Delivering on the Promise of New Therapies for Rare Diseases: An Interview with Adrian Newman-Tancredi, CEO of Neurolixis

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Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will lead to better and faster breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.”

Thanks for taking the time to join us, Adrian! Could you please first introduce yourself for our readers?

Adrian: My name is Adrian Newman-Tancredi. I’m the CEO and co-founder of a bioscience company called Neurolixis. Neurolixis is a small privately held company, which is developing novel treatments for CNS disorders, particularly neurological disorders. My background is in pharmacology. I have a PhD from the University of Kent at Canterbury in the UK and, after a postdoc, I moved into the pharmaceutical industry. I now have over 25 years of pharmaceutical industry experience, essentially in drug discovery and early development of novel neuropsychiatric and neurobiological drug candidates.

Could you tell us what inspired you to work on Fragile X, and what issues are you trying to address?

Adrian: We had previously done a lot of work on drug treatments for different disorders, particularly targeting mood deficits, such as anxiety, depression, and cognitive dysfunction disorders. More recently we became interested in autism spectrum disorders because cognitive deficits, mood deficits, agitation, are also prominent in autism spectrum disorders. We started by doing a lot of work on another autism spectrum disorder, which is Rett syndrome, and we gradually broadened our work to Fragile X syndrome too. In fact, we started a collaboration with UCR, University of California at Riverside.

We entered discussions with Dr. Khaleel Abdul Razak and his postdoctoral researcher Dr. Xin Tao, who have mice modeling Fragile X syndrome, and we were able to collaborate with that team to test our drug candidate. We think that this drug candidate should be able to address several important aspects of Fragile X, notably mood disturbance, but also cognitive deficits and also importantly, the stimulatory hypersensitivity seen in Fragile X. And this was the object of work that we carried out with Dr. Abdul Razak and Dr. Tao.

What unique approaches are you taking? Gene therapy, targeted therapy, drug repurposing or others?

Adrian: Our approach is development of a small molecule novel chemical entity. We call it NLX-101 and it’s a compound which has already undergone extensive investigation for antidepressant properties and procognitive activity and we are repositioning it as a treatment for autism spectrum disorders and notably Fragile X syndrome. NLX-101 is a compound which targets the serotonin system. Serotonin is a neurotransmitter in the brain which is known to be involved in a multiplicity of different brain functions and including autism disorders and is involved in regulation of early development, which is relevant to autism and to Fragile X syndrome,

However, targeting the serotonin system has been a complex challenge for many years, because there are many serotonin receptors and because it’s a very extensive system. The novelty that we are bringing is that our drug candidate, NLX-101, is different because it is exceptionally selective for one particular receptor of the serotonin system, and we think that brings important advantages in its activity.

What is the greatest and differentiated value of your modality or technical approach to Fragile X patients?

Adrian: The major aspect of NLX-101 is that it is very specific in targeting a serotonin receptor, known as the 5-HT1A receptor. 5-HT1A receptors are located in specific brain regions, which mediate control of cognition, mood, and also of sensitivity to stimuli. What we’ve found is that this drug candidate can address, we think, several different dimensions of Fragile X syndrome and notably the stimulatory hypersensitivity, the anxiety symptoms and also the cognitive deficits. We’ve shown that NLX-101 influences neurotrophic factors, increasing levels of BDNF, it favors neuronal plasticity and promotes neurogenesis. So NLX-101 elicits a neuronal remodeling effect, at least in animal models. So to sum this up, the really distinguishing feature about an NLX-101, we think, is that it can address a number of different aspects of Fragile X syndrome because of its specific targeting of serotonergic mechanisms, which control neuronal development.

Could you share with us your progress and your upcoming milestone?

Adrian: Indeed, we’ve made a lot of progress in characterizing NLX101 in a large number of different experimental models, at the laboratory level. We’ve looked at in vitro cellular tests of drug signaling and also at ex vivo measures in different brain regions. We’ve also characterized NLX-101 using brain imaging by microPET imaging and fMRI; we’ve investigated the electrophysiological activity of NLX-101 as well as its neurochemical effects on neurotransmitter release in different brain regions. Most importantly, we’ve shown that these different parameters are influenced in those brain regions which are relevant to autism disorders, such as cortex, hippocampus, and brain stem which are all brain regions involved in different aspects of autism disorders. And just recently we’ve presented some quite striking data at the Gordon Conference on Fragile X syndrome, which took place in June 2022 in Tuscany, Italy.

These data were generated by the collaboration with the University of California at Riverside, and show that NLX-101 almost completely abolishes seizures in transgenic, Fragile X mice, when they are subjected to audiogenic stimuli. In these mice, intense audio stimulation triggers lethal seizures and NLX-101 has a striking protective effect against that. So, this really confirms and extends the extensive preclinical validation of NLX-101’s potential as a treatment for Fragile X syndrome.

Now, the next milestone is to progress into human trials, NLX-101 is clinical trial ready. We have a little human data already, but we need to advance the phase I safety trials in humans. We have an open IND from the FDA in the US and we’ve also got intellectual property filed; we’ve submitted a patent application to the US Patent Office. So we are really ready to move forward rapidly in development of this drug candidate, and we’re looking for partners to take the drug forward as we move into the human trials.

What do you hope the field to do differently in order to advance better medicine faster for Fragile X patients? And what do you hope to see in Fragile X, R&D in the next 10 years?

Adrian: This is an interesting question. The research community has probably been focusing a lot on individual symptoms in Fragile X syndrome, maybe also in other autism disorders. For example, there has been a focus on specific aspects such as agitation, and some antipsychotic drugs have been approved for treatment of agitation in autism spectrum disorders. I think what needs to happen is to take at a more holistic approach in the field. It’s interesting to see, for example, how psychedelics are now being tested more widely; they have quite extensive effects on different aspects of mood and cognition, and they’re being tested also for autism spectrum disorders. Now, one of the things that interests me about that is that psychedelics are serotonergic activators. They stimulate the serotonin system, including serotonin 5-HT1A receptors. So I think there’s an emerging story around serotonin and autism disorders, and I expect that over the next few years we are going to see a lot more discussion about that.

Are there innovative collaboration and partnership models we may pursue to advance the field faster?

Adrian: We are very strong advocates of collaborative models. I mentioned that we’re collaborating with the team of Dr. Abdul Razak at UCR. We are also collaborating with the FRAXA Research Foundation, in discussions with Dr. Michael Tranfaglia. We are now collaborating with a laboratory in Chile led by Dr. Patricia Cogram, who also has a colony of transgenic Fragile X mice, and we will be testing NLX-101 on animals in that colony in order to derive a more extensive profile of NLX-101 in a variety of tests, to complement the data from the audiogenic seizure model and get a broader picture of NLX-101’s activity on Fragile X. So we are very much into collaborations with patient organizations and academic laboratories. At Neurolixis, we bring drug pharmacology and development expertise, but we really rely on these academic teams to bring their neurobiology expertise and on patient organizations to bring really deep knowledge of the patient experience and what medical needs are directly relevant for the patients and for their carers and families.

What does patient-centric drug development mean for you in the Fragile X field?

Adrian: For Fragile X, patient-centric drug development means that there needs to be a variety of different treatments available, to be used either in different patient cohorts, different subgroups of patients, or maybe concurrently, to improve efficacy, maybe as combination treatments. The reason I think that is because, it’s clear that some patients have more accentuated symptoms in one area, others in other areas. So, clearly there are differences in the symptoms and these most likely reflect differences in the underlying neurobiology. So if the underlying neurobiology is different, that means we need to have appropriate treatments targeting different central nervous system mechanisms to deal with that. So I think that patient-centric drug development means having a battery of different treatments available which target different mechanisms, and making those available ultimately to the patients and the clinicians to see what actually suits the different patients best.

Thank you so much for your time. We really appreciate your insights.

Adrian: My pleasure.



Adrian Newman-Tancredi


Dr. Newman-Tancredi has over 30 years’ experience of neuroscience research. He is co-founder and Chief Executive Officer of Neurolixis, a biopharmaceutical company that develops innovative treatments for neurological disorders including autism spectrum disorders (ASD) and Parkinson’s disease (PD). Previously, he was Director of Neurobiology at Pierre Fabre Laboratories, a French pharmaceutical company, and responsible for identifying novel antipsychotic, antidepressant and analgesic drug candidates. Prior to his position at Pierre Fabre, Dr. Newman-Tancredi investigated signal transduction mechanisms of monoamine receptors at the Servier Laboratories (another French pharmaceutical company). He has published over 190 articles in peer-reviewed international scientific journals, is co-inventor on a dozen patents and serves as European Councilor for the International Society for Serotonin Research. His principal current focus of interest is the development of first-in-class direct-acting serotonergic “biased agonists” (also known as “functional selectivity”), notably the Phase 1-ready drug candidate, NLX-101, for the treatment of Fragile X syndrome and other ASDs. Other compounds in the Neurolixis pipeline are befiradol (NLX-112) which is undergoing a Phase 2 proof-of-concept study for treatment of dyskinesia in PD patients, and NLX-204, a preclinical stage antidepressant candidate. Dr. Newman-Tancredi previously characterized several approved drugs, including milnacipran (Savella), piribedil (Trivastal), agomelatine (Valdoxan) and levomilnacipran (Fetzima) for various CNS indications.

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