Manufacture of an intracerebroventricular Enzyme Replacement Therapy for CLN1 Batten Disease

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Summary The neuronal ceroid lipofuscinoses (NCLs) are a group of incurable neurodegenerative storage disorders primarily affecting the brain and the retina of children and young adults, leading to dementia, blindness, epilepsy, and early death, with a prevalence of approximately 1.5 to nine per million population (1.3 to 7 per 100,000 live births). The infantile onset form CLN1 disease is caused by mutations in the CLN1/PPT1 gene, which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) resulting in a reduction or absence of enzyme activity. CLN1 disease usually presents between 6 and 24 months of age and there are 2-3 children with this form identified each year and currently 24 known children with CLN1 in the US and 11 in Brazil (with likely many more undiagnosed). There are currently no treatments available other than palliative therapies and the disease is fatal. Human recombinant PPT1 (rhPPT1) expressed in CHO cells has been previously reported to modify disease phenotypes following a single intrathecal (IT) and intravenous (IV) administration in PPT1 deficient mice (Ppt1-/-). After successful completion of our Phase I SBIR in which we met or exceeded our milestones IT, intracerebroventricular (ICV) as well as combined routes of delivery were compared. We demonstrated that monthly administration of rhPPT1 via ICV produced statistically significant treatment effects in Ppt1-/- mice, such as rescue of more than 60% PPT1 enzyme activity decreased secondary enzyme levels, decreased the loss of neurons in all regions of brain and spinal cord and improved gait and rotarod results. This also illustrated that delivery of enzyme via this route alone may be sufficient rather than using in combination with IT dosing. We have now developed our own PPT1 cell line using CHO-DG44, that is scalable for GMP manufacture and performed initial purification development strategies and we are developing a diagnostic tool for CLN1. The CLN1 ERT data clearly points to ICV dosing as ideal for future studies, which is also a preferred route according to physicians. Collaborations Pharmaceuticals, Inc (CPI) now proposes in this Phase II SBIR to file a preIND (with the assistance of RTI International and Foresight Biosciences), perform manufacturing of PPT1 (with the assistance of Goodwin Biotechnology, Inc. and CMC consultant Dr. Stefan Proniuk), conduct rat and dog IND enabling toxicology studies (with the assistance of Charles River Laboratories) and ultimately filing an IND (with the assistance of RTI International and Foresight Biosciences). We will hire these experienced consultants and clinical research organizations to assist us throughout the process as they have years of experience. These collaborations will enable us to cost effectively and more rapidly translate this potential treatment to the clinic that can potentially save the lives of children living with this devastating disease. We have already obtained an Orphan Drug Designation and rare pediatric disease designation from the FDA for rhPPT1 as a biological product for a “rare pediatric disease” which offers several benefits in future upon FDA approval, including marketing exclusivity for 7 years and the potential to obtain a rare pediatric disease voucher and thus provide a return on investment (current value ~$100 M). We are engaged with CLN1 families communicating with them frequently to provide progress updates and we are now well positioned to continue the development of this potential treatment for a devastating disease. There is an important role to bring treatments to patients with ultra-rare diseases as illustrated by other companies such as Biomarin and Ultragenyx. Our work on developing rhPPT1 as an ERT for CLN1 would position us well to work on further rare diseases in future and grow CPI.