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Aquilus Pharmaceuticals is a privately held biotechnology company specializing in the treatment and management of Amyotrophic Lateral Sclerosis (ALS) and other neurodegnerative diseases.

Matrix Metalloproteinases (MMPs)

Matrix metalloproteinases (MMPs) are a family of around 24 zinc-dependent endopeptidases. As a family, MMPs can cleave virtually any component of the extracellular matrix, and thereby facilitate cell migration and affect cellular signaling that regulates cell proliferation, differentiation, and cell death. In addition to cleaving the structural components of the extracellular matrix, MMPs are involved in the processing & signaling of growth factors and their receptors, cytokines, chemokines, adhesion molecules, and a variety of other enzymes such as caspases. A growing body of evidence has linked MMP-9 and MMP-2 with the severity and rate of progression of ALS. Currently, there are no FDA approved MMP inhibitors.

MMPs and ALS

Aquilus believes that ALS is a result of a systemic wide inflammatory process initiated through a series of mis-folding events that trigger an overexpression and production of MMP-9 in FF motor neurons. Whether the increase in MMP-9 is a result of the trigger inducing an inflammatory response or as a way of activating the process of autophagy to remove the misfolded protein, is not known. Whichever the case we believe that MMP-9 levels rise uncontrollably resulting in the break-down of various vital CNS proteins such as myelin basic protein and neurofilament and the activation of various inflammatory cytokines such as IL-1 beta, IL-6 and TNF-alpha as well as caspases all leading to motor neuron cell death. We believe that introducing a MMP inhibitor such as AQU-118 has a good chance of impacting disease progression.

Aquilus' MMP inhibitor AQU-118

Aquilus has developed an orally bioavailable, dual active MMP-2 and MMP-9 inhibitor, AQU-118, that has exhibited a good safety profile in mice, rats and dogs and has been shown to be efficacious at reducing neuronal damage in several rodent animal models of nerve injury. Aquilus plans to complete all of its Investigational New Drug (IND) enabling studies by end of 2022 and enter clinical development of AQU-118 for the treatment of ALS in 2023.

Publications

1) Henry, M.A.; et al. Effect of a novel, orally active matrix metalloproteinease-2 and-9 inhibitor in spinal and trigeminal rat models of neuropathic pain. J. Oral Fac. Pain Headache 2015, 29, 286–296.

2) Kwan, M.Y.; et al. Biomarker analysis of orally dosed, dual active, matrix metalloproteinase (MMP)-2 and MMP-9 inhibitor, AQU-118, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Int. J. Mol. Sci. 2019, 20, 811.