Weekly Spotlight - 10.10.24

In the News

Neuvivo's ALS Immunotherapy Seeks FDA Approval

Neuvivo has submitted a New Drug Application to the US FDA for NP001, an investigational immunotherapy for amyotrophic lateral sclerosis (ALS). Unlike existing treatments, NP001 aims to restore the balance of pro- and anti-inflammatory processes, potentially preserving lung function and extending survival by up to a year. This approach marks a shift from traditional neurologic mechanisms to an immunologic one, addressing the urgent need for innovative ALS therapies. Current treatments, such as Rilutek and Radicava, offer limited life extension, highlighting the necessity for new solutions.

The development of disease-modifying treatments for ALS has been fraught with challenges due to the disease's complex pathophysiology. Neuvivo's candidate, previously studied by Neuraltus Pharmaceuticals, showed promise in a subgroup of patients despite earlier trial failures. This underscores the difficulty in achieving mechanistic efficacy in ALS treatments. GlobalData's analysis indicates a pipeline of candidates with diverse mechanisms, yet success remains elusive. Neuvivo's efforts reflect a broader scientific endeavour to transcend symptom management and target the underlying disease processes, offering hope for more effective ALS interventions.

New Drug Shows Promise for Motor Neurone Disease Treatment

The recent study conducted by the University of Birmingham and TikoMed AB has demonstrated promising safety and tolerability results for the drug ILB in patients with Amyotrophic Lateral Sclerosis (ALS), a prevalent form of motor neurone disease. This phase II clinical trial involved eleven patients receiving long-term weekly injections of ILB, with the treatment extending up to 38 weeks. The findings revealed that ILB was well tolerated, with minimal side effects, and maintained an acceptable safety profile. Notably, the ALSFRS-R and ALSAQ-40 scores showed minimal changes, suggesting a potential slowing of disease progression in this small cohort.

These results pave the way for a phase IIb multi-centre efficacy trial, marking a significant step forward in ALS research. The study, despite challenges posed by the Covid pandemic, underscores the collaborative efforts between the University of Birmingham and TikoMed AB. Professor Simon Bach and Venkataramanan Srinivasan highlighted the importance of patient participation and the trial's contribution to understanding ILB's potential in managing ALS. This research exemplifies the ongoing commitment to advancing treatment options for motor neurone disease, offering hope for future therapeutic developments.

Riluzole's Mechanism in Treating Hyperexcitable Cells in ALS

The study elucidates the mechanism by which the drug Riluzole, used in treating Amyotrophic Lateral Sclerosis (ALS), stabilises voltage-gated sodium channels (VGSCs) in their inactivated state, thereby reducing hyperexcitability in neurons. Riluzole achieves this by binding within the intramembrane fenestrations of VGSCs, selectively inhibiting the late sodium current (INaL) without blocking the sodium conduction pathway. This unique binding mechanism allows Riluzole to target hyperexcitable cells effectively, offering insights into its potential repurposing for other diseases characterised by elevated INaL.

The research utilises a combination of structural and molecular dynamics simulations to demonstrate Riluzole's interaction with VGSCs, highlighting its ability to normalise pathological INaL levels in disease variants. This study not only advances our understanding of Riluzole's action but also underscores the potential for developing new therapeutics that target specific channel properties without affecting normal cellular functions. The findings pave the way for future drug design aimed at treating a range of hyperexcitability-associated disorders.

Gut Microbiome's Role in ALS: A New Frontier in Research

This study explores the intricate relationship between gut microbiota and short-chain fatty acid (SCFA) production in patients with amyotrophic lateral sclerosis (ALS) shortly after disease onset. The research highlights distinct microbiome characteristics in ALS patients, such as increased Fusobacteria and Acidobacteria, compared to healthy individuals. Although no significant differences in SCFA concentrations were observed, the study suggests that the gut microbiome may influence ALS pathogenesis. The findings underscore the heterogeneity of microbiome constraints in ALS, emphasising the need for personalised approaches in future research to determine whether these differences are causative or consequential.

The study's results contribute to a growing body of evidence indicating the gut microbiome as a promising target for developing novel diagnostic and therapeutic strategies for ALS. By examining the potential relationship between microbiome-derived constraints and SCFA metabolism, the research provides insights into the complex interactions between microbial communities and host physiology. Further investigation is required to elucidate the mechanistic underpinnings of microbiome-host interactions in ALS, potentially leading to more effective dietary and microbiome-targeted interventions.

FGF4 Reduces Astrocyte Activity but Fails to Protect Motor Neurons

The study highlights the potential of FGF4, a growth factor, in reducing the reactivity of astrocytes—star-shaped cells in the brain and spinal cord—associated with amyotrophic lateral sclerosis (ALS). Despite its ability to modulate astrocyte activity, FGF4 does not prevent motor neuron death, a critical aspect of ALS progression. The research underscores the complexity of neuroinflammatory mechanisms in ALS, suggesting that a combination of treatments may be necessary to effectively slow or halt disease progression. The presence of TNF-alpha, a protein that enhances inflammation, was found to negate the benefits of FGF4, indicating the need for further exploration of combination therapies.

The use of human induced pluripotent stem cells (iPSCs) carrying ALS-linked mutations provided a robust model for studying the disease at the cellular level. This approach allows for a detailed examination of astrocyte behaviour and the testing of new therapeutic strategies. The findings emphasise the importance of understanding the intricate interactions between different cell types in ALS, paving the way for future research aimed at developing more effective treatments to enhance neuronal survival and reduce neuroinflammation.