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, C3 glomerulopathy (C3G) and paroxysmal nocturnal hemoglobinuria (PNH) , 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, 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.
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 2,700 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.
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