Development of N-tert-(Butyl)hydroxylamine (NtBuHA) as a therapeutic agent for treating Infantile Neuronal Ceroid Lipofuscinosis (INCL)

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PROJECT SUMMARY/ABSTRACT A significant unmet medical need exists for a therapy to treat patients with Infantile Neuronal Ceroid Lipofuscinosis (INCL, or CLN1 Batten Disease.) There are an estimated <1 in 100,000 INCL patients in the United States that have no current disease-treating options. Circumvent Pharmaceuticals has completed key ADME, PK and toxicity studies enabling selection of N-(tert-butyl)-hydroxylamine (NtBuHA)/CIRC825 as a Clinical Candidate. In this SBIR Phase II program, we propose to complete all studies necessary for an Investigational New Drug (IND) application. Components that will be completed include GMP-ready chemistry, clinic-ready formulation, GLP-toxicology with PK/TK, and GLP-safety pharmacology. If successful, CIRC825 will be the first and only option to treat the underlying cause of INCL, and it will change the clinical practice paradigm from palliative/supportive care toward a curative strategy. During our proposed S.A. 1 program, we will identify an optimal synthetic route that is GMP-ready, obtain associated chemical characterizations and stability, and scale up the synthesis to provide sufficient material for an IND-enabling program. Our S.A. 2 program will focus on developing an oral solution formulation owing to the chronic nature of the disease where more invasive modes of daily administration to a pediatric population (e.g., S.Q., I.V., I.T., etc.) are less desirable. In our proposed S.A. 3 program, we plan to complete all GLP-compliant in vitro toxicity and safety pharmacology assays (hERG, Ames, micronucleus in human peripheral blood lymphocytes) that are necessary for applying for an IND. Our proposed S.A. 4 studies will include all in vivo GLP- compliant toxicology studies (MTD with PK/TK) required to file for an IND. S.A. 4 studies will also include all GLP-compliant in vivo safety pharmacology and genotoxicity studies that will be required to file for an IND (Modified Irwin study, Dog Cardiovascular/Respiratory safety, and Rat micronucleus). Prior to initiating the proposed IND-enabling studies in vertebrates, based on recommendation of the FDA Rare Disease Program, we will request a formal pre-IND meeting with the FDA to evaluate the proposed IND-enabling study designs. Key aims of this proposed work are to identify potential safety hazards, clinical monitoring strategies, the No Observed Adverse Effect Level (NOAEL), the Lowest Observed Adverse Effect Level (LOAEL), all associated systemic exposures, and predicted human starting doses/human equivalent doses to be targeted in the first in human (FIH) trial. On completion of this work, we will file an IND application. Work funded outside of this grant will include a chronic juvenile toxicology studies (in tox species) that will enable entrance into the pediatric patient population for the pivotal clinical trial; PK/PD modeling in a CLN1 disease model to establish the optimal dose/dosing regimen and plasma/brain exposure to achieve optimal efficacy in the pivotal clinical trial in INCL patients; and IND application material preparation, FDA meeting support, and INDA submission.