Development of N-tert-(butyl)hydroxylamine (NtBuHA) as a therapeutic agent for treating CLN1 Batten Disease

PROJECT SUMMARY/ABSTRACT
A significant unmet medical need exists for a therapy to treat patients with CLN1 Batten Disease, who currently
have no disease-treatment options. Circumvent Pharmaceuticals has completed ADME, PK and toxicity
studies enabling selection of N-(tert-butyl)-hydroxylamine (NtBuHA)/CIRC827 as a Clinical Candidate. Further,
Circumvent has completed a Phase II SBIR program that included preparation of a drug substance suitable for
clinical use, verification of a formulation suitable for completion of IND-enabling in-vivo work, completion of all
IND-enabling in-vitro GLP-grade toxicology and safety pharmacology studies, and initiation of in-vivo
GLP-grade toxicology studies. This Phase IIb application has two main goals: (1) Complete all ADME, GLP
toxicology and GLP safety pharmacology studies required for INDA/CTA submissions; and complete all
regulatory filings and meeting preparation for IND applications with the FDA and CTA applications with the
EMA. If successful, CIRC827 will be the first and only option to treat the underlying cause of CLN1 Batten, and
it will change the clinical practice paradigm from palliative/supportive care toward a curative strategy. In S.A. 1,
we will measure the metabolism of NtBuHA with CYP induction studies in human liver microsomes and
hepatocytes to evaluate both the role of metabolism in PK profiles on repeat dosing as well as the potential for
drug-drug interactions from clinically co-administered drugs. In S.A. 2, we will focus on completing our in-vivo
genotoxicity studies using a rat micronucleus assessment. In S.A. 3, we will complete a final GLP dog 28-day
toxicology and TK/PK study, which are designed 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. In S.A. 4, we will complete all GLP-compliant in-vivo safety
pharmacology studies required to file for an IND (Modified Irwin study, Dog Cardiovascular/Respiratory safety).
In S.A. 5, we will complete all remaining activities for IND and CTA approval, as suggested by formal feedback
from the EMA as well as guidance from regulatory consultants Cencora/Pharmalex. These activities will
include clinical protocol finalization, IND-preparation and submission, Fast Track requests, EMA Protocol
Assistance requests, Pediatric Investigational Plan (PIP) preparation and submission, and CTA preparation
and submission. On completion of this work, we will file both IND and CTA applications. Work funded outside
of this grant conducted in parallel, includes chronic juvenile toxicology studies (in-tox species) and 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 CLN1 Batten pediatric patients.

Grant Number: 2R44NS120360-03
NIH Institute/Center: NIH
Principal Investigator: DANIEL CHELSKY