Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hemolytic anemia caused by a loss-of-function mutation (PIGA) in hematopoietic stem cells. PNH is characterized by the destruction of red blood cells, blood clots, and impaired bone marrow function. At the heart of this disease lies unchecked complement activation, particularly via the alternative pathway where complement Factor D is a key player. Factor D, a serine protease, is involved in the alternative complement pathway of the complement system. Besides, Factor D triggers a cascade that intensifies the destructive process seen in PNH. Thus, inhibiting Factor D presents an exciting strategy to counteract this.

Noticeably, Danicopan (ACH-4471), a selective and orally active Factor D inhibitor, has been approved in Japan for the treatment of PNH. Danicopan has high binding affinity to human Factor D, and inhibits alternative pathway of complement (APC) activity.

Danicopan, a Factor D Inhibitor, is active against extravascular hemolysis with PNH.

In vitro, Danicopan inhibits the proteolytic activity of purified Factor D against its natural substrate Factor B in complex with C3b. Thus blocking the production of Bb fragment in a dose-dependent manner with an IC50 value of 0.015 μM. Meanwhile, Danicopan potently inhibits hemolysis with IC50 values ranging from 4 nM to 27 nM. Danicopan also abrogates C3 convertase-associated complement factor B (FB) cleavage to the Bb fragment in serum of patient with atypical hemolytic uremic syndrome (aHUS). In addition, Danicopan (0.1-10 μM) inhibits proliferation of cSCC cells through blockade of ERK1/2 activation. To sum up, Danicopan is a selective and orally active Factor D inhibitor. Danicopan inhibits alternative pathway of complement activity, has potential to block the alternative pathway of complement in PNH and aHUS.


[1] Gerber GF, et al. Blood. 2022 Jun 9;139(23):3361-3365.

[2] Rahmati Nezhad P, et al. Cancers (Basel). 2022 Jan 8;14(2):305.