Matrix Metalloproteinase Inhibitor for the Treatment of ALS
Abstract
Background: Matrix metalloproteinases (MMPs) are a group of enzymes that are responsible for the breakdown of proteins, such as collagen, that are normally found in the spaces between cells in tissues. They are also involved in wound healing and in embryo development. MMPs can also turn on other enzymes that are involved in the inflammatory response to infection and/or disease. The level of active MMPs in adult tissues is quite low. However, a certain subset of these MMPs, specifically MMP-2 and MMP-9, have been observed to be elevated in many diseases of the central nervous system (CNS), including amyotrophic lateral sclerosis (ALS). In people with ALS (PALS), elevated levels of MMP-2 and MMP-9 have been found in blood, skin, and cerebral spinal fluid (CSF). In mouse models of ALS, MMP-9 has been found to be elevated in specifically those regions in the spinal cord that are responsible for motor function. In these same mouse models, blocking the activity of MMP-9 has extended the life of mice by 25%. Aquilus Pharmaceuticals (Aquilus) recently performed a biomarker study in the serum of a group of PALS and found a greater than 7.5-fold increase in MMP-9 as compared to a group of aged-matched healthy controls. Product: The therapeutic product is a compound that is taken orally and inhibits MMP-2 and MMP-9. The compound, which has the designation AQU-118, has demonstrated good safety in mice, rats, and dogs and is in late-stage preclinical development for the treatment of ALS. Specific Aims: An investigational new drug (IND) application is a request for Food and Drug Administration (FDA) authorization to administer an experimental drug to humans to evaluate whether it is safe and effective in treating a disease. Such authorization must be secured prior to any experimental drug being tested in humans. The proposed project will complete all of the remaining toxicity, formulation, and stability studies required to submit an IND application to the FDA for approval to test AQU-118 in PALS. Aquilus plans to also complete important biomarker work in support of a clinical trial of AQU-118 in PALS. This biomarker work will involve completing methods development and validation of an analytical technique that will measure if AQU-118 is working to inhibit MMP-2 and MMP-9 in the blood and CSF of PALS during clinical development (target engagement). Impact: A key goal of the proposed project is to have submitted by the end of the project program an IND application on AQU-118 to the FDA for approval to begin clinical testing in PALS. Once FDA approves the IND, a proof-of-concept (POC) clinical trial can then be started that will test AQU-118 in those PALS that have elevated levels of MMP-9 as compared to aged matched controls. The proposed project is essential at bringing to the clinic an experimental therapeutic to treat ALS that targets, for the first time, a protein that has been involved in inflammation and which Aquilus has recently shown to be extremely elevated in PALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210574
Entities
People
- Irving Sucholeiki
Organizations
- Aquilus Pharmaceuticals (United States)
- United States Army