Systemic Sclerosis
Systemic sclerosis is a chronic, potentially life-threatening autoimmune disease which causes progressive fibrosis and tissue dysfunction in multiple organs. It carries the worst prognosis of all rheumatic diseases.
Disease epidemiology
- Prevalence
- Patient demographics:
- Disease onset usually between 30 – 50 years
- 80% of affected patients are female.
- Disease classification
- Limited cutaneous SSc: Fibrotic skin involvement restricted to the distal part of the limbs, overall slower progression of internal organ fibrosis
- Diffuse cutaneous SSc: More extensive skin and internal organ involvement with more aggressive progression
Current treatment options
No approved therapy for overall disease control. Therapeutic strategies include off-label immunosuppressive drugs and management of symptoms and organ-specific complications.
AX104 scientific rationale
S100A4 is implicated as a key upstream trigger of the inflammatory and fibrotic pathways that drive disease progression.
- S100A4 is elevated manifold both in the skin and systemically in patients with SSc; levels correlate with skin score and extent of organ involvement
- Murine AX104 inhibits TGFb driven activation of fibroblasts
Murine AX104 successfully inhibits fibrosis in both inflammatory and non-inflammatory models of skin fibrosis.
Other Fibrotic Diseases
As cancers develop they enlist the assistance of the surrounding non-malignant cells to provide essential support for further growth. Tumor progression is profoundly influenced by these interactions with the tumor microenvironment which both determines the cancer cells ability to proliferate and spread and also shape the therapeutic response and resistance mechanisms.
AX104 scientific rationale
S100A4 is elevated in lesional tissue from patients with fibrosis where it acts as an upstream trigger of persistent inflammatory and fibrotic responses and contributes to unrestrained, self-sustaining fibroblast activation. Specifically, S100A4 has been shown to sensitize fibroblasts to the stimulatory effects of TGFbeta, drive epithelial-to-mesenchymal transition and modulate the release of inflammatory mediators and the overall immune response. S100A4 has been identified as an important actor in multiple fibrotic diseases, including lung, liver and kidney.
Cancer
As cancers develop they enlist the assistance of the surrounding non-malignant cells to provide essential support for further growth. Tumor progression is profoundly influenced by these interactions with the tumor microenvironment which both determines the cancer cells ability to proliferate and spread and also shape the therapeutic response and resistance mechanisms.
AX104 scientific rationale
S100A4 is a key player in the tumor microenvironment by triggering inflammatory responses and influencing the influx of non-resident immune and stromal cells. Consistent with this, multiple studies have found that patients which cancers express S100A4 have a more rapid progression, higher risk of metastases and an overall worse prognosis. Treatment with murine AX104 is associated with a counteraction of pro-tumorigenic immune responses, slower tumor growth and reduced risk of metastases.
