ODIPARCIL

English

Odiparcil is an orally administered, small molecule with the potential to become the first substrate reduction therapy in several subtypes of mucopolysacharidosis (MPS). In MPS, deficient lysosomal enzymes cause the accumulation of glycosaminoglycans (GAGs) in the lysosomes leading to the development of various serious somatic and neurologic symptoms.

Initially developed for the prevention of thrombosis after surgery, odiparcil induces the production of soluble circulating dermatan sulfate (DS) and chondroitin sulfate (CS), two GAGs inhibiting thrombus formation without causing bleeding. The same GAGs are accumulated in MPS VI and VII and either CS or DS are accumulated in MPS I, II and IVA.

ODIPARCIL IN MUCOPOLYSACHARIDOSIS TYPE VI (MPS VI)

In arylsulfatase B mutant mice, a relevant model for mucopolysacharidosis type VI (MPS VI), odiparcil showed to increase urinary GAG levels in a dose-dependent manner, in line with the mechanism described in the section above.

In addition, there were consistent reductions in GAG levels in tissues and organs relevant to the human disease. More precisely, odiparcil decreased GAG accumulation in the cornea, restored corneal structure, decreased GAG accumulation in cartilage and improved mobility. These observed effects are particularly important as these organs are affected in MPS VI patients where current treatment have no or poor efficacy. 
 
Furthermore, distribution and exposure data generated in mice and rats indicate that the concentration levels reached in the heart, bones, cartilage and eyes are sufficient for the reduction of intracellular GAG content. 
 
Source: Inventiva S.A. proprietary data
 
Source: Inventiva S.A. proprietary data

 

Odiparcil also decreased the intracellular levels of GAGs in leukocytes in vivo in a MPS VI mouse model as well as in vitro in MPS VI patients’ fibroblasts
 

Source: Inventiva S.A. proprietary data

Odiparcil has received orphan drug designation for MPS VI in the USA and the EU and is currently being tested in a Phase IIa clinical trial in adult MPS VI patients, the iMProveS trial. Headline results are expected for the second half of 2019.

Read more on MPS here.

PRECLINICAL IN VIVO SAFETY DATA OF ODIPARCIL

The observed pharmacological active dose of odiparcil in the animal model described in the section above corresponds to a concentration in vitro which leads to a reduction of intracellular GAG levels but not to their complete depletion. Accordingly, the observed pharmacological active dose results in an exposure that was shown to be safe in preclinical in vivo toxicology studies in mice, rats and monkeys (up to 52 weeks) and was also shown to be safe in adults during clinical studies (approx. 1800 healthy volunteers and patients exposed for up to 16 weeks).