SPX-101 - a Peptide Promoter of ENaC Internalization
Spyryx Biosciences’ lead clinical candidate, SPX-101, is a SPLUNC1-derived peptide that is a mimetic of the S18 binding domain of SPLUNC1, replicating its natural regulatory function of binding to, disrupting, and causing the internalization of epithelial sodium channels (ENaC). The effect of SPX-101's mechanism of action is the robust and durable reduction in the cell membrane concentration of active ENaC and a corresponding reduction in sodium absorption. Restoring this down-regulatory control over ENaC and sodium absorption in the lungs of CF patients has the potential to enhance airway surface hydration and promote clearance of mucus and the bacteria, viruses and foreign particles embedded in it.
SPX-101 represents the first therapeutic opportunity to leverage a natural, biological mechanism that is important to the maintenance of normal mucus clearance. Importantly, because it's mechanism of action is independent of the mutations in CFTR, the product has the potential to provide meaningful clinical benefit to all CF patients.
As depicted in the graphic above, SPX-101 (1) binds to the ENaC subunits in a mechanistically similar fashion to SPLUNC1, however, because it is a small, optimized peptide and not the full SPLUNC1 protein, SPX-101 has enhanced drug-like properties, including the ability to preferentially bind ENaC independent of the local pH environment in the lung. This is a key feature to the potential effectiveness of SPX-101 for CF, having overcome the limitations of SPLUNC1 and fostering restoration of ENaC regulation. (2) The further biological effect of SPX-101's binding to ENaC is the disruption of the functional channel into individual subunits, and (3) the initiation of intracellular internalization by endocytosis. The internalized subunit proteins are processed by the cell for degradation or recycling.
SPX-101's mechanism of action and the durable pharmacodynamic effects that result, are in stark contrast to previous ENaC-effecting compounds, like amiloride and its derivatives, which only block the ENaC pore and are quickly washed away. The graph below further demonstrates this difference in mechanism between SPX-101 and amiloride. The data illustrates the robust effect SPX-101 has in reducing the cell membrane concentration of all three ENaC subunits through the internalization pathway described above. Amiloride does not reduce the concentration of ENaC on the cell membrane, and may even slightly increase it.
To demonstrate SPX-101's therapeutic potential, the peptide was tested in multiple in vitro and in vivo preclinical models of CF disease, including the mouse and sheep data presented below. SPX-101 clearly established effectiveness in both models, achieving nearly 100% survival in a 14-day inhaled study in beta-ENaC mice, dosed once-daily, and dose dependent restoration of tracheal mucus velocity in a single dose study in the CFTR(inh)-172 sheep model.