Date: 2014-03-11
Type of information: Production agreement
Compound: adeno-associated viral vector serotype 9 (NAV rAAV9) containing the human sulfamidase gene
Company: Esteve (Spain) Genethon (France)
Therapeutic area: Rare diseases
Type agreement: development
manufacturing
bioproduction
Action mechanism: gene therapy - The investigational gene therapy product consists of the viral NAV rAAV9, licensed from RegenX, which contains a version of the gene that codes for sulfamidase that has been optimized to improve its expression levels. Experimentation using preclinical disease models performed by the CBATEG have validated the potential efficacy of this therapeutic approach. The treatment consists in the administration of gene therapy in the cerebrospinal fluid, the fluid that bathes the brain and spinal cord. The viral vector NAV rAAV9 has the advantage of its high affinity for the brain (main organ affected in this disease) than many of the other adeno-associated viral vectors, is harmless, not being known to cause any disease in humans. For its part, once the gene for the Sulfamidase enzyme reaches the cytoplasm of the neuron, it begins the production of the enzyme. Thus, it is produced enzyme which is secreted into spinal fluid, allowing its distribution throughout the brain and spinal cord and also reaching those neurons in which does not incorporate any viral vector. Furthermore, a small proportion of the gene therapeutic passes from the CSF into the peripheral circulatory system, thereby reaching organs such as the liver where it can enter hepatocytes and subsequently produce and secrete the Sulfamidase enzyme which then distributes throughout the body with the aid of the bloodstream. In the preclinical disease model studied, after administering the gene therapeutic, the levels of Sulfamidase activity significantly increase both in the brain and the rest of the body, the accumulated glycosaminoglycans (substances that build up as a consequence of the disease) are eliminated from within cells, and signs of neuroinflammation disappear. Finally, and most importantly, the behavior is restored and the lifespan is prolonged close to normal.
Disease: mucopolysaccharidosis type IIIA or Sanfilippo syndrome Type A
Details: * On March 11, 2014, the spanish group Esteve has announced the signing of an agreement with the French non for profit organization Généthon. This partneship will enable it to progress the development of its gene therapy for the treatment of mucopolysaccharidosis type IIIA and begin a phase I/II clinical trial in 2015. The agreement with Genethon is for the development of the manufacturing process of the investigational gene therapy product and its production for clinical trial use. The process to be developed will allow the production of the gene therapy product for preclinical toxicology studies, the clinical trial and eventually for commercial use.
This gene therapy program is being developed in a public-private partnership between Esteve and the research team of Dr. Fàtima Bosch at the Center for Biotechnology and Gene Therapy (CBATEG) of the Universitat Autònoma de Barcelona (UAB). The Sanfilippo project is being developed since 2009 within the framework of a public-private partnership between Esteve and the University, aimed at developing gene therapies for the treatment of this syndrome and related diseases called mucopolysaccharidosis. In this partnership, Esteve leads all activities associated with the management and protection of intellectual property, regulatory activities, the coordination and supervision of GMP manufacturing, the preclinical toxicology studies as well as all clinical development. The CBATEG research team at the UAB brings to the partnership their scientific know-how and expertise in gene therapy including viral vector design and the development of preclinical disease models.
At this time the project, which has been granted orphan status by the EMA and the FDA, is in the preclinical development phase, with the manufacturing of early batches expected to begin shortly to support the required preclinical toxicology studies, which, once completed, will allow Esteve to initiate the phase I/II clinical trial in the second half of 2015. The protocol for the clinical trial is in preparation and Esteve is currently working on a draft protocol with 6 patients, pending of final approval by AEMPS, the Spanish Medicines Agency.
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