Focus on Protein Folding Diseases

LSDs are a subset of conformational diseases caused by an inherited error of metabolism affecting various lysosomal functions.

  • GD is one of the largest LSDs, affecting ~15,000 people in the US.
  • There are three types of GD:
    • Type 1 is the adult chronic non-neuronopathic,
    • Type 2 is the infantile, acute neuronopathic
    • Type 3 is the juvenile, sub-acute neuronopathic.
  • Of diagnosed Gaucher Disease patients
    • 90% of the affected population is diagnosed with Type 1 GD,
    • Type 2 & type 3 each account for approximately 5% of GD diagnosis.

 

Gaucher Disease Overview

T1 GD is caused by an accumulation of glucosylceramide and glucosylsphingosine in macrophage lysosomes, due to deficiencies in the activity of a lysosomal enzyme called glucocerebrosidase (Gcase) responsible for the degradation of these compounds:

  • Deficiencies in Gcase are generally due to Gcase mutation.
  • This causes accumulation of glycosylceramide in macrophages and subsequently leads to a spectrum of symptoms.
  • ERTs effectively treat many of the symptoms of T1 GD.

 

T3 GD is very rare (approximately 5% of all GD patients are believed to have T3):

  • Currently, there are no effective treatments for these patients.
  • Most T3 GD patients have very significant cognitive decline by their 18th birthday and the disease typically leads to lack of function before an early death.

 

Gaucher disease is characterized by enlarged liver and spleen, anemia, thrombocytopenia, painful bone lesions, and in some cases, neurological damage.

 

Unmet Clinical Need of Current Therapies FOR T3 GD

Currently available therapeutic strategies for GD are Enzyme Replacement Therapy (ERT), Substrate Depletion or Reduction Therapy (SDT or SRT) and pharmaceutical chaperones:

  • ERTs involve the IV/infused administration of functional recombinant GCase, e.g.,
    • Cerezyme® (imiglucerase)
    • ELELYSO™ (taliglucerase alfa)
    • VPRIV™ (velaglucerase alpha)
  • SDTs involve oral administration of glycosylceramide synthase inhibitor, e.g.,
    • Zavesca™ (miglustat )
    • CERDELGA™ (eliglustat tartrate)
  • PCs such as Ziva assist in the folding of misfolded GCase and facilitate its trafficking from endoplasmic reticulum to lysosomes.

 

Patients with T3 GD have few treatment options and Ziva has potential to be a breakthrough treatment:

  • Unfortunately, each of the ERTs are proteins with limited, if any, access to central nervous system (CNS); therefore, they have little or no efficacy against T3 GD.
  • Miglustat (an approved SDT) has tolerability issues.
  • Monotherapy or combination therapy that includes Ziva may provide promise for treating T3 GD as well as other orphan conditions with neurological symptoms

 

POTENTIAL OPPORTUNITIES BEYOND TYPE 3 GD

Zywie is also evaluating the potential to pursue other indications, including:

  • Type I Gaucher Disease (a substantially larger market than Type 3 GD because there are about 20 times more patients with T1 than with T3 GD)
  • Lewy Body Dementia (a subset of Parkinson’s Disease with significant neurological symptoms)
  • Other subsets of patients with Parkinson’s Disease (which has a similar disease mechanism that is likely to respond to treatment with Ziva).

There’s a significant overlap between Gaucher and Parkinson’s. Please see Publications Section for a large number of both studies and assumptions.