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 C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN), both diseases affecting the kidney, and paroxysmal nocturnal hemoglobinuria (PNH), a blood disorder, as well as several more prevalent indications.

The Company’s first-generation factor D inhibitor, ACH-4471, has demonstrated preliminary clinical proof-of-mechanism in patients with C3G and PNH, and has advanced into Phase 2 proof-of-concept clinical trials in both diseases. In addition to ACH-4471, 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 ACH-4471.

Factor D: A Trigger Point for Complement Activity

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 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 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.