Helena Idborg

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease causing pain, stiffness, and disability. Current treatment mainly relies on nonsteroidal anti-inflammatory drugs (NSAIDs), which, despite their efficacy, are linked to increased cardiovascular risk. This highlights the need for novel, safer therapies suitable for long-term use. We have developed a targeted anti-inflammatory approach by selectively inhibiting microsomal prostaglandin E synthase-1 (mPGES-1), a downstream enzyme in the cyclooxygenase (COX) pathway. While NSAIDs act upstream by inhibiting COX enzymes, our approach reduces pro-inflammatory prostaglandin E₂ (PGE₂) while preserving cardioprotective prostacyclin (PGI₂). Vipoglanstat, a potent mPGES-1 inhibitor, has completed a Phase I trial and a Phase II trial in systemic sclerosis with excellent safety. We now aim to prepare a randomized trial in axSpA comparing Vipoglanstat to NSAIDs, the current standard of care, to assess effects on disease activity, pain, safety, and biomarkers. This project includes study design, power calculations, national collaboration setup, regulatory and ethical preparations, and integration of biomarker analyses alongside clinical outcomes. We aim to establish a clear path towards a phase II clinical trial, addressing the unmet need for effective and safer treatment options in axSpA, potentially transforming care for these patients.

Prostaglandin (PG) E2 is formed from arachidonic acid by the enzymatic actions of either cyclooxygenase (COX)-1 or COX-2 into PGH2, which is further metabolized by microsomal prostaglandin E synthase-1 (mPGES-1) into PGE2. mPGES-1 has emerged as a cardiovascular safe anti-inflammatory drug target. Our characterizations of inhibitors of mPGES-1 demonstrate their potent anti-inflammatory actions while causing relaxation of arteries. mPGES-1 inhibition also significantly protects heart functions following myocardial infarction in vivo. The underlying mechanisms include inhibition of PGE2 biosynthesis, an increase of local prostacyclin formation, no effects on the ADMA-NO pathway and an unbroken formation of anti-inflammatory PGD2/15-deoxy-PGJ2 ( a cyclopentenone). These compounds are considered anti-inflammatory and antiviral and recognized as a part of the family “specialized pro-resolving lipid mediators”. We have identified MGST3 as the key enzyme conjugating cyclopentenone with glutathione. Inhibition of MGST3 leads to increased 15-deoxy-PGJ2 levels with lesser amounts of PGE2. We aim to characterize MGST3 as a novel modulator of inflammation. Furthermore, we will investigate prostaglandins and other lipids as biomarkers for rheumatoid arthritis. We will also characterize our findings demonstrating activation of the thromboxane A2 pathway and platelet activation as a likely mechanism of action for the severe cardiovascular side effects observed for JAK inhibitors.