MPS are a group of rare, progressive genetic disorders which manifest early in life.
Mucopolysaccharidosis (MPS) is a group of rare genetic disorders characterized by a deficiency of lysosomal enzymes responsible for the normal degradation of glycosaminoglycans (GAGs).
The accumulation of GAGs in the lysosomes of cells is the underlying cause of the symptoms of MPS. GAGs are important for the modulation of cell-to-cell signalling and the maintenance of tissue structure and function. Lysosomes are enclosed sacs of enzymes that break down large molecules, including GAGs, so that they can be passed to other parts of the cell or excreted. Due to genetic mutations, lysosomes in patients with MPS produce deficient versions of the enzymes necessary to break down GAGs. As a result, GAGs accumulate within the lysosomes, causing them to swell and interfere with the ordinary functioning of cells, leading to the symptoms associated with MPS. MPS is categorized by subtypes, depending on the enzyme that is deficient and the corresponding GAGs that accumulate.
Existing therapeutic options for MPS patients aim to improve quality of life, slow disease progression or minimize irreversible damage to tissues and organs. The current standard of care for the treatment of patients with MPS is enzyme replacement therapy, or ERT, which requires weekly infusions and is generally administered in an outpatient hospital setting. ERT has shown limited efficacy in reducing GAG accumulation in poorly vascularized tissues and organs, such as cartilage, or in tissues that are protected by a barrier, such as the eye.
The incidence of MPS VI is estimated to be approximately 1 in 240,000 to 400,000 live births, with variations between countries on account of consanguinity.
The life expectancy of MPS VI patients, if untreated, is approximately 20 years for patients with the severe forms of the disease.
In the recently completed iMProveS phase IIa study odiparcil confirmed its favourable safety profile and demonstrated efficacy in adult MPS VI patients, especially in tissues types not reached by standard of care.
How are mucopolysaccharidoses (MPS) diagnosed?
Most MPS patients are diagnosed as young children. Since MPS are rare diseases with only a few thousand patients worldwide for each subtype, family doctors may not be familiar with the diseases and may initially not find the right diagnosis. New-born screening has only been implemented in very few countries and not for all MPS subtypes.
The doctor will initially test the patient’s urine for its GAG content. If elevated GAG levels are found, the doctor will measure enzyme activity in white blood cells or the skin and eventually confirm the diagnosis by testing the patient’s DNA for genetic changes. As MPS are inherited diseases, screening siblings of MPS patients may help diagnose affected children earlier than they would have been otherwise.
Patient associations can be found in almost all countries where people are affected by MPS. A reference to national MPS societies can be found on the website of the MPS Society (UK).
Odiparcil – Our Solution
Inventiva is developing odiparcil for the treatment of several MPS subtypes. Odiparcil is a small orally available molecule that is well distributed in the body, including in cartilage and the eye, which are tissues that are poorly penetrated by enzyme replacement therapy (ERT).
Odiparcil’s ability to produce two forms of soluble GAGs (dermatan sulfates; chondroitin sulfates), which can be excreted via urine, makes it potentially suited to treating MPS I, II, IVA, VI and VII patients, where these types of GAGs accumulate.
In the recently completed iMProveS phase IIa study odiparcil confirmed its favourable safety profile and demonstrated efficacy in adult MPS VI patients, especially in tissues types not reached by standard of care. As a next step a Phase Ib study with odiparcil in pediatric population with MPS VI is in preparation and is due to start in 2020.