For many decades scientists have been trying to develop medicines for Motor Neurone Disease (MND). The diversity of this disease means doing this is very difficult, which is why there hasn’t been much progress on developing treatments.
This diversity makes the risk of failure high, so many organisations focus on re-using existing drugs for other diseases in the hope that they might work to slow or mitigate the progression of MND, while reducing the risk of development time and costs.
Our approach is different. We believe scientists need to develop novel (new) drug compounds to have a chance at halting and reversing this awful disease, which is why we reconsidered the development process. The resulting drug, Ellorarxine, is a new approach to treating MND.
This doesn’t mean it’s certain to succeed, but initial studies and pre-clinical research has indicated significant potential which is why we are moving into human trials this year. The results from these trials will give us human data indicating the effectiveness of Ellorarxine, which we will share when it is available.
There is considerable interest in Ellorarxine, so below we explain how it works, how we plan to proceed into trials and why we are not following a traditional development track.
Ellorarxine is based on the science around the modulation of Retinoic Acid Receptors (RARs), which control thousands on biochemical processes in all mammals. The dysfunction of RAR modulation results in symptoms including memory loss and muscle weakness. Compounds of this type have a long history of successful medical use, ongoing in the clinic today. This means that our drugs have chemical similarities but have better properties – making them considerably more ‘druggable’.
RAR modulators play an important role in maintaining skin, brain and nerve health. This has been reinforced by the findings of recent studies, where it has been suggested that druggable RAR modulators used for cancer and skin conditions may help dementia and other types of diseases, where the brain and nerves die (medically termed as neurodegeneration).
The big difference between current or other RAR modulators, and synthetic variants like those developed by Nevrargenics, are that those currently in use in the clinic do not enter the brain and nerves very well and are difficult to give in tablet or liquid form, so need high doses – doses that cause unwanted side-effects.
Nevrargenics has developed some new, highly potent, RAR modulators that are easier to give to patients, because they are highly efficient at entering the brain and nerves and therefore have the potential to be used at much lower doses and hence, show substantially fewer side-effects. Additionally, these new RAR modulators that we have developed have been studied in detail and published in a number of scientifically robust, peer reviewed internationally recognised journals, and have been shown to:
1) Improve the ability of nerves and brain cells to repair themselves measured by a reduction in the stress nerve cells shown when damaged. Improving how the nerve cells respond to stress caused by oxygen damage - so called ‘oxidative stress’;
2) Counter the inflammation associated with nerve cell damage - measured by the way the protective cells around the nerve cell are reacting to the damage (this is termed gliosis);
3) Help the nerve cells survive or die in a way that does not damage the cells around them (this is termed autophagy);
4) Improve the potential for nerves to reconnect when they have lost connection (this is termed neurite growth);
5) Reduce the symptoms of nerve damage in animals with a disease that resembles Parkinson’s disease - a common disease caused by nerve cell death.
Our new RAR modulators achieve these benefits by changing the way that brain and nerve cells make proteins in response to signals that the nerve cell receives. This is possible because our retinoids change the activity of the Retinoic Acid Receptors (RARs) for vitamin A. The types of RAR targeted by Ellorarxine could be less prone to side effects (and therefore safer) as they change the way in which the cell’s DNA responds and the way the DNA is processed in the cell.
Taken together, these findings, which have been published by other scientists in academic journals, suggest that this new type of RAR modulator drug can reduce, if not reverse, the damage seen when brain and nerve cells die in diseases such as some types of dementia or MND. These new drugs have the option to be given by mouth rather than injected too.
All of this evidence being taken into account means there is significant potential for the RAR modulators developed by Nevrargenics to treat diseases caused by nerve and brain cell death, like MND.
Nevrargenics has taken a different approach to the development of new treatments for nerve death to many other companies. Instead of screening a large number of compounds for a desired effect (a process called drug repurposing or repositioning), Nevrargenics has purposely designed a new molecule with the desired properties of entering the brain and nerves, stimulating nerve cell connections and focusing the effect on the desired retinoid receptors and processes. This process is called rational drug design.
Nevrargenics has identified a retinoid from the compounds it has designed and manufactured with the ideal properties - NVG0645 also called Ellorarxine. Ellorarxine was identified by taking the natural modulators of RARs and changing it in a way to improve its ability to enter the body, improve entry into nerves and the brain, improve potency, and to tailor it for the interactions with the cell processes involved in nerve cell death.
Ellorarxine has been shown to enter the brain more effectively than other RAR modulators including the natural systems. Achieving this is difficult as the ‘blood-brain barrier’ prevents most substances from passing through, which is why many medicines struggle to be developed.
Also, compared to other RAR modulators, Ellorarxine has a larger effect on the ability of neurones to reconnect (neurite outgrowth) and protects both the nerve cells and surrounding cells from damage. Ellorarxine also appears to be less likely to cause side-effects than other RAR modulators in animal models.
Based on our initial evidence, and the incredible unmet medical need of patients with neurodegeneration, Nevrargenics has been working with the regulators in the UK, experts in MND and patients with neurodegeneration to design a clinical trial that seeks to test the benefits of Ellorarxine as quickly and safely as possible.
Nevrargenics, at the suggestion of the MHRA during the scientific advice procedure, has adopted a design of clinical trial more commonly seen in trials of gene therapies and cancer medicines. This design is called the 3+3 plus extension design. In this design, small number of patients up to 20 are screened for safety followed by another 20-40 patients to see if Ellorarxine helps. Nevrargenics has agreed this approach as many sufferers of nerve cell death related disease live for a very short period. Time is of the essence and this design suggested by the MHRA is a major time saving innovation for patients and their families.
In the development of cancer medicines a ‘fail fast’ drug development pathway is often used. In the cancer development pathway, new drugs are often selected on the basis of biological effects in cells and animals and are put into humans at a very early stage. Success in the cancer drug development pathway is not defined in terms of survival at the early stage of development, but by changes in blood proteins and images that measure if the tumour has progressed.
Nevrargenics are adopting – as suggested by the MHRA - this clinical trial model and are seeking to establish the safety of Ellorarxine and its potential benefits in a single trial that uses changes in proteins released by the damaged nerve cells as outputs of the trial - this is called a biomarker driven trial.
The use of a biomarker trial significantly reduces the time a participant will spend in the trial if Ellorarxine proves not to be effective. It is hoped to reduce the time on the trial to as little as 12 weeks, enabling participants to move to other trials if Ellorarxine does not show any evidence of benefit.
Our trial also uses significantly fewer participants than other trials as the trial is not set (or ‘powered’ to use the technical term) to detect a difference in clinical scores, but instead is based on the known changes of the marker proteins (the biomarkers such as neurofilament light (NfL) chain). As biomarkers are less variable than clinical markers, the trial will need to enrol fewer participants for a positive decision to be made on Ellorarxine’s future.
This trial design - the oncology ‘fail fast’ type of design - differs from the design adopted by many development companies in neurodegeneration. Conventional studies in neurodegeneration often complete a phase 1 trial first in healthy volunteers or patients, followed by a phase 2 trial looking for improvement in the measurements of clinical disease - breathing and muscle function, for example.
The process of doing a phase 1 study, followed by a phase 2 study makes the trial process considerably longer. It works well for drugs that have known safety profiles - such as drug repurposing - but does not work very well in novel drugs, as it increases the chances of patients being exposed to ineffective medicines for a long period, which raises ethical considerations for people with a limited life expectancy.
Ellorarxine has received scientific advice from the MHRA on what is needed to proceed into the development program for Ellorarxine. Nevrargenics agrees with this advice and has accordingly started manufacture and the requested animal testing. This is the final stage before formal approval for the trial is given.
The trial is expected to start in 2025. Early results will be reported by the end of the year and completion is expected in 2026.
Please keep up to date with our progress by following our news updates.
