A Therapeutic Strategy for Neurological Disorders

Over 5 million people worldwide suffer from neurodegenerative Parkinson's disease, which manifests itself mainly in motor symptoms, including tremors, muscle stiffness, and slowness of movements. Patients also suffer from non-motor symptoms, such as pain, anxiety, depression, or excessive daytime sleepiness (EDS). This last symptom, which affects 40% of patients, gives rise to an accident-prone risk, which leads to the early institutionalization of many patients.

To date, no drug has been approved to treat this particularly debilitating symptom, and no effective drugs have been developed. However, in March 2020, our biopharmaceutical company, Theranexus, demonstrated the effectiveness of our drug candidate THN102 by validating a phase II study conducted on 75 patients with disabling EDS. The treatment that we have developed has reached the main efficacy criterion with high statistical significance and a high rate of patients with no residual drowsiness after treatment. This success is promising for an important medical service, and will be confirmed within the framework of phase III studies.

We initially conducted this research under the aegis of the French Atomic Energy Commission (CEA) on prion diseases. To understand the neuronal degeneration observed in these indications, we focused on the role of astrocytes in the brain. Astrocytes are glial cells that communicate with each other via an organized network. Although they have historically been viewed primarily as cells that support the activity of neurons, they are also capable of modifying their properties: the activation of a neuron leads to spatial reorganization of the astrocytic network to meet the nutritional demands of the neuron, and changes in the complexity of the network of astrocytes in turn modulate neuronal activity. In other words, there are very fine interactions between these two populations of brain cells. 

Within the astrocytic network, we are focused on one group of proteins essential to this modulation of neuronal activity: connexins. In the course of our work, we have discovered that a joint targeting of neuronal cells and connexins of the astrocyte network can be of therapeutic interest for patients suffering from neurological diseases. In 2008, this new idea was the subject of a family of patents filed by the CEA, for which we obtained an exclusive worldwide exploitation license when we created Theranexus in 2013.

27 Connexin Inhibitors Identified

Owing to the high costs, extended timelines, and significant risks that are involved in bringing new treatments for neurological diseases to the market, we have opted for a therapeutic strategy based on the combination of two already registered drugs. We started by screening nearly 2,000 medicines registered with the EMA, the U.S. FDA, and Asian authorities in order to pre-select those that had exhibited modulatory activity on the organization of the astrocytic network. We identified 27 registered products repositioned by their ability to modulate glial connexins. 

The drugs we are exploring combine the active dose of a psychotropic drug used in neurology to modulate the activity of certain neurons with molecules repositioned in their capacity to modify the properties of astrocytes via the connexins, which we use at lower doses than those conventionally used. We are able to increase the therapeutic index of the psychotropic drug that we know is particularly narrow within the central nervous system — an increase in doses can increase efficacy but leads to a significant increase in undesirable side effects. 

The simultaneous action on astrocytes and neurons makes it possible to potentiate the neuronal effect of the psychotropic drug without reinforcing undesirable effects. The drug candidate developed for the treatment of EDS in Parkinson's disease patients, THN102, combines an arousing molecule (modafinil) with a repositioned antiarrhythmic drug as a modulator of connexins (flecainide). Taking the same approach, we have validated phase Ib in the development of a second drug candidate, THN201, for the treatment of neurocognitive disorders in Alzheimer's disease. We are also preparing a phase II study for a third treatment, THN101, for neuropathic pain. Each of these combinations — regardless of its dose, administration sequence, or dosage form — is protected by a patent similar to that of a new chemical entity.

In just a few years, we have validated several preclinical and clinical phases for all of these treatments. Our rapid development thus far is partly due to our strategic choice to use drugs already registered with regulatory authorities, beginning with an understanding of the mode of action, active dose, effects on healthy volunteers, their side effects, and other factors. To continue developing THN102 into phase III, we are now pursuing an industrial license partnership. We will apply this business model to all treatments that target broad indications (such as Alzheimer's disease and neuropathic pain) for which we have demonstrated value in patients. For niche indications (such as rare diseases), we can evolve this business model toward the marketing of drugs, which we are pursuing for the drug candidate BBDF101, an API developed by the American foundation BBDF in Batten's disease (a fatal lysosomal disease affecting children beginning at 4 years of age) for which we have obtained an exclusive worldwide operating license at the end of 2019.

Connexins to All Astrocytic Proteins

Theranexus is pioneering the pharmaceutical development of drugs acting at the neuron/astrocyte interface by targeting connexins. We have demonstrated our proof of concept in humans and shown effectiveness in patients. Our goal is to become a leader in the field of interactions between neurons and glial cells in terms of the therapeutic targeting of neurological diseases. We plan to further our portfolio of astrocytic proteins. Since we have succeeded in identifying connexin, we believe that others among the 15,000 proteins expressed in astrocytes may also be of therapeutic interest. To identify and characterize new drug candidates more broadly, we are building a new platform that combines innovative neuroscience approaches and artificial intelligence tools. 

This next-generation platform is being deployed as part of a project in collaboration with the CEA and the College of France and co-funded by BPI France (the French Public Bank for Investment). For a given neurological disease, our goal is to systematically assess the diversity of drug combinations in order to identify which are most effective. For a psychotropic drug of interest, we will be able to screen all possible combinations between it and the drugs already registered. In collaboration with our academic partners, we will carry out this screening in vitro on co-cultures of neurons and astrocytes produced from human stem cells, then observe the effect of combinations of drugs on the interactions between these different brain cells in vivo. Thanks to this new platform and the contribution of systematic analysis of the data available on registered drugs, we are looking forward to information with very high added value to progress more quickly and with a higher probability of success toward clinical developments. 

Franck Mouthon

Franck Mouthon created Theranexus with Mathieu Charvériat in 2013. He has been serving as Chief Executive Officer and Chairman since the company was founded. He is currently the President of France Biotech, an independent association that brings together HealthTech entrepreneurs and their expert partners. Before Theranexus, Franck was head of a research group focused on neurological disorders within the French Alternative Energies and Atomic Energy Commission (CEA). A neuroscientist by training, Franck Mouthon graduated from Ecole Normale Supérieure de Paris.