Curlim

Context

The project is focused on the development of an innovative compound, CLM001, designed to treat peripheral neuropathies, with a special attention to Charcot-Marie-Tooth disease 1A (CMT1A). Current therapeutic strategies for these conditions are limited and symptomatic, lacking a pharmacological treatment. 

Solution

The technology is innovative due to the use of cellulose nanocrystals for enhanced penetration of curcumin into cells, the solubilization and protection of curcumin by beta-cyclodextrin, and a significant increase in curcumin's bloodstream lifespan (bioavailability multiplied by a factor 250!). 

Challenges include producing a stable medication, deciding the possibility of oral administration, and setting up the best administration route and effective dose for humans. 

Team and partnerships

Partnerships for the DEVNA project include the University of Limoges, with its laboratories NEURIT and LABCiS, and various funding and support initiatives. The company, CURLIM, is a SAS with a capital of 80,000 € and is incubated at the University of Limoges. 

The team is composed of three founders, Prof. Franck STURTZ, Prof. Alexis DESMOULIERE and Prof. Vincent SOL who will appoint Laurent RICHEBOURG as president in March 2024 

The Market

The commercial goals are to offer a medical treatment for patients with peripheral neuropathies. The first market is focused on CMT1A, with an estimated 100,000 patients in the EU and US, and potential expansion to other neuropathies such as diabetic neuropathy and SLA. 

The prevalence of CMT, all types combined, is 1:2,500. Initial market (limited to CMT1A) : in the EU and US, around 100,000 patients and 310,000 patients if extended to other forms of CMT diseases.

First assumptions would give a Total Available Market including diabetic neuropathies and CMT worth 351 Billion $, Serviceable available market (CMT1A only) : 2,03 Billion $ and Serviceable obtainable market 1,01 B$

Competition

Several therapeutic strategies have been developed to reduce the overexpression of the PMP22 gene. Unfortunately, none of the phase 2 clinical studies using these strategies have shown beneficial results in patients with CMT1A. Same fate with 2 phase III studies.

There are also several pre-clinical developments using different modalities: gene therapy, small molecules, RNAi, siRNA, gene editing. Additionally, solutions based on gene therapy, siRNA, CRISPR and other gene-specific approaches are limited to the CMT1A target compared to an application area for CLM001 that can go beyond CMT.

Results

CLM001, a nanodrug based on cellulose nanocrystals, cationic cyclodextrin, and curcumin, has shown significant improvement in neurological symptoms in 2 animal models without clear toxicity, and is moving towards clinical trials under the DEVNA project. What has been demonstrated:

• Motor nerve conduction speeds significantly improved.
• Improved balance and motor skills of animals “return to normal balance.”

The main advantage is the demonstration of therapeutic effectiveness on 2 animal models of different species. Indeed, demonstrating the effectiveness of a product on 1 animal model always raises the question of whether the effectiveness is specific to the species. When a product is effective on 2 species, it is much more legitimate to think that it will be effective on a 3rd species such as Man (Homo sapiens) and this is often what regulatory agencies (ANSM, EMEA, FDA) before authorizing a human clinical trial.

But a second advantage of the product is that it will perhaps be effective on many genetic neuropathies, or even non-genetic neuropathies (diabetic for example). Indeed, pure Curcumin, despite its low bioavailability and its short lifespan, has therapeutic power on these neuropathies. It is therefore legitimate to think that it will be more active in the form of CLM001 on these neuropathies. This is not the case for so-called targeted therapies (antisense RNA, gene therapy, CRISPR-cas9, etc.)

Experimentally, improvements were explained by following mechanism of actions:

• A very clear reduction in oxidative stress both in cells in culture and in vivo
• An increase in the production of PMP22 and MPZ
• A very clear reduction in Endoplasmic Reticulum stress
• A marked improvement in nerve myelination with a reduction in the G-ratio

CLM001 did not present any toxicity in those trials.

In total, these results, the fruit of more than 8 years of investigations, look sufficiently interesting and comprehensive to justify complete clinical development. It is therefore appropriate to plan and finance the next steps towards a human clinical trial.

Millions of patients with neuropathies are expecting a relief for their disease...