Nomacopan is a bifunctional molecule that inhibits complement C5 while also completely and independently binding tightly (KD 0.2nM) to leukotriene B4 (LTB4) a member of the eicosanoid family of lipid mediators.
Akari has also developed compounds that only inhibit LTB4, and is developing compounds targeting other eicosanoids such as thromboxane A2 (TXA2).
Phylogenetic analysis has shown that nomacopan started as an LTB4 inhibitor, and through evolution subsequently acquired the ability to inhibit C5. This indicates that inhibition of both C5 and LTB4 at an inflammatory site is of benefit to feeding ticks, as these inflammatory mediators are often co-located, making nomacopan a more potent inhibitor of inflammation than a molecule that targets either C5 or LTB4. The benefit of dual inhibition has been illustrated in an animal model of immune complex alveolitis (Roversi et al, 2013). Akari is currently undertaking further work to explore diseases where inhibition of both C5 and LTB4 or LTB4 alone are likely to be of most clinical benefit.
Role of LTB4 in inflammation and disease
LTB4 plays an important early role in the initiation and amplification of inflammation: it attracts and activates white blood cells in areas of inflammation. The roles that LTB4 plays in the amplification of immune responses are still emerging, but LTB4 activity has been implicated in diseases as diverse as asthma and COPD, blistering skin disease, pulmonary arterial hypertension (PAH), thrombosis, diabetes, and metastatic cancer.
LTB4 is synthesized in the body from arachidonic acid in response to a variety of inflammatory signals, and primarily acts through two G protein-coupled receptors: BLT1 and BLT2. LTB4’s stimulatory effects on white blood cells include chemokinesis, chemotaxis, lysosomal enzyme release, superoxide anion production, adhesion to endothelial cells, C3b receptor expression, CD11b up-regulation, generation of ROS, induction of the IL-2 receptor and IL-2 production. LTB4 has also been observed to enhance activation, proliferation and differentiation of human B-lymphocytes, T-lymphocytes, granulocytes, macrophages, monocytes, eosinophils, NK cells and to induce vascular permeability, hyperalgesia, and bronchoconstriction.
Mode of action
Nomacopan and Akari’s LTB4-only development compounds both act through ligand capture, which is a unique mode of action compared to other specific LTB4-targeted drugs which inhibit BLT1, BLT2, or the production of LTB4. Nomacopan captures LTB4 within a cavity, thereby removing it from the area of inflammation, by disrupting the chemical gradient of LTB4 that attracts and activates white blood cells.
Other drugs being developed to inhibit the effects of LTB4 may have unanticipated side effects or fail to specifically block target. For example:
Inhibition of LOX-5 may cause a shunt away from leukotriene production to prostanoid production and prevent the production of leukotrienes with anti-inflammatory activities
Inhibition of LTA4H can inhibit hydrolysis of the proinflammatory molecule proline-glycine-proline (PGP) by LTA4H.
Inhibition of either BLT1 or BLT2 will not block the LTB4 signaling via both GPCRs.
By specifically capturing LTB4, nomacopan will block both G-protein-coupled receptors (GPCRs), and not will not produce off-target effects such as shunt to prostanoid synthesis or inhibition of proline-glycine-proline (PGP) cleavage.
