nizubaglustat (AZ-3102) / Azafaros - LARVOL DELTA

A Study to Evaluate the Safety and Efficacy of Oral Nizubaglustat (AZ-3102) in Late-infantile and Juvenile Forms of GM1 Gangliosidosis or GM2 Gangliosidosis (clinicaltrials.gov) - P3 | N=75 | Recruiting | Sponsor: Azafaros A.G.

New P3 trial • Genetic Disorders • Lysosomal Storage Diseases

A Study to Evaluate the Safety and Efficacy of Oral Nizubaglustat (AZ-3102) in Late-infantile and Juvenile Forms of Niemann-Pick Type C Disease (NPC) (clinicaltrials.gov) - P3 | N=72 | Recruiting | Sponsor: Azafaros A.G.

New P3 trial • Genetic Disorders • Lysosomal Storage Diseases

A Study to Evaluate the Safety and Efficacy of Oral Nizubaglustat (AZ-3102) in Late-infantile and Juvenile Forms of Niemann-Pick Type C Disease, GM1 Gangliosidosis or GM2 Gangliosidosis (clinicaltrials.gov) - P3 | N=147 | Recruiting | Sponsor: Azafaros A.G. | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Lysosomal Storage Diseases

A Study to Evaluate the Safety and Efficacy of Oral Nizubaglustat (AZ-3102) in Late-infantile and Juvenile Forms of Niemann-Pick Type C Disease, GM1 Gangliosidosis or GM2 Gangliosidosis (clinicaltrials.gov) - P3 | N=147 | Not yet recruiting | Sponsor: Azafaros A.G.

New P3 trial • Genetic Disorders • Lysosomal Storage Diseases

RAINBOW: Phase 2 Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral AZ-3102 in Patients with GM2 Gangliosidosis or Niemann-Pick Type C Disease (clinicaltrials.gov) - P2 | N=13 | Active, not recruiting | Sponsor: Azafaros A.G. | Trial completion date: Dec 2024 ➔ Mar 2026

Trial completion date • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Azafaros granted important regulatory designations and clearance by European authorities for global Phase 3 studies, to be initiated in 2025 (Businesswire) - "Azafaros B.V. today announced that its lead asset, nizubaglustat, has been granted orphan drug designation from regulatory authorities in both the United States and the European Union for the treatment of GM1 gangliosidosis. Additionally, the company’s Clinical Trial Application (CTA) for two global Phase 3 studies investigating the drug’s efficacy and safety in GM1/GM2 gangliosidoses and Niemann-Pick Type C (NPC) was approved by multiple European countries. Azafaros expects to initiate the two global trials in Q2, 2025."

New P3 trial • Orphan drug • Lysosomal Storage Diseases • Metabolic Disorders

Structural insights into the inhibition mechanism of glucosidase inhibitors toward kojibiose hydrolase belonging to the glycoside hydrolase family 65. (PubMed, Biosci Biotechnol Biochem) - "Compared with the glucose-complex structure, the conformation of Tyr337 was changed in the CSP-complex structure. These results provide new structural insights into the mechanism of inhibition against GH65 α-glucoside hydrolases."

Journal

BLINDED SAFETY DATA OF NIZUBAGLUSTAT PHASE 2 STUDY FOR GM2 GANGLIOSIDOSIS AND NPC DISEASE (SSIEM 2024) - "Background: Nizubaglustat (AZ-3102) is an orally available, brain-penetrant, highly potent, highly selective inhibitor of glucosylceramide synthase and non-lysosomal neutral glucosylceramidase...Also had to be miglustat naïve or stop it for safety/tolerability issues at least 1 month before baseline... Nizubaglustat was safe and well tolerated in treated GM2/NPC patients. In line with previous studies, it was not associated with gastrointestinal AE. Safety profile and clinical impact will be assessed during the extension phase."

Clinical • P2 data • CNS Disorders • Epilepsy • Gastrointestinal Disorder • Genetic Disorders • Lysosomal Storage Diseases

Coumarin-azasugar-benzyl conjugates as non-neurotoxic dual inhibitors of butyrylcholinesterase and cancer cell growth. (PubMed, Org Biomol Chem) - "Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC50 = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI50 = 5.6 ± 1.1 μM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity."

Journal • Alzheimer's Disease • CNS Disorders • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pain • Solid Tumor

Protein engineering of transaminase facilitating enzyme cascade reaction for the biosynthesis of azasugars. (PubMed, iScience) - "Molecular dynamics (MD) simulations revealed that the mutation sites of H69R and K145R in M9-1 played crucial roles in the binding of the amino acceptor and donor, leading to the stable conformation of substrates within the active pocket. An enzyme cascade reaction was developed using M9-1 and the dehydrogenase from Paenibacillus polymyxa (GutB1) for the production of mannojirimycin (MJ), which provided a new idea for the in vitro biosynthesis of 1-DNJ."

Journal

Synthesis and bio-evaluation of newer dihydropyridines and tetrahydropyridines based glycomimetic azasugars. (PubMed, Bioorg Chem) - "Majority of the screened compounds displayed excellent inhibition with IC50 values ranging from 2.12 to 75.11 μM, when compared to the standard drug Acarbose. Their specific binding patterns have been analysed with the binding sites of Saccharomyces cerevisiae α-glucosidase. These findings suggest these candidates as the potential leads for the anti-diabetic activity."

Journal • Diabetes • Metabolic Disorders

Role of the thiosugar ring in the inhibitory activity of salacinol, a potent natural α-glucosidase inhibitor. (PubMed, RSC Adv) - "Herein, ring-cleaved (24) and truncated (25) analogues of an azasugar, 1-deoxynojirimycin (23), exhibited inhibitory activity (Ki = 4-10 μM) equal to that of the parent compound (1, Ki = 14 μM)...Bioassay results revealed that all the synthetics were inactive, indicating that the 5-membered thiosugar ring of 1 played an essential role in the potent activities of sulfonium-type inhibitors. The present findings are interesting and important in understanding the function of salacinol, considering that the observed inhibitory activity trend was contrary to the SAR observed in aza-compounds (23, 24, and 25) in a previous study, which suggested that the cyclic structure did not contribute to their strong inhibitory activity."

Journal

First-in-human single-dose study of nizubaglustat, a dual inhibitor of ceramide glucosyltransferase and non-lysosomal glucosylceramidase: Safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses in healthy adults. (PubMed, Mol Genet Metab) - "Only treatment-emergent adverse events with preferred terms belonging to the system organ class skin and subcutaneous disorders of mild intensity were reported as drug-related in the nizubaglustat arm, in line with the pharmacological mechanism targeting glucosylceramide metabolism. Taken together, these data support QD dosing of nizubaglustat and its ongoing development in patients with primary and secondary forms of gangliosidoses."

Journal • P1 data • PK/PD data • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

RAINBOW: Phase 2 Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral AZ-3102 in Patients With GM2 Gangliosidosis or Niemann-Pick Type C Disease (clinicaltrials.gov) - P2 | N=13 | Active, not recruiting | Sponsor: Azafaros A.G. | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2023 ➔ Dec 2024 | Trial primary completion date: Oct 2023 ➔ Mar 2024

Enrollment closed • Trial completion date • Trial primary completion date • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

Potent and Selective Cell-Active Iminosugar Inhibitors of Human α-N-Acetylgalactosaminidase (α-NAGAL). (PubMed, Chemistry) - "Moreover, in vitro and in cell assays to assess levels of lysosomal b-hexosaminidase substrate ganglioside GM2 show that DGJGuan is selective whereas DGJNAc exhibits off-target inhibition both in vitro and within cells. DGJNGuan is a readily produced and selective tool compound that should prove useful for investigating the physiological roles of α-NAGAL."

Journal • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Mono- and three-tailed sugar and iminosugar decorated benzenesulfonamide carbonic anhydrase inhibitors. (PubMed, Org Biomol Chem) - "A collection of novel mono- and three-tailed derivatives based on a sugar (glucose) or an iminosugar (trihydroxy piperidine) featuring a terminal benzenesulfonamide were synthesized to investigate the so-called "sugar" and "azasugar" approach with the aim of exploring the activity and selectivity towards the inhibition of human carbonic anhydrases (hCAs)...Among the sugar-based inhibitors, the single-tailed compound 10 was identified as a better inhibitor than the reference compound (AAZ) towards three different hCAs, while, among the three sugar tailed derivatives, potent and selective inhibition was found for compounds 25 and 26. A promising and selective inhibitory activity was discovered for the iminosugar single-tailed compound 31 towards hCA VII (Ki = 9.7 nM)."

Journal

RAINBOW: Phase 2 Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral AZ-3102 in Patients With GM2 Gangliosidosis or Niemann-Pick Type C Disease (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: Azafaros A.G. | Not yet recruiting ➔ Recruiting

Enrollment open • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders

RAINBOW: Phase 2 Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral AZ-3102 in Patients With GM2 Gangliosidosis or Niemann-Pick Type C Disease (clinicaltrials.gov) - P2 | N=12 | Not yet recruiting | Sponsor: Azafaros A.G.

New P2 trial • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders