Achillion Pharmaceuticals

Science & Technology

Complement Factor D

The Complement System

Complement Role in Disease

Complement is comprised of a group of serum proteins that become activated through sequential steps, leading to a cascade of effects that contribute to immune response. Composed of three segments, the complement pathway, a part of the innate immune system, embodies the first line of defense to various insults such as trauma, infection, and bleeding via activation of the classical, lectin, and/or alternative pathways. The complement pathway is a validated therapeutic target in two rare diseases, paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), both of which are caused by dysregulation of the complement alternative pathway (AP). Ample scientific evidence also implicates dysregulation of AP in an array of other serious diseases.

The Alternative Pathway

It is becoming recognized that, regardless of the initial activation mechanism, alternative-pathway amplification is required to produce active complement components in sufficient quantities to cause disease. The alternative pathway of complement activation is an attractive therapeutic target due to continuous activity and the presence of key events that amplify all pathways of complement activation.

Factor D

Factor D, a serine protease that has the lowest plasma concentration (1-2 mcg/ml) of all complement components, occupies an upstream position in the complement alternative cascade. It plays a central role in AP and, subsequently, overall complement activation through what is called the amplification loop. Representing an attractive “control point” for complement activation, factor D is not only amenable to potent inhibition by small-molecule drugs dosed orally once- or twice-daily but also provides a promising therapeutic target 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 1,300 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.

A number of these compounds have demonstrated low to sub-nanomolar potency in in vitro studies.

AP Hemolysis IC50 (nM) Number of Inhibitors Number of Chemical
Series Represented
≤10 64 6
10-15 36 5
16-25 66 6
26-50 84 8
51-100 106 8
<100 356 8

Furthermore, Achillion has presented preclinical data that demonstrated the inhibition of complement activation in NHP model after oral or intravenous dosing of these factor D inhibitors. The chart below illustrates results with ACH-4471. In non-human primates, oral dosing of 200 mg/kg every 12 hours resulted in complete and sustained suppression of the complement alternative pathway for more than 24 hours.

Oral Dosing in non-human primates sustained suppression of AP Activity after oral dosing

In vitro Results of Factor D inhibitors for PNH and aHUS

Recent research demonstrates that Achillion’s compounds, potentially the first-ever oral complement inhibitors, effectively block the breakdown of PNH cells and mitigate the accumulation of C3 fragments on cells which leads to extravascular hemolysis. Furthermore, the effect observed with these inhibitors for aHUS was observed in the first reliable human, in vitro model of the disease.

Broad Intellectual Property Footprint

Achillion’s complement factor D program is protected by a strong intellectual property estate, with nine (9) patent applications published covering a wide range of novel complement factor D inhibitors with nanomolar activity. Multiple additional patent applications have been filed, significantly extending the scope of Achillion’s proprietary coverage for factor D inhibitors.

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