Evaluation of Clinical Outcome Assessment (COA) and Potential Biomarkers to Facilitate Interventional Trial for Mucopolysaccharidosis IIID Patients

Project Summary Sanfilippo disease (mucopolysaccharidosis type III; MPS III) is a devastating neurodegenerative lysosomal storage disorder of childhood whose pathologic features are neurologic: slowing of development, severe behavioral problems, progressive cognitive decline, dementia, and decline in motor skills leading to immobility, unresponsiveness, and death. We have focused on MPS IIID caused by a deficiency of alpha-N- acetylglucosamine-6-sulfatase (GNS). Because MPS IIID is rare (1 in a million) and affects the brain (which is difficult to treat) no cure or treatment is available and there are at least five patients in the USA to our knowledge. Sanfilippo patient organizations have 19 additional cases registered around the world (see letter of support). Dr. Patricia Dickson and Dr. Tsui-Fen Chou (LABioMed) have developed an enzyme replacement treatment (ERT) for MPS IIID. Our strategy proposes to deliver recombinant human alpha-N-acetylglucosamine-6-sulfatase (rhGNS) via intracerebroventricular infusion to effectively treat the underlying causes of the neurologic symptoms that dominate MPS III pathology. ERTs can have a dramatic effect on the quality of life and patient development especially when administered early in developments. There are several examples of successfully commercialized ERT’s (e.g. laronidase (MPS I), idursulfase (MPS II), etc.) and BioMarin recently received approval for an ERT for a form of Batten disease, CLN2. Other ERTs for MPS I, II, and IIIB are in Phase I trials. Both the FDA and investors are familiar with ERT and its commercialization path, which will greatly increase the chances of reaching a clinical trial. LABioMed has filed a US patent on rhGNS and Phoenix Nest, Inc. has licensed it. Our pivotal nonclinical and manufacturing plans are on track. We had a positive interaction with the FDA and got guidance for moving our program into the clinics. In preparation for the interventional study the recommendation was for a thorough natural history study (NHS) in the available patient population with a broad net to capture endpoints that are most likely to predict the clinical benefits in each individual. Since the number of diagnosed patients is small the collected data form each individual would be their own control at the time of intervention, where the patient will receive the recombinant enzyme. Most of the work will be executed by contracted service providers. The clinical trial itself will be conducted at Columbia University under the guidance of Dr. Chung. She has experience with over 10 clinical trials interventional and observational. The clinical protocol was designed by the team at Phoenix Nest with help of KOLs and clinical experts in the MPS III field. We have engaged expert third party clinical service providers to help with the execution, monitoring and data collection. Crucial data collected from the patients on this study will help us develop clinical outcomes that will be tools for measuring the efficacy of our rhGNS therapy and will be primary endpoints on the pivotal study. The success on this trial will put a step closer to executing the pivotal trial to assess the efficacy of our experimental therapy and its commercialization.