Research in Charcot–Marie–Tooth Disease Type 1A (CMT1A)

CMT1A BIOTECH ALLIANCE PARTNERS

Academic Medical Center, Amsterdam, Netherlands; Max Planck Institute, Göttingen, Germany; Psychogenics; Cleveland Clinic; Charles River

The CMTA has established a unique capability to develop new therapies directly with companies and to expertly test those potential therapy candidates. This allows a company interested in positioning a therapy for CMT to access the infrastructure needed to evaluate the therapy without committing significant time and money up front. The CMTA has acquired and characterized best-in-class mouse and rat models of CMT1A so we know when to test a drug, for how long and what signifiers of improvement need to be measured. Currently, six models are well characterized and available, representing four different types of CMT. Expert contract research organizations have been engaged to perform the testing under CMTA direction and our agreement structure lowers common barriers to entry such as confidentiality, retention of intellectual property and long-term financial commitment.

Addex Therapeutics

Addex Therapeutics is a clinical-stage pharmaceutical company pioneering allosteric modulation-based drug discovery and development. CMTA and Addex formed a collaboration to investigate a potential therapy for CMT type 1A (CMT1A). The primary goal of the collaboration was to evaluate the benefit of Addex’s proprietary positive allosteric modulator’s (PAM’s) targeting the gamma-Aminobutyric acid subtype B (GABAB) receptor in rodent models of CMT1A. The GABAB receptor has previously been shown to be instrumental in controlling the overexpression of Peripheral Myelin Protein-22 (PMP22) in a rat model of CMT1A. Elevated PMP22 is closely associated with the disabling peripheral neuropathy that accompanies CMT1A. The research alliance with Addex concluded with joint study planning aimed at the chronic dosing of select GABAB PAM’s in rodent models of CMT1A, followed by detailed assessments aimed at measuring the improvement of key outcomes. These outcome measures include biomarkers, motor function, electrophysiology and peripheral nerve histology.

Confidential Partner A

Confidential Partner A owns a drug candidate derived from a program at a major pharmaceutical company. Based on known evidence of the drug target’s possible role in CMT disorders, the company pursued evaluation in both Type 1 (CMT1A) and Type 2 CMT animal models. We provided partial evidence of effect in CMT1A, and very detailed data that the drug’s effect was primarily on sensory, not motor, nerves. From this data the company concluded that the benefit of using this drug class in CMT therapy was not sufficiently compelling and the effort was ended.

Confidential Partner B

Confidential Partner B, our first alliance partner in this area has been evaluating the delivery of its gene modifying system, packaged inside an AAV virus, to nerves in CMT1A animals. The testing resource is “therapy agnostic” and can be used to evaluate gene therapy approaches as well as ASOs, biologicals and small molecules. The gene localization studies are still in progress, and if delivery is sufficiently effective, this will be followed in 2021 by a complete series of preclinical efficacy studies to determine if the approach can correct the CMT1A defect and restore normal function in the animals.

Confidential Partner C

Confidential Partner C is developing a novel biological approach to treat CMT and asked for our help in evaluating their candidate in both Type 1 (CMT1A) and Type 2 models. These studies showed promising results in both models, and together we are pursuing studies to determine the site of action of the candidate therapeutic, which may not be directly in the nerve but at the junction of nerve and muscle. Additional studies are being discussed that would examine further biomarker elevation in both models and assess the survival of peripheral nerve in the completed studies.

InFlectis BioScience

InFlectis BioScience, a French startup company, is working to develop a new approach to CMT1B and CMT1A. Sponsored research studies have been performed in the CMTA-STAR consortium to assess drug effects in both animal models and InFlectis is currently raising funds for clinical trial testing of the molecule in patients.

Ionis Pharmaceuticals

Ionis was the first partner to demonstrate that a genetic modifier of the PMP22 gene (anti-sense oligonucleotides or ASOs) could effectively repair CMT1A defects in animal models of the disease. Since then, Ionis has been working to solve a generally understood limitation of its technology—the delivery of the ASO to the target Schwann cells. They have acquired from us CMT1A stem cell lines in the NYSCF repository for use in testing different approaches to enhance ASO delivery. We are awaiting results from this work, which would allow their CMT1A effort to advance if successful.

New York Stem Cell Foundation

In addition to the validated CMT animal models, the CMTA and the New York Stem Cell Foundation (NYSCF) have put together a collection of patient-derived stem cell lines for CMTs, including CMT1A. These cell lines give companies the ability to test therapies on patients’ own genes, the first step to enabling a personalized medicine strategy.

Orthogonal Neuroscience

Through a Preclinical Testing Alliance, Orthogonal has gained access to the CMTA’s service research providers and preclinical testing network. The CMTA provided bespoke support around selection of appropriate models, design of the experiments, data interpretation and guidance regarding what future experimentswould be needed to take the project forward. The CMTA also made introductions to key clinicians and thought leaders tofacilitate future clinical trials in CMT patients. The CMTA Preclinical Testing Alliance facilitated ORT247 testsin CMT1A (demyelinating) and 2E (axonopathy) mouse modelsand the results show an improvement in several disease endpoints.

Pharnext

Pharnext is an advanced clinical-stage biopharmaceutical company developing novel therapeutics for orphan and common neurodegenerative diseases that currently lack curative and/or disease-modifying treatments. PXT3003 completed an international Phase III trial with positive topline results for the treatment of Charcot-Marie-Tooth disease type 1A (‘CMT1A’) and benefits from orphan drug status in Europe and the United States. An international pivotal Phase III study of PXT3003 in CMT1A, the PREMIER trial, is currently ongoing.

Regenacy Pharmaceuticals

The CMTA and Regenacy Pharmaceuticals, a clinical-stage biopharmaceutical company developing breakthrough treatments for diabetic and other peripheral neuropathies, engaged in a collaboration to validate the role of HDAC6 in multiple forms of Charcot-Marie-Tooth (CMT). Regenacy had an opportunity to expand on the groundbreaking work of Dr. Ludo van den Bosch at University of Leuven (published) and Dr. Andrew Grierson at University of Sheffield to show the role of HDAC6 in several forms of CMT. The collaboration focused on evaluating the efficacy of ricolinostat in animal models of CMT through the extensive preclinical testing capabilities the CMTA has assembled. Although Regenacy decided to conclude testing, the CMTA continues to explore the role of HDAC6 inhibitors.

Sanofi

Sanofi was our first alliance partner for CMT1A and in 2020 evaluated small molecules that came from this joint program as potential new alliance partners have expressed interest in acquiring them. In addition, Sanofi has asked the CMTA to lead testing of a new small-molecule approach that has been advancing for a different but related disease area. In 2020 Sanofi restructured their organization, with closure of their neuroscience unit in Boston.

Shift Pharmaceuticals

Shift Pharmaceuticals, a privately held company that is developing antisense oligonucleotides (ASOs) to treat a variety of genetic disorders, and the Charcot-Marie-Tooth Association (CMTA) are collaborating to use ASOs to treat CMT1A, which is caused by a duplication in the PMP22 gene. ASOs are drugs that can alter RNA and reduce, restore or modify protein expression. Shift Pharmaceuticals will be taking advantage of the CMTA’s comprehensive suite of expert preclinical testing capabilities to evaluate the therapeutic potential of their drug candidate. The findings from this Alliance Partnership initiative will be critical in advancing research that will lead to clinical trials for CMT1A patients.

ToolGen

ToolGen, a biotechnology company focusing on development of the genome editing platform technology and its applications in human therapeutics and agriculture, and the CMTA established a collaboration to investigate a potential therapy for CMT type 1A (CMT1A), using CRISPR gene editing technology. The primary goal of the collaboration is to facilitate the development of a novel gene-editing therapy for CMT1A that seeks to suppress overactivity of the causative disease gene, PMP22. The testing alliance with ToolGen involves access to the STAR Scientific and Clinical advisors of the CMTA, animal testing of the approach in the CMTA preclinical testing alliance network, and assistance with the planning of clinical trials in the USA.