Our lead program in GM1 and GM2 gangliosidoses
GM1 and GM2 gangliosidoses are two rare neurogenetic lysosomal storage disorders
Lysosomal storage diseases such as GM1 and GM2 gangliosidoses, Niemann-Pick disease Type C, or Gaucher disease, are a group of rare genetic metabolic disorders caused by lysosomal functional defects. Lysosomes are cellular compartments hosting a variety of enzymes, activators and transporters. Physiologically, lysosomal catalytic enzymes are responsible for the turn-over and degradation of proteins, polysaccharides, nucleic acids or lipids. Failure of the aforementioned enzymes due to genetic mutations, particularly in the central nervous system, results in the pathological accumulation of metabolites, the malfunction of diverse brain cells and neuroinflammation.
GM1 and GM2 gangliosidoses, two rare life-threatening neurogenetic lysosomal storage disorders, are caused by mutations in the genes encoding for β galactosidase 1 and β-hexosaminidase, respectively, two enzymes involved in the metabolism of glycosphingolipids. The resulting enzyme defects lead to accumulation of GM1 or GM2 gangliosides, particularly in the brain, which are the underlying cause of severe symptoms including neurodevelopmental delays, seizures, respiratory infections, loss of vision and hearing, and cognitive dysfunction. For more information on lysosomal storage disorders, please see here.
Due to the hereditary nature of these diseases, they can have very early onset in life with significant risk of premature death of new-borns and young children. They may also affect adolescents and adults. These are diseases for which there is only palliative care.
AZ-3102, our lead clinical program for the treatment of GM1 and GM2 gangliosidoses
In recent years, it appeared that several enzymes involved in glucosylceramide metabolism are relevant targets for the development of therapeutic candidates for neurodegenerative lysosomal storage disorders. Moreover, and in contrast to the scientific dogma of compound selectivity, it is hypothesized that the most eﬀective compounds should inhibit a combination of glucosylceramide processing enzymes (see Ghisaidoobe et al., 2014, J Med Chem).
Our clinical candidate AZ-3102 is a first-in-class, orally available azasugar molecule designed to reach the central nervous system and to interfere with the metabolism of glycosphingolipids and to affect several key disease pathways through a unique and selective dual mode of action with equally potent inhibition of glucosylceramide synthase (GCS) and non-lysosomal glucosylceramidase (GbA2). With this new paradigm, AZ-3102 has the potential to reduce harmful metabolite accumulation and to ameliorate the function of the impaired lysosome. Azafaros’ initial objective with AZ-3102 is to develop a disease-modifying therapy for GM1 and GM2 gangliosidoses.
Currently, our double-blind, placebo-controlled Phase 1 study is evaluating the safety and tolerability of ascending single- (SAD) and multiple-doses (MAD) of AZ-3102 administered orally to healthy subjects. The pharmacokinetics properties of AZ-3102 and its pharmacodynamic effects on specific glycosphingolipid biomarkers, will also be assessed. The results of this study will support establishing the dose levels and dosage regimen suitable for administration to patients in future clinical studies.
AZ-3102 belongs to a library of novel patented compounds discovered by internationally recognized experts in the field, Professor Hans Aerts, PhD, Professor Hermen Overkleeft, PhD, Professor Stan van Boeckel, PhD, and their co-workers currently at the Leiden Institute of Chemistry, Leiden University (see Ghisaidoobe et al., 2014, J Med Chem).
Our drug discovery program
Next to our lead program, we have embarked in a medicinal chemistry drug discovery program with the goal to identify and develop new orally available small molecules to expand our pipeline into another family of rare metabolic indications.