monepantel (NUZ-001) / Neurizon Therapeutics - LARVOL DELTA

INVESTIGATING THE PHARMACOLOGICAL ACTIVITY OF NUZ -001 ON AUTOPHAGY IN THE NSC -34 MOTOR NEURON CELL LINE (ADPD 2025) - "TDP - 43 proteinopathies, including the Q331K mutation, have been strongly implicated in MND pathology, highlighting the importance of investigating autophagy in this context... NSC-34 cells will be treated with various concentrations of NUZ -001 (1 μM, 10 μM, 50 μM), and an autophagy activator Rapamycin for different time points (6, 12, and 24 hours)... NUZ-001 may represent a novel therapeutic approach for MND by modulating autophagy in motor neurons, particularly in TDP -43-related pathology. This study will lay the groundwork for further investigation of NUZ -001's therapeutic potential in preclinical mo dels of MND."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Proteinopathy • Solid Tumor

In vitro analysis of the activities of commercial anthelmintics in the presence of inhibitors of xenobiotic detoxification pathways in Haemonchus contortus exsheathed L3 stage. (PubMed, Parasitol Res) - "To explore this hypothesis, inhibitors of xenobiotic detoxification pathways were tested on the activity (IC50) of four anthelmintics-monepantel (MOP), levamisole (LEV), ivermectin (IVM), and albendazole sulfoxide (ABZ SO)-in xL3 using an automated motility assay. The inhibitors used were piperonyl butoxide (PBO) for phase I metabolism, 5-nitrouracil (5-NU) for phase II metabolism, and zosuquidar (ZOS) inhibiting efflux transport proteins...The use of inhibitors of xenobiotic detoxification pathways led to significant changes in the in vitro activity of the anthelmintics evaluated in H. contortus xL3 stage. Further studies, as ex vivo parasite diffusion assays in the xL3 stage, should be conducted to directly assess the impact on detoxification pathways."

Journal • Preclinical • Infectious Disease

Unraveling anthelmintic targets and mechanisms of action of trans-cinnamaldehyde from cinnamon essential oil. (PubMed, Sci Rep) - "TCA screening of mutant worms lacking Cys-loop receptors reveal multiple receptor targets, including the levamisole-sensitive nicotinic ACh receptor (L-AChR), GABA-activated chloride channel (UNC-49) and glutamate-activated chloride channel...Thus, by acting through a different mechanism to that of classical anthelmintics, TCA may be beneficial to counteract resistance in combined anthelmintic therapies. Our findings underscore the potential of the multitarget compound TCA as a valuable tool in integrated pharmacological strategies."

Journal • Infectious Disease

A systematic review of the molecular mechanisms related to anthelmintic resistance in Haemonchus contortus: A contemporary narrative. (PubMed, Vet Parasitol) - "Additionally, resistance mechanisms to levamisole (LEV) and monepantel are discussed, showing evidence of polymorphisms in genes related to the nicotinic acetylcholine receptors (nAChR)...We suggest that new publications on drug resistance should adopt the approaches and refer to this new era of scientific discoveries. Consistent data interpretation, including artificial intelligence (AI) support, will help us to suggest novel biological mechanisms involved in drug resistance and predict its evolution, allowing a more comprehensible approach toward sustainable parasite control strategies."

Journal • Review • Gastrointestinal Disorder

Neurizon Files IND Application to Support HEALEY ALS Platform Trial (PRNewswire) - "Neurizon...is pleased to announce the filing of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for its lead candidate, NUZ-001. This milestone is a pivotal step in enabling the commencement of a Phase 2/3 clinical trial within the HEALEY ALS Platform Trial framework...Pending FDA clearance of the IND application, Neurizon anticipates Massachusetts General Hospital (MGH) filing a protocol amendment to their IND for the HEALEY ALS Platform Trial to incorporate our regimen specific appendix in Q1 CY2025. Neurizon expects to initiate patient enrollment in the HEALEY ALS Platform Trial in H1 CY2025."

IND • New P2/3 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

Neurizon's NUZ-001 Reduces Aggregation of Key ALS Disease Target TDP-43 in Preclinical Study (PRNewswire) - "The first study evaluated the ability of NUZ-001 and its major active metabolite (NUZ-001 Sulfone) to reduce TDP-43 aggregation in M337V Motor Neurons co-cultured with astrocytes in response to a stressor...The results show NUZ-001 and NUZ-001 Sulfone significantly and dose-dependently reduced TDP-43 aggregation in M337V Motor Neurons treated simultaneously with aggregation stressor MG-132 by ~50% and ~55%, respectively; The second study evaluated the ability of NUZ-001 and NUZ-001 Sulfone to restore the normal electrophysiological function of TDP-43 mutated M337V Motor Neurons...NUZ-001 and NUZ-001 Sulfone rescued the electrical activity of TDP-43 M337V Motor Neurons, by increasing bursting and network burst activity, and reducing inter-burst intervals to wild type Motor Neuron activity levels."

Preclinical • Amyotrophic Lateral Sclerosis

Neurizon Therapeutics Receives Positive Opinion on Orphan Medicinal Product Designation for NUZ-001 in Europe (PRNewswire) - "Neurizon Therapeutics Limited...is pleased to announce it has received notice of a positive opinion from the European Medicines Agency (EMA) for Orphan Medicinal Product Designation (OMPD) following its application for its lead drug candidate, NUZ-001, for the treatment of Amyotrophic Lateral Sclerosis (ALS). The European Commission is scheduled to issue the official decision on the Orphan Designation in December...Neurizon is advancing NUZ-001 through a Phase 2/3 clinical study as part of the HEALEY ALS Platform Trial, with patient enrolment expected to commence in early H1 CY2025."

New P2/3 trial • Orphan drug • Amyotrophic Lateral Sclerosis • CNS Disorders

Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23. (PubMed, EMBO J) - "Although the pore remains closed in betaine-bound state, monepantel binding results in an open channel by wedging into the cleft between the transmembrane domains of two neighboring subunits, which causes dilation of the ion conduction pore. By combining structural analyses with site-directed mutagenesis, electrophysiology and in vivo locomotion assays, we provide insights into the mechanism of action of the anthelmintics monepantel and betaine."

Journal

High rates of benzimidazole-resistance-associated alleles in Haemonchus contortus and detection of resistance against macrocyclic lactones in strongylids from German alpaca herds. (PubMed, Parasit Vectors) - "However, the generally low egg counts in SACs complicate the application of resistance tests in the field...A FECRT was performed on six of these farms with moxidectin (three farms), monepantel (two farms) and ivermectin (one farm)...This study showed an advanced level of BZ resistance in H. contortus of SACs and the development of AR against macrocyclic lactones on some farms. Thus, constant monitoring of AH treatment and sustainable worm control methods both need to be applied."

Journal • Infectious Disease

Interaction between bacterial microbiota and nematode parasite communities in sheep's gastrointestinal tract. (PubMed, PLoS One) - "The aims of this work were to investigate the impact of the oxytetracycline-mediated manipulation of the gut microbial community on the composition of GI nematode populations in naturally infected sheep and to explore changes in the GI microbial communities after nematode population treatment with the anthelmintic compound monepantel...While a comprehensive evaluation of the interactions among GI mycoplasma, methanobacteria and nematode populations deserves further assessment, the bacteria-nematode population interactions should be included in future control programs in livestock production. Understanding how bacteria and parasites may influence each other in the GI tract environment may substantially contribute to the knowledge of the role of microbiota composition in nematode parasite establishment and the role of the parasites in the microbiota composition."

Journal • Gastrointestinal Disorder • Infectious Disease

Role of the Abcg2 transporter in plasma, milk, and tissue levels of the anthelmintic monepantel in mice. (PubMed, Chem Biol Interact) - "Finally, despite the lack of a difference between groups, we investigated potential differences in MNP and MNPSO2's plasma and tissue accumulation levels between wild-type and Abcg2-/- male mice. In this study, we demonstrated that MNPSO2 milk levels were affected by Abcg2, with potential pharmacological and toxicological consequences, contributing to the undesirable xenobiotic residues in milk."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • ABCG2

PharmAust set to transform MND therapy landscape as monepantel receives FDA orphan drug designation (Small Caps) - "PharmAust...has achieved a major breakthrough in plans to commercialise its monepantel (MPL) treatment for motor neurone disease with the receipt of an orphan drug designation (ODD) from the US Food and Drug Administration (FDA)....Amyotrophic lateral sclerosis (ALS) is a subtype of MND....'We are now increasingly optimistic as we progress to our pivotal registration adaptive Phase 2/3 study, which will commence in H2 CY2024.'...PharmAust’s application to the FDA was based on preclinical mechanistic data that demonstrates MPL can induce autophagy in diseased cells, considering the pathology of the disease."

New P2/3 trial • Orphan drug • Amyotrophic Lateral Sclerosis • CNS Disorders

Faecal egg count reduction tests and nemabiome analysis reveal high frequency of multi-resistant parasites on sheep farms in north-east Germany involving multiple strongyle parasite species. (PubMed, Int J Parasitol Drugs Drug Resist) - "Here, the faecal egg count reduction test (FECRT) was performed on eight farms using fenbendazole, ivermectin and moxidectin and on four farms using only moxidectin...Nematode species composition in pre- and post-treatment samples was analysed with the nemabiome approach...Resistance against both drug classes on the same farm was common. Further studies including additional drugs (levamisole, monepantel, closantel) should combine sensitive FECRTs with nemabiome data to comprehensively characterise the anthelmintic susceptibility status of sheep nematodes in Germany."

Journal • Gastrointestinal Disorder

PharmAust eyes FDA orphan drug designation for monepantel after positive MND/ALS trial results (Small Caps) - "...PharmAust...has filed supplementary positive data from a Phase 1 MEND trial of lead drug monepantel with the US Food and Drug Administration’s (FDA) Office of Orphan Products Development. The data was packaged as a formal amendment to an orphan drug designation request submitted in November for monepantel in the treatment of motor neurone disease (MND) and amyotrophic lateral sclerosis (ALS)."

FDA event • Amyotrophic Lateral Sclerosis • CNS Disorders

Revisiting anthelmintic resistance in sheep flocks from São Paulo State, Brazil. (PubMed, Int J Parasitol Drugs Drug Resist) - "In each one of the 15 flocks evaluated, animals (n ≥ 7) were allocated into at least five groups and treated as follows: 1) untreated control; 2) albendazole; 3) levamisole; 4) ivermectin; and 5) monepantel...Only in two farms, levamisole presented a relatively high percentage of reduction in the FECRT about 90%, while ivermectin and moxidectin presented the worst mean efficacy of 34% and 21% among all farms, respectively...The research suggests that nematodes are becoming more and more resistant to various anthelmintic compounds, which has made the problem worse. This circumstance highlights the necessity to put into practice sustainable and long-lasting methods to prevent gastrointestinal nematode infections in sheep husbandry."

Journal • Gastrointestinal Disorder • Infectious Disease

PharmAust’s monepantel study shows 58% slowdown in MND progression (Small Caps) - P1 | N=12 | NCT04894240 | Sponsor: PharmAust Ltd | "A Phase 1 trial into the effects of lead candidate monepantel (MPL) on patients with motor neurone disease MND / amyotrophic lateral sclerosis (ALS) has delivered top-line results for clinical-stage biotech PharmAust (ASX: PAA)....Preliminary efficacy data showed a 58% reduction in the rate of disease progression for Cohort 2 using the US Food and Drug Administration’s (FDA) primary efficacy endpoint ALS functional rating scale-revised (ALSFRS-R)....The Phase 1 study showed that MPL displays superior safety and tolerability compared to the leading FDA-approved drug Relyvrio, which is a prescription oral therapy for adults living with ALS and has been shown to help slow disease progression."

P1 data • Amyotrophic Lateral Sclerosis • CNS Disorders

Concurrent use of two dual-combination drenches containing monepantel/abamectin and oxfendazole/levamisole in sheep: effect on marker residues 21 and 28 days after administration. (PubMed, N Z Vet J) - "To determine the concentration, in comparison with the maximum residue limit (MRL), of anthelmintic marker residues in the target tissues (liver and fat) of sheep treated concurrently with two oral drenches, one containing monepantel and abamectin and the other oxfendazole and levamisole. These results suggest that concurrent administration of Zolvix Plus and Scanda to sheep is unlikely to result in an extended residue profile for any of the active ingredients, with all analytes measured being under the approved New Zealand MRL 21 days after treatment. This work was not completed in line with guidance for establishing official residue profiles, nor is it sufficient to propose a new withholding period."

Journal

An Open Label Extension Study of Monepantel in Individuals With Motor Neurone Disease (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: PharmAust Ltd | Not yet recruiting ➔ Recruiting

Enrollment open • Amyotrophic Lateral Sclerosis

A Study of Monepantel in Individuals With Motor Neurone Disease (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: PharmAust Ltd | Recruiting ➔ Completed | Trial completion date: May 2023 ➔ Nov 2023 | Trial primary completion date: Dec 2022 ➔ Nov 2023

Trial completion • Trial completion date • Trial primary completion date • Amyotrophic Lateral Sclerosis

An Open Label Extension Study of Monepantel in Individuals With Motor Neurone Disease (clinicaltrials.gov) - P1 | N=12 | Not yet recruiting | Sponsor: PharmAust Ltd

New P1 trial • Amyotrophic Lateral Sclerosis

Simultaneous resistance to multiple anthelmintic classes in nematode parasites of cattle in New Zealand. (PubMed, Vet Parasitol) - "Faecal egg count reduction tests involved 15 animals per treatment group, individual egg counts (paired samples) conducted pre- and post-treatment, with eggs counted to ≤ 15 eggs per g faeces and larval cultures for morphological identification. The results clearly demonstrate the emergence of simultaneous resistance to oxfendazole, levamisole and the macrocyclic lactone anthelmintics. Despite years of advice and recommendations to change farming practices away from intensive monocultures, many farmers have continued with the practice, and some are now faced with the very real possibility of being unable to control cattle parasites on their farms."

Journal

PharmAust completes dosing in phase one MND trial (The Market Herald) - "PharmAust...has completed dosing all patients in cohort four of its phase one MEND study using monepantel (MPL) at 10 milligrams per kilogram to treat Motor Neurone Disease (MND)....The company reported it will use the results, which have been collected over 12 months, to support orphan drug designation (ODD) and to open an investigational new drug (IND) application. These processes await approval from the United States Food and Drug Administration (FDA) in order for Pharmaust to commence a phase two study in the first half of the 2024 calendar year....PharmAust expects to begin the OLE study early in the new year to conduct a second round of 12-month analysis. Meanwhile, patients from phase one will undergo a final follow-up appointment before data is collated for release early next year."

New P2 trial • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders

PharmAust’s interim Phase 1 data suggests MPL may inhibit motor neurone disease (Small Caps) - P1 | N=12 | NCT04894240 | Sponsor: PharmAust Ltd | "An interim analysis of data from a Phase 1 clinical trial of PharmAust’s...lead drug candidate monepantel (MPL) has shown that neurofilament light chain (Nfl) protein concentrations in patient plasma do not increase following treatment....Research suggests a correlation between an increase in Nfl and the progression of motor neurone disease however only one patient over three cohorts was reported to have shown any increase over a 10-month period. The remaining 11 patients displayed no significant change in Nfl, which is believed to correspond to a stabilised progression of MND."

P1 data • CNS Disorders

Establishment and application of unbiased in vitro drug screening assays for the identification of compounds against Echinococcus granulosus sensu stricto. (PubMed, PLoS Negl Trop Dis) - "The standard drugs albendazole, buparvaquone, mefloquine, MMV665807, monepantel, niclosamide and nitazoxanide were included...Similar results were observed for both species with praziquantel and its enantiomers against protoscoleces. In conclusion, in vitro culture techniques and drug screening methods previously established for E. multilocularis were successfully implemented for E. granulosus s.s., allowing comparisons of drug efficacy between the two species. This study provides in vitro culture techniques for the reliable generation of E. granulosus s.s. metacestode vesicles and GL cell cultures and describes the validation of standardized in vitro drug screening methods for E. granulosus s.s."

Journal • Preclinical

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