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