Our lead program AZ-3102 in lysosomal storage disorders

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.

Our clinical program with AZ-3102 for the treatment of GM1 and GM2 Gangliosidoses

In recent years, data has emerged supporting 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).

Azafaros’ proprietary clinical candidate AZ 3102 is an orally available low-molecular weight azasugar, originally based on discoveries from Leiden University and Amsterdam University Medical Center. It is designed to selectively inhibit two enzymes involved in glycolipid metabolism, called glucosylceramide synthase (GCS) and non-lysosomal neutral glucosylceramidase (GbA2). This dual mode of action aims to reduce toxic glycolipid accumulation and ameliorate impaired lysosomal functions, two key factors driving the neuromotor defects caused by lysosomal storage disorders. As an initial validation of AZ-3102’s potential, Azafaros has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for AZ-3102 in GM2 Gangliosidosis.

AZ-3102 has advanced through a double-blind, placebo-controlled Phase 1 study evaluating the safety and tolerability of ascending single- (SAD) and multiple-doses (MAD) of AZ-3102 in healthy subjects. The results, presented at the 18th Annual WORLDSymposium™ in February 2022, show a positive safety profile and provide the first clinical proof of the compound’s dual mechanism of action, strongly supporting AZ-3102’s potential as a disease-modifying treatment option for children living with GM1 and GM2 Gangliosidoses. Azafaros is committed to an accelerated development for AZ-3102, with a Phase 2 pivotal study planned to initiate by the end of 2022.

AZ-3102’s potential in other lysosomal storage disorders

Based on promising preclinical data in a Niemann-Pick disease type C mouse model showing reduction of tremor levels and sparing of cerebellar Purkinje cell depletion, two hallmarks in the untreated disease model, and supported by the Orphan Drug Designation we received from the FDA, we plan to advance AZ-3102 as a potential disease-modifying treatment for Niemann-Pick type C disease.

Niemann-Pick Type C

Niemann-Pick type c disease (NP-C) is caused by mutations in the NPC1 gene (NPC type 1C) or the NPC2 gene (NPC type 2C) and is inherited in an autosomal recessive manner. NP-C is a fatal genetic lysosomal storage disorder due to the abnormal function of proteins which regulate the transport of cholesterol from the lysosome to cytoplasm of the cells in numerous organs, including the liver, the spleen, the lungs and the brain. In the brain, the intracellular accumulation of cholesterol contributes to the accumulation of glycosphingolipids, similar to GM2 Gangliosidosis.

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 further expand our pipeline into another family of rare metabolic indications.