Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired blood disease in which constitutive activation of the complement alternative pathway leads to the destruction of red blood cells (RBCs) known as hemolysis. Due to a change in their bone marrow stem cells, patients with PNH chronically produce RBCs without the key complement regulatory proteins, CD59 and CD55. In the absence of these two complement regulators on the RBCs, the alternative pathway is overactivated to destroy these PNH clones both inside the blood vessels (intravascular hemolysis) and outside the blood vessels (extravascular hemolysis).
The disease is estimated to affect up to 16 persons per million globally, including 8,000 to 10,000 patients across the United Stated and the EU5. Eculizumab, an approved therapy for PNH patients, is a complement component 5 (C5) inhibitor administered intravenously every two weeks; however, up to 75% of PNH patients on Eculizumab remain anemic of which approximately 15-20% are severely anemic and transfusion-dependent.
A treatment strategy of targeting C5-alone aims to reduce intravascular hemolysis – one of the two destructive processes to RBCs. However, selective inhibition of the alternative pathway has the potential to benefit patients with PNH by addressing both destructive processes of RBCs in PNH – intravascular and extravascular hemolysis.
Achillion is investigating convenient, oral administration of factor D inhibitors as a potential treatment strategy for patients with PNH. To learn more about the global, Phase 2 clinical program please see the Pipeline.
C3 Glomerulopathy (C3G)
C3 glomerulopathy (C3G) is a rare, chronic disease affecting the kidneys in which the alternative pathway of the complement system is dysregulated due to genetic mutations or autoantibodies affecting the regulation of the alternative pathway.
This lack of regulation results in the alternative pathway overactivation and the excessive deposition of C3 protein fragments in the glomeruli, a key filtration component of the kidney, often leading to serious kidney damage.
C3G is estimated to affect 8 to 12 persons per million worldwide, with 1 to 2 per million diagnosed annually. Patients with C3G, including the disease subtypes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), are in significant need of new treatment options. There are no approved treatments for patients with the disease. Current standard of care is focused on supportive care with use of anti-hypertensive and immunosuppressant medications. Up to 50% of patients diagnosed with C3G progress to kidney failure within 10 years, requiring lifelong dialysis treatment or a kidney transplant. Recurrence of C3G is common after a kidney transplant, as transplantation does not address the underlying development of the disease, an overactive alternative pathway. As such, recurrent disease may lead to the loss of the transplanted kidney is some patients.
Factor D inhibition has the potential to selectively modulate an overactive alternative pathway, reducing the underlying disease. Achillion is studying its investigational oral factor D inhibitor, danicopan, as a potential treatment for patients with C3G. To learn more about the ongoing global, phase 2 clinical program, please visit the Pipeline.