First-In-Human Trial of Nurr1 Activator HL192 in Parkinson Disease Initiated

Sean Jeong, MD

According to a recent announcement from HanAll Biopharma, Daewoong Pharmaceuticals, and NurrOn Pharmaceuticals, first-in-human dosing has begun in the phase 1 clinical trial of HL192, a small molecule in development for Parkinson disease (PD). The agent focuses on activating Nurr1, a master regulator associated with the development and maintenance of dopaminergic neurons.¹

Supported by a grant from The Michael J. Fox Foundation for Parkinson’s Research, the trial will assess the safety, tolerability, and pharmacokinetics of both single and multiple doses of orally administered HL192 in healthy individuals aged 18 to 80 years. Initial results of the study are expected to be announced in the second half of 2024.

"HanAll, Daewoong, and NurrOn share the common goal of developing transformative treatments for PD. Our collaboration has shown promise, and we will continue to build on this joint effort," Sean Jeong, MD, chief executive officer, HanAll Biopharma, said in a statement.¹ "Today, we stand at a significant juncture, having achieved the start of our first-in-human trial for HL192. Having reached this key milestone, our next steps involve assessing HL192's broader impact for patients with Parkinson's disease globally as well as for other neurodegenerative conditions."

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NurrOn believes this therapy could be disease-modifying for patients with PD, for which there are currently no such treatments available. The disease is mainly managed through symptomatic approaches, including standard carbidopa levodopa. In animal models of PD, HL192, a Nurr1 activator, has shown to improve behavioral deficits. Based on the unique dual role of Nurr1 for the development and maintenance of dopaminergic neurons and their protection from inflammation-induced death, the company feels as though Nurr1 can be a molecular target for paradigm changing therapeutic development for PD.

A 2015 proof-of-principle study further supported the notion that small molecules targeting Nurr1 ligand binding domain (LBD) can be used as a mechanism-based and neuroprotective strategy for PD. Using high throughput cell-based assays, the investigators identified small molecules, AQ and CQ, which can activate Nurr1 through its LBD and significantly improve motor impairments without dyskinesia-like adverse effects. Above all, the evidence supported that these compounds enhanced the contrasting dual functions of Nurr1, activation of mDA neuron-specific function and repression of microglial activation, and neurotoxic cytokine gene expression, thus leading to significant neuroprotective and/or neurorestorative effects.²

"We are excited to begin the first step in the clinical development of ATH-399A (HL192). We look forward to completing the healthy participant study and advancing ATH-399A for a Phase 2 study in PD patients," Deog Joong Kim, PhD, chief executive officer, NurrOn Pharmaceuticals, said in a statement.¹ "We are grateful to HanAll and Daewoong for their collaboration and to MJFF for funding the Phase 1 trial of ATH-399A."

REFERENCES
1. HanAll Biopharma, Daewoong Pharmaceutical and NurrOn Pharmaceuticals initiate first-in-human phase 1 clinical trial study of HL192. News release. HanAll Biopharma. October 12, 2023. Accessed October 20, 2023. https://www.prnewswire.com/news-releases/hanall-biopharma-daewoong-pharmaceutical-and-nurron-pharmaceuticals-initiate-first-in-human-phase-1-clinical-study-of-hl192-301954586.html
2. Kim CH, Han BS, Moon J, et al. Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease. PNAS Neuroscience. 2015;112(28):8756-8761. Doi:10.1073/pnas.1509742112