Preclinical Studies for the Therapeutic Development of a Novel Neuroprotectant for ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disorder of the motor neurons for which there is no cure. Since 2007, over 80 phase 2 or 3 clinical trials have been conducted leading to U.S. Food and Drug Administration (FDA) approval of only one drug substance with limited efficacy, in addition to Riluzole, which was approved in the 1990s. There is an urgent need for a treatment able to slow down disease progression, also called a disease-modifying treatment. We have discovered that depletion in a metabolite called nicotinamide dinucleotide (NAD) induces a major energetic deficiency and neuronal demise in ALS. Most importantly, we have shown that restoring healthy NAD levels protects neurons against the mechanism of toxicity operating in ALS. Based on these findings, we initiated and implemented a large drug discovery effort that led to identification of a neuroprotective molecule called VITNP1. When administered to ALS mice in drinking water, VITNP1 delayed motor impairment and loss of muscle strength and increased brain NAD levels. By performing iterative rounds of chemical modifications and testing of biological properties, we have further improved the compound s safety, stability, and brain penetration, leading to the drug candidate VITNP1.2. Herein, we propose to perform studies that will support the transition of VITNP1.2 to clinical trials in ALS patients. We will determine the optimal doses needed to safely restore NAD levels and provide therapeutic benefit. Since ALS is a heterogenous disease, with patients having different genetic make-up, clinical presentation, and disease progression rate, we will test VITNP1.2 in two different mouse models of ALS to demonstrate that our drug candidate will help a large proportion, and maybe all, ALS patients. We will test VITNP1.2 s therapeutic efficiency when administered after disease onset in mice, to show its potential as a treatment for ALS, as opposed to a prophylaxis. Our aim is to develop an oral treatment improving the patient condition and slowing disease progression in familial and sporadic ALS. Our data in mice show that VITNP1.2 allows for NAD restoration without the side effects observed with high doses of NAD precursors, so-called NAD boosters, and that it can be administered safely to mice over several months. VITNP1.2 dosage, safety, and therapeutic efficacy data will be important to support the FDA application for an investigational new drug by the small company Vova Ida Therapeutics, Inc. (VIT) with which we are partnering. VIT will perform regulatory studies and is planning to initiate a first-in-human clinical trial within 24 months. We will also measure NAD in blood and cerebrospinal fluid of VITNP1.2 and placebo-treated mice to show that the treatment efficacy can be monitored by using NAD as a biomarker. This will be important to provide a way to quickly evaluate if VITNP1.2 is biologically active in humans in the phase IIa clinical trial, and to be able to start a larger clinical trial enrolling more ALS patients as soon as possible. In this project, we will also evaluate if NAD levels measured in blood and CSF at various stages of disease reflect disease progression, such that NAD could be used as a novel biomarker supporting clinical trials for other candidate therapeutics. Therefore, our project will accelerate the development of new therapeutics for ALS by providing a novel drug candidate with disease-modifying properties to be tested in clinical trials, and by providing a new tool to accelerate clinical trials for drugs developed by other investigators.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310080
Entities
People
- Corinne Lasmezas
Organizations
- United States Army
- University of Florida