AAV is a rare, life-threatening autoimmune disease with a relapsing nature, characterized by necrotizing vasculitis (inflammation of blood vessels) predominantly affecting small vessels associated with anti-neutrophil cytoplasmic antibodies, or ANCA, directed to myeloperoxidase (MPO), or proteinase 3 (PR3). The disease involves three disease entities: 1) GPA, granulomatosis with polyangiitis (known as Wegener's Granulomatosis); 2) MPA, microscopic polyangiitis; and 3) eGPA, eosinophilic granulomatosis with polyangiitis (known as Churg-Strauss syndrome).
AAV is registered as an orphan disease with a prevalence of one to five per 10,000 and a reported incidence between 0.07 and 1.2 per 100,000, with approximately 40,000 patients in the US and 75,000 in Europe (SOURCE: www.orpha.net; Watts et al 2015).
The disease is characterized by life-threatening flare phases affecting kidney function and other organs leading to organ dysfunction and failure and is fatal unless treated appropriately. Since AAV is life-threatening, it is crucial to induce remission rapidly when presenting with a flare. The treatment to induce remission differs from maintenance therapy.
The disease-promoting role of C5a for this disease has been well established in published scientific literature, whereby a priming effect of C5a for neutrophils appears to be the essential factor leading to neutrophil-related damage of the endothelial cells in blood vessels. In addition, patients with acute AAV disease have significantly elevated complement activation parameters in their plasma when compared to AAV patients in remission. Numerous groups have established the importance of C5a for this disease while C6 deficiency in mice does not lead to improvement, indicating that MAC formation may not play a major role in this disease.
The current treatment regimen to induce remission uses a combination of High Dose Glucocorticoids (HDGCs), together with either rituximab or cyclophosphamide. The long lasting HDGC therapy is associated with significant side effects and additional life-threatening risks for patients. Even in patients achieving remission, major relapses can occur over time. Thus, a high unmet medical need for these patients exists for more effective and less side effect carrying therapies.
Based on the eminent role of C5a in the progression of inflammation in this life-threatening disease, InflaRx conducted clinical testing in AAV in the US Phase II IXPLORE study and the EU Phase II IXCHANGE study.
In October 2018, we dosed the first patient in the randomized, triple blind, placebo-controlled US Phase II IXPLORE study with vilobelimab in patients with AAV. The main objective of the study was to evaluate the efficacy and safety of two dosing regimens of vilobelimab in patients with moderate to severe AAV, when dosed in addition to standard of care, which includes treatment with high dose glucocorticoids and either cyclophosphamide or rituximab. The primary endpoint of the study was the number and percentage of subjects who experience at least one treatment-emergent adverse event (TEAE) per treatment group at week 24. It was originally planned that we would enroll approximately 36 patients at centers in the US. After a blinded interim analysis was conducted as well as an assessment of the potential impact of the COVID-19 pandemic, we decided to finalize enrollment at 19 patients. In May 2021, InflaRx reported topline data from the US IXPLORE Phase II study. The results indicated that vilobelimab, when given in addition to best standard of care, was well tolerated.
In May 2019, we initiated a randomized, double-blind, placebo-controlled European Phase II IXCHANGE clinical study with vilobelimab in patients with AAV. The main objective of the study was to evaluate the efficacy and safety of vilobelimab in patients with moderate to severe AAV. The primary endpoint of the study was a 50% reduction in Birmingham Vasculitis Activity Score (BVAS) at week 16. The study was being conducted in two parts. In Part 1, patients were randomized to receive either vilobelimab plus a reduced dose of glucocorticoids, or placebo plus a standard dose of glucocorticoids. Patients in both arms received standard of care dosing of rituximab or cyclophosphamide. In Part 2 of the study, patients were randomized to receive either vilobelimab plus placebo, glucocorticoids or placebo plus a standard dose of glucocorticoids (both in addition to standard of care therapy consisting of rituximab or cyclophosphamide). After analyzing the impact of the ongoing COVID-19 pandemic on the study, we conducted a blinded interim analysis of Part 1. Based on our analysis, we decided to continue with Part 2 of the study but decreased the number of enrolled patients. In November 2021, we announced that the study achieved its principal objective, demonstrating comparable clinical response of vilobelimab to standard of care, while significantly reducing the need for glucocorticoid (GC) treatment in this life-threatening indication.
The Company plans to discuss the data from both the US and EU studies with regulatory authorities to determine next steps with the program.