Pipeline

Complement Mediated Diseases

Scientific and clinical research has implicated the complement system, and specifically the complement Alternative Pathway (AP), in numerous devastating diseases and conditions. Achillion has prioritized the clinical development of its lead investigational oral factor D inhibitors, in rare complement-mediated disorders where overactivation of the AP is recognized as the underlying cause of the disease.

C3 Glomerulopathy (C3G)

C3 glomerulopathy (C3G) is a rare, chronic disease affecting the kidneys in which the alternative pathway (AP) of the complement system is dysregulated due to genetic mutations or autoantibodies affecting the regulation of AP activity. This lack of regulation results in AP 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 1-2 per million diagnosed annually. There are no approved treatments for patients with the disease. Current standard of care is focused on supportive care with extensive use of anti-hypertensive and broad-acting immunosuppressant medications. Up to 50% of patients diagnosed with C3G progress to kidney failure within 10 years, requiring lifelong dialysis treatment or kidney transplantation. Recurrence of C3G is common after kidney transplantation, as transplantation does not address the underlying disease pathogenesis, an overactive AP. As such, recurrent disease may lead to the loss of the transplanted kidney is some patients.

Patients with C3G, including the disease subtypes Dense Deposit Disease (DDD) and C3 glomerulonephritis (C3GN), are in significant need of new treatment options. Factor D inhibition has the potential to selectively modulate an overactive AP, reducing the underlying disease pathogenesis. Achillion is studying its investigational oral factor D inhibitors, ACH-4471 as a potential treatment for patients with C3G. To learn more about the ongoing global, phase 2 clinical program, please visit.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired blood disorder in which chronic activation of the complement Alternative Pathway (AP) 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 system regulatory proteins, CD59 and CD55, known as PNH clones. In the absence of these two complement regulators on the RBCs, the AP is overactivated to attack and destroy these PNH clones both inside the blood vessels (intravascular hemolysis) and outside the blood vessels (extravascular hemolysis).

  • Absence of CD59 leads to uncontrolled formation of the membrane attack complex on PNH clones resulting in intravascular hemolysis
  • Absence of CD55 leads to uncontrolled deposition of C3 fragments on PNH clones resulting in extravascular hemolysis



PNH is a life-threatening disease that has led to death in up to 35% of untreated patients within 10 years of their diagnosis. The disorder 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. The standard of care for PNH patients is treatment with a complement 5 (C5) inhibitor administered intravenously every two weeks; however, 25-40% of patients have a suboptimal response to treatment. In fact, ~1 in every 6 patients continue to require ongoing blood transfusions while treated with a C5 inhibitor.

A treatment strategy of targeting C5 aims to reduce intravascular hemolysis – one of the two destructive processes to RBCs in PNH – by reducing uncontrolled formation of the membrane attack complex. We believe this treatment approach leaves most patients with incomplete coverage of their PNH, as C5 inhibition does not address the uncontrolled deposition of C3b fragments on RBCs that may be occurring upstream in the AP, leading to opsonization and chronic extravascular hemolysis. A treatment strategy with selective inhibition of the AP has the potential to benefit patients with PNH by addressing both destructive processes of RBCs in PNH – intravascular and extravascular hemolysis. Further, selective inhibition of AP may allow the Classical and Lectin Pathways to remain active and protect against serious infections.

Achillion is investigating a convenient, oral administration of a factor D inhibitor as a potential treatment strategy for patients with PNH. To learn more about the global, Phase 2 clinical program for ACH-4771, an oral factor D inhibitor, please visit Pipeline.