Sjögren’s syndrome, a chronic autoimmune condition, is characterized by symptoms such as dry eyes, dry mouth, joint pain, and fatigue. While treatments currently exist to manage symptoms, none target the root cause of the disease—an overactive immune response that attacks the body’s moisture-producing glands.
Recent clinical advancements, including a promising Phase 2 trial for Amgen’s drug, dazodalibep, offer a potential breakthrough. Dazodalibep is a fusion protein that acts as a CD40 ligand antagonist, aiming to block the immune pathway that causes inflammation in patients with Sjögren’s disease.
Immune Overreaction and Sjögren’s Disease
Sjögren’s disease primarily affects exocrine glands, such as tear ducts and salivary glands, but it can also lead to more severe organ damage in some patients. The condition predominantly affects women and is one of the most common autoimmune diseases, yet there are currently no approved medications that directly address the underlying immune dysfunction.
In autoimmune diseases like Sjögren’s, the CD40/CD40 ligand pathway plays a pivotal role in the immune response. CD40 is found on B cells, while its ligand is present on T cells. An overactive interaction between the two can lead to chronic inflammation. By targeting this pathway, dazodalibep aims to halt the immune system’s attack on the body’s own tissues.
Dazodalibep: How It Works
Dazodalibep’s mechanism of action is unique in its design. Unlike earlier treatments that also targeted the CD40/CD40 ligand pathway, dazodalibep’s fusion protein structure does not contain an Fc region. This is important because previous attempts using monoclonal antibodies, which contain an Fc region, inadvertently triggered immune activation, leading to serious side effects like deep vein thrombosis and pulmonary embolisms.
By binding to both serum albumin and the CD40 ligand, dazodalibep blocks the CD40/CD40 ligand interaction without causing unintended immune system activation. This innovative approach has set it apart from other CD40 inhibitors in development.
Encouraging Phase 2 Results
The Phase 2 trial of dazodalibep, which was published last summer, showed statistically significant improvements in both disease activity and symptom severity among patients with moderate-to-severe systemic disease activity, as well as those with moderate-to-severe symptoms but low systemic disease activity.
While the drug was generally well tolerated, Phase 2 trials did report some adverse events, such as infections, which are common when blocking T cell activation. The company plans to monitor these potential risks further in Phase 3 trials to ensure the benefits outweigh any side effects.
“The data from our Phase 2 trial have been encouraging, and we are hopeful that Phase 3 trials will build on these results,” said Sumita Bhatta, Vice President of Global Development Therapeutic Area Head for Rare Disease at Amgen.
Overcoming Development Challenges
Developing a drug for a disease with no approved therapies comes with its own set of challenges. Bhatta emphasized the importance of ensuring that clinical trial endpoints are meaningful to patients. To better assess the impact of dazodalibep, Amgen has incorporated Patient-Reported Outcomes (PROs) into their Phase 3 trials. These endpoints will help determine how the drug improves quality of life, not just clinical markers of disease activity.
Hope for the Future
For Bhatta and her team, the potential to bring an effective treatment to the thousands of people living with Sjögren’s disease is deeply rewarding.
“There is a real opportunity to improve the lives of patients who have no other alternatives,” Bhatta said. “Working on a rare disease like Sjögren’s, where we can make such a profound difference, is incredibly motivating.”
As Phase 3 trials continue, the medical community watches closely, hopeful that dazodalibep could become the first drug to directly target the root cause of Sjögren’s disease, offering long-awaited relief to those affected.
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