HBI-002 to Treat Parkinson’s Disease

PROJECT SUMMARY
The goal of the proposed project is to evaluate the potential of HBI-002, a novel oral formulation of carbon
monoxide (CO), as a neuroprotective agent in Parkinson’s disease (PD). A growing body of research
suggests that low doses of CO - and the heme oxygenase (HO) enzymes that generate endogenous CO -
protect against neuronal cell loss in PD, and epidemiologic studies have associated cigarette smoking with a
lower risk of PD. Together, these observations suggest that low doses of CO may be neuroprotective in PD.
Nicotine does not appear to underlie the protective effect of tobacco, as a clinical study of nicotine in PD did
not show significant improvement. At low levels (andlt;10% CO-hemoglobin [COHb]), such as found in smokers,
CO has been shown to have marked anti-apoptotic, anti-oxidant, and anti-inflammatory properties, and it has
become a promising therapeutic under study for multiple neurologic and non-neurologic diseases. CO is
generated by heme oxygenase 1 (HO-1) and 2 (HO-2), which transform the toxic species heme into CO,
biliverdin, and iron. Converging evidence links the function of HO-1 and HO-2 to neuroprotection in PD, and
the literature indicates that CO is protective in a PD model.
The clinical safety and tolerability of CO at levels up to 13.9% COHb has been demonstrated in 25 Phase 1
and Phase 2 clinical trials (not in PD, but including in subarachnoid hemorrhage) using a variety of forms of CO
administration, and there are ongoing clinical studies with CO. The absence of toxicity of CO at low COHb
levels has been well demonstrated in the literature, providing supportive safety data for the COHb levels under
consideration for PD. However, barriers to chronic dosing of CO with prior therapeutic administrative
approaches have prevented the development of a CO therapeutic for chronic use, as would be the case in PD.
HBI-002, a novel oral CO drug product, is being developed for the treatment of PD. The administration of a
defined dose of CO delivered by oral administration of HBI-002 enables further development of CO as a
therapeutic while obviating the problems associated with previously studied CO administration strategies,
including, for inhaled CO, accidental inhalation exposure due to the need for compressed CO cylinders and
imprecise dosing, and, for carrier molecule-bound CO (CORMs), toxicological concerns with carrier molecules.
Pharmacokinetic and pharmacodynamic studies in mice, rats, pigs, and dogs with oral HBI-002 have
demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development, as
presented in this proposal, is to confirm the neuroprotective potential of HBI-002 in animal models of PD and to
better understand the mechanisms of neuroprotection. For this purpose, we will assess the efficacy of HBI-002
in multiple in vivo PD models in two different species. In these models we will assess HBI-002 rescue of striatal
dopamine loss, substantia nigra dopamine cell loss, and motor impairment; and we will explore the impact of
HBI-002 on inflammatory cascades, Nrf-2 and HO-1 pathways, and mitochondrial biogenesis.PROJECT NARRATIVE
This application aims to evaluate whether HBI-002, an oral carbon monoxide (CO) therapeutic, can improve
outcomes in rodent models of Parkinson’s disease (PD). If successful, this research will provide critical proof-
of-concept for further development of HBI-002 in PD to prevent the progression of this devastating disease.