Our Science

Our Science

Achillion has discovered and is developing a complement inhibitor platform, directed at advancing small molecule compounds that have the potential to be used in the treatment of immune-related diseases associated with the alternative pathway of the complement system. The complement system is a part of the human innate immune system and is believed to be comprised of three pathways: the alternative pathway, the lectin pathway and the classical pathway. Achillion is advancing novel small molecule inhibitors from this platform which target complement factor D, an essential protein upstream of C3 convertase and also within the amplification loop of the alternative pathway.

Experts believe the alternative pathway plays a critical role in a number of disease conditions including rare orphan conditions such as paroxysmal nocturnal hemoglobinuria (PNH), a blood disorder, C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN), both diseases affecting the kidney, as well as several more prevalent indications.

The Company’s first-generation factor D inhibitor, danicopan (ACH-4471), has demonstrated preliminary clinical proof-of-mechanism in patients with PNH and C3G, and has advanced into Phase 2 proof-of-concept clinical trials in both diseases. In addition to danicopan, we have two potent orally-administered second-generation factor D inhibitors in Phase 1 clinical trials, ACH-5228 and ACH-5548. The second-generation compounds will potentially have improvements in potency, half-life and safety margin over danicopan.

Factor D: A Trigger Point for Complement Activity

The Complement System

Complement Role in Disease

Complement is comprised of a group of proteins present in the blood that become activated through sequential steps, leading to a cascade of effects that contribute to immune response by the body. The complement system, a part of the innate immune system, is composed of three pathways (classical, lectin and alternative) and embodies the first line of defense to various insults such as clotting and infection via activation of one, two, or all three pathways.



The Alternative Pathway

The alternative pathway, in addition to its constitutive activation,  amplifies the classical pathway and lectin pathway activity through what is termed the amplification loop to produce active complement components in sufficient quantities. However, loss of control and overactivity of this process can occur leading to the damage of healthy cells in the body.  As such, the alternative pathway of complement activation is an attractive therapeutic target because there is a large body of evidence that shows its dysregulation may be the cause of multiple diseases.

Factor D

Factor D, a serine protease that has amongst the lowest plasma concentration (1-2 mcg/ml) of all complement components, occupies an upstream position in the complement alternative pathway. It plays a central role in activating the alternative pathway and, subsequently, overall complement activation through the amplification loop. Representing an attractive “control point” within the alternative pathway for complement activation, factor D is amenable for small-molecule inhibitors dosed orally and also provides a promising therapeutic target to selectively block the alternative pathway, and finally to be used in a variety of rare diseases and more common serious conditions.

Complement Factor D Inhibitor Platform



Structurally Diverse, Potent Factor D Inhibitors

Leveraging its deep internal expertise in infectious disease and protease inhibition and guiding molecular design with high-resolution, three-dimensional X-ray structural imaging of inhibitor-enzyme complexes, Achillion has generated over 3000 small-molecule compounds that are potent and specific inhibitors of complement factor D.

Excellent Profile of Achillion Factor D Inhibitors

Achillion’s library of factor D inhibitors includes compounds with physicochemical properties suitable for oral, intraocular or inhalational routes of administration. In vitro data generated to date suggest these compounds bind to factor D with high affinity resulting in inhibition of AP-mediated complement pathway activation; effectively block C3 fragment deposition on cells, in contrast to C5-targeted therapies; and demonstrate complete suppression of complement AP activity after oral dosing to non-human primates.

Furthermore, Achillion has advanced two next-generation compounds, ACH-5228 and ACH-5548, into Phase 1 clinical development and IND-enabling studies, respectively.

For more information about the complement factor D inhibitor program, please see the related links on this page or visit Resources.