EXR-101 for Late-Onset Tay-Sachs

EXR-202 for Gaucher disease

About Tay-Sachs and EXR-101

About Gaucher Disease and EXR-202


EXR-101 for Late-Onset Tay-Sachs
ExSAR is developing EXR-101 for the treatment of Late-Onset Tay-Sachs (LOTS). EXR-101 is a small molecule pharmacological chaperone that binds to and stabilizes HexosaminidaseA (HexA). EXR-101 has been approved by the Food and Drug Administration (FDA) for other indications, can be administered orally and has shown remarkable efficacy in cell lines derived from LOTS patient fibroblasts. The body of supporting pre-clinical data and ExSAR’s Phase I clinical development plan earned its Investigational New Drug Authorization (IND) and Phase I clinical trial support from the FDA in April and September 2007, respectively. ExSAR has also applied for FDA orphan designation. The Orphan Drug Act grants special status to products by providing a seven year window of market exclusivity and tax incentives. Orphan designation for EXR-101 is currently pending positive clinical outcome.

EXR-202 for Gaucher disease
ExSAR is developing EXR-202 for the treatment of Gaucher disease. As with EXR-101, EXR-202 is also a small molecule pharmacological chaperone that binds to and stabilizes acid beta-glucocerebrosidase (GCase). EXR-202 has been approved by European and other foreign regulatory agencies for use in other indications, can be administered orally and has shown remarkable efficacy in cell lines derived from GCase patient fibroblasts. An IND is currently in preparation and Phase I clinical trial planned for in 2009.

About Tay-Sachs and EXR-101
Tay-Sachs disease is a progressive neurological lysosomal storage disorder resulting from deficiencies in the ability of HexA to catabolize GM2 ganglioside. The excessive neuronal accumulation of GM2 ganglioside is accompanied by progressive neurological deterioration affecting motor, cerebral and spinocerebellar functions. These diseases are rare genetic conditions (<1000 people in the US and Canada) for which there is no effective treatment.

Tay-Sachs is categorized by onset and severity into three clinical-subtypes: Classic Infantile, Juvenile and Late-Onset (also called Adult-Onset). Onset and disease progression is a reflection of lysosomal HexA concentrations and activity. Classic Infantile Tay-Sachs is caused by a null mutation in hexA, the gene that encodes one of the two evolutionarily related HexA subunits. The complete absence of HexA in Classic Infantile Tay-Sachs is associated with the most severe form of the disease. Disease progression is characterized by a rapid and relentless deterioration of mental and physical abilities until death typically by age 3 or 4. Late-Onset Tay-Sachs (LOTS) is caused by a reduction as opposed to complete loss in HexA activity. Pharmacological chaperones may represent a relevant form of therapy provided that some amount of HexA is minimally present as it is with Juvenile Tay-Sachs and LOTS. Initial symptoms of Juvenile and LOTS may include clumsiness, mood alterations, and muscle weakness. As affected individuals age, they may exhibit tremors, muscle twitching, slurred speech, and an inability to coordinate voluntary movements. Approximately 40% of LOTS patients experience significant depression or bipolar disorder. It is believed that progress with a safe and effective treatment for LOTS will facilitate the development of a therapeutic for Juvenile Tay-Sachs.

About Gaucher Disease and EXR-202
Gaucher disease is the most prevalent lysosomal storage disorder, with an estimated incidence of 1 in 40,000–50,000 in the general population and 1:800 among the Ashkenazi Jewish population. Gaucher disease can lead to liver and spleen enlargement, anemia, painful bone lesions and in some cases neurological damage. Gaucher disease results from an accumulation of glucosylceramide in macrophage lysosomes due to deficiencies in the enzymatic activity of lysosomal GCase.

Gaucher disease is further categorized into three clinical subtypes: Type I - Chronic Non-neuronopathic, Type II - Acute Neuronopathic and Type III - Subacute Neuronopathic. The most frequently occurring subtype, Type I, accounts for 98% of affected Ashkenazi Jews and 56% of affected non-Jews. Symptoms of Type I usually appear in adulthood. These include enlarged spleen and liver, anemia, low platelet counts and fractures and bone pain. Patients do not experience the neurological features associated with Types II and III. The clinical severity of Type I is extremely variable, some patients experiencing the full range of symptoms, while others remain asymptomatic throughout most of their lives. Type II symptoms typically appear by three months of age with rapid neurodegeneration, extensive visceral involvement and death before two years of age (typically due to respiratory complications). The clinical presentation in Type II is typically more uniform than that of Type I. Type III symptoms can appear either in infancy or early childhood, with neurological, visceral and bone complications. Although disease severity can vary widely, progression is typically slower than Type II.

The prevalent form of treatment currently available involves enzyme replacement therapy with recombinant GCase (Cerezyme, Genzyme Corporation). We believe that the use of EXR-202 for Gaucher disease patients who respond to the drug may have advantages relative to the use of Cerezyme. Animal studies show that EXR-202 is well distributed throughout the body and can cross the blood brain barrier. Because Cerezyme is a large protein molecule, it is believed to have difficulty penetrating some tissue and cell types. In particular, it is widely believed that Cerezyme is unable to cross the blood brain barrier and thus unlikely to address the neurological symptoms of Type II and Type III Gaucher disease. Cerezyme treatment is inconvenient in that it requires intravenous infusions, typically on a bi-weekly basis. Oral treatment with EXR-202 is more convenient and avoids the health risk of frequent intravenous infusions.

Lysosomal Storage Disorders and Protein Misfolding | Product Pipeline | Clinical Trials
EXR-101 for Late-Onset Tay-Sachs | Tay-Sachs and EXR-101 | EXR-202 for Gaucher disease | Gaucher Disease and EXR-202