Amsterdam institute for Immunology and Infectious Diseases

A grant has been awarded to the Amsterdam UMC departments of Oral and Maxillofacial Surgery (Derk Jan Jager, Hakki Karagozoglu, Jean-Pierre Ho, and Marco Helder), Pharmacy (Imke Bartelink), and Radiology (Joost Bot) to set up a study on the safety and efficacy of a drug (AZD9056) for patients with Sjögren’s syndrome. This study will examine whether the drug is able to preserve the function of the salivary glands in patients with Sjögren's syndrome. This research program will be set up in collaboration with the UMCG (Arjan Vissink), ACTA (Henk Brand) and the universities of Missouri (Gary Weisman) and Florida (Seunghee Cha). The NIH/NIAID R34 Clinical Trial Planning Grant (200,000 euros) was awarded by the National Institutes of Health (NIH) in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID). The NIH Planning Grant Program (R34) provides support for the development of a clinical trial or research project.

Sjögren's syndrome (SS) is an autoimmune disorder characterized by progressive lymphocytic infiltration of the exocrine glands, particularly the lacrimal and salivary glands. SS is a form of rheumatism in which patients suffer from inflammation of the tear and salivary glands, which causes dry eyes and a dry mouth. In addition, people with SS often suffer from fatigue and joint pain. After rheumatoid arthritis (RA), SS is considered the most common rheumatoid autoimmune disorder and it predominantly affects women, with a striking 9:1 ratio. In most people, SS occurs as an isolated condition, but it can also co-occur with other rheumatic conditions, such as rheumatoid arthritis (RA) or systemic lupus erythematodus (SLE). The pathogenesis of SS is still largely unknown. It has become clear that disturbances of the immune system play a central role, but whether this is a primary cause or a consequence of a previous (viral) infection or other extrinsic factors remains uncertain.

SS is characterized by mononuclear infiltrates and IgG-producing plasma cells in the salivary and lacrimal glands. This infiltration leads to destruction of glandular tissue resulting in decreased salivary secretion, leading to hyposalivation. Hyposalivation is associated with dental caries, yeast and bacterial infections, speech disorders, digestive disorders, loss of taste and burning sensations, which severely reduces the quality of life of SS patients.

Treatments are limited to external hydration, artificial saliva or muscarinic receptor agonists that induce salivary secretion from residual acinar cells. Such remedies are universally considered inadequate for patients with SS, so development of effective SS treatments is essential. Systemic treatment with antirheumatic drugs is effective in some patients but has minimal impact on salivary gland function, causes side effects and is effective only in subgroups of SS patients. Thus, novel approaches are needed to improve saliva flow and prevent salivary gland degeneration in SS patients.

AZD9056: A drug that preserves salivary gland function

In the search for a better treatment for Sjogren's syndrome (SS), aimed at improving salivary flow and preventing salivary gland degeneration, Dr. Jager and colleagues are on the right track. They will use the drug AZD9056 to help patients with SS; this drug is expected to preserve salivary gland function in patients with Sjögren's syndrome. AZD9056 blocks the P2X7 receptors, which are highly expressed on salivary gland cells in Sjögren's syndrome and cause an inflammatory response. AZD9056 has previously been tested in patients with ulcerative colitis and rheumatoid arthritis. Here, however, it was not sufficiently effective.

No remedy for Crohn's disease and rheumatoid arthritis

Dr. Jager: “For Crohn’s disease, systemic use of AZD9056 resulted in a decrease in disease activity for the CDAI subcomponents (CDAI: Crohn’s Disease Activity Index, determines the severity of Crohn’s disease at a given time), pain and general well-being. There was no decrease in serum C-reactive protein and fecal calprotectin concentrations during treatment. It was concluded that the lack in change of inflammatory biomarkers calls into question the anti-inflammatory potential of AZD9056 for patients with Crohn’s disease. Underdosing and underpowering were given as possible reasons for these results.”

AZD9056 has also been studied in patients with rheumatoid arthritis (RA) in a phase 2 trial. Dr. Jager explains: “In phase IIa, 65% of AZD9056 recipients responded to ACR20 at 400 mg/day compared to 27% of placebo-treated patients. A significant reduction in the number of swollen and tender joints was observed in the actively treated group compared with the placebo group, while no effect on acute-phase response was observed. Unfortunately, AZD9056 (all doses) had no clinically or statistically significant effect on RA compared to placebo in the sufficiently powered phase IIb study, as measured by the percentage of patients meeting ACR20 criteria at 6 months, and further supported by secondary endpoints."

Dr. Jager: “However, these earlier studies did show that the drug was safe when administered systemically. You can administer a very high dose, much higher than we consider necessary in patients with Sjögren's syndrome based on our preclinical studies. There are also no known serious side effects.”

Local application

Dr. Jager and colleagues want to achieve a high dose of AZD9056 in the salivary gland of patients with Sjögren’s Syndrome by applying it locally. Dr. Jager: “We want to use sialendoscopy to insert this drug into the salivary gland. Preclinical studies have shown that this drug can inhibit the inflammatory process in Sjögren's Syndrome when inserted directly into the salivary gland. In addition, we also showed that we could increase salivary secretion in patients with Sjögren's syndrome by flushing the glands with an endoscope. Unfortunately, this effect was only temporary (1 year). We believe that the combination with this drug can produce a longer-lasting effect.”

The expectation of Dr. Jager and colleagues is that AZD9056 will be sufficiently effective for patients with Sjögren’s Syndrome because of their localized approach. With this endoscopic approach they are able to deliver high doses of medication into the gland and maximize receptor exposure to AZD9056. Another advantage is that they will be able to monitor the penetration of AZD9056 into the salivary glands in real time. Dr. Jager: “In one of the study arms we are planning to combine this local application with systemic application of AZD9056 ensuring maximum exposure. In addition, we know that P2X7 receptors are overexpressed on acinar cells of SS patients and we have strong evidence from preclinical models that AZD9056 could block these receptors.”

The clinical trial

Over the next year, Dr. Jager and colleagues will work on the most optimal design for their clinical trial. In it, they will compare oral medication administration alone with oral administration combined with administration via sialendoscopy. In their clinical trial they will assess the safety, maximum tolerated dose, pharmacokinetic and pharmacodynamic properties and clinical efficacy of AZD9056. Dr. Jager: “We are also considering to use historical data from patients in whom only sialendoscopy was performed, or a group of patients followed over time without interventions. You see this more often in rare diseases, because otherwise, the required patient numbers for the study will not be met. That is why we are now also combining a safety study (phase 1) and efficacy study (phase 2)."

Across borders

The clinical research program is being set up in cooperation with the UMCG (Arjan Vissink), ACTA (Henk Brand) and the universities of Missouri (Gary Weisman) and Florida (Seunghee Cha). This collaboration got off the ground when Gary Weisman of the University of Missouri and Dr. Jager presented one after the other at a symposium about Sjögren’s syndrome in London.

Dr. Jager: "Gary talked about his work with P2X7 receptor antagonists and I talked about our research on sialendoscopic treatment of salivary glands in patients with Sjogren's syndrome. Afterwards, we had a conversation with the chair of the symposium, Seunghee Cha, University of Florida, and then the idea for our international collaboration was born. Soon the suggestion came up to apply for a grant based on the work we had already done. I then asked my Dutch colleagues at Amsterdam UMC (divisions: Oral and Maxillofacial Surgery, Pharmacy and Radiology), UMC Groningen and ACTA, with whom I often collaborate, to participate. We then worked on this grant application for ± 2 years. For the subsequent clinical trial, we want to expand our team with colleagues from the Department of Rheumatology at Amsterdam UMC."

Amsterdam Institute for Infection and Immunity (AII) would like to congratulate Dr. Derk Jan Jager and colleagues on being awarded this grant. We wish you the best of luck in conducting the clinical trial and look forward to the final study results.

For more information contact Dr. Derk Jan Jager or read the several scientific publications that led to this collaborative research project:

Photo (from left to right): Derk Jan Jager, Jean-Pierre Ho, and Hakki Karagozoglu

Text: Esmée Vesseur