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Atacicept

Atacicept is a recombinant fusion protein that contains the soluble TACI receptor that binds to the cytokines BLyS and APRIL. These cytokines are members of the tumor necrosis factor family that promote B-cell survival and autoantibody production associated with certain autoimmune diseases such as IgA Nephropathy (IgAN) and lupus nephritis (LN). Blocking these cytokines with atacicept has been shown in clinical trials to reduce disease causing antibodies.

Vera holds an exclusive worldwide license for the development and commercialization of atacicept in all indications from Merck KGaA, Darmstadt, Germany, a leading science and technology company.

IgAN, also known as Berger’s disease, is an autoimmune disease driven by the deposition of abnormal immune complexes that accumulate in the kidneys, causing inflammatory tissue damage and kidney failure.

LN is a severe renal manifestation of systemic lupus erythematosus (SLE). SLE is a chronic and disabling autoimmune disease in which the body’s own immune system attacks itself. When LN is diagnosed in a patient, mortality risk dramatically increases.

BLyS = B lymphocyte stimulator; APRIL = a proliferation-inducing ligand

IgA Nephropathy (IgAN)

IgAN is a rare but devastating disease and is a common cause of kidney disease, behind chronic hypertension and diabetes.

Up to 50% of IgAN patients progress to end-stage renal disease, requiring dialysis or kidney transplant.

Current standard of care includes angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs), which provide limited clinical benefits with known safety and toxicity issues.

There is a high unmet medical need for safe and effective new medications to treat IgAN.

Target the Source:

Hover over the pathway below to see how Atacicept acts on IgAN Pathophysiology

1

Atacicept blocks BLyS, a factor important for B cell survival and maturation, resulting in reduced numbers of disease-causing B cells.

2

Atacicept blocks APRIL, a factor important for Plasma cell survival, resulting in reduced numbers of disease-causing Plasma cells.

3

Reductions in Plasma cells and in antibody class switching to IgA reduces production of pathogenic Gd-IgA.

4

Reductions in B cells, Plasma cells, and Gd-IgA work together to cause a reduction in production of Autoantibodies to Gd-IgA.

5

Therefore, formation of immune complexes is greatly reduced.

6

This in turn, reduces immune complex deposition in glomeruli and reduces complement activation.

7

Ultimately, progressive renal injury is reduced.

Atacicept Mechanism of Action in IgAN

Atacicept:
  • A novel biologic investigational therapeutic that is a dual inhibitor of BLyS and APRIL, which targets B cells and plasma cells, and reduces disease causing autoantibodies
  • Self-administered once weekly by sub-cutaneous injection
  • Uniquely able to substantially reduce galactose deficient-IgA1 (Gd-IgA1), the core of the immune complexes that cause disease progression and mortality in IgAN patients
  • Well-tolerated safety profile in clinical studies of >1,000 patients with autoimmune disease
Chart: Gd-IgA1 Impact on Renal Survival

Clinical Data

The molecule Gd-IgA1 is the core of the immune complexes that cause disease progression and mortality in IgAN patients. High serum Gd-1gA1 levels are highly associated with poor renal outcomes in IgAN.

The Phase 2a JANUS study conducted by Merck KGaA evaluated the efficacy and safety of atacicept in IgA nephropathy. Atacicept demonstrated a 60% reduction in Gd-IgA1, becoming the first molecule to achieve a reduction of this magnitude.

Chen P. et al. CJASN 2019; Suzuki Y et al. Clin Exp Nephrol. 2014; Yanagawa H PLoS One 2014; Zhao N et al. Kidney Int 2012; Berthoux F et al. J Am Soc Nephrol 2012; Camilla R et al. Clin J Am Soc Nephrol. 2011; Schena FP et al. Clin Exp Immunol 1989; Czerinsky C et al. J Clin Invest 1986; Coppo R et al. Clin Exp Immunol 1984

The Phase 2b ORIGIN Study

The Phase 2b ORIGIN clinical trial is a dose-ranging study evaluating the safety and efficacy of atacicept in patients with IgA Nephropathy (IgAN) who continue to have persistent proteinuria and remain at high risk of disease progression.

Lupus Nephritis (LN)

Severe renal manifestation of systemic lupus erythematosus (SLE).
Approximately 25% of LN patients develop end stage renal disease.
Current treatment involves combination immunosuppressants and steroids.
Recently approved therapies, yet unmet need for effective and safe therapies remain.
Target the Source:

Hover over the pathway below to see how Atacicept acts on LN Pathophysiology

 

Steps that Atacicept targets Cytokine Abnormalities Patients with systemic lupus erythematosus may have higher levels of BAFF and APRIL, contributing to the pathogenesis of lupus nephritis 1 Heterotrimer BAFF BAFF BAFF APRIL APRIL APRIL Heterotrimer BAFF BAFF APRIL Heterotrimer BAFF Heterotrimer Glomerulonephritis 4 Autoantibodies and immune complexes deposit in glomeruli Glomerulus Imma t u r e B - cells s urvi v e and ma t u r e 2a B - cells di f f e r entia t e and cla s s swi t ch 2b Pla s ma cells p r oli f e r a t e and c r ea t e au t oantibodies 2c A u t oantibodies ci r cula t e and f orm im m une compl ex es 2d B-Cell Dysregulation BAFF and APRIL promote the survival, maturation and differentiation of B cells and plasma cells that then produce disease-causing antinuclear and anti-DNA autoantibodies 2 B cell B cell
Glomerulus Glomerulonephritis Progressive renal injury 4 Autoantibodies and immune complexes deposit in glomeruli Immature B-cells survive and mature 2a B-cells differentiate and class switch 2b Plasma cells proliferate and create autoantibodies 2c Autoantibodies circulate and form immune complexes 2d B-Cell Dysregulation BLyS and APRIL promote the survival, maturation and differentiation of B-cells and plasma cells - that then produce disease-causing antinuclear and anti-DNA autoantibodies 2 Cytokine Abnormalities Patients with Systemic Lupus Erythematosus may have higher levels of BLyS and APRIL, contributing to the pathogenesis of Lupus Nephritis 1 Heterotrimer BLyS BLyS BLyS APRIL APRIL APRIL Heterotrimer BLyS BLyS APRIL Heterotrimer BLyS Heterotrimer
Steps that Atacicept targets Cytokine Abnormalities Patients with systemic lupus erythematosus may have higher levels of BAFF and APRIL, contributing to the pathogenesis of lupus nephritis 1 Heterotrimer BAFF BAFF BAFF APRIL APRIL APRIL Heterotrimer BAFF BAFF APRIL Heterotrimer BAFF Heterotrimer Glomerulonephritis 4 Autoantibodies and immune complexes deposit in glomeruli