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

A Human iPSC-Based Platform for Functional and Molecular Evaluation of ALS Therapeutics Targeting TDP-43 Pathology (Neuroscience 2025) - "Collectively, these results underscore the predictive power of Ncardia's iPSC-based ALS platform for evaluating therapeutic compounds targeting TDP-43. The integration of molecular, cellular, and functional endpoints in a human-relevant system enhances translational value and provides a powerful tool for advancing ALS drug discovery."

Amyotrophic Lateral Sclerosis • CNS Disorders • STMN2 • TARDBP

Leveraging external controls from PRO-ACT for exploratory efficacy assessment in Early-Phase ALS trials (ALS-MND 2025) - "However, the use of ECs is methodologically complex due to potential heterogeneity between trial participants and external data sources... This study highlights the potential of using ECs derived from the PRO-ACT database to enhance exploratory efficacy assessment in single-arm early-phase ALS trials. While challenges remain, especially in mitigating unmeasured confounding, PS-based methods provide a viable framework for comparative analysis in the absence of randomization. These findings support the integration of EC methodologies in early-phase ALS trial designs to better inform clinical development strategies."

Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Using the new guideline for diagnosing anthelmintic resistance of gastrointestinal nematodes to different chemical components in sheep in the Rio Grande do Norte State, Brazil. (PubMed, Rev Bras Parasitol Vet) - "The faecal egg count reduction test (FECRT) was carried out to evaluate the pre- and post-treatment of anthelmintics, including albendazole, closantel, disophenol, ivermectin, levamisole, monepantel, moxidectin and trichlorfon, using the new classification criteria to analyze the results of an FECRT, which defined three possible classifications: susceptible, resistant and inconclusive...Two drugs (trichlorfon and monepantel) proved to be highly effective in treating gastrointestinal nematodes, presenting CI varying from 98 to 100% and 97 to 100%, respectively. Gastrointestinal nematodes from sheep raised in the in the Rio Grande do Norte State, Brazil are susceptible to the active principles trichlorfon and monepantel."

Journal

Neurizon Therapeutics Limited announced that the U.S. FDA has lifted the clinical hold on its investigational drug, NUZ-001… (TipRanks) - "This clearance allows Neurizon to proceed with the Phase 2/3 development of NUZ-001 as part of the HEALEY ALS Platform Trial, expected to start in Q4 2025."

FDA event • New P2/3 trial • Amyotrophic Lateral Sclerosis

PHASE 1 OPEN LABEL EXTENSION STUDY OF AN MTOR INHIBITOR IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS (PACTALS 2025) - "Here, we investigate the long-term safety, tolerability, and efficacy of orally administered NUZ-001 in up to 12 evaluable subjects with ALS who previously completed the Phase 1 MON-2021- 001 Study The Phase 1 open-label extension study was a multicenter study of NUZ-001 administered orally for a duration of 12 months to up to 12 evaluable subjects with ALS. The following were assessed during the study: long-term safety and tolerability, efficacy (ALS Functional Rating Scale–Revised, ALSSQOL-R Quality of Life Questionnaire, Edinburgh Cognitive and Behavioural ALS Screen [ECAS], seated Slow Vital Capacity [SVC]), and biomarker measures (plasma and CSF neurofilament/light chain [NfL] and urinary p75ECD levels)."

Clinical • P1 data • Amyotrophic Lateral Sclerosis • CNS Disorders • NEFL • Plasma NfL • TARDBP

FDA Extends Review Timeline for Neurizon’s NUZ-001 Clinical Hold Response (finnewsnetwork) - "The FDA’s decision is now anticipated by October 3, 2025."

FDA event • Amyotrophic Lateral Sclerosis

Neurizon’s ALS drug shows safety and extended survival in open-label extension study (The Australian) - "Slow Vital Capacity (SVC) decline is a validated marker of disease progression and survival in ALS. In the OLE study, the mean vital capacity per cent predicted (VC PP) at baseline 72.4% and this declined gradually to 62.3% after 12 months....Biomarker data supported these findings, with plasma NfL (neurofilament light) levels staying mostly stable over 12 months and urinary p75ECD falling by about 17%."

Clinical data • Amyotrophic Lateral Sclerosis

Old world camels in Germany: parasitic nematode communities characterized by nemabiome analysis showed reduced anthelmintic efficacy according to the fecal egg count reduction test. (PubMed, Parasit Vectors) - "This study shows the insufficient efficacy of standard treatments chosen by farmers/veterinarians for OWCs in Germany. Since treatment eliminated some species but did not eliminate others, not underdosing but resistant nematode species presumably led to treatment failure. However, owing to the small sample size, assessment of animal weight only by visual estimation, and no drugs licensed for OWCs in Europe, the term resistance should be used with care. The species T. colubriformis and H. contortus that survived after anthelmintic treatment are also frequently resistant in ruminants in Germany."

Journal

Neurizon Therapeutics Advances ALS Drug with FDA Submission (TipRanks) - "Neurizon Therapeutics Limited has submitted a formal response to the FDA to address the clinical hold on its investigational drug, NUZ-001, intended for ALS treatment. This submission includes new pharmacokinetic data from animal studies, demonstrating significant safety margins and supporting dose selection for further clinical evaluation. The FDA’s review is expected to conclude within 30 days, and Neurizon aims to participate in the HEALEY ALS Platform Trial by Q4 2025, contingent upon regulatory clearance. This development marks a critical step in advancing NUZ-001 as a potential first-in-class therapy for ALS, reflecting Neurizon’s commitment to delivering meaningful treatment options ahead of schedule."

FDA event • Amyotrophic Lateral Sclerosis

Neurizon on track to lift FDA clinical hold on ALS drug, eyes Healey trial in Q4 CY25 (The Australian) - "Neurizon Therapeutics has announced it has received positive feedback from the US Food and Drug Administration (FDA) on its strategy to lift the clinical hold on its lead drug NUZ-001. The Company expects to enter the HEALEY amyotrophic lateral sclerosis (ALS) platform trial in Q4 CY25....Following recent formal interactions, the FDA has provided positive written feedback to Neurizon Therapeutics (ASX:NUZ) on its strategy of conducting two preclinical pharmacokinetic (PK) studies to lift the clinical hold on NUZ-001. Neurizon has already completed the two PK studies ahead of schedule, enabling continued momentum towards initiating the HEALEY ALS platform trial, a significant ongoing trial in the US aimed at accelerating ALS treatment development....Neurizon anticipates submitting the complete response containing data from these two PK studies to the FDA in the coming weeks as part of the formal hold resolution process."

FDA event • New trial • Amyotrophic Lateral Sclerosis

Neurizon inks global licensing deal with NYSE-listed Elanco (The Australian) - "Neurizon...said the license agreement represents a critical inflection point, further strengthening its strategic outlook for development, manufacturing and potential future commercialisation of NUZ-001...Under the deal Neurizon is granted exclusive global rights to Elanco’s data package and related intellectual property for monepantel to develop and commercialise NUZ-001 and its related compounds for the treatment, palliation, prevention, or cure of neurodegenerative diseases in humans...Elanco will receive total development milestone payments for the initial and subsequent licensed products, indications, or presentations of US$9.75 million and US$5.2m respectively....Elanco will also be eligible for milestone payments of up to US$65m based on sales milestones....Neurizon said the two companies remained focused on finalising a supply agreement, with a follow-up announcement anticipated in H2 CY25."

Licensing / partnership • Amyotrophic Lateral Sclerosis

Neurizon confirms positive results for prospective ALS treatment (Pharmafile) - "Neurizon Therapeutics has announced new preclinical data confirming that NUZ-001 and its active metabolite, NUZ-001 Sulfone, effectively cross the blood-brain barrier (BBB) and reach concentrations in the brain sufficient to reverse toxic TDP-43 protein aggregation – a key driver of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS)...In a rodent pharmacokinetic study, both compounds achieved brain concentrations that closely matched the levels shown to significantly reduce TDP-43 aggregation in patient-derived neurons in vitro. The data provides critical translational validation for NUZ-001’s mechanism of action, reinforcing its therapeutic potential not only in ALS, but also in other TDP-43 proteinopathies such as frontotemporal dementia, Alzheimer’s disease, and limbic predominant age-related TDP-43 encephalopathy."

Preclinical • Amyotrophic Lateral Sclerosis

Positive preclinical data supports potential of Neurizon’s NUZ-001 in Huntington’s disease (The Australian) - "Neurizon Therapeutics...has rolled out new preclinical data demonstrating significant neuroprotective effects of NUZ-001 and its active metabolite NUZ-001 Sulfone, in a zebrafish model of Huntington’s disease....Neuronal cell death was significantly higher in the Htt knockdown group, while treatment with 1 μM and 10 μM NUZ-001, and 10 μM NUZ-001 Sulfone, significantly reduced apoptosis Haemoglobin levels were significantly decreased in the Htt knockdown group but partially restored by both concentrations of NUZ-001 and NUZ-001 Sulfone; and Expression of BDNF transcripts was significantly rescued with 10 μM NUZ-001 and 10 μM NUZ-001 Sulfone."

Preclinical • Huntington's Disease

An Open Label Extension Study of Monepantel in Individuals With Motor Neurone Disease (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Neurizon Therapeutics Limited | Active, not recruiting ➔ Completed

Trial completion • Amyotrophic Lateral Sclerosis

An Open Label Extension Study of Monepantel in Individuals With Motor Neurone Disease (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: Neurizon Therapeutics Limited | Recruiting ➔ Active, not recruiting

Enrollment closed • Amyotrophic Lateral Sclerosis

Neurizon to Present at 4th Annual ALS Drug Development Summit (Neurizon Press Release) - P1| N=NA | "Positive preclinical results in human iPSC-derived motor neuron models of ALS, demonstrating that NUZ-001: Significantly decreased cytoplasmic TDP-43 aggregation; Increased STMN2 protein levels; Activated autophagy (indicated by p62 accumulation and LC3 vesicle formation); Delivered functional neuroprotective effects, including enhanced neurite outgrowth and preserved motor neuron function. Preliminary results from Neurizon’s Phase 1 clinical trial in patients with ALS, confirming that NUZ-001 is well tolerated, with a favourable safety profile and pharmacokinetics, alongside early indications of efficacy and biomarker modulation, supporting continued clinical development as a potential disease-modifying therapy."

P1 data • Preclinical • Amyotrophic Lateral Sclerosis

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