocking T cell activation, we may need to look for things like infections. We'll know more from our Phase 3 data to determine whether or not the benefits outweigh the risks, but as far as we can tell from Phase 2, this drug was generally safe, well tolerated, and had a good efficacy profile.

The fact that this trial had encouraging results and now has led us to pursue the Phase 3 trials in the same populations has actually been a nice story in drug development. We hope that the results of the Phase 3 trials will mimic or improve upon what we saw in Phase 2.

What challenges have you faced in developing dazodalibep?

A disease that has no effective approved therapies is a little bit of uncharted territory, so we took our time to establish endpoints in our Phase 3 trials that were meaningful for patients. We've incorporated things like Patient Reported Outcomes as endpoints in these trials to really assess the effectiveness of the therapies.

What has been most rewarding about studying dazodalibep as a potential drug for Sjögren’s disease?

Here's a disease for which there is no available treatment. To see something that has the potential to improve symptoms for these patients is quite rewarding. I've worked across multiple disease areas now, and I'm incredibly excited to work on a rare disease like Sjögren’s because of the potential to make such a dramatic difference for patients who really have no alternative options.

This interview has been condensed and edited for clarity.

References

1. Karnell, J.L. et al. Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond. Adv Drug Deliv Rev  141, 92-103 (2019).
2. Colafrancesco, S. & Prioric, R. Sjögren's disease: a new era for clinical trials? Lancet 404, 498-499 (2024).
3. St. Clair, E.W. et al. CD40 ligand antagonist dazodalibep in Sjögren’s disease: a randomized, double-blinded, placebo-controlled, phase 2 trial. Nat Med 30, 1583-1592 (2024).
4. Carsons, S.E. & Patel, B.C. Sjogren Syndrome. StatPearls (StatPearls Publishing), 2025.