Neuron23 Files for IPO: Advancing Precision Therapies for Parkinson’s Disease with AI-Driven LRRK2 Inhibitor NEU-723

For more than 200 years, people have never stopped exploring the treatment of Parkinson's disease (PD), but there is still no cure.

Currently, PD has become the second-largest neurodegenerative disease, only after Alzheimer's disease. According to data released by the World Health Organization, the prevalence of PD worldwide has doubled in the past 25 years, with approximately 8.5 million PD patients globally in 2019. Epidemiological studies show that the prevalence of PD in people over 60 years old is 1% in European and American countries, exceeding 4% in those over 80 years old, while the prevalence rate in people over 65 years old in China is 1.7%, similar to that in European and American countries. With the increase in the elderly population, the number of PD patients will continue to grow.

Notably, PD is not an "exclusive disease" of the elderly, as it can occur in all age groups from teenagers to the elderly. Patients with early-onset PD account for 5%-10% of the total number of PD patients. The 2015 Global Burden of Disease study estimated that by 2040, approximately 13 million people will be affected by this condition.

The growing number of patients implies a huge demand for treatment. A report issued by Mordor Intelligence shows that the global PD drug market size is expected to grow from USD 5.37 billion in 2023 to USD 6.4 billion in 2028, with a compound annual growth rate (CAGR) of 3.58% during the forecast period (2023-2028).

The continuously growing market urgently needs more effective PD innovative drugs to meet patients' needs. Currently, people can alleviate PD symptoms through medication, surgery, rehabilitation, and psychological counseling, but there is still a long way to go before achieving a cure for this disease. This has led more pharmaceutical companies to focus on this area, hoping to bring more treatment options to PD patients through innovative technologies and drug development.

Neuron23 is an innovative company focused on providing drug treatments for patients with neurodegenerative diseases such as PD and autoimmune diseases like multiple sclerosis (MS). Utilizing AI technology and a biomarker platform, Neuron23 has developed its leading candidate drug for PD treatment—NEU-723. The NEU-723 pipeline is currently in Phase I clinical trials.

In October 2018, the German biotechnology company Origenis GmbH, in collaboration with the American venture capital firm KPCB (Kleiner Perkins Caufield & Byers), launched an innovative small-molecule drug project targeting neurodegenerative diseases. The project utilizes Origenis' platform technology to accelerate the identification of new molecular targets, aiming to develop novel small-molecule drugs for treating neurodegenerative diseases such as PD and AD, as well as autoimmune diseases like MS, thereby creating more effective precision therapies. Thus, Neuron23 was born.

In December 2020, Neuron23 emerged from stealth mode, publicly disclosing its financing and pipeline information. During that year, Neuron23 completed Series A and B funding rounds, raising a total of $113 million. In 2022, it secured an additional $100 million in Series C financing, led by SoftBank Vision Fund 2, with participation from Westlake Village BioPartners, Kleiner Perkins, Redmile Group, and other investment firms. The over $200 million in financing has advanced Neuron23's development of two key pipelines targeting LRRK2 and TYK2.

In addition to the backing of star capital, Neuron23 is also supported by an experienced team.

Nancy Stagliano, Ph.D., Chief Executive Officer and Chair of the Board, received her Ph.D. in Neuroscience from the University of Miami Miller School of Medicine and conducted postdoctoral research at Harvard Medical School. She is also a co-inventor on 19 patents.

Before joining Neuron23, Nancy served as the CEO of True North Therapeutics, iPierian, and CytomX Therapeutics. During her tenure at True North, the company's monoclonal antibody drug Enjaymo (Sutimlimab) was acquired by Sanofi and approved by the FDA for the treatment of cold agglutinin disease. Additionally, she has served as an advisor to Westlake Village BioPartners and New Leaf Venture Partners.

Chief Medical Officer Dr. Sam Jackson joined Neuron23 in 2022. Sam has extensive experience in clinical drug development. Prior to joining Neuron23, he served as Senior Vice President of Clinical Development at biopharmaceutical company Alector, where he was responsible for overseeing clinical development and operations while leading drug development programs for Alzheimer's disease and frontotemporal dementia. Additionally, he previously served as Chief Medical Officer at pharmaceutical company Alkahest.

Steve Wood, Executive Vice President of Drug Discovery, is a pharmaceutical industry veteran with over 30 years of experience in drug research and development. Before joining Neuron23, Steve spent more than 20 years at Amgen's neuroscience division, where he led the company’s neurodegenerative disease discovery research efforts. During his time at the clinical diagnostics company SmithKline Beecham, he and his colleagues helped elucidate the pathological mechanisms of abnormal protein aggregation in the field of neurodegenerative diseases.

In addition, Neuron23 recently appointed Andrew Yost as the company’s Chief Business Officer (CBO) this year. Before joining Neuron23, Andrew served as the CBO of TenSixteen Bio, a novel drug discovery company. He also previously held the position of Senior Vice President of Development at ReGenXBio, a gene therapy company, where he led business development, strategic transactions, alliance management, and corporate development planning, playing a key role in the company’s IPO process. After seven years of development, Neuron23 now needs to strengthen external collaborations while advancing its core technology pipeline. With his extensive business development (BD) experience, Andrew Yost’s appointment will provide strong support for the company moving forward.

At this point, Neuron23 has built a team with an average of 10 years of experience in the field of neurodegenerative disease drug research and development. Core team members have come from multinational pharmaceutical companies such as Amgen, Genentech, Takeda, and AbbVie, providing research and development momentum for the advancement of Neuron23's core pipeline.

PD is considered a complex, multisystem neurodegenerative disease rather than a simple brain disorder. Its primary pathological change is the degeneration and death of dopaminergic (DA) neurons in the substantia nigra of the midbrain, leading to a significant reduction in DA content in the striatum, as well as the appearance of eosinophilic inclusions, known as Lewy bodies, in the cytoplasm of residual neurons in the substantia nigra. The main component of Lewy bodies is α-synuclein. Over 90% of PD cases are sporadic, with only 5%-10% of patients having a family history.

Leucine-rich repeat kinase 2 (LRRK2) is a large multi-domain ROCO family protein composed of 2527 amino acids, containing two functional enzyme (GTPase and Ser/Thr kinase) domains, as well as several protein-protein interaction domains such as armadillo, ankyrin, leucine-rich repeat (LRR), and WD40. It plays a role in many cellular functions, including vesicle trafficking, autophagy, lysosomal and mitochondrial function, neurotransmission, as well as immune and microglial responses.

In 2004, a study by Paisan-Ruiz et al. found that mutations in the LRRK2 gene are toxic to neurons, and mutations in this protein are associated with the hereditary form of PD. Overactivation of LRRK2 leads to lysosomal dysfunction, which in turn causes the accumulation of α-synuclein and the disruption of neuronal health¹. Since then, LRRK2 has been identified as a pathogenic genetic factor for familial PD.

Since then, research on LRRK2 has been increasing, and the LRRK2 target has been dubbed the "rising star" in PD drug research. Existing research results show that more than 100 mutations in LRRK2 can lead to or increase the risk of PD, and there is a clear link between LRRK2 kinase activity and PD penetrance. Additionally, Neuron23 discovered in clinical research that sporadic PD is also driven by LRRK2.

In 2018, Roberto Di Maio et al. published an article in *SCIENCE TRANSLATIONAL MEDICINE* showing that LRRK2 plays a critical role in the development of PD, regardless of mutation status. Idiopathic PD patients without mutations also exhibit overactivation of the LRRK2 protein and impaired autophagic function in neurons, leading to abnormal accumulation of α-synuclein.

These findings suggest that inhibiting LRRK2 activity and improving membrane trafficking and lysosomal function can protect neurons. Therefore, small-molecule LRRK2 inhibitors have become another innovative drug for treating PD.

In the LRRK2 inhibitor field, in addition to Neuron23, biotech giants such as Pfizer, Merck, GlaxoSmithKline, and Genentech have long been involved. They have been studying LRRK2 for over a decade, but progress has been slow, and currently, most pipelines remain in the preclinical development stage.

Among them, some companies are making rapid progress. Denali Therapeutics, a biopharmaceutical company, has collaborated with Biogen to develop BIIB122/DNL151, a targeted drug for LRRK2, which is currently in Phase III clinical trials.

NEU-723 is a selective small-molecule LRRK2 inhibitor under development by Neuron23. Administered orally, the drug penetrates the brain and targets the LRRK2 kinase, thereby blocking and inhibiting the activity of the mutant LRRK2 protein. Clinical studies conducted by Neuron23 have shown that, compared to other candidate drugs in development, NEU-723 demonstrates superior efficacy and a broader therapeutic range. It can more precisely target LRRK2 and, in addition to treating patients with LRRK2 mutations, will also identify and treat sporadic PD patients.

In February 2023, Neuron23 initiated the Phase I clinical trial of the NEU-723 pipeline. This clinical trial aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral NEU-723 in healthy adult subjects through single and multiple ascending dose studies. Currently, Neuron23 has completed the first patient dosing. The study is expected to be completed on September 30, with results anticipated to be released by the end of this year.

In addition to NEU-723, Neuron23's R&D pipeline also includes a drug candidate targeting Tyrosine Kinase 2 (TYK2). TYK2 is a non-receptor intracellular signaling kinase, and the signaling pathways it mediates are crucial in the chronic inflammatory cycle of immune-mediated diseases, such as the signaling of various dysregulated cytokines involved in MS. Current research indicates that loss-of-function mutations leading to reduced TYK2 kinase activity have a protective effect against central nervous system diseases (such as MS) and peripheral autoimmune diseases (such as psoriasis and ankylosing spondylitis).

Therefore, the TYK2 inhibitor has also become a key development focus for Neuron23. Currently, its TYK2 pipeline is in the preclinical development stage.

The advancement of the clinical pipeline is only one aspect; Neuron23 is also actively promoting external collaborations.

In September 2022, Neuron23 collaborated with CDMO company QIAGEN to co-develop a Companion Diagnostic (CD) method to identify subgroups of PD patients. Reportedly, although these patients do not carry pathogenic mutations associated with LRRK2, they may still respond to LRRK2 inhibitors.

According to the cooperation agreement, QIAGEN will develop a clinical trial assay for Neuron23 to detect its biomarker panel, which aims to predict the response of PD patients to LRRK2 inhibitors. Subsequently, they will integrate the prediction results into QIAGEN's next-generation sequencing (NGS) workflow. Finally, Neuron23 will submit a pre-market approval (PMA) application for the NGS companion diagnostic test to the FDA based on the generated results, along with a new drug application (NDA) for NEU-723.

Although the road to PD drug development is still long, in the future, LRRK2 inhibitors may become a hope for PD patients to摆脱疾病困扰.

References:

1. Coro Paisán-Ruı́z et al.Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease.VOLUME 44, ISSUE 4, P595-600, NOVEMBER 18, 2004.DOI:https://doi.org/10.1016/j.neuron.2004.10.023

2. Roberto Di Maio et al. LRRK2 activation in idiopathic Parkinsons disease.Sci. Transl. Med.10,eaar5429(2018).DOI:10.1126/scitranslmed.aar5429